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Disorders of the Thyroid Gland in Infancy, Childhood and Adolescence

Last Updated: March 21, 2012 Authors Rosalind S. Brown, M.D. Director, Clinical Trials Research Division of Endocrinology, Children s !ospital "oston #ssociate $rofessor of $ediatrics !arvard Medical %chool &00 Long'ood #ve( "oston, M# 0211) University of Massach*setts Medical Center Depart+ent of $ediatrics )) La,e #ven*e -orth .orcester, M# 01/)) Tel: 10)0101)/02210 3a4: 10)0101)/02215 Thyroid hor+one is essential for the gro'th and +at*ration of +any target tiss*es, incl*ding the 6rain and s,eleton( #s a res*lt, a6nor+alities of thyroid gland f*nction in infancy and childhood res*lt not only in the +eta6olic conse7*ences of thyroid dysf*nction seen in ad*lt patients, 6*t in *ni7*e effects on the gro'th and 8or +at*ration of these thyroid hor+one0dependent tiss*es as 'ell( 9n +ost instances, there are critical 'indo's of ti+e for thyroid hor+one0dependent develop+ent and so the specific clinical conse7*ence of thyroid dysf*nction depends on the age of the infant or child( 3or e4a+ple, ne'6orn infants 'ith congenital hypothyroidis+ fre7*ently have hyper6ilir*6ine+ia, and delayed s,eletal +at*ration, reflecting i++at*rity of liver and 6one, respectively, and they are at ris, of per+anent +ental retardation if thyroid hor+one therapy is delayed or inade7*ate: their si;e at 6irth, ho'ever, is nor+al( 9n contrast, hypothyroidis+ that develops after the age of three years <'hen +ost thyroid hor+one0dependent 6rain develop+ent is co+plete= is characteri;ed predo+inantly 6y a deceleration in linear gro'th and s,eletal +at*ration 6*t there is no per+anent effect on cognitive develop+ent( 9n general, infants 'ith severe defects in thyroid gland develop+ent or in6orn errors of thyroid hor+onogenesis present in infancy 'hereas 6a6ies 'ith less severe defects or ac7*ired a6nor+alities, partic*larly a*toi++*ne thyroid disease, present later in childhood and adolescence( 9n the ne'6orn infant , thyroid f*nction is infl*enced not only 6y the neonate > s o'n thyroid gland 6*t 6y the transplacental passage fro+ the +other of factors that affect the fetal thyroid gland( 9n the last several decades, there have 6een e4citing advances in o*r *nderstanding of fetal and neonatal thyroid physiology, and screening for congenital hypothyroidis+ has ena6led the virt*al eradication of the devastating effects of +ental retardation d*e to sporadic congenital hypothyroidis+ in +ost developed co*ntries of the 'orld( 9n addition, advances in +olec*lar 6iology have led to ne' insights regarding the early events in thyroid gland e+6ryogenesis and +echanis+s of thyroid action in the 6rain( #t the sa+e ti+e, the +olec*lar 6asis for +any of the in6orn errors of thyroid hor+onogenesis and thyroid hor+one action is 6eing *nraveled( !o'ever, ne' 7*estions and ne' challenges arise( 9n partic*lar, the s*rvival of increasingly s+all and pre+at*re fet*ses has res*lted in a gro'ing n*+6er of neonates 'ith a6nor+alities in thyroid f*nction and a contin*ing controversy as to 'hich of these infants re7*ire therapy( This chapter 'ill foc*s on c*rrent concepts regarding the ontogenesis of thyroid f*nction in the fet*s and 'ill revie' the +a?or disorders of thyroid gland f*nction in infants and children(

Ontogenesis of thyroid function in the fetus and infant

The ontogeny of +at*re thyroid f*nction involves the organogenesis and +at*ration of the hypothala+*s, pit*itary, and thyroid glands as 'ell as the +at*ration of thyroid hor+one +eta6olis+ and thyroid hor+one action( The placenta also plays a ,ey role in the transfer of hor+ones and factors other than T2 that i+pact on thyroid f*nction( 9n the first half of pregnancy, +aternal T2 provides an i+portant so*rce of hor+one for the developing fet*s( M*ch of o*r ,no'ledge derives fro+ 'or, in ani+al +odels, partic*larly sheep and rat( 9n interpreting these data, it is i+portant to re+e+6er potential li+itations in these +odels 6eca*se of differences 6oth in the str*ct*re of the placenta and ti+ing of +at*ration( 3or e4a+ple, the rat thyroid gland is +*ch less +at*re at 6irth than its h*+an co*nterpart and significant +at*ration of the thyroid gland and of the hypothala+ic0pit*itary0thyroid a4is in this species occ*rs in the first 2 or & 'ee,s after 6irth in the a6sence of placental or +aternal infl*ence, as co+pared 'ith the third tri+ester in h*+an infants(

Thyroid gland e !ryogenesis

Thyroid gland develop+ent is e4tensively revie'ed in an earlier chapter and is sho'n diagra++atically in 3ig*re 1( 9n 6rief, the thyroid gland is derived fro+ the f*sion of a +edial o*tpo*ching fro+ the floor of the pri+itive pharyn4, the prec*rsor of the thyro4ine <T2=0prod*cing follic*lar cells, and 6ilateral evaginations of the fo*rth pharyngeal po*ch, 'hich gives rise to the parafollic*lar, or calcitonin <C= secreting cells( Co++it+ent to'ards a thyroid0specific phenotype as 'ell as the gro'th and descent of the thyroid anlage into the nec, res*lts fro+ the coordinate action of a n*+6er of transcription factors, incl*ding thyroid transcription factor 1 < TTF1 , no' called NKX2. <1= =, TTF2 <no' called FOXE1 = and PAX8 < 1, 2= . "eca*se these transcription factors are also e4pressed in a li+ited n*+6er of other cell types, it appears to 6e the specific co+6ination of transcription factors and possi6ly non0D-# 6inding cofactors acting coordinately that deter+ine the phenotype of the cell( @ther transcription factors and gro'th factors that play a role in early thyroid gland organogenesis incl*de HHEX1 , HOXA3 , <&= and +e+6ers of the fi6ro6last gro'th factor fa+ily, e(g(, FGF10 , 6*t the initial ind*ctive signal is *n,no'n( # role of the neigh6oring heart pri+ordi*+ in the specification of the thyroid anlage has 6een post*lated( %t*dies of cadherin e4pression s*ggest that the ca*dal translocation of the thyroid anlage +ay also arise indirectly, as a res*lt of the gro'th and e4pansion of ad?acent tiss*es, incl*ding the +a?or 6lood vessels <2= ( 9n late organogenesis, the sonic hedgehog < SHH = gene and its do'nstrea+ target TBX1 appear to play an i+portant role in the sy++etric 6ilo6ation of the thyroid <)= : SHH also s*ppresses the ectopic e4pression of thyroid follic*lar cells </= ( D*ring ca*dal +igration the pharyngeal region of the thyroid anlage contracts to for+ a narro' stal,, ,no'n as the thyroglossal d*ct, 'hich s*6se7*ently atrophies( Us*ally no l*+en is left in the tract of its descent 6*t, occasionally, an ectopic thyroid and8or persistent thyroglossal d*ct or cyst for+ if thyroid descent is a6nor+al(

3ig*re 1)0 1( #ppro4i+ate ti+ing of thyroid gland +at*ration in the h*+an fet*s( 9n the h*+an, e+6ryogenesis is largely co+plete 6y 10 to 12 'ee,s gestation #t this stage, tiny follicle prec*rsors can 6e seen, iodine 6inding can 6e identified and thyroglo6*lin <Tg= detected in follic*lar spaces <5, 1= ( Thyroid hor+ones are detecta6le in fetal ser*+ 6y gestational age 11 to 12 'ee,s 'ith 6oth thyro4ine <T2= and triiodothyronine <T&= 6eing +eas*ra6le( !o'ever, as disc*ssed in f*rther detail 6elo', it is li,ely that a fraction of the hor+ones detecta6le at this early stage is contri6*ted 6y the +other thro*gh transplacental transfer( Thyroid hor+ones contin*e to increase grad*ally over the entire period of gestation as does ser*+ thyro4ine06inding glo6*lin <T"A = <B , 10= ( T"A is present at levels of 100 n+ol8L <) +g8L= at gestational age 12 'ee,s and progressively increases *p to the ti+e of 6irth, reaching concentrations of )00 n+ol8L <2) +g8L=( The ser*+ T"A concentrations are higher in the infant then in ad*lt h*+ans as a conse7*ence of placental estrogen effects on the fetal liver( 9n addition to the increase in total T2 there is also a progressive increase of the free T2 concentration indicating a +at*ration of the hypothala+ic0 pit*itary0 thyroid a4is( The increased total T2 8 thyrotropin < T%!= and free T2 8T%! ratios also indicate an increased a6ility of the thyroid gland to respond to T%! d*e to *preg*lation of the T%! receptor <11= ( .hereas the T"A and total T2 levels rise thro*gho*t gestation, the concentrations of free T2, and T%! rise *ntil &1 to &2 'ee,s, declining thereafter to ter+ <12= ( Tg can 6e identified in the fetal thyroid as early as the )th 'ee,, and is certainly present in follic*lar spaces 6y 10 to11 'ee,s, 6*t +at*ration of Tg secretion ta,es +*ch longer and it is not ,no'n 'hen circ*lating Tg first appears in the fetal ser*+ <not sho'n=( "y the ti+e of gestational age 25 to 21 'ee,s, ho'ever, Tg levels average appro4i+ately 100 +g8L, +*ch higher than in the ad*lt and they re+ain appro4i+ately sta6le *ntil the ti+e of 6irth <1& , 12= ( 9odide concentrating capacity can 6e detected in the thyroid of the 10 to 11 'ee, fet*s, 6*t +at*ration of the .olff0Chai,off effect <red*ction of iodide trapping in response to e4cess iodide= does not appear *ntil &/ to 20 'ee,s

gestation( Th*s the pre+at*re fet*s is +ore sensitive than the f*ll ter+ neonate to the thyroid0 s*ppressive effects of iodine e4pos*re(

The hy"othala ic#"ituitary a$is

T%! is detecta6le at levels of & to 2 +U8L at gestational age 12 'ee,s and increases +oderately over the last t'o tri+esters to levels of / to 1 +U8L <1 , B= (The +at*ration of the negative feed6ac, control of thyroid hor+one synthesis is o6served 6y appro4i+ately +id0gestation <3ig*re 1= , 'ith elevated ser*+ T%! concentrations 6eing o6served in hypothyroid infants as early as 21 'ee,s <1= ( .hen T%!0 Releasing !or+one <TR!= is given to +others, a rise in T%! in the fetal circ*lation has 6een noted as early as 2) 'ee,s gestation <1)= ( 9t is of interest that the fetal T%! incre+ent after TR! is greater than is the paired0+aternal response, a conse7*ence either of enhanced T%! release or i+paired T%! degradation, perhaps d*e to i++at*rity of the hepatic glycoprotein +eta6olic clearance syste+( %i+ilarly T%! is red*ced in the cord ser*+ of infants 'ith neonatal thyroto4icosis d*e to the transplacental passage of thyroid0sti+*lating anti6odies fro+ +others 'ith Araves disease as early as the end of the 2nd tri+ester( %er*+ levels of TR! are higher in the fetal circ*lation than in +aternal 6lood, the res*lt 6oth of e4trahypothala+ic TR! prod*ction <placenta and pancreas= and the decreased TR! degrading0activity in fetal ser*+( The physiological significance of these increased levels of TR! in the fetal circ*lation is not ,no'n(

Maturation of "eri"heral thyroid hor one


#s disc*ssed in an earlier chapter , there are three iodothyronine deiodinases involved in the activation and inactivation of thyroid hor+one <3ig*re 2=( #ll three are coordinately reg*lated d*ring gestation and f*nction to closely reg*late the s*pply of T& to developing tiss*es 'hile at the sa+e ti+e protecting the fet*s against the effects of e4cess thyroid hor+one( The physiological rationale for the +aintenance of red*ced circ*lating T& concentrations thro*gho*t fetal life is still *n,no'n, 6*t it has 6een s*ggested that its f*nction +ay 6e to avoid tiss*e ther+ogenesis and potentiate the ana6olic state of the rapidly gro'ing fet*s 'hile at the sa+e ti+e per+itting highly reg*lated, tiss*e0 specific +at*ration in an orderly, te+poral se7*ence( The seleno0en;y+e type 1 iodothyronine deiodinase <D1=, an i+portant activating en;y+e in ad*lt life, is lo' thro*gho*t gestation( 9n addition to cataly;ing T2 to T& conversion, D1 cataly;es the inactivation of the s*lfated con?*gates of T2( #s a conse7*ence, circ*lating T& concentrations in the fet*s are 7*ite lo' 'hereas the ser*+ levels of the 6iologically inactive iso+er reverse T& and of T& s*lfate <not pict*red= are increased10( Unli,e D1, 6oth the Type 2 deiodinase <D2=, an activating en;y+e and D&, an inactivating en;y+e are present in fetal 6rain as early as 5 'ee,s > gestation <1/= ( D2 converts T2 to T& 'hile D& converts T2 to reverse T& <3ig*re &=( D2 and D& are the +a?or isofor+s present in the fet*s and are especially i+portant in defining the level of T& in the 6rain and pit*itary( The highest concentration of D2 is in 6rain, pit*itary, placenta and 6ro'n adipose tiss*e( D& is present in +any fetal tiss*es, +ost pro+inently the 6rain, *teroplacental *nit, s,in, and gastrointestinal tract <15= ( This is consistent 'ith the ,ey role of D& in protecting fetal tiss*es against high +aternal T2 concentrations present either in the placenta or in a+niotic fl*id(

3ig*re 1)02( Molec*lar str*ct*re of the +a?or thyroid hor+ones and the action of the +onoiodothyronine deiodinase en;y+es( The type l <D1= and ll <D2= deiodinases are activating deiodinases 6eca*se they deiodinate the o*ter <phenol= ring to for+ +eta6olically active T&( The type lll deiodinase <D&= is an inactivating deiodinase 6eca*se it deiodinates the inner <tyrosyl= ring to for+ inactive reverse <r= T&( D1 can also f*nction as an inactivating deiodinase( Thyroid hor+one is also +eta6oli;ed 6y other +echanis+s, incl*ding s*lfation, gl*c*ronidation( 9n the presence of hypothyroidis+, D2 activity increases 'hile D& decreases These coordinate activities have 6een fo*nd to 6e critically i+portant in defending the rat fet*s against the effects of fetal hypothyroidis+ as long as +aternal T2 levels are +aintained at nor+al concentrations <11, 1B=( Despite the lo' levels of circ*lating T&, 6rain T& levels are /0010C those of the ad*lt 6y fetal age 2002/ 'ee,s <20= ( Th*s, 'hereas the physiological interrelationships 6et'een the vario*s deiodinases in the fet*s and placenta see+ designed to +aintain circ*lating T& concentrations at a red*ced level, specific +echanis+s have evolved for +aintaining 6rain T& concentrations so that nor+al develop+ent can proceed(

Role of the %lacenta

Contri!utions of the aternal thyroid to fetal thyroid econo y.
9n the h*+an infant *nder nor+al circ*+stances, the placenta has only li+ited per+ea6ility to thyroid hor+one and the fetal hypothala+ic0pit*itary0 thyroid syste+ develops relatively independent of +aternal infl*ence( The relative i+per+ea6ility of the h*+an placenta to thyroid hor+one is d*e to the presence of D& 'hich serves to inactivate +ost of the thyroid hor+one presented fro+ the +aternal or

fetal circ*lation( The iodide released in this 'ay can then 6e *sed for fetal thyroid hor+one synthesis( 9nterest in the potential role of +aternal T2 in the fetal thyroid econo+y 'as rea'a,ened 'ith the recognition that in infants 'ith the congenital a6sence of thyroid pero4idase, the cord ser*+ concentration of T2 is nonetheless 6et'een 2) and )0C of nor+al <21= ( %ince these infants are co+pletely *na6le to synthesi;e T2, the +eas*red hor+one +*st 6e +aternal in origin( %i+ilar res*lts are o6tained in retrospective st*dies of cord ser*+ in infants 'ith sporadic congenital athyreosis( This +aternal T2 disappears rapidly fro+ the ne'6orn circ*lation 'ith a half0life of appro4i+ately & to 2 days( There is also evidence that +aternal0fetal T2 transfer occ*rs in the first half of pregnancy, 'hen fetal thyroid hor+one levels are lo' <1B, 22= ( Lo' concentrations of T2, pres*+a6ly of +aternal origin, have 6een detected in h*+an e+6ryonic coelo+ic fl*id as early as / 'ee,s gestation and in fetal 6rain as early 10 'ee,s gestation prior to the onset of fetal thyroid f*nction( 3*rther+ore, 6oth D2 and D& activity as 'ell as thyroid hor+one receptor <TR= isofor+s are present in lo' concentrations in h*+an fetal 6rain fro+ the +id first tri+ester, indicating that the +achinery to convert T2 to T& and to respond to T& is present( 9t see+s li,ely that 'hen fetal thyroid f*nction is nor+al, the net fl*4 of T2 fro+ +other to fet*s is relatively li+ited( !o'ever, 'hen the fet*s is hypothyro4ine+ic, there is significant 6*l, transfer of T2 to the fetal circ*lation( This can occ*r 6oth at the level of the placental +aternal capillary interface and via *pta,e of thyroid hor+one fro+ the a+niotic fl*id thro*gh the i++at*re epider+is( T2 *pta,e 6y the fet*s can also occ*r via fetal ingestion of a+niotic fl*id( .hile the T2 concentrations in a+niotic fl*id appear +odest, the fraction of T2 free in a+niotic fl*id is appro4i+ately ten0fold higher than that of ser*+ and th*s the free T2 concentration in a+niotic fl*id is appro4i+ately e7*al to that in fetal ser*+ at 20 'ee,s gestation( 9t has 6een sho'n on n*+ero*s occasions in 6oth ani+als and h*+ans that a+niotic fl*id iodothyronine concentrations reflect those in the +aternal circ*lation <2&= (

Significance of Maternal T&

-one of the ne*rological feat*res of severe ende+ic cretinis+ <22= d*e to iodine deficiency are fo*nd in infants 'ith sporadic congenital hypothyroidis+ 'hose +others have nor+al thyroid f*nction and 'ho receive early and ade7*ate postnatal treat+ent ( %i+ilarly, i+paired hearing, 'hen fo*nd is +*ch +ilder and less fre7*ent <2)= ( This 'o*ld appear to provide *ne7*ivocal evidence that the ne*rological da+age s*stained 6y infants 'ith ende+ic cretinis+ can 6e largely prevented 6y +aternal T2( 9n addition to ende+ic cretinis+, significant develop+ental delay despite early and ade7*ate postnatal therapy has also 6een reported in other +odels of co+6ined +aternal0fetal hypothyroidis+, s*ch as +aterno0fetal $@U131 deficiency <2/= and T%! receptor 6loc,ing anti6ody0ind*ced congenital hypothyroidis+ <25=( Maternal hypothyroidis+ alone has also 6een associated 'ith an i+pair+ent in psycho+otor develop+ent in the offspring, a res*lt first noted 6y Man <21= ( Unli,e the severe develop+ental delay associated 'ith *ntreated +aterno 0fetal hypothyroidis+ , 6 oth the +agnit*de and critical 'indo' d*ring pregnancy of the effect of isolated +aternal hypothyroidis+ re+ain controversial ( !addo' et al detected a 2 point 9D deficit in 5 to B year old children 'hose +others 'ere retrospectively fo*nd to have 6een hypothyroid at 15 'ee,s gestation , tho*gh the difference fro+ nor+al 'as not statistically significant <2B= ( 9n s*pport of this o6servation, $op et al de+onstrated that even 6a6ies 6orn to 'o+en 'hose free T2 levels 'ere in the lo'est 10C of nor+al at 12 'ee,s gestation had a +eas*ra6le i+pair+ent in psycho+otor develop+ent at 2 years of age as co+pared 'ith the rest of the pop*lation 6*t this effect 'as not o6served if +aternal thyroid f*nction 'as nor+al at &2 'ee,s <&0= ( These res*lts 'ere 'idely interpreted as s*pporting an i+portant role of +aternal thyr oid hor+one early in

pregnancy o n fetal 6rain develop+ent( #t variance 'ith the afore+entioned st*dies, Li* et al , and +ore recently, Mo+ota+i et al failed to de+onstrate any 9D deficit in 6a6ies 6orn to hypothyroid +others as long as the hypothyroidis+ 'as corrected 6y the end of the second tri+ester <&1a, &16= ( %i+ilar res*lts 'ere o6tained 6y Do'ning et al in & children 6orn after severe feto0+aternal hypothyroidis+ d*e to T%! receptor 6loc,ing anti6odies <&1c= (Recently a large prospective rando+i;ed controlled trial failed to de+onstrate any 6enefit of L0thyro4ine treat+ent given to hypothyroid +others fro+ the 1& th 'ee, of gestation on the cognitive f*nction of the offspring at & years of age <&2= ( #nother large rando+i;ed control trial of early L0thyro4ine therapy 'ith cognitive eval*ation at ) years of age is c*rrently *nder'ay( The incidence of +aternal hypothyroidis+ d*ring pregnancy <& per 1000 in iodine0s*fficient pop*lations <&&= = is al+ost ten ti+es that of congenital hypothyroidis+ for 'hich ro*tine pop*lation screening is 'idespread( "eca*se +aternal hypothyroidis+ has 6een associated not only 'ith potential adverse effects on fetal 6rain develop+ent 6*t an increased ris, of preter+ delivery and of +iscarriage as 'ell <&&6= so+e have arg*ed that all pregnant 'o+en sho*ld 6e screened for hypothyroidis+, a position that has 6een endorsed 6y so+e 6*t not other professional societies

%lacental "er ea!ility to factors

aternal TR', TS', and to other

#s noted, the placenta is freely per+ea6le to TR! and to iodide <1)= ( The placenta is also per+ea6le to certain dr*gs, hor+ones and to i++*noglo6*lins <9gs= of the 9gA class( Th*s, the ad+inistration to the +other of e4cess iodide, dr*gs <especially propylthio*racil or +ethi+a;ole=, or the transplacental passage of T%! receptor anti6odies fro+ +others 'ith severe Araves disease or severe hypothyroidis+ d*e to chronic ly+phocytic thyroiditis +ay have significant effects on fetal and neonatal thyroid f*nction( Maternal T%! does not cross the placenta( %i+ilarly, Tg is *ndetecta6le in the ser*+ of athyreotic infants, indicating the a6sence of any transplacental passage of this large protein(

Thyroid (unction in the )eonate, the Infant, and During Childhood

The full#ter neonate
Mar,ed changes occ*r in thyroid physiology at the ti+e of 6irth in the f*ll ter+ ne'6orn( @ne of the +ost dra+atic changes is an a6r*pt rise in the ser*+ T%! 'hich occ*rs 'ithin &0 +in*tes of delivery , reaching concentrations as high as /0 to 50 +U8L <1= ( This ca*ses a +ar,ed sti+*lation of the thyroid and an increase in the concentrations of 6oth ser*+ T2 and T& <&2= ( These consist of an appro4i+ate )0C increase in the ser*+ T2 and an increase of three0 to fo*r0fold in the concentration of ser*+ T& to ad*lt levels at 1 to 2 days of life ( %er*+ levels of T2, free T2 and T"A re+ain elevated over cord levels at 5 days of postnatal life <3ig*re &=, decreasing thereafter( The T& concentration rises stri,ingly at Day 5, and contin*es to rise for the first 21 days( @pposite effects are noted in the reverse T& levels and T& s*lfate <not pict*red=( %t*dies in e4peri+ental ani+als s*ggest that the increase in T%! is a conse7*ence of the relative hypother+ia of the a+6ient e4tra*terine environ+ent( !o'ever, 'hile a significant portion of the

+ar,ed increase in T& fro+ its lo' 6asal levels in cord ser*+ can 6e e4plained 6y the a6r*pt increase in T%!, the si+*ltaneo*s fall in reverse T& and T& s*lfate are consistent 'ith an increase in D1 activity occ*rring at the sa+e ti+e( D2 has 6een identified in h*+an 6ro'n adipose tiss*e as 'ell as 6rain and the ac*te increase in T& in adipose tiss*e at 6irth is re7*ired for opti+al *nco*pling protein synthesis and ther+ogenesis < &), &/ =(

%re ature infants

Thyroid f*nction in the pre+at*re infant reflects, in part, the relative i++at*rity of the hypothala+ic0 pit*itary0thyroid a4is that is fo*nd in co+para6le gestational age infants in *tero( 3ollo'ing delivery, there is a s*rge in T2 and T%! analogo*s to that o6served in ter+ infants, 6*t the +agnit*de of the increase is less in pre+at*re neonates <1= 9n infants E&1 'ee,s, the circ*lating T2 concentration +ay not increase and +ay even fall in the first 1 to 2 'ee,s of life <&5=<3ig*re 2=( This decrease in the T2 concentration is partic*larly significant in very pre+at*re infants, in 'ho+ the ser*+ T2 +ay occasionally 6e *ndetecta6le( 9n +ost cases, the total T2 is +ore affected than the free T2 <&1=, a conse7*ence of a6nor+al protein 6inding and8or the decreased T"A in these 6a6ies 'ith i++at*re liver f*nction(

3ig*re 1)0&( $ostnatal changes in of T2, free T2, T"A, T&, rT& and T%! according to gestational age( -ote the increase in T2, free T2 and T"A in the f*ll ter+ infant in the first 'ee, of life( T& also rises stri,ingly, 'hile rT& and T%! decline( The increase in T2 and free T2 is 6l*nted in infants E&) 'ee,s, and not seen at all in very pre+at*re infants in 'ho+ thyroid hor+one levels +ay act*ally decline( <Redra'n fro+ .illia+s et al10( %ee te4t for details(= The ca*ses of the decrease in T2 o6served postnatally in pre+at*re infants are co+ple4( 9n addition to the clearance of +aternal T2 fro+ the neonatal circ*lation, preter+ 6a6ies have decreased thyroidal

iodide stores <&B= <a pro6le+ of partic*lar significance in 6orderline iodine0deficient areas of the 'orld=, they are fre7*ently sic,er than their +ore +at*re co*nterparts, are less a6le to reg*late iodide 6alance, and they +ay 6e treated 6y dr*gs that affect neonatal thyroid f*nction <partic*larly dopa+ine and steroids=( 9n addition, since the capacity of the i++at*re thyroid to adapt to e4ogeno*s iodide is red*ced, there is an increase in sensitivity to the thyroid0s*ppressive effects of e4cess iodide fo*nd in certain s,in antiseptics and dr*gs to 'hich these 6a6ies are fre7*ently e4posed <see 6elo'=( Despite the red*ced total T2 o6served in so+e preter+ 6a6ies, the T%! concentration is not significantly elevated in +ost of these infants( 9n so+e 6a6ies, transient elevations in T%! are seen, the finding of a T%! concentration F20 +U8L 6eing +ore fre7*ent the greater the degree of pre+at*rity( 3ran, et al fo*nd, for e4a+ple, that the prevalence of a T%! concentration F20 +U8L in very lo' 6irth 'eight, <E1() ,g=, i(e(, very pre+at*re, infants 'as 10fold higher and in lo' 6irth 'eight, <1() ,g02() ,g= neonates 20fold higher than the prevalence in ter+ 6a6ies <20=( .hereas in so+e cases, an elevated T%! concentration +ay reflect tr*e pri+ary hypothyroidis+, in other instances this increase in T%! +ay reflect the elevated T%! o6served in ad*lts 'ho are recovering fro+ severe illness( %*ch individ*als +ay develop transient T%! elevations that are associated 'ith still red*ced ser*+ T2 and T& concentrations( These have 6een interpreted as reflecting a G re0a'a,ening H of the illness0ind*ced s*ppression of the hypothala+ic pit*itary a4is( #s the infant recovers fro+ pre+at*rity associated illnesses s*ch as respiratory distress syndro+e <RD%=, a recovery of the illness0ind*ced s*ppression of the hypothala+ic0 pit*itary0 thyroid a4is 'o*ld also occ*r(

3ig*re 1)02 ( Cord 6lood levels of T2, free T2, T"A, T&, reverse T& and T%! in the h*+an infant( -ote the lo' T& and high reverse T& concentrations as 'ell as the discrepancy 6et'een the total T2 and free T2 levels in very pre+at*re 6a6ies, <Redra'n fro+ .illia+s et al(10%ee te4t for details= %o+e'hat s*rprisingly, given the relative i++at*rity of the thyroid gland, ser*+ Tg concentrations are higher in the pre+at*re than in the f*ll ter+ infant <21=, partic*larly in those 'ho are sic, 'ith

respiratory distress syndro+e 9n vie' of the atten*ated postnatal T%! rise in the latter 6a6ies, it is li,ely that i+paired clearance and8or degradation of this glycoprotein fro+ the circ*lation rather than increased secretion plays an i+portant role(

S all#for#gestational#age *SGA+ infants

%A# infants have significantly higher T%! and lo'er total and free T2 val*es than do infants of nor+al 'eight <22=( This can 6e related to the severity of the +aln*trition in these infants, as 'ell as to fetal hypo4e+ia and acide+ia( 9+paired placental perf*sion and chronic starvation +ay also play a role( This pattern of red*ced T2 and elevated T%! differs fro+ the response to starvation in older individ*als and healthy ad*lts in 'ho+ T%! is red*ced( The e4planation for the relatively higher T%! in s*ch infants is not ,no'n(

Infants and Children

3ollo'ing the ac*te pert*r6ations of the neonatal period there is a slo' and progressive decrease in the concentrations of T2, free T2, T& and T%! d*ring infancy and childhood <2&= ( Io*nger children tend to have slightly higher ser*+ concentrations of T& and T%!, so age0specific nor+ative val*es sho*ld al'ays 6e cons*lted( The ser*+ concentration of reverse T& re+ains *nchanged or increases slightly( %er*+ Tg levels also fall over the first year of life reaching concentrations typical of ad*lts 6y a6o*t / +onths of age( #nother i+portant aspect of thyroid physiology in the infant and child is the +ar,edly higher T2 t*rnover in this age gro*p relative to that in the ad*lt( 9n infants, T2 prod*ction rates are esti+ated to 6e on the order of ) to / +cg8,g per day decreasing slo'ly over the first fe' years of life to a6o*t 2 to & +cg8,g8day at ages & to B years( This is to 6e contrasted 'ith the prod*ction rate of T2 in the ad*lt 'hich is a6o*t 1() 1()+cg8,g8day( The si;e of the infant thyroid gland increases 7*ite slo'ly( The thyroid gland of the ne'6orn 'eighs appro4i+ately 1 gra+ and increases a6o*t 1 gra+ per year *ntil age 1) 'hen it has achieved its ad*lt si;e of a6o*t 1) to 20 g( 9n general, the si;e of the thyroid lo6e is co+para6le to that of the ter+inal phalan4 of the infant or child > th*+6(

Thyroid Disease in Infancy

Congenital 'y"othyroidis
-on ende+ic congenital hypothyroidis+ is one of the co++onest treata6le ca*ses of +ental retardation( #ltho*gh in the initial st*dies, an incidence of 6et'een 1 in &000 and 1 in 2000 infants 'orld'ide 'as o6tained, the c*rrent esti+ate is even higher < F1 in 2,)00= <22= ( .orld'ide, ' hether this higher fig*re is d*e to a greater sensitivity of present screening +ethods or the incl*sion of infants 'ith transient disease is not clear( 9n -e' England, these e4cess n*+6ers are d*e +ostly to the incl*sion of +ildly affected infants and those 'ith delayed presentation < J atypical congenital hypothyroidis+ > = 6*t the incidence of severe per+anent congenital hypothyroidis+ has not changed <226= ( The proportion of patients 'ith transient disease is not ,no'n 'ith certainty( The association 6et'een goitro*s hypothyroidis+ and +ental retardation 'as first noted +ore than 200 years ago 6y $aracels*s in 1)25, and Tho+as C*rling first descri6ed sporadic nongoitro*s hypothyroidis+ in 11)0( !o'ever, despite the de+onstration 6y M*rray in 11B1 that thyroid e4tract co*ld a+eliorate +any of the feat*res of *ntreated cretinis+, it 'as not *ntil the 1B50 > that the i+portance of early treat+ent in di+inishing the ne*ro0psychological a6nor+alities of congenital

hypothyroidis+ 'as de+onstrated convincingly( 9n a st*dy 6y Klein et al, 51C of infants 'ith congenital hypothyroidis+ treated 6efore & +onths of age 6*t 0C treated after / +onths of age had an intelligence 7*otient <9D= a6ove 1), the +ean 9D of the early treated gro*p 6eing 1B, co+pared 'ith an 9D of )2 in those treated late <2)=( Unfort*nately, only 10C of affected infants 'ere diagnosed clinically 'ithin the first +onth of life and only &)C 'ithin the first & +onths of life( The develop+ent 6y D*ssa*lt et al of a sensitive and specific radioi++*noassay f or the +eas*re+ent of T2 in dried 'hole 6lood el*ted fro+ filter paper <and later tests for T2 and T%! *sing 181 L discs= provided the technical +eans to screen all ne'6orns for congenital hypothyroidis+ prior to the develop+ent of clinical +anifestations <2/= ( Th*s, as s*++ari;ed 6y Delange, congenital hypothyroidis+ incl*des all the characteristics of a disease for 'hich screening is ?*stified: 1= it is co++on <20) ti+es +ore co++on than phenyl,eton*ria for 'hich screening progra+s 'ere initially developed=: 2= to prevent +ental retardation, the diagnosis +*st 6e +ade early, prefera6ly 'ithin the first fe' days of life: &= at that age, clinical recognition is diffic*lt if not i+possi6le: 2= sensitive, specific screening tests and )= si+ple, cheap effective treat+ent are availa6le: and /= the 6enefit0cost ratio is highly favora6le <appro4i+ately 1081, a ratio that does not incl*de the loss of ta4 inco+e that 'o*ld res*lt fro+ i+paired intellect*al capacity in the *ntreated, 6*t non0instit*tionali;ed, person= <25= ( %ince the develop+ent of the first pilot screening progra+ for the detection of congenital hypothyroidis+ in D*e6ec in 1B52, ne'6orn screening progra+s have 6een introd*ced thro*gho*t the ind*striali;ed nations and are *nder develop+ent in +any other parts of the 'orld( 9t has 6een esti+ated that as of 1BBB, so+e 1)0 +illion infants had 6een screened for congenital hypothyroidis+ 'orld'ide 'ith 22,000 cases detected <2/= ( #ltho*gh there contin*es to 6e so+e disagree+ent as to 'hether +inor ne*ro0intellect*al se7*elae re+ain in the +ost severely affected infants, acc*+*lating evidence s*ggests that a nor+al o*tco+e is possi6le even in the latter gro*p of 6a6ies as long as treat+ent is started s*fficiently early and is ade7*ate < 210)0= Certainly, the +ain o6?ective of screening, the eradication of +ental retardation, has 6een achieved( #n additional 6enefit of ne'6orn screening has 6een the el*cidation of the prevalence of the vario*s ca*ses of congenital hypothyroidis+, incl*ding a series of transient disorders fo*nd predo+inantly in pre+at*re infants(

Screening Strategies for Congenital 'y"othyroidis

Meas*re+ent of T2 and8or T%! is perfor+ed on an el*ate of dried 'hole 6lood collected on filter paper 6y s,in p*nct*re on day 102 of life( T'o screening strategies for the detection of congenital hypothyroidis+ have evolved( 9n the pri+ary T2 86ac,*p T%! +ethod, still favored in +*ch of -orth #+erica and the -etherlands, T2 is +eas*red initially 'hile T%! is chec,ed on the sa+e 6lood spot in those speci+ens in 'hich the T2 concentration is lo'( .hereas initially a c*toff of the &rd percentile <T2 E/ +cg8dL or 55 n+ol8L= 'as e+ployed, +ost progra+s no' *se the 10th percentile <T2 B *g8dL or 11/ n+ol8L= or even the 20th percentile as a threshold to +eas*re T%!( This has 6een done in order to detect patients 'ith s*6clinical hypothyroidis+, a finding in so+e infants 'ith ectopic thyroids <the +ost co++on ca*se of per+anent congenital hypothyroidis+=( "a6ies in 'ho+ the initial 6lood T%! concentration is F20 +U8L are li,ely to have per+anent congenital hypothyroidis+ and are recalled i++ediately <)1= ( @n the other hand, appro4i+ately 5)C of infants 'hose initial T%! concentration is 6et'een 20 and &B +U8L 'ill have a nor+al val*e <E20+U8L= on repeat testing < G false positive H =( Therefore a confir+atory dried 6lood speci+en only is re7*ested initially in the latter gro*p of 6a6ies( 9n the pri+ary T%! approach, favored in +ost parts of E*rope and Mapan, 6lood T%! is +eas*red initially( The T2 concentration is +eas*red in the initial 6lood spot in all 6a6ies in 'ho+ the screening T%! is 6et'een 20 and )0 +U8L( "a6ies 'hose initial ser*+ T%! is F)0 +U8L or 'hose screening T%! is 2002B +U8L 6*t 'hose T2 val*e is E/2 n+ol8L <) +cg8dL= are recalled i++ediately <25= ( %i+ilar to the e4perience 'ith the pri+ary T2 86ac,*p T%! +ethod, 6a6ies 'hose initial T%! is F)0

+U8L are +ost li,ely to have per+anent congenital hypothyroidis+ 'hile a T%! 6et'een 20 and 2B +U8L is fre7*ently a false positive, or represents transient hypothyroidis+, a pro6le+ that is partic*larly co++on in pre+at*re infants in 6orderline iodine deficient areas of E*rope( Each screening strategy has its advantages and disadvantages, 6*t the t'o approaches appear to 6e e7*ivalent in the detection of 6a6ies 'ith per+anent for+s of congenital hypothyroidis+ <)2= ( # pri+ary T2 86ac,*p T%! progra+ 'ill detect overt pri+ary hypothyroidis+, secondary or tertiary hypothyroidis+, 6a6ies 'ith a lo' ser*+ T2 level 6*t delayed rise in the T%! concentration, T"A deficiency and hyperthyro4ine+ia: this approach +ay, ho'ever, +iss s*6clinical hypothyroidis+ ( # pri+ary T%! strategy, on the other hand, 'ill detect 6oth overt and s*6clinical hypothyroidis+, 6*t 'ill +iss secondary or tertiary hypothyroidis+, a delayed T%! rise, T"A deficiency and hyperthyro4ine+ia( There are fe'er false positives 'ith a pri+ary T%! strategy( "oth progra+s 'ill +iss the rare infant 'hose T2 level on initial screening is nor+al 6*t 'ho later develops lo' T2 and elevated T%! concentrations <E0()C of infants, +ost co++only pre+at*re 6a6ies 'ith transient hypothyroidis+=( This pattern has 6een ter+ed J atypical > congenital hypothyroidis+ or J delayed T%! > and is o6served +ost co++only in pre+at*re 6a6ies 'ith transient hypothyroidis+ or infants 'ith less severe for+s of per+anent disease( %o+e progra+s have responded 6y perfor+ing a second screen on all infants at the ti+e of their ret*rn visit to their pediatrician at 2 to / 'ee,s of age <)&= ( 9n addition, so+e of these progra+s re7*est follo' *p ser*+ on any 6a6y 'ith a very lo' T2 val*e <E&rd percentile= on t'o occasions or a very lo' filter paper T2 6elo' a critical val*e <E& *g8dL= on one occasion( $rogra+s that perfor+ a second screen report the detection of an additional 10C of congenital hypothyroidis+ cases, 6*t this practice greatly increases the cost of screening( @ther screening progra+s ro*tinely perfor+ a second screen only on patients at high ris, of delayed T%! elevation, s*ch as very lo' 6irth 'eight infants and 6a6ies in the neonatal intensive care *nit <)2= ( The latter progra+s report a 120fold increased incidence of atypical hypothyroidis+ in very lo' 6irth 'eight infants( #s noted previo*sly, in so+e of these cases, it +ay not 6e certain as to 'hether the elevated T%! level is pathological or represents an appropriate co+pensatory response follo'ing hypothyro4ine+ia secondary to sic, e*thyroid syndro+e( @ther gro*ps at high0ris, of delayed T%! rise are 6a6ies 'ith cardiovasc*lar ano+alies, patients 'ith Do'n syndro+e and +ono;ygotic t'ins <))= ( 9n the latter gro*p of infants, fetal cord +i4ing +ay occ*r and initially +as, the presence of congenital hypothyroidis+( # f*rther refine+ent in screening is one e+ployed 6y the -etherlands 'here, in addition to a pri+ary T2 86ac,*p T%! approach, T"A is assessed in those filter paper speci+ens 'ith the lo'est )C of T2 val*es <)/= ( The T2 8T"A ratio is *sed as an indirect reflection of the free T2, 'hich cannot 6e +eas*red directly in dried 6lood spots( This approach has 6een reported to res*lt in i+proved sensitivity and specificity in detecting +ilder cases of pri+ary congenital hypothyroidis+ that +ight other'ise 6e +issed( #n additional reported advantage 'as the identification of FB0C of infants 'ith central hypothyroidis+ co+pared 'ith only 22C 'ith pri+ary T2 screening and none 'ith a pri+ary T%! approach ( %ince on s*6se7*ent testing F 10C of the 6a6ies 'ith central hypothyroidis+ had +*ltiple pit*itary hor+one deficiencies, a disorder associated 'ith high +or6idity and +ortality for 'hich effective treat+ent e4ists <)5=, and i n vie' of an apparent fre7*ency <1 in 1/,000= si+ilar to that of phenyl,eton*ria <1 in 11,000 =, the a*thors have arg*ed that the goals of ne'6orn thyroid screening sho*ld 6e e4tended to incl*de the detection of 6a6ies 'ith central hypothyroidis+( 9n contrast to the D*tch e4perience, in a retrospective st*dy of 22 children 'ith central hypothyroidis+ identified in 9ndiana over a 15 year period d*ring ti+e 'hich a co+6ined T28T%! screening strategy 'as e+ployed only 1 doc*+ented cases <1BC= had an initial T2 concentration E) +cg8dL leading the a*thors to ca*tion that an initially nor+al T2 concentration on ne'6orn screen +ight led to a false sense of sec*rity(

Recently 'ith the develop+ent of +ore sensitive, non0radioisotopic T%! assays, Canada and so+e states in the United %tates have s'itched to a pri+ary T%! progra+( 9n practice, the screening strategy *tili;ed is chosen 6y the screening progra+( -e'6orn screening 'as perfor+ed initially at 6et'een & and 2 days of life and the nor+al val*es that 'ere derived reflected this postnatal age( The practice of early discharge fro+ the hospital of other'ise healthy f*ll ter+ infants has res*lted in a greater proportion of 6a6ies 6eing tested 6efore this ti+e( 3or e4a+ple, it has 6een esti+ated that in -orth #+erica 2)C or +ore of ne'6orns are no' discharged 'ithin 22 ho*rs of delivery and 20C in the second 22 ho*rs of life <)1= ( "eca*se of the neonatal T%! s*rge and the dyna+ic changes in ser*+ T2 and T& concentrations that occ*r 'ithin the first fe' days of life, early discharge increases the n*+6er of false positive res*lts( 9n California, the ratio of false positive to confir+ed congenital hypothyroidis+ has increased fro+ 2():1 to appro4i+ately ):1, an appro4i+ate do*6ling( %o+e progra+s have responded 6y increasing their threshold val*e for T%! 'ithin the first day of life( # potential pro6le+, ho'ever, is the possi6ility of +issing infants 'ith a slo'ly rising T%!( #nother co+plicating factor for ne'6orn screening progra+s in recent years is the dra+atically increased s*rvival of very pre+at*re infants, d*e, in part, to the advent of s*rfactant therapy( Nery pre+at*re infants greatly increase the cost of screening progra+s for t'o reasons( #s disc*ssed in detail a6ove, 6lood T2 concentrations are lo'er and the incidence of transient hypothyroidis+ is +*ch higher in the+ as co+pared 'ith f*ll ter+ 6a6ies( 9t has 6een esti+ated that 'hereas very lo' 6irth 'eight infants constit*te only 0(1C of the pop*lation, they increase the n*+6er of T2 assays in a pri+ary T%! progra+ 6y BC <20= ( %i+ilarly, very lo' 6irth 'eight infants acco*nt for 1C of all T%! assays perfor+ed in a pri+ary T2 progra+( $hysicians caring for infants need to appreciate that there is al'ays the possi6ility for h*+an error in failing to identify affected infants, 'hichever screening progra+ is *tili;ed( This can occ*r d*e to poor co++*nication, lac, of receipt of re7*ested speci+ens, or the fail*re to test an infant 'ho is transferred 6et'een hospitals d*ring the neonatal period <)1=( Therefore if the diagnosis of hypothyroidis+ is s*spected clinically, the infant sho*ld al'ays 6e tested <3ig*re )=( %i+ilarly, as is o6vio*s fro+ the disc*ssion earlier in the chapter, ad*lt nor+ative val*es, provided 6y +any general hospital la6oratories, differ fro+ those in the ne'6orn period and sho*ld never 6e e+ployed( -or+al val*es according to 6oth gestational and postnatal age for cord 6lood T2, free T2, T"A, T&, reverse T&, and T%! *p to 21 days of life <10= are sho'n in 3ig*re &( -or+al ser*+ levels of Tg in pre+at*re and f*ll0ter+ infants <1&, 12 = and nor+al ser*+ levels of free T2 and T%! in the first 'ee, of life <)B= have also 6een p*6lished, tho*gh it sho*ld 6e noted that precise val*es +ay vary so+e'hat, depending on the specific assays *sed(

3ig*re 1)0) ( Three +onth old +ale infant 'ho 'as diagnosed clinically 'hen he presented 'ith a history of poor feeding at & +onths of age( The child 'as 6orn in $*erto Rico prior to the develop+ent

of ne'6orn screening and +oved to the United %tates shortly thereafter( -ote the d*ll facies, perior6ital ede+a and large tong*e(

Causes of %er anent Congenital 'y"othyroidis

Thyroid Dysgenesis
Unli,e in iodine0deficient areas of the 'orld 'here ende+ic cretinis+ contin*es to 6e a +a?or health ha;ard, the +a?ority <1) to B0C= of cases of per+anent congenital hypothyroidis+ in -orth #+erica, .estern E*rope and Mapan are d*e to an a6nor+ality of thyroid gland develop+ent < thyroid dysgenesis =( Thyroid dysgenesis +ay res*lt in the co+plete a6sence of thyroid tiss*e <agenesis= or it +ay 6e partial <hypoplasia=: the latter often is acco+panied 6y a fail*re to descend into the nec, <ectopy=( 3e+ales are affected t'ice as often as +ales( 9n the United %tates, thyroid dysgenesis, is less fre7*ent a+ong #frican #+ericans and +ore co++on a+ong !ispanics and #sians( "a6ies 'ith congenital hypothyroidis+ have an increased incidence of cardiac ano+alies, partic*larly atrial and ventric*lar septal defects </0= ( #n increased prevalence of renal and *rinary tract ano+alies has also 6een reported recently </1= ( Most cases of thyroid dysgenesis are sporadic( #ltho*gh 6oth genetic and environ+ental factors have 6een i+plicated in its etiology, in +ost cases the ca*se is *n,no'n( The occasional fa+ilial occ*rrence, the higher prevalence of thyroid dysgenesis in 6a6ies of certain ethnic gro*ps and in fe+ale vers*s +ale infants as 'ell as the increased incidence in 6a6ies 'ith Do'n syndro+e </2= all s*ggest that genetic factors +ight play a role in so+e patients( The transcription factors NKX 2(1 < TTF 1=, FOXE 1 < TTF 2= and PAX 1 'o*ld appear to 6e o6vio*s candidate genes in vie' of their i+portant role in thyroid organogenesis and in thyroid0specific gene e4pression( To date, ho'ever, a6nor+alities in these genes have 6een fo*nd in only a s+all proportion of affected patients, *s*ally in association 'ith other develop+ental a6nor+alities( 3or e4a+ple, the syndro+e of congenital hypothyroidis+ associated 'ith *ne4plained neonatal respiratory distress, ata4ia, and develop+ental delay has 6een fo*nd in a n*+6er of patients 'ith genetic a6nor+alities of NKX 2(1, analogo*s to the findings of a6nor+al thyroid, l*ng, pit*itary, and fore6rain develop+ent in +ice 'ith a targeted disr*ption of this gene </&= ( 9n contrast, no ger+line +*tations in NKX 2(1 gene 'ere fo*nd in a total of 5/ patients 'ith isolated C! < /2, /) =( # si+ilar sit*ation has 6een fo*nd 'ith FOXE 1 < TTF 2=, a +*tation 'hich has 6een reported in 2 si6lings 'ith the co+6ination of thyroid agenesis, cleft palate, spi,y hair and choanal atresia <//= ( 9n a different st*dy, ger+line +*tations of PAX 1 'ere fo*nd in only 2 of 12) 9talian patients 'ith sporadic thyroid dysgenesis st*died( 9n one of these latter patients, the thyroid gland 'as hypoplastic and ectopic 'hile in the other patient the thyroid gland 'as hypoplastic 6*t located in a nor+al position in the nec,( %ince PAX 1 is also involved in renal develop+ent it 'ill 6e i+portant to deter+ine 'hether this gene is related to the increased prevalence of renal *rinary tract ano+alies that has 6een noted recently( 9t is possi6le that thyroid dysgenesis is a polygenic disease 'ith varia6le penetrance depending on the genetic 6ac,gro*nd </5= ( #lternately, epigenetic +odifications, early so+atic +*tations or stochastic develop+ental events +ay play a role( Ta6le 1( s*++ari;es ,no'n +olec*lar defects in transcription factors and other ca*ses of congenital hypothyroidis+( Ta!le , . Aenetic ca*ses of per+anent congenital hypothyroidis+( A!nor ality Gene Gene locus Inheritance Abnormal thyroid land d!"!lo#m!nt$mi ration O TTF1$NKX2.1 % 1271& #DP TTF2$FOXE1 % B722 #RPP

PAX8 Abnormal&thyroid&hormono !n!'i' Decreased T2 synthesis N(S TPO )*OX2 + TG )EHA,1 S,-2.A/$P)S Decreased T%! synthesis @ther pit*itary hor+one deficits P0OP1 PO*1F1 ,HX3 ,HX/ HESX1 9solated decreasedT%! T0H T0H0 TSH 1 Decreased T%! response TSH0 G' 2 Abnormal&thyroid&hormon!&a3tion



1Bp1201&(2 2p2) 1)71)(& 1722 /72202) 57&1

#R #R #R #R,#D #R #R

)7 &p11 B7&2(& 172) &p21(20p21(2 &p 127&1 1p1& 127&1 2071&(2

#R #R,#D #R #R,#D #R,#D #R #R #R #R #D

T0 1 &p22(& #D 4-T8 Q71&(2 Q0lin,ed SE-(SBP2 B722(2 #R O*s*ally sporadic, P#D, a*toso+al do+inant, PP #R, a*toso+al recessive, % 5'5ally 'yndromi3 + #!rman!nt 6h!n biall!li37 tran'i!nt 6h!n monoall!li37

In!orn -rrors of Thyroid 'or onogenesis

9n6orn errors of thyroid hor+onogenesis are responsi6le for +ost of the re+aining cases <1)C= of neonatal hypothyroidis+( # n*+6er of different defects have 6een characteri;ed and incl*de: 1= decreased T%! responsiveness, 2= fail*re to concentrate iodide, &= defective organification of iodide d*e to an a6nor+ality in the pero4idase en;y+e or in the !2@2 generating syste+, 2= defective Tg synthesis or transport, and )= a6nor+al iodotyrosine deiodinase activity </1= ( The association of an organification defect 'ith sensorine*ral deafness is ,no'n as $endred syndro+e( Tho*gh *s*ally incl*ded in ca*ses of congenital hypothyroidis+ 6eca*se it is ca*sed 6y a genetic defect, $endred syndro+e rarely presents in the ne'6orn period( Unli,e thyroid dysgenesis, a sporadic condition, these in6orn errors of thyroid hor+onogenesis are co++only associated 'ith an a*toso+al recessive for+ of inheritance, consistent 'ith a single gene a6nor+ality( 9t is not s*rprising, therefore, that a +olec*lar 6asis has no' 6een identified in all of the+(

These incl*de defects in the genes for the T%! receptor < TSH0 =, the sodi*+0iodide sy+porter < N(S =, T$@ , d*al o4idase <DU@Q= 2, Tg, and iodotyrosine deiodinase < )EHA,1 =( $endred syndro+e is no' ,no'n to 6e ca*sed 6y +*tations in the pendrin gene < P)S , no' called S,-2.A 2=, 'hich encodes a s*lfate transporter of iodide on the apical s*rface of the thyroid follic*lar cell as 'ell as the cochlea < /1=( M*tations in this gene have also 6een fo*nd to 6e an i+portant genetic ca*se of isolated sensorine*ral deafness( M*tations in )*OX2 , i+portant in hydrogen pero4ide generation, have 6een sho'n to ca*se 6oth transient and per+anent for+s of congenital hypothyroidis+, depending *pon 'hether the +*tation is +onoallelic or 6iallelic( 9n6orn errors of thyroid hor+onogenesis are s*++ari;ed in Ta6le 1 and disc*ssed in f*rther detail in else'here( #ll of the in6orn errors of thyroid hor+onogenesis e4cept decreased T%! responsiveness are associated 'ith a nor+ally placed < > e*topic > thyroid gland that +ay 6e increased in si;e at 6irth and this feat*re for+s the 6asis for the clinical distinction fro+ thyroid dysgenesis( 9n contrast, +ost 6a6ies 'ith T%! resistance have a nor+al or hypoplastic, e*topic gland that +ay in so+e cases +i+ic an a6nor+ality of thyroid gland develop+ent < /B, 50 =: in rare cases no thyroid gland at all is discerni6le on thyroid i+aging, a pict*re indisting*isha6le fro+ thyroid agenesis <51=( %i+ilar to the varia6ility o6served in thyroid gland si;e in this condition, the clinical findings in T%! resistance have varied fro+ s*6clinical to overt hypothyroidis+ depending on the severity of the f*nctional defect( %o+e of these patients have 6een fo*nd to have a loss of f*nction +*tation of the T%! receptor, analogo*s to the hyt8hyt +o*se <52= ( 9n a fe' affected infants, a discrepancy 6et'een pres*+ed athyreosis on thyroid scintigraphy and the detection of either a J nor+al > ser*+ Tg concentration or gland*lar tiss*e on *ltraso*nd e4a+ination has 6een noted <51= , a feat*re that +ay 6e helpf*l diagnostically( The relative fre7*ency of T%! receptor gene +*tations as a ca*se of T%! resistance is not ,no'n( 9n one st*dy, inactivating +*tations of the T%! receptor gene 'ere fo*nd in only 1 of 100 patients 'ith congenital hypothyroidis+, indicating that a6nor+alities in this gene are not a co++on ca*se of thyroid hypoplasia or aplasia <5&= ( # si+ilar concl*sion +ay 6e dra'n fro+ the fail*re to de+onstrate lin,age to the T%! receptor gene in 2& fa+ilies in a +a?ority of 'hich there 'ere t'o or +ore children affected 6y congenital hypothyroidis+ and in 'ho+ there 'as apprecia6le consang*inity of the parents <52= ( !o'ever, a recent st*dy s*ggests that +*tations in this gene +ay 6e +ore co++on, partic*larly in certain pop*lations <5)= ( Most fa+ilial cases of T%! resistance have an a*toso+al recessive for+ of inheritance( Rarely T%! resistance +ay 6e d*e to an inactivating +*tation of the sti+*latory g*anine n*cleotide06inding protein <As alpha0gene <pse*dohypoparathyroidis+, type la or #l6right > s hereditary osteodystrophy=( Us*ally the latter patients have transient hypothyroidis+ in the ne'6orn period or a +ild f*nctional defect that res*lts in s*6clinical hypothyroidis+ later in life <5/= ( #l6right > s hereditary dystrophy has an a*toso+al do+inant inheritance 'ith varia6le e4pression depending *pon 'hether the +*tant gene is paternally or +aternally derived(

Secondary and.or Tertiary 'y"othyroidis

Central hypothyroidis+ 'as previo*sly tho*ght to occ*r in 1 in )0,000 to 1 in 100,00 0 ne'6orn infants, 6*t, as noted previo*sly, it +ay 6e +*ch +ore co++on < 22=( T%! deficiency +ay 6e isolated or it +ay 6e associated 'ith other pit*itary hor+one deficiencies( 3a+ilial cases of 6oth T%! deficiency and TR! deficiency have 6een descri6ed( # reported ca*se of isolated T%! deficiency is the C#AIC +*tation in the gene for the T%! 6eta +olec*le( # +*tation in the TR! receptor gene has also 6een descri6ed in a child in 'ho+ secondary hypothyroidis+ 'as +issed on ne'6orn screening( 9n the latter patient, the diagnosis 'as s*spected clinically 6eca*se of an a6sent T%! and prolactin response to TR! despite a nor+al pit*itary gland on i+aging <55= <Ta6le 1=( T%! deficiency in association 'ith other pit*itary hor+one deficiencies +ay 6e associated 'ith

a6nor+al +idline facial and 6rain str*ct*res <partic*larly cleft lip and palate, and a6sent sept*+ pell*cid*+ and8or corp*s callos*+= and sho*ld 6e s*spected in any +ale infant 'ith +icrophall*s and persistent hypoglyce+ia <51= ( @ne of the +ore co++on of these syndro+es, septo0optic dysplasia, has 6een related in so+e cases to a +*tation in the HESX 1 ho+eo6o4 gene in so+e cases <5B= ( @ther genetic ca*ses of congenital hypopit*itaris+ incl*de +olec*lar defects in the genes for the transcription factors ,HX3 < 10= , ,HX/7 PO*1F 1 <11= or P0OP 1 <11= ( PO*1F 1 <$it01 in +ice= is essential for the differentiation of 6oth thyrotrophs, lactotrophs and so+atotrophs 'hile P0OP 1, a ho+eodo+ain protein that is e4pressed 6riefly in the e+6ryonic pit*itary, is necessary for PO*1F 1 e4pression( The +olec*lar 6asis for pit*itary hypoplasia associated 'ith an ectopic posterior pit*itary gland <51= has not 6een el*cidated (

Decreased T 4 Action
Until recently, the only ,no'n ca*se of decreased thyroid hor+one action 'as a +olec*lar defect in the thyroid hor+one receptor <TR= 6eta that rendered the cell *na6le to respond( Recently t'o additional ca*ses have 6een recogni;ed: inade7*ate intracell*lar T2 transport, and an a6nor+ality in the synthesis of D2 leading to a defect in T2 to T& conversion( i+ Decreased Cellular Trans"ort Decreased T2 *pta,e into 6rain cells is a ne'ly recogni;ed congenital a6nor+ality of thyroid hor+one action( 9n this syndro+e +*tations in the +onocar6o4ylate transporter 1 < 4-T 1 gene, located on the Q0chro+oso+e, have 6een associated 'ith +ale0 li+ited hypothyroidis+ and severe ne*rological a6nor+alities, incl*ding glo6al develop+ental delay, dystonia, central hypotonia, spastic 7*adriplegia, rotary nystag+*s and i+paired ga;e and hearing <12= ( !etero;ygo*s fe+ales had a +ilder thyroid phenotype and no ne*rological defects( ii+ Thyroid 'or one Resistance Aenerali;ed resistance to thyroid hor+one <ART!=, the classical ca*se of inade7*ate T2 action, is *s*ally diagnosed later in life, 6*t +ay 6e identified in the ne'6orn period 6y neonatal screening progra+s that deter+ine pri+arily T%! < 1&=( #ffected 6a6ies *s*ally are not sy+pto+atic: later in life they +ay fail to thrive, have attention deficit disorder, a s+all goiter and *ne4plained tachycardia( Most cases of ART! res*lt fro+ a +*tation in the TR 6eta gene and follo' an a*toso+al do+inant pattern of inheritance( Recently a patient 'ith a de novo hetero;ygo*s nonsense +*tation in the gene encoding TR alpha has 6een descri6ed <1&6=( 9n this patient, adverse effects on gro'th and s,eletal develop+ent 'ere +ore pro+inent( Thyroid hor+one resistance is disc*ssed in greater detail else'here( iii+ A!nor al thyroid hor one eta!olis

Decreased T2 action +ay 6e the res*lt of a ho+o;ygo*s +*tation in SE-(SBP 2, a gene re7*ired for the incorporation of selenocysteine into D212( This res*lts in decreased activation of T2 to T&( #ffected patients have a6nor+al thyroid f*nction 6*t are other'ise nor+al(

Causes of transient neonatal hy"othyroidis

Transient neonatal hypothyroidis+ sho*ld 6e disting*ished fro+ a J false positive > res*lt in 'hich the screening res*lt is a6nor+al 6*t the confir+atory ser*+ sa+ple is nor+al( 9n -orth #+erica, the original esti+ate 'as 1 in 20,000 infants, e7*ivalent to appro4i+ately 10C of all cases of congenital

hypothyroidis+( Recent data s*ggest that the condition is no' +ore than three0fold +ore co++on <1 in 11,000 to 1 in 12,000= < 22=, pro6a6ly d*e, at least in part, to the s*rvival of increasingly pre+at*re infants( Ca*ses of transient a6nor+alities of thyroid f*nction in the ne'6orn period are listed in Ta6le 2( .hile iodine deficiency, iodine e4cess, dr*gs and +aternal T%! receptor 6loc,ing anti6odies are the +ost co++on ca*ses of transient hypothyroidis+, in so+e cases the ca*se is *n,no'n(

i+ Iodine Deficiency or -$cess

Transient hypothyroidis+ d*e to 6oth iodine deficiency and iodine e4cess is +ore co++on in relatively iodine0deficient areas of E*rope than in -orth #+erica, an iodine0s*fficient region < 25=( 9n "elgi*+, for e4a+ple, prior to the instit*tion of ro*tine iodine s*pple+entation in pre+at*re infants, transient hypothyroidis+ 'as reported in 20C of pre+at*re infants, an 10fold higher prevalence than in -orth #+erica( $re+at*re infants are *n*s*ally s*scepti6le to the effects of iodine deficiency not only 6eca*se of decreased thyroidal iodine stores acc*+*lated in *tero, 6*t 6eca*se of i++at*rity in 6oth the capacity for thyroid hor+onogenesis, the hypothala+ic0pit*itary0thyroid a4is, and in the a6ility to convert T2 to the +ore +eta6olically active T& ( 3*rther+ore, pre+at*re infants are in negative iodine 6alance for the first 1 or 2 'ee,s of postnatal life < &B=( Ta!le / ( Ca*ses of Transient #6nor+alities of Thyroid 3*nction in the -e'6orn $eriod %ri ary hy"othyroidis $renatal or postnatal iodine deficiency or e4cess Maternal antithyroid +edication Maternal T%! receptor 6loc,ing anti6odies Monoallelic +*tation in )*OX 2 Central hy"othyroidis $renatal e4pos*re to +aternal hyperthyroidis+ $re+at*rity <partic*larly E25 'ee,s gestation= Dr*gs Miscellaneous 9solated hyperthyrotropine+ia %ic, e*thyroid syndro+e Maln*trition T"A deficiency 9n addition to iodine deficiency, 6oth the fet*s and ne'6orn infant are sensitive to the thyroid0 s*ppressive effects of e4cess iodine, 'hether ad+inistered to the +other d*ring pregnancy, lactation or directly to the 6a6y < 1)=( This occ*rs, in part 6eca*se, as noted earlier, recovery fro+ the thyroid0 s*ppressive effect of iodine does not +at*re 6efore &/ 'ee,s gestation: ho'ever, other factors, incl*ding increased s,in a6sorption are also li,ely to play a role( Reported so*rces of iodine have incl*ded dr*gs <e(g(, potassi*+ iodide, a+iodarone=, radiocontrast agents and antiseptic sol*tions <e(g(, povidone0iodine= *sed for s,in cleansing or vaginal do*ches( 9n contrast to E*rope, iodine0ind*ced transient hypothyroidis+ has not 6een doc*+ented fre7*ently in -orth #+erica < 1/=(

ii+ Maternal Antithyroid Medication

Transient neonatal hypothyroidis+ +ay develop in 6a6ies 'hose +others are 6eing treated 'ith antithyroid +edication <either propylthio*racil, $TU or +ethi+a;ole, MM9= for the treat+ent of Araves > disease( Even +aternal $TU doses of 200 +g or less have 6een associated 'ith an effect on neonatal thyroid f*nction, ill*strating the increased fetal sensitivity to these dr*gs < 15=( "a6ies 'ith $TU0 or MM90ind*ced hypothyroidis+ characteristically develop an enlarged thyroid gland and if the dose is s*fficiently large, respiratory e+6arrass+ent +ay occ*r( "oth the hypothyroidis+ and goiter resolve spontaneo*sly 'ith clearance of the dr*g fro+ the 6a6y > s circ*lation( Us*ally replace+ent therapy is not re7*ired(

iii+ Maternal TS' Rece"tor Anti!odies

Maternal T%! receptor 6loc,ing anti6odies, a pop*lation of anti6odies closely related to the T%! receptor sti+*lating anti6odies in Araves disease, +ay 6e trans+itted to the fet*s in s*fficient titer to ca*se transient neonatal hypothyroidis+( The incidence of this disorder has 6een esti+ated to 6e 1 in 110,000 < 11=( T%! receptor 6loc,ing anti6odies +ost often are fo*nd in +others 'ho have 6een treated previo*sly for Araves disease or 'ho have the non goitro*s for+ of chronic ly+phocytic thyroiditis <pri+ary +y4ede+a=( @ccasionally these +others are not a'are that they are hypothyroid and the diagnosis is +ade in the+ only after congenital hypothyroidis+ has 6een recogni;ed in their infants < 1B=( Unli,e T%! receptor sti+*lating anti6odies that +i+ic the action of T%!, T%! receptor 6loc,ing anti6odies inhi6it 6oth the 6inding and action of T%! <see 6elo'=( "eca*se T%!0ind*ced gro'th is 6loc,ed, these 6a6ies do not have a goiter( %i+ilarly, inhi6ition of T%!0ind*ced radioactive iodine *pta,e +ay res*lt in a +isdiagnosis of thyroid agenesis < B0=( Us*ally the hypothyroidis+ resolves in & or 2 +onths( "a6ies 'ith T%! receptor 6loc,ing0anti6ody ind*ced hypothyroidis+ are diffic*lt to disting*ish at 6irth fro+ the +ore co++on thyroid dysgenesis 6*t they differ fro+ the latter in a n*+6er of i+portant 'ays <Ta6le &=( They do not re7*ire lifelong therapy, and there is a high rec*rrence rate in s*6se7*ent offspring d*e to the tendency of these anti6odies to persist for +any years in the +aternal circ*lation( Unli,e 6a6ies 'ith thyroid dysgenesis in 'ho+ a nor+al cognitive o*tco+e is fo*nd if postnatal therapy is early and ade7*ate, 6a6ies 'ith +aternal 6loc,ing0anti6ody ind*ced hypothyroidis+ +ay have a per+anent deficit in intellect*al develop+ent if feto0+aternal hypothyroidis+ 'as present in *tero < 25=(

i0 DUOX /
.hereas a 6iallelic +*tation in DU@Q2 is associated 'ith per+anent congenital hypothyroidis+, 'hen a +onoallelic +*tation is fo*nd the co*rse of the congenital hypothyroidis+ is transient( Ta!le 1.Clinical feat*res of thyroid dysgenesis vers*s T%! receptor 6loc,inganti6ody0ind*ced Congenital !ypothyroidis+( Dysgenesis "loc,ing #6 %everity of C! R to RRRR R to RRRR $alpa6le thyroid -o -o 12&9 *pta,e -one to lo' -one to nor+al Clinical Co*rse $er+anent Tran'i!nt 3a+ilial ris, -o 8!' T$@ #6s Naria6le Naria6le T%! Receptor #6s #6sent Pot!nt




Transient Central 'y"othyroidis

i+ Maternal hy"erthyroidis
@ccasionally, 6a6ies 6orn to +others 'ho 'ere hyperthyroid d*ring pregnancy develop transient hypothala+ic0pit*itary s*ppression < B1=( This hypothyro4ine+ia is *s*ally self0li+ited, 6*t in so+e cases it +ay last for last years and re7*ire replace+ent therapy < B2=( 9n general the titer of T%! receptor sti+*lating anti6odies in this pop*lation of infants is lo'er than in those 'ho develop transient neonatal hyperthyroidis+ <see 6elo'=(

ii+ %re aturity

!ypothyro4ine+ia in the presence of a J nor+al > T%! occ*rs +ost co++only in pre+at*re infants in 'ho+ it is fo*nd in )0C of 6a6ies of less than &0 'ee,s gestation( @ften the free T2 'hen +eas*red 6y e7*ili6ri*+ dialysis is less affected than the total T2 <B&=( The reasons for the hypothyro4ine+ia of pre+at*rity are co+ple4( #s 'ell as hypothala+ic0pit*itary i++at*rity +entioned earlier, pre+at*re infants fre7*ently have T"A deficiency d*e to 6oth i++at*re liver f*nction and *ndern*trition, and they +ay have G sic, e*thyroid syndro+e H ( They +ay also 6e treated 'ith dr*gs that s*ppress the hypothala+ic0pit*itary0thyroid a4is(

iii+ Drugs
Dr*gs that s*ppress the hypothala+ic0pit*itary a4is incl*de ,no'n agents s*ch as steroids and dopa+ine, 6*t also a+inophylline, caffeine and dia+orphine, other co++only *sed in sic, pre+at*re infants < B2=(

Miscellaneous A!nor alities

i+ Idio"athic hy"er thyrotro"ine ia
#n elevated ser*+ T%! concentration 'ith nor+al circ*lating T2 and free T2 levels has 6een noted, often in screening progra+s that *tili;e a pri+ary T%! +ethod and is +ost co++on in pre+at*re infants( #s a gro*p, 6a6ies diagnosed 'ith hyperthyrotropine+ia in infancy have a higher ser*+ T%! concentration co+pared to control children 'hen ree4a+ined in early childhood < B)=( 9n addition these infants have a higher prevalence of 6oth thyroid +orphological a6nor+alities, antithyroid anti6odies, and +*tations in thyropero4idase and T%! receptor genes than do controls < B/=, s*ggesting that the elevated ser*+ T%! concentration is related to +ild hypothyroidis+( %*6clinical hypothyroidis+ needs to 6e disting*ished fro+ delayed +at*ration of the hypothala+ic0 pit*itary a4is < B5=, a transient condition, and the cold0ind*ced T%! s*rge o6served postnatally( %everal years ago, a +aternal heterophile anti6ody that cross0reacted in the T%! radioi++*noassay in ro*tine *se at the ti+e 'as i+plicated <B1= (

Clinical Manifestations
Clinical findings are *s*ally diffic*lt to appreciate in the ne'6orn period e4cept in the *n*s*al

sit*ation of co+6ined +aternal0fetal hypothyroidis+( Many of the classic feat*res <large tong*e, hoarse cry, facial p*ffiness, *+6ilical hernia, hypotonia, +ottling, cold hands and feet and lethargy=, 'hen present, are s*6tle and develop only 'ith the passage of ti+e( 9n addition to the afore+entioned findings, nonspecific signs that sho*ld s*ggest the diagnosis of neonatal hypothyroidis+ incl*de: prolonged, *ncon?*gated hyper6ilir*6ine+ia, gestation longer than 22 'ee,s, feeding diffic*lties, delayed passage of stools, hypother+ia or respiratory distress in an infant 'eighing over 2() ,g < BB=( # large anterior fontanelle and8or a posterior fontanelle F 0() c+ is fre7*ently present in affected infants 6*t +ay not 6e appreciated( 9n general, the e4tent of the clinical findings depends on the ca*se, severity and d*ration of the hypothyroidis+( "a6ies in 'ho+ severe feto0+aternal hypothyroidis+ 'as present in *tero tend to 6e the +ost sy+pto+atic at 6irth( %i+ilarly, 6a6ies 'ith athyreosis or a co+plete 6loc, in thyroid hor+onogenesis tend to have +ore signs and sy+pto+s at 6irth than infants 'ith an ectopic thyroid, the +ost co++on ca*se of congenital hypothyroidis+( Unli,e ac7*ired hypothyroidis+, 6a6ies 'ith congenital hypothyroidis+ are of nor+al si;e( !o'ever, if diagnosis is delayed, s*6se7*ent linear gro'th is i+paired( The finding of palpa6le thyroid tiss*e s*ggests that the hypothyroidis+ is d*e to an a6nor+ality in thyroid hor+onogenesis or in thyroid hor+one action, or that it 'ill 6e transient(

2a!oratory -0aluation
9nfants fo*nd to have a6nor+al thyroid f*nction tests 6y ne'6orn screening sho*ld have a confir+atory ser*+ sa+ple eval*ated 'itho*t delay, prefera6ly 'ithin 22 ho*rs( The diagnosis of neonatal hypothyroidis+ is confir+ed 6y the de+onstration of a decreased concentration of free T2 for age and an elevated T%! level <F 20 +U8L after one day of life= in ser*+ #s noted previo*sly, +ost infants 'ith per+anent a6nor+alities of thyroid f*nction have a ser*+ T%! concentration F20 +U8L( 9n so+e screening progra+s infants 'ith +ilder thyroid a6nor+alities, partic*larly pre+at*re infants, are follo'ed 'ith repeat filter paper speci+ens in anticipation that the a6nor+ality 'ill 6e transient( $ostnatal and gestational age0related nor+ative val*es sho*ld al'ays 6e *sed and not the ad*lt val*es that are co++only provided in +any general hospital la6oratories( Meas*re+ent of T& is of little val*e in the diagnosis of congenital hypothyroidis+( # 6one age +ay 6e perfor+ed as a reflection of the d*ration and severity of the hypothyroidis+ in *tero 6*t is perfor+ed +*ch less fre7*ently no' than in the past ( # radion*clide scan <either 12&9 or pertechnetate= provides infor+ation a6o*t the location, si;e and trapping a6ility of the thyroid gland: ectopic thyroid glands, fre7*ently s*6ling*al, +ay 6e located any'here along the path'ay of thyroid descent fro+ the fora+en cec*+ to the anterior +ediastin*+( Thyroid i+aging is helpf*l in verifying 'hether a per+anent a6nor+ality is present and aids in genetic co*nseling since thyroid dysgenesis is al+ost al'ays sporadic condition 'hereas a6nor+alities in thyroid hor+onogenesis tend to 6e a*toso+al recessive( %cintigraphy 'ith 12&9, if availa6le, is *s*ally preferred 6eca*se of the greater sensitivity and 6eca*se, 12&9, *nli,e pertechnetate is organified( Therefore, i+aging 'ith this isotope allo's 7*antitative *pta,e +eas*re+ents and tests for 6oth iodine transport defects and a6nor+alities in thyroid o4idation( The lo'est possi6le dose of 12&9, *s*ally 2) +cCi, sho*ld 6e *sed( #dvantages of pertechnetate, on the other hand, are that it is cheaper and +ore 'idely availa6le( Therapy need not 6e delayed as long as scintiscan is perfor+ed 'ithin ) to 5 days, and8or the ser*+ T%! concentration is F&0 +U8L( 9f there is no *pta,e on scintiscan, an *ltraso*nd st*dy sho*ld 6e perfor+ed to confir+ the a6sence of thyroid tiss*e( There is so+e disagree+ent as to 'hether a thyroid scan sho*ld 6e perfor+ed in all 6a6ies 6eca*se of the *n,no'n ris, of radiation e4pos*re, partic*larly in centers 'here only 1&1 09 is *sed and relatively large doses of isotope are ad+inistered( $artly for this reason, *ltrasonography has 6eco+e an

increasingly pop*lar alternative to thyroid scintigraphy to provide infor+ation a6o*t the si;e and location of the thyroid gland and so, disting*ish a6nor+alities of thyroid develop+ent <al+ost al'ays sporadic conditions= fro+ either a6nor+alities of thyroid hor+onogenesis <+ostly a*toso+al recessive= or transient a6nor+alities( Ultraso*nd appears to 6e so+e'hat less sensitive than a radion*clide scan in detecting ectopic thyroid tiss*e and does not provide infor+ation a6o*t f*nction, so interpretation of the res*lts needs to 6e co+6ined 'ith other infor+ation, e(g(, the ser*+ Tg concentration( 9n one report, color Doppler *ltrasonography 'as al+ost as good as scintiscan, a finding that needs to 6e confir+ed < 100=( @ccasionally, apparent thyroid agenesis is d*e to the presence of +aternal T%! receptor 6loc,ing anti6odies, 'hich, if present in a s*fficiently high titer, co+pletely inhi6it T%!0ind*ced thyroidal *pta,e of radioisotope <B0= ( 9n these cases, thyroid *ltraso*nd reveals the presence of a nor+al or s+all, e*topic gland( The presence of a*toi++*ne thyroid disease in the +other or a history of a previo*sly affected si6ling sho*ld alert the physician to the possi6ility of this diagnosis 6*t this infor+ation is not al'ays ,no'n and sho*ld not 6e relied *pon( # radio0receptor or EL9%# assay is appropriate for screening: a co++ercial 6ioassay for 6loc,ing #6s has recently 6eco+e availa6le in the United %tates( This topic is disc*ssed in f*rther detail later in the chapter( 9n cases of T%! receptor anti6ody0ind*ced congenital hypothyroidis+, the 6loc,ing activity is e4tre+ely potent, half0+a4i+al T%! 6inding0inhi6ition 6eing reported 'ith as little as a 1820 to 18)0 dil*tion of ser*+: a 'ea, or 6orderline res*lt sho*ld ca*se a reconsideration of this diagnosis( %i+ilarly, T$@ anti6odies, altho*gh fre7*ently detecta6le in 6a6ies 'ith 6loc,ing anti6ody0ind*ced congenital hypothyroidis+, are neither sensitive nor specific in predicting the presence of transient congenital hypothyroidis+ <B0=( @ther disorders that +ay +i+ic thyroid agenesis on thyroid scintigraphy incl*de loss of f*nction +*tations of the T%! receptor, iodine e4cess, or an iodide concentrating a6nor+ality( $otential cl*es to the diagnosis of a loss of f*nction +*tation of the T%! receptor incl*de a nor+al Tg and8or evidence of a thyroid gland on *ltraso*nd e4a+ination despite the fail*re to vis*ali;e thyroid tiss*e on i+aging st*dies < 51=( Ulti+ately verification of this diagnosis resides in the de+onstration of a genetic a6nor+ality in the T%! receptor gene( Meas*re+ent of *rinary iodine is helpf*l if a diagnosis of iodine0ind*ced hypothyroidis+ is s*spected( #n iodide0concentrating defect sho*ld 6e s*spected in patients 'ith a fa+ily history of congenital hypothyroidis+, partic*larly if an enlarged thyroid gland is present( # s*ggested eval*ation of infants is sho'n in 3ig*re / ( Meas*re+ent of Tg is +ost helpf*l 'hen a defect in Tg synthesis or secretion is 6eing considered( 9n the latter condition the ser*+ Tg concentration is lo' or *ndetecta6le despite the presence of a nor+al or enlarged, e*topic thyroid gland( %er*+ Tg concentration also reflects the a+o*nt of thyroid tiss*e present and the degree of sti+*lation( 3or e4a+ple, Tg is *ndetecta6le in +ost patients 'ith thyroid agenesis, inter+ediate in 6a6ies 'ith an ectopic thyroid gland and +ay 6e elevated in patients 'ith a6nor+alities of thyroid hor+onogenesis not involving Tg synthesis and secretion( Considera6le overlap e4ists, and so, the Tg val*e needs to 6e considered in association 'ith the findings on i+aging( 9n patients 'ith inactivating +*tations of the T%! receptor a discordance 6et'een findings on thyroid i+aging and the ser*+ Tg concentration has 6een descri6ed in so+e 6*t not all st*dies < 51=(

9n 6a6ies in 'ho+ hypothyro4ine+ia *nacco+panied 6y T%! elevation is fo*nd, a free T2 sho*ld 6e +eas*red, prefera6ly 6y a n e7*ili6ri*+ dialysis +ethod and the T"A concentration sho*ld 6e eval*ated as 'ell( The finding of a lo' free T2 in the presence of a nor+al T"A +ay s*ggest the diagnosis of central hypothyroidis+( $it*itary f*nction testing and 6rain i+aging sho*ld also 6e perfor+ed in these infants( The *tility of TR! testing, *sed for +any years to disting*ish 6et'een a hypothala+ic or pit*itary defect, has 6een 7*estioned < 101=( 9n any case, TR! is no longer availa6le for testing in the U%( 9n pre+at*re, lo' 6irth 'eight or sic, 6a6ies in 'ho+ a lo' T2 and a J nor+al > T%! are fo*nd, the free T2 'hen +eas*red 6y a direct dialysis +ethod, fre7*ently is not as lo' as the total T2( 9n the latter infants T2 <and8or free T2=, and T%! sho*ld 6e repeated every 2 to 2 'ee,s *ntil the T2 nor+ali;es 6eca*se of the rare occ*rrence of delayed T%! rise < )&, 102 =( %i+ilarly, any 6a6y s*spected of 6eing hypothyroid clinically sho*ld have repeat thyroid f*nction testing 6eca*se of rare errors in the screening progra+(

Replace+ent therapy 'ith L0thyro4ine sodi*+ sho*ld 6e 6eg*n as soon as the diagnosis of congenital hypothyroidis+ is confir+ed( 9n 6a6ies 'hose initial res*lts on ne'6orn screening are s*ggestive of severe hypothyroidis+ <e(g(, T2 E) +cg8dL /2 n+ol8L= and8or T%! F)0 +U8L=, therapy sho*ld 6e 6eg*n i++ediately 'itho*t 'aiting for the res*lts of the confir+atory ser*+( #s noted a6ove, treat+ent need not 6e delayed in anticipation of perfor+ing thyroid i+aging st*dies as long as the latter are done 'ithin )05 days of initiating treat+ent <6efore s*ppression of the ser*+ T%!=( $arents sho*ld 6e co*nseled regarding the ca*ses of congenital hypothyroidis+, the i+portance of co+pliance and the e4cellent prognosis in +ost 6a6ies if therapy is initiated s*fficiently early and is ade7*ate and ed*cational +aterials sho*ld 6e provided < 10&=( #n initial dosage of 1001) +cg8,g is generally reco++ended so as to nor+ali;e the T2 as soon as possi6le( # recent st*dy in a s+all gro*p of patients has s*ggested that an even higher initial dose <12 to 15 +cg8,g, e7*ivalent to )0 +cg in a f*ll ter+ 6a6y= +ay 6e even 6etter < 102=( "a6ies 'ith +ild

hypothyroidis+ sho*ld 6e started on the lo'er dosage, 'hile those 'ith severe congenital hypothyroidis+ <e(g(, T2 E) +cg8,g8dL </2 n+ol8L==, s*ch as those 'ith thyroid agenesis, sho*ld 6e started on the higher dosage( Thyroid hor+one +ay 6e cr*shed and ad+inistered 'ith ?*ice or for+*la, 6*t care sho*ld 6e ta,en that all of the +edicine has 6een s'allo'ed( Thyroid hor+one sho*ld not 6e given 'ith s*6stances that interfere 'ith its a6sorption, s*ch as iron, soy, or fi6er( Many 6a6ies 'ill s'allo' the pills 'hole or 'ill che' the ta6lets 'ith their g*+s even 6efore they have teeth( Relia6le li7*id preparations are not availa6le co++ercially in the U%, altho*gh they have 6een *sed s*ccessf*lly in E*rope( The ai+s of therapy are to nor+ali;e the T2 as soon as possi6le, to avoid hyperthyroidis+ 'here possi6le, and to pro+ote nor+al gro'th and develop+ent( .hen an initial dosage of 1001) +cg8,g is *sed, the T2 'ill nor+ali;e in +ost infants 'ithin 1 'ee, and the T%! 'ill nor+ali;e 'ithin 1 +onth( .hen a higher dosage is *sed <12015 +c g8,g= nor+ali;ation is even faster <& days and 1 'ee,, respectively= < 102=( %*6se7*ent ad?*st+ents in the dosage of +edication are +ade according to the res*lts of thyroid f*nction tests and the clinical pict*re( @ften s+all incre+ents or decre+ents of L0 thyro4ine <12() +cg= are needed( This can 6e acco+plished 6y 182 ta6let changes, 6y giving an alternating dosage on s*6se7*ent days, or 6y giving an e4tra ta6let once a 'ee,( %o+e infants 'ill develop s*praphysiologic ser*+ T2 val*es on this a+o*nt of thyroid replace+ent 6*t the ser*+ T& concentration *s*ally re+ains nor+al, affected infants are not sy+pto+atic, and availa6le infor+ation s*ggests that these short0ter+ T2 elevations are not associated 'ith any adverse effects on gro'th, 6ony +at*ration, or cognitive develop+ent( # persistently elevated ser*+ T%! level associated 'ith a nor+al or increased ser*+ T2 concentration is seen less often no' than in the past, possi6ly 6eca*se of the higher initial L0thyro4ine dose e+ployed( Relative pit*itary resistance has 6een i+plicated as a ca*se of this finding, 6*t nonco+pliance sho*ld al'ays 6e e4cl*ded( 9n these cases, the T2 val*e is *sed to titrate the dosage of +edication( @ne *s*ally ai+s to +aintain the T2 a6ove 10 +cg8dL <121(5 n+ol8L= and the T%! at less than 10 +U8L( Close follo'0*p is necessary( C*rrent reco++endations are to repeat the T2 and T%! at 2 and 2 'ee,s after the initiation of L0thyro4ine treat+ent, every 102 +onths d*ring the first year of life, every 20& +onths 6et'een 1 and & years of age, and every &012 +onths thereafter *ntil gro'th is co+plete( 9n hypothyroid 6a6ies in 'ho+ an organic 6asis 'as not esta6lished at 6irth and in 'ho+ transient disease is s*spected, a trial off replace+ent therapy can 6e initiated after the age of & years 'hen +ost thyro4ine0dependent 6rain +at*ration has occ*rred( #lternatively, reco+6inant hT%!, 'hich has the advantage that therapy need not 6e discontin*ed, +ay 6eco+e the preferred +ethod in the f*t*re < 10)=( .hether or not pre+at*re infants 'ith hypothyro4ine+ia sho*ld 6e treated re+ains controversial at the present ti+e < 10/=( #ltho*gh several retrospective, cohort st*dies have doc*+ented a relationship 6et'een severe hypothyro4ine+ia and 6oth develop+ental delay and disa6ling cere6ral palsy in preter+ infants E&2 'ee,s gestation a ca*sal relationship co*ld not 6e deter+ined since the ser*+ T2 in pre+at*re infants, as in ad*lts, has 6een sho'n to reflect the severity of illness and ris, of death < 10/=( 9n the +ost thoro*gh st*dy to date, Nan .assenaer et al carried o*t a place6o0controlled, do*6le 6lind trial of L0thyro4ine treat+ent, 1 +cg 8,g per day for / 'ee,s in 200 infants less than &0 'ee,s gestation < 105=( #ltho*gh overall no difference in cognitive o*tco+e 'as fo*nd, there 'as an 110point increase in the "ayley Mental Develop+ent 9nde4 score in the s*6gro*p of T2 0treated infants E25 'ee,s gestation 'hen reeval*ated at 2 years of age( @f so+e concern 'as the additional finding that treat+ent 'as associated 'ith a 100point decrease in +ental score <pS0(0&= in infants F25 'ee,s gestation( .hen the cohort 'as reeval*ated at 10 years of age the difference in 9D 'as no longer significant, altho*gh +odest differences in +otor achieve+ent and the need for special ed*cation persisted < 101=( 9n a recent +*lticenter colla6orative pilot st*dy L0thyro4ine, at a dosage of 1 +c0

g8,g8day co*pled 'ith T& for the first 2 'ee,s of postnatal life 'as associated 'ith s*ppression of T%! and an increased incidence of necroti;ing enterocolitis, s*ggesting that this dose +ight 6e e4cessive( .hile the cognitive o*tco+e data of these 6a6ies is not yet ,no'n , it is clear that +ore data are needed( 9n the +eanti+e, it 'o*ld see+ reasona6le to treat only pre+at*re infants 'ith hypothyro4ine+ia and a nor+al T%! only in the conte4t of a clinical trial( 9n all pre+at*re every effort sho*ld 6e +ade to ass*re ade7*ate iodine inta,e, treat the pri+ary illness and to avoid, if possi6le, dr*gs <e(g(,dopa+ine, steroids, a+inophylline, caffeine and dia+orphine= that have 6een sho'n to s*ppress T%! < 10/=, 'ith close follo' *p of circ*lating thyroid hor+one levels *ntil they nor+ali;e( .hether or not these infants sho*ld 6e treated 'ith T2 and at 'hat dosage re+ains to 6e deter+ined(

#ltho*gh all are agreed that the +ental retardation associated 'ith *ntreated congenital hypothyroidis+ has 6een eradicated 6y ne'6orn screening, controversy persists as to 'hether s*6tle cognitive and 6ehavioral deficits re+ain, partic*larly in the +ost severely affected infants < 21, 2B, 10B0112 =( "oth the initial treat+ent dose <at least 10 +cg01) +cg8,g= and early onset of treat+ent <6efore 2 'ee,s= are i+portant( Ti+e to nor+ali;ation of circ*lating thyroid hor+one levels, the initial free T2 concentration, +aternal 9D, socioecono+ic and ethnic stat*s have also 6een related to o*tco+e < 21, 110, 112 =( The long ter+ pro6le+s for these 6a6ies appear to 6e in the areas of +e+ory, lang*age, fine +otor, attention and vis*al spatial( 9nattentiveness can occ*r 6oth in patients 'ho are overtreated and those in 'ho+ treat+ent 'as initiated late or 'as inade7*ate( 9n addition to ade7*ate dosage, ass*rance of co+pliance and caref*l longter+ +onitoring are essential for an opti+al develop+ental o*tco+e(

Causes of Transient )eonatal 'y"erthyroidis
Unli,e congenital hypothyroidis+ 'hich *s*ally is per+anent, neonatal hyperthyroidis+ al+ost al'ays is transient and res*lts fro+ the transplacental passage of +aternal T%! receptor sti+*lating anti6odies( !yperthyroidis+ develops only in 6a6ies 6orn to +others 'ith the +ost potent sti+*latory activity in ser*+ < 11&, 112 =( This corresponds to 102C of +others 'ith Araves disease, or 1 in )0,000 ne'6orns, an incidence that is appro4i+ately fo*r ti+es higher than is that for transient neonatal hypothyroidis+ d*e to +aternal T%! receptor 6loc,ing anti6odies( %o+e +others have +i4t*res of sti+*lating and 6loc,ing anti6odies in their circ*lation, the relative proportion of 'hich +ay change over ti+e( -ot s*rprisingly, the clinical pict*re in the fet*s and neonate of these +others is +ore co+ple4 and depends not only on the relative proportion of each activity in the +aternal circ*lation at any one ti+e 6*t on the rate of their clearance fro+ the neonatal circ*lation postpart*+( Th*s, one affected +other gave 6irth, in t*rn, to a nor+al infant, a 6a6y 'ith transient hyperthyroidis+, and one 'ith transient hypothyroidis+ < 11)=( 9n another neonate, the onset of hyperthyroidis+ did not 6eco+e apparent *ntil 102 +onths postpart*+ 'hen the higher affinity 6loc,ing anti6odies had 6een cleared fro+ the neonatal circ*lation < 11/=( 9n the latter case, +*ltiple T%! receptor sti+*lating and 6loc,ing anti6odies 'ere isolated fro+ the +aternal peripheral ly+phocytes( Each +onoclonal anti6ody recogni;ed different antigenic deter+inants < G epitopes H = on the receptor and had different f*nctional properties < 115=( @ccasionally, neonatal hyperthyroidis+ +ay even occ*r in infants 6orn to hypothyroid +others( 9n these sit*ations, the +aternal thyroid has 6een destroyed either 6y prior radioa6lation, s*rgery or 6y

coincident destr*ctive a*toi++*ne processes so that potent thyroid sti+*lating anti6odies, present in the +aternal circ*lation, are silent in contrast to the neonate 'hose thyroid gland is nor+al < 115=(



#ltho*gh +aternal T%! receptor anti6ody0+ediated hyperthyroidis+ +ay present in *tero, +ost often the onset is d*ring the first 'ee, of life( This is d*e 6oth to the clearance of +aternally0ad+inistered antithyroid dr*g <propylthio*racil, $TU, +ethi+a;ole or car6i+a;ole= fro+ the infant > s circ*lation and to the increased conversion of T2 to the +ore +eta6olically active T& after 6irth( Rarely, as noted earlier, the onset of neonatal hyperthyroidis+ +ay 6e delayed *ntil later if higher affinity 6loc,ing anti6odies are also present( 3etal hyperthyroidis+ is s*spected in the presence of fetal tachycardia <p*lse greater than 1/08+in= especially if there is evidence of fail*re to thrive( 9n the ne'6orn infant, characteristic signs and sy+pto+s incl*de tachycardia, irrita6ility, poor 'eight gain, and pro+inent eyes <3ig*re 5=( Aoiter, 'hen present, +ay 6e related to +aternal antithyroid dr*g treat+ent as 'ell as to the neonatal Araves disease itself(

3ig*re 1)05( # 6a6y 'ith neonatal hyperthyroidis+ secondary to +aternal Arave s disease( -ote the pro+inent eyes in the 6a6y and +other in 'ho+ Araves disease developed after radioiodine therapy for !odg,ins disease( 9n contrast, the father 'as *naffected( Rarely, infants 'ith neonatal Araves disease present 'ith thro+6ocytopenia, ?a*ndice, hepatospleno+egaly, and hypoprothro+6ine+ia, a pict*re that +ay 6e conf*sed 'ith congenital infections s*ch as to4oplas+osis, r*6ella, or cyto+egalovir*s < 111=( 9n addition, arrhyth+ias and cardiac fail*re +ay develop and +ay ca*se death, partic*larly if treat+ent is delayed or inade7*ate( 9n addition to a significant +ortality rate that appro4i+ates 20C in so+e older series, *ntreated fetal and neonatal hyperthyroidis+ is associated 'ith deleterio*s long0ter+ conse7*ences, incl*ding pre+at*re

clos*re of the cranial s*t*res <cranial synostosis=, fail*re to thrive, and develop+ental delay < 11B=( The half0life of T%! receptor anti6odies is 1 to 2 'ee,s( The d*ration of neonatal hyperthyroidis+, a f*nction of anti6ody potency and the rate of their +eta6olic clearance, is *s*ally 2 to & +onths 6*t +ay 6e longer(

2a!oratory -0aluation
"eca*se of the i+portance of early diagnosis and treat+ent, fet*ses and infants at ris, for neonatal hyperthyroidis+ sho*ld *ndergo 6oth clinical and 6ioche+ical assess+ent as soon as possi6le( %it*ations that sho*ld pro+pt consideration of neonatal hyperthyroidis+ are listed in Ta6le 2( # high inde4 of s*spicion is necessary in 6a6ies of 'o+en 'ho have had thyroid a6lation 6eca*se in the+ a high titer of T%! receptor anti6odies 'o*ld not 6e evident clinically( %i+ilarly, 'o+en 'ith persistently elevated T%! receptor anti6odies and 'ith a high re7*ire+ent for antithyroid +edication are at an increased ris, of having an affected child( The diagnosis of hyperthyroidis+ is confir+ed 6y the de+onstration of an increased concentration of circ*lating T2 <and free T2, and T&, if possi6le= acco+panied 6y a s*ppressed T%! level in neonatal or fetal 6lood( The latter can 6e o6tained 6y cordocentesis if so+eone e4perienced in this techni7*e is availa6le( Res*lts sho*ld 6e co+pared 'ith nor+al val*es d*ring gestation ( 3etal *ltrasonography +ay 6e helpf*l in detecting the presence of a fetal goiter and in +onitoring fetal gro'th( De+onstration in the 6a6y or +other of a high titer of T%! receptor anti6odies 'ill confir+ the etiology of the hyperthyroidis+ and, in 6a6ies 'hose thyroid f*nction testing is nor+al initially, indicate the degree to 'hich the 6a6y is at ris,( Ta!le &. %it*ations That %ho*ld $ro+pt Consideration of -eonatal !yperthyroidis+ Une4plained tachycardia, goiter or stare Une4plained petechiae, hyper6ilir*6ine+ia, or hepatospleno+egaly !istory of persistently high T%! receptor anti6ody titer in +other d*ring pregnancy !istory of persistently high re7*ire+ent for antithyroid +edication in +other d*ring pregnancy !istory of thyroid a6lation for hyperthyroidis+ in +other !istory of previo*sly affected si6ling #s noted in the case of T%! receptor 6loc,ing anti6ody0ind*ced congenital hypothyroidis+, the radioreceptor assay or EL9%# is a cost0effective, rapid and technically feasi6le approach( 9f desired, 6ioassay can 6e perfor+ed s*6se7*ently to de+onstrate the 6iological activity of the anti6odies if the 6inding assay is positive( 9n general, 6a6ies li,ely to 6eco+e hyperthyroid have the highest T%! receptor anti6ody titer 'hereas if T%! receptor anti6odies are not detecta6le, the 6a6y is +ost *nli,ely to 6eco+e hyperthyroid < 11B0121=( 9n the latter case, it can 6e anticipated that the 6a6y 'ill 6e e*thyroid, have transient hypothala+ic0pit*itary s*ppression or have a transiently elevated T%!, depending on the relative contri6*tion of +aternal hyperthyroidis+ vers*s the effects of +aternal antithyroid +edication, respectively < 120=( Therapy is rarely necessary( This is tr*e 'hether T%! receptor anti6odies are +eas*red 6y a 6inding assay or 6y 6ioassay( @n the other hand, if T%! receptor anti6ody potency is inter+ediate, it is li,ely that the 6a6y 'ill 6e e*thyroid, have a transiently elevated T2 or have transient hypothala+ic pit*itary s*ppression < 1200122=( 9t is i+portant to appreciate that the sensitivity of T%! receptor assays in different la6oratories varies( Therefore, specific val*es that are reco++ended in the literat*re sho*ld 6e interpreted 'ith ca*tion and, ideally, each la6oratory sho*ld deter+ine its o'n range( Close follo' *p of all 6a6ies 'ith a6nor+al thyroid f*nction tests or detecta6le T%! receptor anti6odies is +andatory(

9n the fet*s, treat+ent is acco+plished 6y +aternal ad+inistration of antithyroid +edication( Until recently $TU 'as the preferred dr*g for pregnant 'o+en in -orth #+erica, 6*t c*rrent reco++endations s*ggest the *se of MM9 rather than $TU after the first tri+ester 6eca*se of concerns a6o*t potential $TU0ind*ced hepatoto4icity < 12&= <disc*ssed *nder Araves disease, 6elo'=( The goals of therapy are to *tili;e the +ini+al dosage necessary to nor+ali;e the fetal heart rate and render the +other e*thyroid or slightly hyperthyroid( 9n the neonate, treat+ent is e4pectant( Either $TU <) to10 +g8,g8day= or MM9 <0() to 1(0 +g8,g8day= has 6een *sed initially in & divided doses( 9f the hyperthyroidis+ is severe, a strong iodine sol*tion <L*gols sol*tion or %%K9, 1 drop every 1 ho*rs= is added to 6loc, the release of thyroid hor+one i++ediately( @ften the effect of $TU and MM9 is not as delayed in infants as it is in older children or ad*lts, a conse7*ence of decreased intrathyroidal thyroid hor+one storage( Therapy 'ith 6oth antithyroid dr*g and iodine is ad?*sted s*6se7*ently, depending on the response( $ropranolol <2 +g8,g8day in 2 or & divided doses= is added if sy+pathetic oversti+*lation is severe, partic*larly in the presence of prono*nced tachycardia( 9f cardiac fail*re develops, treat+ent 'ith digo4in sho*ld 6e initiated, and propranolol sho*ld 6e discontin*ed( Rarely, prednisone <2 +g8,g8day= is added for i++ediate inhi6ition of thyroid hor+one secretion( Meas*re+ent of T%! receptor anti6odies in treated 6a6ies +ay 6e helpf*l in predicting 'hen antithyroid +edication can 6e safely discontin*ed < 112=( Lactating +others on antithyroid +edication can contin*e n*rsing as long as the dosage of $TU or MM9 does not e4ceed 200 +g or 20 +g, respectively( The +il,8ser*+ ratio of $TU is 1810 that of MM9, a conse7*ence of p! differences and increased protein 6inding, so one +ight anticipate less trans+ission to the infant, 6*t concerns a6o*t potential $TU to4icity need to 6e considered( #t higher dosages of antithyroid +edication, close s*pervision of the infant is advisa6le(

%er anent neonatal hy"erthyroidis

Rarely, neonatal hyperthyroidis+ is per+anent and is d*e to a ger+line +*tation in the T%! receptor res*lting in its constit*tive activation < 1220125=( # gain of f*nction +*tation of the T%! receptor sho*ld 6e s*spected if persistent neonatal hyperthyroidis+ occ*rs in the a6sence of detecta6le T%! receptor anti6odies in the +aternal circ*lation( Most cases res*lt fro+ a +*tation in e4on 10 'hich encodes the trans+e+6rane do+ain and intracytoplas+ic tail of the T%! receptor, a +e+6er of the A protein co*pled receptor s*perfa+ily < 1220125=( Less fre7*ently, a +*tation encoding the e4tracell*lar do+ain has 6een descri6ed < 121=( #n a*toso+al do+inant inheritance has 6een noted in +any of these infants: other cases have 6een sporadic, arising fro+ a de novo +*tation( Early recognition is i+portant 6eca*se the thyroid f*nction of affected infants is fre7*ently diffic*lt to +anage +edically < 12)0125=, and, 'hen diagnosis and therapy is delayed, irreversi6le se7*elae, s*ch as cranial synostosis and develop+ental delay +ay res*lt < 125=( 3or this reason early, aggressive therapy 'ith either thyroidecto+y or even radioa6lation has 6een reco++ended(

Thyroid Disease in Childhood and Adolescence

Causes of 'y"othyroidis in childhood and adolescence

Chronic 2y "hocytic Thyroiditis The ca*ses of hypothyroidis+ after the neonatal period are listed in Ta6le )(The +ost co++on ca*se is chronic ly+phocytic thyroiditis an a*toi++*ne disease that is closely related to Araves disease( chronic ly+phocytic thyroiditis, li,e Araves disease is a co+ple4 genetic disorder in 'hich as +any as 200/0 i++*nos*scepti6ility genes, each 'ith s+all effect, have 6een post*lated < 12B= and in 'hich the trigger is *n,no'n( "oth thyroid0specific genes and genes involved in i++*ne recognition and8or response have 6een identified < 1&0=( %o+e genes are co++on to 6oth disorders and so+e tend to predo+inate only in Araves disease( .hereas in chronic ly+phocytic thyroiditis, ly+phocyte and cyto,ine0+ediated thyroid destr*ction predo+inates, in Araves disease anti6ody0+ediated thyroid sti+*lation occ*rs, 6*t overlap +ay occ*r in so+e patients( "oth a goitro*s <!ashi+otos thyroiditis= and a nongoitro*s <atrophic thyroiditis, also called pri+ary +y4ede+a= variant of chronic ly+phocytic thyroiditis have 6een disting*ished( The disease has a stri,ing predilection for fe+ales and a fa+ily history of a*toi++*ne thyroid disease <6oth chronic ly+phocytic thyroiditis and Araves disease= is fo*nd in &0C to 20C of patients( D*ring childhood the +ost co++on age at presentation is adolescence, 6*t the disease +ay occ*r at any age, even infancy < 1&1=( There is an increased prevalence of chronic ly+phocytic thyroiditis in patients 'ith ins*lin dependent dia6etes +ellit*s, 20C of 'ho+ have positive thyroid anti6odies and )C of 'ho+ have an elevated ser*+ T%! level < 1&2=( chronic ly+phocytic thyroiditis +ay also occ*r as part of an a*toi++*ne polygland*lar syndro+e <#$%= < 1&&=( 9n #$% 1, a poly gland*lar a*toi++*ne disorder that tends to present in childhood, chronic ly+phocytic thyroiditis is fo*nd in appro4i+ately 10C of patients( #$% 1, is characteri;ed pri+arily 6y +*coc*taneo*s candidiasis, hypoparathyroidis+ and adrenal deficiency and res*lts fro+ a +*tation in the #9RE <a*toi++*ne reg*lator= gene < 1&2, 1&) =( Chronic ly+phocytic thyroiditis and dia6etes +ellit*s 'ith or 'itho*t adrenal ins*fficiency <#$% 2, also referred to as %ch+idt syndro+e= tends to occ*r later in childhood or in the ad*lt( Chronic ly+phocytic thyroiditis has also 6een descri6ed in children 'ith i++*nodysreg*lation polyendocrinopathy enteropathy Q0lin,ed <9$EQ= syndro+e, a polygland*lar disorder characteri;ed 6y early0onset dia6etes and colitis <1&)6=( 9n addition to these polygland*lar syndro+es, there is an increased incidence of chronic ly+phocytic thyroiditis in patients 'ith certain chro+oso+al a6nor+alities <Do'n syndro+e, T*rner syndro+e, Klinefelter syndro+e= as 'ell as in patients 'ith -oonan syndro+e(CLT +ay 6e associated 'ith chronic *riticaria < 1&/= and rarely 'ith 'ith i++*ne0 co+ple4 glo+er*lonephritis < 1&5=( #nti6odies to Tg and T$@, the thyroid anti6odies +eas*red in ro*tine clinical practice, are detecta6le in over B)C of patients 'ith chronic ly+phocytic thyroiditis( Therefore, they are *sef*l as +ar,ers of *nderlying a*toi++*ne thyroid da+age, T$@ anti6odies 6eing +ore sensitive( T%! receptor anti6odies also are fo*nd in a s+all proportion of patients 'ith chronic ly+phocytic thyroiditis( .hen sti+*latory T%! receptor anti6odies are present, they +ay give rise to a clinical pict*re of hyperthyroidis+, the coe4istence of chronic ly+phocytic thyroiditis and Araves disease 6eing ,no'n as !ashito4icosis( 9n one st*dy, 6 loc,ing anti6odies 'ere fo*nd in E10C of children and adolescents 'ith chronic ly+phocytic thyroiditis, patients overall, 6*t in 15(1C of those 'ith severe

hypothyroidis+ <defined as a ser*+ T%! concentration F20 +U8L=( Unli,e in ad*lts, they 'ere fo*nd in goitro*s as 'ell as nongoitro*s patients , and, 'hen present at a high concentration, appeared to persist indefinitely, s*ggesting that the presence of potent T%! receptor 6loc,ing #6s in adolescent fe+ales +ight identify patients at ris, of having 6a6ies 'ith transient congenital hypothyroidis+ in the f*t*re <1&1=( Ta!le 3. Differential Diagnosis of M*venile !ypothyroidis+ Chronic 2y "hocytic Thyroiditis 0Aoitro*s <!ashi+oto>s= 0#trophic <$ri+ary My4ede+a= Congenital A!nor ality 0Thyroid dysgenesis 09n6orn error of thyroid hor+onogenesis Iodine Deficiency <ende+ic goiter= Drugs or Goitrogens 0 #ntithyroid dr*gs <$TU, MM9, car6i+a;ole= 0 #nticonv*lsants 0 @ther <lithi*+, thiona+ides, a+inosalicylic acid, a+inogl*tethi+ide= 0 Aoitrogens <cassava, 'ater poll*tants, ca66age, s'eet potatoes, ca*liflo'er, 6roccoli, soya 6eans= Miscellaneous 0C ystinosis 0Langerhans Cell !istiocytosis 09rradiation of the Thyroid < radioactive iodine , e4ternal irradiation of nonthyroid t*+ors = 0%*rgery Aoiter, present in appro4i+ately t'o0thirds of children 'ith chronic ly+phocytic thyroiditis res*lts pri+arily fro+ ly+phocytic infiltration and in so+e patients, fro+ a co+pensatory increase in T%!( The role of anti6odies in goitrogenesis is controversial < 1&B=( Children 'ith chronic ly+phocytic thyroiditis +ay 6e e*thyroid, or +ay have s*6clinical or overt hypothyroidis+( @ccasionally, children +ay e4perience an initial thyroto4ic phase d*e to the discharge of prefor+ed T2 and T& fro+ the da+aged gland( #lternatively, as indicated a6ove, thyroto4icosis +ay 6e d*e to conco+itant thyroid sti+*lation 6y T%! receptor sti+*latory anti6odies <!ashito4icosis=( Long ter+ follo' *p st*dies of children 'ith chronic ly+phocytic thyroiditis have s*ggested that 'hile +ost children 'ho are hypothyroid initially re+ain hypothyroid, spontaneo*s recovery of thyroid f*nction +ay occ*r, partic*larly in those 'ith initial co+pensated hypothyroidis+ < 120012&=( @n the other hand, so+e initially e*thyroid patients 'ill 6eco+e hypothyroid 'ith o6servation( Therefore, close follo' *p is necessary( Thyroid Dysgenesis and In!orn -rrors of Thyroid 'or onogenesis @ccasionally, patients 'ith thyroid dysgenesis 'ill escape detection 6y ne'6orn screening and present later in childhood 'ith non goitro*s hypothyroidis+ or 'ith an enlarging +ass at the 6ase of the tong*e

or along the co*rse of the thyroglossal d*ct( %i+ilarly, children 'ith in6orn errors of thyroid hor+onogesis +ay only 6e recogni;ed later in childhood 6eca*se of the detection of a goiter( Drugs or Goitrogens 9n addition to antithyroid +edication, a n*+6er of dr*gs *sed in childhood +ay affect thyroid f*nction, incl*ding certain anticonv*lsants, lithi*+, a+iodarone, a+inosalicylic acid, a+inogl*tethi+ide and sertraline < 122, 12) =( %i+ilarly, a large n*+6er of nat*rally occ*rring goitrogens <6roccoli, ca66age, s'eet potatoes, ca*liflo'er, soya 6eans, cassava and 'ater poll*tants= have 6een identified( "oth radioiodine therapy and thyroidecto+y, occasionally *sed in childhood for the definitive treat+ent of Araves disease, fre7*ently ca*se per+anent hypothyroidis+( .orld'ide, iodine deficiency contin*es to 6e an i+portant ca*se of hypothyroidis+, affecting at least 100 +illion people living largely in developing co*ntries( 9n addition, even in certain parts of E*rope, an esti+ated 1000120 +illion individ*als are tho*ght to have 6orderline iodine deficiency < 12/=( #ltho*gh one rarely sees iodine deficiency in -orth #+erica, an iodine s*fficient area, a / year old 6oy 'ith goitro*s hypothyroidis+ has 6een descri6ed in 'ho+ iodine deficiency 'as d*e to +*ltiple food allergies and severe dietary restriction < 125=( 9n addition, the child cons*+ed a large inta,e of thiocyanate0containing foods that 6loc,ed organification of iodine( Miscellaneous Causes of Ac4uired 'y"othyroidis Rarely, the thyroid gland +ay 6e involved in generali;ed infiltrative or infectio*s disease processes that are of s*fficient severity to res*lt in a dist*r6ance in thyroid f*nction <e(g(, <Langerhans cell histiocytosis= < 121=( #lternatively, hypothyroidis+ +ay 6e a long ter+ co+plication of +antle irradiation for !odg,ins disease or ly+pho+a( E4ternal irradiation of 6rain t*+ors in the posterior fossa of the 6rain +ay 6e associated 'ith 6oth pri+ary and secondary hypothyroidis+ 6eca*se of the incl*sion of the nec, in the radiation field( Rarely, hypothyroidis+ has 6een reported in infants 'ith large he+angio+as < 12B=( 9n these cases, the hypothyroidis+ 'as sho'n to 6e d*e to increased inactivation of T2 6y the D& activity of these t*+ors( Secondary or Tertiary 'y"othyroidis %econdary or tertiary hypothyroidis+ in less severely affected children 'ith the congenital a6nor+alities noted earlier in this chapter, +ay 6e recogni;ed only later in childhood( #lternatively, secondary or tertiary hypothyroidis+ +ay develop as a res*lt of ac7*ired da+age to the pit*itary or hypothala+*s, e(g(, 6y t*+ors <partic*larly craniopharyngio+a=, gran*lo+ato*s disease, head irradiation, infection <+eningitis=, s*rgery or tra*+a( Us*ally other trophic hor+ones are affected, partic*larly gro'th hor+one(

Thyroid 'or one Resistance

9n contrast to the neonatal period, children 'ith thyroid hor+one resistance *s*ally co+e to attention 'hen thyroid f*nction tests are perfor+ed 6eca*se of poor gro'th, hyperactivity, a learning disa6ility or other nonspecific signs or sy+pto+s( # s+all goiter +ay 6e appreciated( #ffected patients have a high incidence of attention deficit hyperactivity disorder < 1)0=( Thyroid hor+one resistance has also 6een descri6ed in patients 'ith cystinosis < 1)1=(

Clinical Manifestations
The onset of hypothyroidis+ in childhood is insidio*s( #ffected children often are recogni;ed either 6eca*se of the detection of a goiter on ro*tine e4a+ination or 6eca*se of a poor interval gro'th rate present for several years prior to diagnosis( "eca*se the deceleration in linear gro'th tends to 6e +ore affected than 'eight gain, these children are relatively over'eight for their height, altho*gh they rarely are significantly o6ese <3ig*re 1=( 9f the hypothyroidis+ is severe and longstanding, i++at*re facies 'ith an *nderdeveloped nasal 6ridge and i++at*re 6ody proportions <increased *pper0lo'er 6ody ratio= +ay 6e noted( Dental and s,eletal +at*ration are delayed, the latter often significantly( $atients 'ith central hypothyroidis+ tend to 6e even less sy+pto+atic than are those 'ith pri+ary hypothyroidis+(

3ig*re 1)01 ( %e7*ential changes in physical appearance in a yo*ng girl 'ho presented at 1) years of age 'ith a+enorrhea and hyperprolactine+ia secondary to severe hypothyroidis+( -ote her poor linear gro'th since at least 11 years of age( The classical clinical +anifestations of hypothyroidis+ can 6e elicited on caref*l eval*ation, tho*gh they often are not the presenting co+plaints( These incl*de lethargy, cold intolerance, constipation, dry s,in or hair te4t*re, and perior6ital ede+a( %chool perfor+ance is not *s*ally affected, in contrast to the severe irreversi6le ne*ro0intellect*al se7*elae that occ*r fre7*ently in inade7*ately treated 6a6ies 'ith congenital hypothyroidis+( Ca*ses of hypothyroidis+ associated 'ith a goiter <CLT, in6orn errors of thyroid hor+onogenesis, thyroid hor+one resistance= sho*ld 6e disting*ished fro+ non goitro*s ca*ses <pri+ary +y4ede+a, thyroid dysgenesis, central hypothyroidis+=( The typical thyroid gland in chronic ly+phocytic thyroiditis is diff*sely enlarged and has a r*66ery consistency( #ltho*gh the s*rface is classically descri6ed as > pe66ly > or 6osselated, occasionally asy++etric enlarge+ent occ*rs and +*st 6e disting*ished fro+ thyroid neoplasia( # palpa6le ly+ph node s*perior to the isth+*s < J Delphian node > = is often fo*nd and +ay 6e conf*sed 'ith a thyroid nod*le( The thyroid gland, in thyroid hor+one synthetic defects, on the other hand, tends to 6e softer and diff*sely enlarged( # delayed rela4ation ti+e of the deep tendon refle4es +ay 6e appreciated in +ore severe cases( 9n patients 'ith severe hypothyroidis+ of longstanding d*ration, the sella t*rcica +ay 6e enlarged d*e to thyrotrope hyperplasia( There is an increased incidence of slipped fe+oral capital epiphyses in hypothyroid children( The co+6ination of severe hypothyroidis+ and +*sc*lar hypertrophy 'hich gives the child a > !erc*lean > appearance is ,no'n as the Kocher0De6re0%e+elaign e syndro+e < 1)2=( $*6erty tends to 6e delayed in hypothyroid children in proportion to the retardation in the 6one age, altho*gh in longstanding severe hypothyroidis+, se4*al precocity has 6een descri6ed( 3e+ales 'ith se4*al precocity have +enstr*ation, and 6reast develop+ent 6*t relatively little se4*al hair( M*lticystic ovaries, the etiology of 'hich is *n,no'n, +ay 6e de+onstrated on *ltrasonography( 9n other cases, galactorrhea or severe +enses have 6een the presenting feat*res( 9n 6oys, testic*lar enlarge+ent +ay 6e fo*nd < 1)&=( #n elevation in ser*+ prolactin, the latter possi6ly d*e to elevated TR! 'hich is

,no'n to sti+*late prolactin as 'ell as T%!, has 6een descri6ed in so+e cases, 6*t gonadotropin levels are not consistently elevated( 9t has 6een hypothesi;ed that this syndro+e of pse*dop*6erty in hypothyroid patients is d*e to cross0 interaction of the e4tre+ely elevated ser*+ T%! 'ith the 3%! receptor < 1)2=( Consistent 'ith the latter hypothesis, there is little increase in ser*+ testosterone as +ight 6e e4pected if the 3%!, 6*t not l*teini;ing hor+one <L!= receptor is involved and ser*+ gonadotropins are fre7*ently not increased(

2a!oratory -0aluation
Meas*re+ent of T%! is the 6est initial screening test for the presence of pri+ary hypothyroidis+( 9f the T%! is elevated, then eval*ation of the free T2 or free T2 inde4 <total T2 +*ltiplied 6y the T& resin *pta,e= 'ill disting*ish 'hether the child has s*6clinical <nor+al free T2 or free T2 inde4= or overt <lo' free T2 or free T2 inde4= hypothyroidis+( Meas*re+ent of T%!, on the other hand, is not helpf*l in central hypothyroidis+( 9n these cases hypothyroidis+ is de+onstrated 6y the presence of a lo' free T2 <or free T2 inde4= acco+panied 6y an inappropriately J> T%!( 9n the past TR! testing <TR! 5 +cg8,g= 'as so+eti+es *tili;ed to disting*ish a hypothala+ic vers*s pit*itary origin of the hypothyroidis+: in hypothala+ic hypothyroidis+ there tends to 6e a delayed pea, in T%! secretion < /00B0 +in*tes vers*s the nor+al +a4i+al response at 1)0&0 +in*tes= 'hereas in hypopit*itaris+ there *s*ally is little or no T%! response( TR! is no longer availa6le in the U%#, ho'ever( 3*rther+ore, the relia6ility of this test in the pediatric range has 6een 7*estioned < 101=( @ccasionally +ild T%! elevation is seen in individ*als 'ith hypothala+ic hypothyroidis+, a conse7*ence of the secretion of a T%! +olec*le 'ith i+paired 6ioactivity 6*t nor+al i++*noreactivity( Thyroid hor+one resistance is characteri;ed 6y elevated levels of T2 and T& and an inappropriately nor+al or elevated T%! concentration( # diagnosis of chronic ly+phocytic thyroiditis is +ade 6y the de+onstration of elevated titers of anti0 Tg and8or anti0T$@ anti6odies( Meas*re+ent of T%! receptor 6loc,ing anti6odies sho*ld 6e considered in adolescent patients 'ith severe hypothyroidis+ 6eca*se of the potential ris, of 6loc,ing anti6ody0ind*ced hypothyroidis+ to any *n6orn child in the f*t*re < 1&1=( 9+aging st*dies <thyroid *ltrasonography and8or thyroid *pta,e and scan= +ay 6e perfor+ed if thyroid anti6ody tests are negative or if a nod*le is palpa6le, 6*t are rarely necessary( @ccasionally the finding of heterogeneo*s echogenecity on *ltraso*nd e4a+ination has 6een descri6ed prior to the appearance of anti6odies( !o'ever, the typical pict*re of spotty *pta,e of radioactive iodine that is seen in ad*lts is rare in children < 1))=( 9f thyroid anti6ody tests are negative and no goiter is present, i+aging st*dies are helpf*l in identifying the presence and location of thyroid tiss*e, and therefore, of disting*ishing pri+ary +y4ede+a fro+ thyroid dysgenesis( 9n6orn errors of thyroid hor+onogenesis 6eyond a trapping defect are *s*ally s*spected 6y an increased radioiodine *pta,e, and a large gland on scan( @ther etiologies of hypothyroidis+ *s*ally are evident on history(

9n contrast to neonatal hypothyroidis+, rapid replace+ent is not essential in the older child( This is partic*larly tr*e in children 'ith long standing, severe thyroid *nderactivity in 'ho+ rapid nor+ali;ation +ay res*lt in *n'anted side effects <deterioration in school perfor+ance, short attention span, hyperactivity, inso+nia, and 6ehavior diffic*lties= < 1)/=( 9n these children it is prefera6le to increase the replace+ent dose slo'ly over several 'ee,s to +onths( %everely hypothyroid children sho*ld also 6e o6served closely for co+plaints of severe headache 'hen therapy is initiated 6eca*se of the rare develop+ent of pse*dot*+or cere6ri < 1)5=( 9n contrast, f*ll replace+ent can 6e initiated at once 'itho*t +*ch ris, of adverse conse7*ences in children 'ith +ild hypothyroidis+(

Treat+ent of children and adolescents 'ith s*6clinical hypothyroidis+ <nor+al free T2, elevated T%!= is controversial( 9n ad*lts in 'ho+ the ris, of progression to overt hypothyroidis+ is significant, partic*larly if they are over the age of /0 years, treat+ent has 6een reco++ended 'henever the ser*+ T%! concentration is F10 +U8L: if the T%! is /010 +U8L treat+ent on a case 6y case 6asis is s*ggested < 1)1=( 9n children and adolescents 'ith s*6clinical hypothyroidis+ d*e to chronic ly+phocytic thyroiditis, availa6le data s*ggests a significant li,elihood of re+ission, at least for several years( Conse7*ently, if there is not a strong fa+ily history of hypothyroidis+ and the patient is not sy+pto+atic, a reasona6le option is to reassess thyroid f*nction in &0 / +onths prior to initiating therapy 6eca*se of the possi6ility that the thyroid a6nor+ality 'ill 6e transient( The typical replace+ent dose of L0thyro4ine in childhood is appro4i+ately 100 +cg8M2 or 2 to / +c0 g8,g for children 1 to ) years of age, & to 2 +c g8,g for those ages / to 10 years, and 2 to & +cg8,g for those 11 years of age and older( 9n patients 'ith a goiter a so+e'hat higher L0thyro4ine dosage is *sed so as to ,eep the T%! in the lo' nor+al range <0(& to 1(0 +U8L in an *ltrasensitive assay=, and there6y +ini+i;e its goitrogenic effect( T2 and T%! sho*ld 6e +eas*red after the child has received the reco++ended dosage for at least /01 'ee,s( @nce a e*thyroid state has 6een achieved, patients sho*ld 6e +onitored every / to 12 +onths( Close attention is paid to interval gro'th and 6one age as 'ell as to the +aintenance of a e*thyroid state( Thyroid hor+one replace+ent is not associated 'ith significant 'eight loss in over'eight children, *nless the hypothyroidis+ is severe < 1)B=( %o+e children 'ith severe, long standing hypothyroidis+ at diagnosis +ay not achieve their ad*lt height potential even 'ith opti+al therapy < 1/0=, e+phasi;ing the i+portance of early diagnosis and treat+ent( Treat+ent is *s*ally contin*ed indefinitely(

Asy "to atic goiter

Chronic ly "hocytic thyroiditis
Aoiter, the +ost co++on thyroid disorder in pediatrics, occ*rs in 1(2C of school children in -orth #+erica < 120=( Li,e thyroid disease in general, there is a fe+ale preponderance, the fe+ale: +ale ratio 6eing 2 to &:1( $atients 'ith goiter +ay 6e e*thyroid, hypothyroid or hyperthyroid, e*thyroid goiters 6eing 6y far the +ost co++on( The +ost fre7*ent ca*se of asy+pto+atic goiter in -orth #+erica is chronic ly+phocytic thyroiditis, disc*ssed a6ove( Ca*ses of goiter that are associated 'ith a6nor+al thyroid f*nction are disc*ssed else'here in this chapter(

Colloid or Si "le *)onto$ic+ Goiter

Colloid goiter is the second +ost co++on ca*se of e*thyroid thyroid enlarge+ent in childhood( The etiology of colloid goiter is *n,no'n( -ot infre7*ently there is a fa+ily history 6oth of goiter, chronic ly+phocytic thyroiditis and Araves disease, leading to the s*ggestion that colloid goiter, too, +ight 6e an a*toi++*ne disease( 9++*noglo6*lins that sti+*lated thyroid gro'th in "itro have 6een identified in a proportion of patients 'ith si+ple goiter < 1/1=, 6*t their etiological role is controversial < 1&B=( 9t is i+portant to disting*ish patients 'ith colloid goiter fro+ chronic ly+phocytic thyroiditis 6eca*se of the ris, of developing hypothyroidis+ in patients 'ith chronic ly+phocytic thyroiditis, 6*t not colloid goiter( .hereas +any colloid goiters regress spontaneo*sly, others appear to *ndergo periods of gro'th

and regression, res*lting *lti+ately in the large nod*lar thyroid glands later in life(

Clinical Manifestations and 2a!oratory In0estigation

Eval*ation of thyroid f*nction 6y +eas*re+ent of the ser*+ T%! concentration is the initial approach to diagnosis( 9n e*thyroid patients, the +ost co++on sit*ation, chronic ly+phocytic thyroiditis sho*ld 6e disting*ished fro+ colloid goiter( Clinical e4a+ination in 6oth instances reveals a diff*sely enlarged thyroid gland( Therefore, the distinction is dependent *pon the presence of elevated titers of T$@ and Tg anti6odies in chronic ly+phocytic thyroiditis 6*t not colloid goiter( #ll patients 'ith negative thyroid anti6odies initially sho*ld have repeat e4a+inations 6eca*se so+e children 'ith chronic ly+phocytic thyroiditis 'ill develop positive titers 'ith ti+e(

Thyroid s*ppression in children 'ith a e*thyroid goiter is controversial < 1/2, 1/& =( # significant decrease in goiter si;e in patients 'ith chronic ly+phocytic thyroiditis as assessed 6y standard deviation score on *ltrasonography has 6een de+onstrated recently in patients treated for & years < 1/&=( !o'ever, the a6sol*te difference 7*antitatively 'as not reported and so, 'hether or not this difference 'as signicant clinically re+ains *nclear( Aiven the varia6ility in response in different patients, it 'o*ld 6e reasona6le to atte+pt a therape*tic trial in patients 'hose goiter is large(

%ainful thyroid
$ainf*l thyroid enlarge+ent is rare in pediatrics and s*ggests the pro6a6ility of either ac*te <s*pp*rative= or s*6ac*te thyroiditis( Rarely chronic ly+phocytic thyroiditis +ay 6e associated 'ith inter+ittent pain and 6e conf*sed 'ith the latter disorders( 9n ac*te thyroiditis, progression to a6scess for+ation +ay occ*r rapidly so pro+pt recognition and anti6iotic therapy are essential( Rec*rrent attac,s and involve+ent of the left lo6e s*ggest a pyrifor+ sin*s fist*la 6et'een the oropharyn4 and the thyroid as the ro*te of infection < 1/2=( 9n the latter case, s*rgical e4tirpation of the pyrifor+ sin*s 'ill fre7*ently prevent f*rther attac,s( %*6ac*te thyroiditis, rare in childhood, is disc*ssed else'here(

Gra0es Disease
More than B)C of cases are d*e to Araves disease, an a*toi++*ne disorder that, li,e chronic ly+phocytic thyroiditis, is a co+ple4 genetic trait that occ*rs in a genetically predisposed pop*lation < 1&0=( There is a strong fe+ale predisposition, the fe+ale:+ale ratio 6eing / to 1:1( Araves disease is +*ch less co++on in childhood than in the ad*lt( #ltho*gh it can occ*r at any age in the pediatric range , it is +ost co++on in adolescence( $rep*6ertal children tend to have +ore severe disease, to re7*ire longer +edical therapy and to achieve a lo'er rate of re+ission as co+pared 'ith p*6ertal children < 1/)=( This appears to 6e partic*larly tr*e in children 'ho present at E) years of age < 1//=( Araves disease has 6een descri6ed in children 'ith other a*toi++*ne diseases, 6oth endocrine and non

endocrine( These incl*de dia6etes +ellit*s, #ddison > s disease, vitiligo, syste+ic l*p*s erythe+atosis, rhe*+atoid arthritis, +yasthenia gravis, periodic paralysis, idiopathic thro+6ocytopenia p*rp*ra and pernicio*s ane+ia( There is an increased ris, of Araves disease in children 'ith Do'n syndro+e <triso+y 21= <1/5=( Unli,e chronic ly+phocytic thyroiditis in 'hich thyrocyte da+age is predo+inant, the +a?or clinical +anifestations of Araves disease are hyperthyroidis+ and goiter( Araves disease is ca*sed 6y T%! receptor anti6odies that +i+ic the action of T%!( "inding of ligand res*lts in sti+*lation of adenyl cyclase and thyroid hor+onogenesis and gro'th < 1/1,1/B=( #s noted earlier, T%! receptor 6loc,ing anti6odies, in contrast, inhi6it T%!0ind*ced sti+*lation of adenyl cyclase( "oth sti+*latory and 6loc,ing T%! receptor anti6odies 6ind to the e4tracell*lar do+ain of the receptor and appear to recogni;e apparently discrete linear epitopes in the conte4t of a three0di+ensional str*ct*re < 1/B=( # n*+6er of different +onoclonal sti+*lating #6s incl*ding one derived fro+ a patient 'ith Araves disease have no' 6een generated < 150= and the crystal str*ct*re of the h*+an +onoclonal sti+*lating T%! receptor #6 co+ple4ed 'ith a portion of the T%! receptor ectodo+ain has 6een acco+plished < 151=( Ta,en together, a pict*re has e+erged of distinct 6*t overlapping 6inding sites of 6oth sti+*lating and 6loc,ing T%! receptor #6s and of T%! to the le*cine rich T%! receptor ectodo+ain <152=( C*rrent evidence s*ggests that it is the shed # s*6*nit rather than the intact, holoreceptor that ind*ces T%! receptor #6s leading to hyperthyroidis+ < 152=( %t*dies e+ploying +onoclonal T%! receptor anti6odies cloned fro+ patients and reco+6inant +*tant T%! receptor have de+onstrated that there e4ist +*ltiple T%! receptor anti6odies each 'ith different specificities and f*nctional activities( There is evidence that sti+*latory anti6odies are +ostly la+6da and of the 9gA1 s*6class, strongly s*ggesting that they are +onoclonal or pa*ciclonal < 15&=( "loc,ing anti6odies, on the other hand, are not si+ilarly restricted(

Rarer causes of hy"erthyroidis

Rarely, hyperthyroidis+ +ay 6e ca*sed 6y a f*nctioning thyroid adeno+a, 6y constit*tive activation of the T%! receptor or it +ay 6e seen as part of the McC*ne #l6right syndro+e <Ta6le /=( Recently an adolescent fe+ale 'as descri6ed in 'ho+ hyperthyroidis+ res*lted fro+ an hCA0secreting hydatidifor+ +ole < 152=( !yperthyroidis+ also +ay 6e d*e to the inappropriate secretion of T%! 6y a pit*itary adeno+a 6*t thyroid hor+one resistance sho*ld 6e e4cl*ded( 9n adolescents, pregnancy +ay 6e associated 'ith an elevation in circ*lating T2 and a lo'0nor+al or s*ppressed ser*+ T%! concentration( .hen a high total T2 concentration is associated 'ith a nor+al free T2 and T%! level, T"A e4cess, either genetic or ac7*ired <e(g(, d*e to oral contraceptive *se= sho*ld 6e considered( Miscellaneo*s ca*ses of thyroto4icosis incl*de the to4ic phase of chronic ly+phocytic thyroiditis, +entioned a6ove s*6ac*te thyroiditis and thyroid hor+one ingestion <thyroto4icosis factitia=(

Clinical Manifestations
#ll 6*t a fe' children 'ith Araves disease present 'ith so+e degree of thyroid enlarge+ent, and +ost have sy+pto+s and signs of e4cessive thyroid activity, s*ch as tre+ors, ina6ility to fall asleep, 'eight loss despite an increased appetite, pro4i+al +*scle 'ea,ness, heat intolerance and tachycardia( @ften the onset is insidio*s( %hortened attention span, and e+otional la6ility +ay lead to 6ehavioral and school diffic*lties( %o+e patients co+plain of poly*ria and of noct*ria, the res*lt of an increased glo+er*lar filtration rate( #cceleration in linear gro'th +ay occ*r, often acco+panied 6y advance+ent in s,eletal +at*ration <6one age=( #d*lt height is not affected( 9n the adolescent child, p*6erty +ay 6e delayed( 9f +enarche has occ*rred, secondary a+enorrhea is a co++on conco+itant( 9f sleep is dist*r6ed, the patient +ay co+plain of fatig*e(

Ta!le 5 ( Differential diagnosis of thyroto4icosis in childhood( 'y"erthyroidis 0 Diff*se to4ic goiter <Araves disease= 0 3*nctioning thyroid adeno+a 0 To4ic +*ltinod*lar goiter 0 Aain of f*nction +*tation of T%! receptor 0 McC*ne #l6right disease 0 !ydatidifor+ +ole TS'#induced hy"erthyroidis 0 T%!0prod*cing pit*itary adeno+a Causes of Transient Thyroto$icosis 0 Chronic ly+phocytic thyroiditis 0 %*6ac*te thyroiditis 0 Thyroid hor+one ingestion Miscellaneous 0 @ral contraceptive *se 0 $regnancy 0 Congenital T"A e4cess 0 Dysal6*+ine+ic hyerthyro4ine+ia 0 Thyroid hor+one resistance $hysical e4a+ination reveals a diff*sely enlarged, soft or G fleshy H thyroid gland, s+ooth s,in and fine hair te4t*re, e4cessive activity, and a fine tre+or of the tong*e and fingers( # thyroid 6r*it +ay 6e a*di6le( 9n contrast, the finding of a thyroid nod*le s*ggests the possi6ility of a to4ic adeno+a( The hands are often 'ar+ and +oist( Tachycardia, a 'ide p*lse press*re, and a hyperactive precordi*+ are co++on( CafT a* lait spots, partic*larly in association 'ith precocio*s p*6erty, on the other hand, s*ggests a possi6le diagnosis of McC*ne #l6right syndro+e 'hile if a goiter is a6sent, thyroto4icosis factitia sho*ld 6e considered( The ophthal+opathy characteristic of Araves disease in ad*lts is considera6ly less co++on in children, altho*gh a stare and +ild proptosis are o6served fre7*ently(

2a!oratory -0aluation
The clinical diagnosis of hyperthyroidis+ is confir+ed 6y the finding of increased concentrations of circ*lating thyroid hor+ones <T2 or, prefera6ly, free T2 <or free T2 inde4= and T&=( 9n hyperthyroidis+, the circ*lating T& concentration fre7*ently is elevated o*t of proportion to the T2 6eca*se, li,e T%!, T%! receptor anti6odies sti+*late increased T2 to T& conversion( De+onstration of a s*ppressed T%! e4cl*des +*ch rarer ca*ses of thyroto4icosis, s*ch as T%!0ind*ced hyperthyroidis+ and thyroid hor+one resistance in 'hich the T%! is inappropriately > nor+al > or slightly elevated( 9f the latter diseases are s*spected, free alpha s*6*nit sho*ld 6e +eas*red( #lternatively, an elevated T2 level in association 'ith an inappropriately J nor+al > T%! +ay 6e d*e to an e4cess of thyro4ine06inding glo6*lins <either fa+ilial or ac7*ired, for e4a+ple a res*lt of oral contraceptive *se= or rarer 6inding

protein a6nor+alities <for e4a+ple, fa+ilial dysal6*+ine+ic hyperthyro4ine+ia= < 15)=( 9n the latter cases, ser*+ T"A concentration or electrophoresis of T2 6inding proteins, respectively, sho*ld 6e +eas*red( 9f pregnancy or an hCA0secreting t*+or are s*spected, ser*+ or *rinary hCA concentration can 6e +eas*red( # lo' ser*+ Tg can 6e de+onstrated if thyroto4icosis factitia is s*spected < 15/=( The diagnosis of Araves disease is confir+ed 6y the de+onstration of T%! receptor anti6odies in ser*+( The availa6ility of co++ercial ,its, and the develop+ent of 6oth +olec*larly0engineered cells, and a sti+*lating h*+an anti0T%! receptor +onoclonal anti6ody have greatly i+proved the perfor+ance of T%! receptor anti6ody assays availa6le 6oth clinically and in a research setting( T'o +ain classes of assays can 6e disting*ished( Co+petitive 6inding assays <radioreceptor assay or, +ore recently, en;y+e0lin,ed i++*nosor6ent assay UEL9%#V, ta,e advantage of the a6ility of these anti6odies to inhi6it the 6inding of T%! to either porcine thyroid +e+6ranes or to reco+6inant h*+an T%! receptor transfected into Chinese ha+ster ovary <C!@= cells( "ioassays +eas*re directly the sti+*lation <or inhi6ition= of T%!0ind*ced sti+*lation of adenyl cyclase( The EL9%# <also called > coated t*6e > assay= is +ore sensitive than the radioreceptor assay < 155, 151 =, partic*larly 'hen en;y+e0lin,ed +onoclonal T%! receptor anti6ody is s*6stit*ted for T%! as ligand < 15B=( %ince 6oth sti+*latory and 6loc,ing anti6odies inhi6it T%! 6inding to the receptor, the radioreceptor assay or EL9%# are e4cellent screening +ethods to test for the presence of T%! receptor anti6odies 6*t they do not provide infor+ation a6o*t f*nction( C*rrent EL9%#s in clinical practice are highly sensitive and specific, 6eing positive in *p to BBC of ad*lts and children 'ith Araves disease < 1/B, 155015B =( Res*lts in 6ioassays are +ore varia6le( #ltho*gh 6ioassays are highly sensitive in a research setting < 110=, they are +ore fastidio*s and so res*lts fro+ so+e clinical la6oratories appear to 6e less sensitive < 111, 112 =( Recently, a sensitive co++ercial 6ioassay for T%! receptor anti6odies has 6een developed that +ay i+prove the feasi6ility of +eas*ring 6ioactivity <1126= ( "ioassay is partic*larly *sef*l in the occasional patient 'ith Araves disease 'ith negative T%! receptor anti6odies 6y EL9%# or in treated patients 'hose clinical pict*re is discordant 'ith res*lts in the 6inding assay( $roperly perfor+ed, 6ioassays are the +ost definitive and sensitive +ethod to doc*+ent that the hyperthyroidis+ is d*e to sti+*latory T%! receptor # 6s, 6*t the ne'er, i+proved +ethods are +ore e4pensive and so have not 6een *niversally adopted to date( T%! receptor anti6odies +eas*red 6y 6inding assay are called T%! receptor anti6odies, TR#6s or T%! 6inding0inhi6itory 9gAs, T"99= 'hereas those +eas*red 6y 6ioassay are *s*ally referred to as thyroid0 sti+*lating i++*noglo6*lins, T%9, 9t +*st al'ays 6e ,ept in +ind that precise val*es o6tained 'ith different assays cannot 6e co+pared since res*lts depend on the sensitivity of the assay *sed and there is no *nifor+ standard e+ployed( %o+e individ*als, initially reported to 6e negative in the radioreceptor assay, 6eco+e positive several 'ee,s later < 110=( 9t has 6een hypothesi;ed that in these patients, T%! receptor anti6ody synthesis is restricted at first to 'ithin the thyroid gland itself, or, alternately, that T%! receptor anti6odies escape detection 6eca*se of 6inding 6y sol*6le T%! receptor circ*lating in ser*+( !o'ever, the proportion of patients 'ho are T%! receptor anti6ody positive has increased 'ith the introd*ction of 2nd generation and no' &rd generation assays, strongly s*ggesting that li+ited assay sensitivity is the +ost li,ely reason in +ost cases( Meas*re+ent of T%! receptor anti6odies +ay 6e *sef*l in disting*ishing the to4ic phase of chronic ly+phocytic thyroiditis <T%! receptor anti6ody negative= fro+ Araves disease( Tg and T$@ anti6odies are positive in 50C of children and adolescents 'ith Araves disease 6*t their +eas*re+ent is not as sensitive or specific as +eas*re+ent of T%! receptor anti6odies( 9n contrast to ad*lts, radioactive iodine *pta,e and scan are *sed to confir+ the diagnosis of Araves disease only in atypical cases <for e4a+ple, if +eas*re+ent of T%! receptor anti6odies is negative, or if a f*nctioning thyroid nod*le is s*spected=(

The choice of 'hich of the three therape*tic options <+edical therapy, radioactive iodine, or s*rgery= to *se, sho*ld 6e individ*ali;ed and disc*ssed 'ith the patient and his8her fa+ily( Each approach has its advantages and disadvantages 'ith respect to efficacy, 6oth short and long ter+ co+plications, the ti+e re7*ired to control the hyperthyroidis+, and the re7*ire+ent for co+pliance( 9n general, +edical therapy 'ith +ethi+a;ole <MM9= is the initial choice of +ost pediatricians altho*gh radioiodine is gaining increasing acceptance, partic*larly in non co+pliant adolescents, in children 'ho are develop+entally delayed, and in those a6o*t to leave ho+e <for e4a+ple, to go to college=( #lternately, s*rgery, the oldest for+ of therapy, +ay 6e the initial choice in specific cases if an e4perienced pediatric thyroid s*rgeon is availa6le(

Medical Thera"y
The thio*racil co+po*nds $TU, MM9 and car6i+a;ole <converted to MM9= e4ert their antithyroid effect 6y inhi6iting the organification of iodine and the co*pling of iodotyrosine resid*es on the Tg +olec*le to T& and T2( MM9 is generally preferred over $TU 6eca*se for an e7*ivalent dose it re7*ires ta,ing fe'er ta6lets, it has a longer half0life <and so, re7*ires less fre7*ent +edication= and 6eca*se it has a +ore favora6le safety profile( Recent reports have s*ggested that the ris, of hepatoto4icity 'ith $TU +ay 6e greater in the yo*ng < 11&011)=, leading to the reco++endation that $TU 6e *sed only in pediatric patients 'ho are allergic to MM9, and in 'ho+ per+anent for+s of therapy are not possi6le < 12&=( $TU *se has also 6een advocated in the first tri+ester of pregnancy( %ince $TU 6*t not MM9 inhi6its the conversion of T2 to the +ore active iso+er T&, $TU +ay have a role in the treat+ent of thyroid stor+ and8or if the thyroto4icosis is severe( The initial dosage of MM9 is 0() +g8,g8day given every 12 ho*rs and of $TU is ) +g8,g8day given every 1 ho*rs( 9n severe cases, a 6eta0adrenergic 6loc,er <atenolol, 2) to )0 +g daily or t'ice daily= can 6e added to control the cardiovasc*lar overactivity *ntil a e*thyroid state is o6tained( $atients sho*ld 6e follo'ed every 2 to / 'ee,s *ntil the ser*+ concentration of T2 <or free T2 and total T&= nor+ali;es( 9t sho*ld 6e noted that the T%! concentration +ay not ret*rn to nor+al *ntil several +onths later( Therefore, +eas*re+ent of T%! is *sef*l as a g*ide to therapy only after it has nor+ali;ed 6*t not initially( @nce the T2 and T& have nor+ali;ed, one can either decrease the dosage of thioa+ide dr*g 6y &0C to )0C or, alternatively, 'ait *ntil the T%! 6egins to rise and add a s+all, s*pple+entary dose of l0thyro4ine <e(g(, 1 +g8,g8day=( Monotherapy has the advantage that disease activity can 6e assessed and a s+aller dr*g dosage is *sed( The latter is an advantage since to4ic reactions to MM9 appear to 6e dose0related( Maintenance doses of MM9 +ay 6e ad+inistered once daily( $TU +ay 6e given t'ice daily( Us*ally patients can 6e follo'ed every 20/ +onths once thyroid f*nction has nor+ali;ed( 9n +ost children and adolescents, circ*lating thyroid hor+one levels can 6e nor+ali;ed readily 'ith antithyroid +edication as long as co+pliance is not a pro6le+( The opti+al d*ration of therapy is controversial( There is no do*6t that +ost children and adolescents, partic*larly prep*6ertal ones, re7*ire a longer co*rse of therapy than ad*lts( Therefore treat+ent g*idelines developed for older individ*als sho*ld not 6e applied to the yo*ng( 9n one retrospective st*dy, T%! receptor #6s disappeared fro+ the circ*lation in E20C of patients after 1&022 +onths of +edical therapy < 11/= in contrast to ad*lts in +ost of 'ho+ T%! receptor #6s nor+ali;e 6y / to 12 +onths <115011B=( 9n another st*dy, appro4i+ately 2)C of children re+itted 'ith every 2 years of therapy *p to / years of treat+ent < 1B0=( E7*ivalent res*lts have 6een o6tained 6y others < 1/)=(9n a recent prospective trial of 1)2 children 'ith ne'ly diagnosed Araves disease treated 'ith car6i+a;ole , 20C of children re+itted after 2 years of therapy, &5C after / years and 2)C after 1 years( <1/)6=( The +edian d*ration of

therapy in +ost st*dies is & to 2 years years, 6*t therapy sho*ld 6e individ*ali;ed( 9n patients treated 'ith antithyroid dr*gs alone, a s+all dr*g re7*ire+ent, s+all goiter, and lac, of or6itopathy are favora6le indicators that dr*g therapy can 6e tapered grad*ally and 'ithdra'n( Lo'er initial degree of hyperthyro4ine+ia <T2E20 +cg8dL <2)5(2 n+ol8L=: T&:T2 ratio E20= , lo'er initial T%! receptor #6 concentration <F2Q *pper li+it of nor+al <1/)c= and postp*6ertal age are favora6le prognostic indicators( $ersistence of T%! receptor anti6odies, on the other hand, indicates a high li,elihood of relapse( 9nitial st*dies s*ggesting that co+6ined therapy <i(e(, antithyroid dr*g pl*s L0thyro4ine= +ight 6e associated 'ith an i+proved rate of re+ission < 1B1= have not 6een confir+ed <1B2=( To4ic dr*g reactions <erythe+ato*s rashes, *rticaria, arthralgias, transient gran*locytopenia, <E1)00 gran*locytes8++&=, have 6een reported in )C to 12C of children( Rarely, +ore severe se7*elae, s*ch as hepatitis, a l*p*s li,e syndro+e, thro+6ocytopenia, and agran*locytosis, <E)00 gran*locytes8++&= +ay occ*r( Most reactions are +ild and do not contraindicate contin*ed *se( The ris, of agran*locytosis appears to 6e greatest 'ithin the first & +onths of therapy 6*t it can occ*r at any ti+e( There is so+e evidence that close +onitoring of the 'hite 6lood cell co*nt d*ring this initial ti+e period +ay 6e *sef*l in identifying agran*locytosis prior to the develop+ent of a fever and infection < 1B&=, 6*t +ost a*thors do not consider the lo' ris, to 6e 'orth the cost of close +onitoring( Many clinicians prefer to chec, the 'hite 6lood cell prior to therapy 6eca*se Araves disease itself can 6e associated 'ith a6nor+alities in these para+eters( @n the other hand, ro*tine +onitoring of liver f*nction tests is not *s*ally reco++ended( 9t is i+portant to ca*tion all patients to stop their +edication i++ediately and cons*lt their physician sho*ld they develop *ne4plained fever, sore throat, or gingival sores or ?a*ndice( Unli,e $TU, MM9 is rarely associated 'ith hepatocell*lar in?*ry( #ppro4i+ately 10C of children treated +edically 'ill develop long ter+ hypothyroidis+, a conse7*ence of coincident cell and cyto,ine0+ediated destr*ction and8or the develop+ent of T%! receptor 6loc,ing anti6odies(

Radioacti0e Iodine
Definitive therapy 'ith either +edical <radioactive iodine= or s*rgical thyroid a6lation is *s*ally reserved for patients 'ho have failed dr*g therapy, developed a to4ic dr*g reaction, or are nonco+pliant( 9n recent years, ho'ever, radioactive iodine is 6eing favored increasingly, even as the initial approach to therapy < 1B2=( The advantages are the relative ease of ad+inistration, the red*ced need for +edical follo' *p and the lac, of de+onstra6le long ter+ adverse effects < 1B2=( #ltho*gh a dose of )0 to 200 WCi of 1&198esti+ated gra+ of thyroid tiss*e has 6een *sed, the higher dosage is reco++ended, partic*larly in yo*nger children, in order to co+pletely a6late the thyroid gland and there6y red*ce the ris, of f*t*re neoplasia( The si;e of the thyroid gland is esti+ated, 6ased on the ass*+ption that the nor+al gland is 0()01(0 g+s8year of age, +a4i+*+ 1)020 g+s( The for+*la *sed is: Esti+ated thyroid 'eight in gra+s Q )00200 +cCi 1&1 098fractional 1&19 22 ho*r *pta,e Radioactive iodine therapy sho*ld 6e *sed 'ith ca*tion in children E10 years of age and partic*larly in those E) years of age 6eca*se of the increased s*scepti6ility of the thyroid gland in the yo*ng to the proliferative effects of ioni;ing radiation < 1B)=( $retreat+ent 'ith antithyroid dr*gs prior to R#9 therapy is advisa6le if the hyperthyroidis+ is severe( Editors note09t is of interesting to calc*late the possi6le ris, for ind*ction of cancer *sing the data presented 6y Riv,ees et al <1B2=, 'ho are proponents of *se of R#9 for therapy in yo*ng children((The ris, of death fro+ any cancer <not thyroid cancer= d*e specifically to radiation e4pos*re is noted 6y these a*thors to 6e 0(1/C8re+ for children, and the 'hole 6ody radiation e4pos*re fro+ R#9 treat+ent at age 10 to 6e 1(2) re+8+Ci ad+inistered( Riv,ees et al advise treat+ent 'ith doses of R#9 greater then 1/0 *Ci8gra+ thyroid, to achieve a thyroidal radiation dose of at least 1)0Ay<a6o*t 1)000 rads=(

#ss*+ing a reasona6le R#9U of )0C and gland si;e of 20 g+, the ad+inistered dose 'o*ld 6e 20<g+= 4 1/0*Ci8g+ 4 2 <to acco*nt for )0C *pta,e= S12(1 +Ci( Th*s the long ter+ cancer death ris, 'o*ld 6e 12(1 <+Ci= 4 1(2) re+ <per +Ci= 4 0(1/C <per re+= S &C( 3or a dose of 1)+Ci the incre+ental ris, a of cancer +ortality 'o*ld 6e 2C at age ), 2C at age 10, and 1C at age 1)( .hether or not accepting a specific incre+ental 20)C ris, of death fro+ cancer 6eca*se of R#9 treat+ent is of co*rse a +atter of ?*dg+ent 6y the physician and fa+ily( !o'ever, this 'o*ld see+ to +any persons to constit*te a significant ris, that sho*ld 6e avoided( Thyroid hor+one concentrations +ay rise transiently 2 to 10 days after R#9 ad+inistration d*e to the release of prefor+ed hor+one fro+ the da+aged gland( "eta 6loc,ers +ay 6e *sef*l d*ring this ti+e period( %i+ilarly, analgesics +ay 6e e+ployed if there is +ild disco+fort d*e to radiation thyroiditis( @ther ac*te co+plications of R#9 therapy <na*sea, significant nec, s'elling= are rare( @ne *s*ally sees a therape*tic effect 'ithin / 'ee,s to & +onths( .orsening of ophthal+opathy, descri6ed in ad*lts after R#9, does not appear to 6e co++on in childhood( !o'ever, if significant ophthal+opathy is present R#9 therapy sho*ld 6e *sed 'ith ca*tion and pretreat+ent 'ith steroids +ay 6e effective( #lternately, another per+anent treat+ent +odality <s*rgery= sho*ld 6e considered( 9n appro4i+ately 1000 children 'ith Araves disease treated 'ith R#9 and follo'ed for E) to F20 years to date, there does not appear to 6e any increased rate of congenital ano+alies in offspring nor in thyroid cancer( !o'ever, long ter+ follo' *p data in a larger cohort are still lac,ing(

%*rgery, the third therape*tic +odality, is perfor+ed less fre7*ently no' than in the past( #n advantage of this for+ of therapy is the rapid resol*tion of the hyperthyroidis+( -ear0total thyroidecto+y is the proced*re of choice in order to +ini+i;e the ris, of rec*rrence( %*rgery *s*ally is reserved for patients 'ho have failed +edical +anage+ent, 'ho have a +ar,edly enlarged thyroid, 'ho ref*se radioactive iodine therapy, and for the rare patient 'ith significant ophthal+opathy in 'ho+ radioactive iodine therapy is contraindicated( The +ost co++on potential co+plication is transient hypocalce+ia 'hich occ*rs in appro4i+ately 10C of patients( @ther, less co++on potential co+plications are ,eloid for+ation <2(1C=, rec*rrent laryngeal nerve paralysis <2C=, hypoparathyroidis+ <2C=, and, rarely <0(01C=, death < 1B2=( There are fe'er co+plications 'ith an e4perienced s*rgeon and 'hen +odern +ethods of anesthesia and pain control are *sed < 1B/=( $rior to s*rgery, it is i+portant to treat 'ith antithyroid +edication in order to render the child e*thyroid and prevent thyroid stor+( 9odides <L*gols sol*tion, ) to 10 drops tid or potasi*+ iodide, 2 to 10 drops daily or -a ipodate, 0()01 g+ every & days= are added for 5 to 12 days prior to s*rgery in order to decrease the vasc*larity of the gland( 3ollo'ing 6oth +edical and s*rgical thyroid a6lation +ost patients 6eco+e hypothyroid and re7*ire lifelong thyroid replace+ent therapy( @n the other hand, if therapy is inade7*ate, hyperthyroidis+ +ay rec*r( Therefore longter+ follo'*p is +andatory(

Thyroid nodules and cancer

Thyroid nod*les are rare in the first 2 decades of life, 6*t 'hen fo*nd, they are +ore li,ely to 6e carcino+ato*s than are si+ilar +asses in ad*lts < 1B5=( 3ollic*lar adeno+as and colloid cysts acco*nt for the +a?ority of 6enign nod*les( @ther ca*ses of nod*lar enlarge+ent incl*de chronic ly+phocytic thyroiditis and e+6ryological defects, s*ch as intrathyroidal thyroglossal d*ct cysts or *nilateral thyroid agenesis( Li,e in ad*lts, the +ost co++on for+ of thyroid cancer in childhood and adolescence is papillary thyroid carcino+a, 6*t other histological types fo*nd in the ad*lt +ay also occ*r < 1B1=( # high inde4 of s*spicion is necessary if the nod*le is painless, of fir+ or hard consistency, if it is fi4ed

to s*rro*nding tiss*es or if there is a fa+ily history of thyroid cancer( @ther 'orriso+e findings incl*de a history of rapid increase in si;e, associated cervical adenopathy, hoarseness or dysphagia( Even the findings of a cystic co+ponent or a f*nctioning nod*le, co++only *sed as favora6le signs in ad*lt patients, do not co+pletely e4cl*de the possi6ility of neoplasia < 1BB=( @ccasionally, thyroid cancer presents in childhood as *ne4plained cervical adenopathy, or neoplasia is fo*nd in patients 'ho also have chronic ly+phocytic thyroiditis < 1BB=( The possi6ility of a rare +ed*llary thyroid carcino+a sho*ld 6e considered if there is a fa+ily history of thyroid cancer or pheochro+ocyto+a or if the child has +*ltiple +*cosal ne*ro+as and a +arfanoid ha6it*s, findings s*ggestive of +*ltiple endocrine neoplasia <ME-= types 2# and8or 2" < 200=( Children e4posed previo*sly to thyroid irradiation co+prise a high0ris, gro*p( The increased ris, of thyroid cancer in ad*lts e4posed d*ring childhood to lo' levels of thyroid irradiation for 6enign conditions of the head and nec, is 'ell ,no'n < 201=( The increased incidence of 6oth 6enign and carcino+ato*s nod*les in patients 'ith !odg,in disease 'ho had received radiotherapy to the nec, d*ring childhood is also 6eing doc*+ented increasingly < 202, 20& =( Thyroid cancer is no' ,no'n to 6e the +ost co++on second +alignancy in childhood s*rvivors of !odg,ins and is also seen 'ith increased fre7*ency in le*,e+ia s*rvivors < 202=( %i+ilarly, children e4posed to high levels of radioactive iodine in the first decade of life or in *tero, a conse7*ence of the Cherno6yl disaster, are at a +ar,edly increased ris, of developing papillary thyroid cancer < 1B)=( The ris, of thyroid cancer is related to the dose of e4ternal irradiation and, *nli,e the 1B year average latency after lo' dose irradiation, the average latent period in s*rvivors of !odg,in disease appears to 6e only B years < 20&=( 9n Cherno6yl victi+s, the latency 'as only 2 years < 1B)=( #s co+pared 'ith ad*lts, there appears to 6e a higher prevalence of gene rearrange+ents in children 'ith differentiated thyroid cancer, the clinical significance of 'hich is *nclear < 202=( 9nitial investigation of a thyroid nod*le incl*des eval*ation of thyroid f*nction and T$@ and Tg anti6odies( # s*ppressed ser*+ T%! concentration acco+panied 6y an elevation in the circ*lating T2 and8or T& s*ggests the possi6ility of a f*nctioning nod*le, 'hich can 6e confir+ed 'ith a radion*clide scan( The finding of positive anti6odies, on the other hand, *s*ally indicates the presence of *nderlying chronic ly+phocytic thyroiditis, 6*t in so+e cases, positive anti6odies +ay si+ply constit*te evidence of an i++*ne response to the presence of neoplastic cells( Ultrasonography provides infor+ation a6o*t 'hether the nod*le is solid or cystic, and 'hether it is single or +*ltifocal 3ine0needle aspiration 6iopsy, pop*lar in the investigation of thyroid carcino+a in ad*lts, is gaining increasing acceptance and is no' considered to 6e the proced*re of choice in the eval*ation of nod*les F0() c+ < 20)=( There is an increased incidence of 6oth cervical node involve+ent and of p*l+onary +etastases at the ti+e of diagnosis in children 'ith thyroid carcino+a < 1B1=( -onetheless, the long ter+ cancer specific +ortality rate is no greater in children than in ad*lts E20 years of age < 20/=( Th*s, the approach to treat+ent is si+ilar( <%ee also Chapter 11=( E4cision of the t*+or or lo6e is the appropriate treat+ent for 6enign t*+ors and cysts, 'hereas total thyroidecto+y 'ith preservation of the parathyroid glands and rec*rrent laryngeal nerves is the initial therapy for +alignant thyroid t*+ors( The latter proced*re is follo'ed 6y radioa6lation if there is evidence of resid*al gland or t*+or after s*rgery( The iss*e of prophylactic ly+ph node dissection is controversial < 202=( #fter radioiodine therapy, the dose of thyro4ine is ad?*sted to ,eep the ser*+ T%! concentration s*ppressed <6et'een 0(0) +U8L and 0(1 +U8L in a sensitive assay=( Meas*re+ent of ser*+ Tg, a thyroid follic*lar cell0specific protein, is *sed to detect evidence of +etastatic disease in differentiated for+s of thyroid cancer, s*ch as papillary or follic*lar carcino+a( This is 6est perfor+ed after a period <*s*ally / 'ee,s= of thyro4ine 'ithdra'al or after the e4ogeno*s ad+inistration of reco+6inant T%! < 205=( Manage+ent of differentiated thyroid cancer in children and adolescents has 6een descri6ed in detail recently < 202, 2026 =( Meas*re+ent of circ*lating calcitonin is *sed as a t*+or +ar,er for +ed*llary thyroid cancer <MTC=, a

C0cell derived +alignancy < 201=( M*tations of the RET protooncogene, detecta6le in nearly all fa+ilial for+s of MTC, is of val*e in screening fa+ily +e+6ers < 200, 201 =( 9n fa+ilies affected 'ith +*ltiple endocrine neoplasia type 2, screening of children as yo*ng as ) years follo'ed 6y total thyroidecto+y has 6een s*ccessf*l in c*ring patients 'ith +icroscopic MTC, an other'ise highly +alignant neoplas+ 'ith a poor prognosis < 200=( @pti+al +onitoring of patients 'ith a history of thyroid irradiation d*ring childhood re+ains controversial( "eca*se of the insensitivity of clinical palpation, reg*lar assess+ent of thyroid f*nction <T%! and, as necessary free T2= as 'ell as *ltraso*nd e4a+inations sho*ld 6e perfor+ed( There is evidence that thyroid s*ppression is associated 'ith a red*ction in the develop+ent of ne' nod*les after partial s*rgical resection of an irradiated thyroid gland < 20B= 6*t 'hether it plays any role if the T%! is not elevated or in preventing neoplasia is *n,no'n(

1( Missero C, Co6ellis A, De 3elice M, Di La*ro R( Molec*lar events involved in differentiation of thyroid follic*lar cells( Mol Cell Endocrinol 1BB1:120<102=:&502&( 2( De 3elice M, Di La*ro R( Thyroid develop+ent and its disorders: genetics and +olec*lar +echanis+s( Endocr Rev 2002:2)<)=:52202/( &( Manley -R, Capecchi MR( The role of !o4a0& in +o*se thy+*s and thyroid develop+ent( Develop+ent 1BB):121<5=:1B1B0200&( 2( 3ag+an !, Arande M, Eds6agge M, %e+6 !, -ilsson M( E4pression of classical cadherins in thyroid develop+ent: +aintenance of an epithelial phenotype thro*gho*t organogenesis( Endocrinology 200&:122<1=:&/11022( )( 3ag+an !, Liao M, .esterl*nd M, #ndersson L, Morro' "E, -ilsson M( The 22711 deletion syndro+e candidate gene T641 deter+ines thyroid si;e and positioning( !*+ Mol Aenet 2005:1/<&=:25/01)( /( 3ag+an !, Arande M, Aritli0Linde #, -ilsson M( Aenetic deletion of sonic hedgehog ca*ses he+iagenesis and ectopic develop+ent of the thyroid in +o*se( #+ M $athol 2002:1/2<)=:11/)052( 5( "*rro' A-, 3isher D#, Larsen $R( Maternal and fetal thyroid f*nction( - Engl M Med 1BB2:&&1<1/=:105201( 1( 3isher D#, Klein #!( Thyroid develop+ent and disorders of thyroid f*nction in the ne'6orn( Engl M Med 1B11:&02<12=:502012( B( Thorpe0"eeston MA, -icolaides K!, McAregor #M( 3etal thyroid f*nction( Thyroid 1BB2:2<&=:2050 15( 10( .illia+s 3L, %i+pson M, Delah*nty C, et al( Develop+ental trends in cord and postpart*+ ser*+ thyroid hor+ones in preter+ infants( M Clin Endocrinol Meta6 2002:1B<11=:)&12020( 11( "ro'n R%, %halho*6 N, Co*lter %, et al( Develop+ental reg*lation of thyrotropin receptor gene e4pression in the fetal and neonatal rat thyroid: relation to thyroid +orphology and to thyroid0specific gene e4pression( Endocrinology 2000:121<1=:&200)( 12( !*+e R, %i+pson M, Delah*nty C, et al( !*+an fetal and cord ser*+ thyroid hor+ones: develop+ental trends and interrelationships( M Clin Endocrinol Meta6 2002:1B<1=:20B5010&( 1&( De -ayer $, Cornette C, Nandersch*eren M, et al( %er*+ thyroglo6*lin levels in preter+ neonates(

Clin Endocrinol <@4f= 1B12:21<2=:12B0)&( 12( %o6rero A, M*no; L, "a;;ara L, et al( Thyroglo6*lin reference val*es in a pediatric infant pop*lation( Thyroid 2005:15<11=:102B0)2( 1)( Roti E, An*di #, "raver+an LE( The placental transport, synthesis and +eta6olis+ of hor+ones and dr*gs 'hich affect thyroid f*nction( Endocr Rev 1B1&:2<2=:1&102B( 1/( Kester M!, Kaptein E, Nan Di?, C!, et al( Characteri;ation of iodothyronine s*lfatase activities in h*+an and rat liver and placenta( Endocrinology 2002:12&<&=:1120B( 15( Nan der Aeyten %, %egers 9, Aere6en ", et al( Tra nscriptional reg*lation of iodothyronine deiodinases d*ring e+6ryonic develop+ent( Mol Cell Endocrinol 2001:11&<102=:10B( 11( R*i; de @na C, @6regon MM, Esco6ar del Rey 3, Morreale de Esco6ar A( Develop+ental changes in rat 6rain )X0deiodinase and thyroid hor+ones d*ring the fetal period: the effects of fetal hypothyroidis+ and +aternal thyroid hor+ones( $ediatr Res 1B11:22<)=:)110B2( 1B( Morreale de Esco6ar A, @6regon MM, Esco6ar del Rey 3( 9s ne*ropsychological develop+ent related to +aternal hypothyroidi s+ or to +aternal hypothyro4ine+iaY M Clin Endocrinol Meta6 2000:1)<11=:&B5)015( 20( 3erreiro ", "ernal M, Aoodyer CA, "ranchard CL( Esti+ation of n*clear thyroid hor+one receptor sat*ration in h*+an fetal 6rain and l*ng d*ring early gestation( M Clin Endocrinol Meta6 1B11:/5<2=:1)&0/( 21( N*ls+a T, Aons M!, de Ni?lder MM( Maternal0fetal transfer of thyro4ine in congenital hypothyroidis+ d*e to a total organification defect or thyroid agenesis( - Engl M Med 1B1B:&21<1=:1&0 /( 22( Calvo RM, Ma*nia*4 E, A*l6is ", et al( 3etal tiss*es are e4posed to 6iologically relevant free thyro4ine concentrations d*ring early phases of develop+ent( M Clin Endocrinol Meta6 2002:15<2=:15/1055( 2&( Meinhold !, D*denha*sen M., .en;el K., %aling E( #+niotic fl*id concentrations of &,&X,)X0tri0 iodothyronine <reverse T&=, &,&X0di0iodothyronine, &,),&X0tri0iodothyronine <T&= and thyro4ine <T2= in nor+al and co+plicated pregnancy( Clin Endocrinol <@4f= 1B5B:10<2=:&))0/)( 22( "oyages %C( Clinical revie' 2B: 9odine deficiency disorders( M Clin Endocrinol Meta6 1BB&:55<&=:)150B1( 2)( Rovet M, .al,er ., "liss ", "*chanan L, Ehrlich R( Long0ter+ se7*elae of hearing i+pair+ent in congenital hypothyroidis+( M $ediatr 1BB/:121</=:55/01&( 2/( de Zegher 3, $ernasetti 3, Nanhole C, Devlieger !, Nan den "erghe A, Martial M#( The prenatal role of thyroid hor+one evidenced 6y feto+aternal $it01 deficiency( M Clin Endocrinol Meta6 1BB):10<11=:&1250&0( 25( Mats**ra -, Konishi M( Transient hypothyroidis+ in infants 6orn to +others 'ith chronic thyroiditis[a nation'ide st*dy of t'enty0three cases( The Transient !ypothyroidis+ %t*dy Aro*p( Endocrinol Mpn 1BB0:&5<&=:&/B05B( 21( Man E", Mones .%, !olden R!, Mellits ED( Thyroid f*nction in h*+an pregnancy( 1( Retardation of progeny aged 5 years: relationships to +aternal age and +aternal thyroid f*nction( #+ M @6stet Aynecol 1B51:111<5=:B0)01/( 2B( !addo' ME, $alo+a,i AE, #llan .C, et al( Maternal thyroid deficiency d*ring pregnancy and s*6se7*ent ne*ropsychological develop+ent of the child( - Engl M Med 1BBB:&21<1=:)2B0))(

&0( $op NM, K*i?pens ML, van "aar #L, et al( Lo' +aternal free thyro4ine concentrations d*ring early pregnancy are associated 'ith i+paired psycho+otor develop+ent in infancy( Clin Endocrinol <@4f= 1BBB:)0<2=:12B0) ) &1a( Li* !, Mo+otani -, -oh MI, 9shi,a'a -, Ta,e6e K, 9to K( Maternal hypothyroidis+ d*ring early pregnancy and intellect*al develop+ent of the progeny( #rch 9ntern Med 1BB2:1)2<5=:51)05( &1 6( Mo+otani M, 9'a+a %, Mo+otani K( -e*rodevelop+ent in children 6orn to hypothyroid +others restored to nor+al thyro4ine <T2= 6y late pregnancy in Mapan: -o apparent infl*ence of +aternal T2 deficiency( M Clin Endocrinol Meta6 2012, in press( &1 c( Do'ning %D, !alpern L, Cars'ell M et al, %evere early +aternal hypothyroidis+ prior to the third tri+ester associated 'ith nor+al cognitive o*tco+e in the offspring( Thyroid, , in press( & 2( L a;ar*s M!, "est'ic, M$, Channon % et al( #ntenatal thyroid screening and childhood cognitive f*nction( - Engl M Med 2012:&//:2B&0)01( &&( Klein RZ, !addo' ME, 3ai4 MD, et al( $revalence of thyroid deficiency in pregnant 'o+en( Clin Endocrinol <@4f= 1BB1:&)<1=:210/( &2( #6*id M, %tinson D#, Larsen $R( %er*+ triiodothyronine and thyro4ine in the neonate and the ac*te increases in these hor+ones follo'ing delivery( M Clin 9nvest 1B5&:)2<)=:11B)0B( &)( "ianco #C, %ilva ME( 9ntracell*lar conversion of thyro4ine to triiodothyronine is re7*ired for the opti+al ther+ogenic f*nction of 6ro'n adipose tiss*e( M Clin 9nvest 1B15:5B<1=:2B)0&00( &/( !o*ste, M, Ni;e, K, $avel,a %, et al( Type 99 iodothyronine ) X 0deiodinase and *nco*pling protein in 6ro'n adipose tiss*e of h*+an ne'6orns( M Clin Endocrinol Meta6 1BB&:55<2=:&1205( &5( Mercado M, I* NI, 3rancis 9, %;y+ono'ic; ., Aold !( Thyroid f*nction in very preter+ infants( Early ! *+ Dev 1B11:1/<20&=:1&1021( &1( -elson MC, .eiss RM, .ilco4 R"( Underesti+ates of ser*+ free thyro4ine <T2= concentrations 6y free T2 i++*noassays( M Clin Endocrinol Meta6 1BB2:5B<1=:5/0B( &B( #res %, Esco6ar0Morreale !3, D*ero M, et al( -eonatal hypothyro4ine+ia: effects of iodine inta,e and pre+at*re 6irth( M Clin Endocrinol Meta6 1BB5:12</=:1502012( 20( 3ran, ME, 3ai4 ME, !er+os RM, et al( Thyroid f*nction in very lo' 6irth 'eight infants: effects on neonatal hypothyroidis+ screening( M $ediatr 1BB/:121<2=:)210)2( 21( Ko, M!, Tegelaers .!, de Ni?lder MM( %er*+ thyroglo6*lin levels in preter+ infants 'ith and 'itho*t the respiratory distress syndro+e( 9( Cord 6lood st*dy( $ediatr Res 1B1/:20<10=:BB/01000( 22( Thorpe0"eeston MA, -icolaides K!, %ni?ders RM, 3elton CN, McAregor #M( Thyroid f*nction in s+all for gestational age fet*ses( @6stet Aynecol 1BB1:55<)=:5010/( 2&( Z*ra,o's,i D, Di Can;io M, Ma?;o*6 M#( $ediatric reference intervals for ser*+ thyro4ine, triiodothyronine, thyrotropin, and free thyro4ine( Clin Che+ 1BBB:2)<5=:10150B1( 22( 3isher D( -e4t generation ne'6orn screening for congenital hypothyroidis+Y M Clin Endocrinol Meta6 200):B0</=:&5B50B( 226( Marvin L( Mitchell, !o0.en !s*, 9nderneel %ahai and the Massach*setts $ediatric Endocrine .or, Aro*pPThe increased incidence of congenital hypothyroidis+: fact or fancyY Clin Endocrinol 2011:5):10/010( 2)( Klein #!, Melt;er %, Kenny 3M( 9+proved prognosis in congenital hypothyroidis+ treated 6efore age three +onths( M $ediatr 1B52:11<)=:B120)( 2/( D*ssa*lt M!( The anecdotal history of screening for congenital hypothyroidis+( M Clin Endocrinol

Meta6 1BBB:12<12=:2&&202( 25( Delange 3( -eonatal screening for congenital hypothyroidis+: res*lts and perspectives( !or+ Res 1BB5:21<2=:)10/1( 21( "ongers0%cho,,ing MM, de M*inc, Kei;er0%chra+a %M( 9nfl*ence of ti+ing and dose of thyroid hor+one replace+ent on +ental, psycho+otor, and 6ehavioral develop+ent in children 'ith congenital hypothyroidis+( M $ediatr 200):125</=:5/1052( 2B( !eyerdahl %, @er6ec, "( Congenital hypothyroidis+: develop+ental o*tco+e in relation to levothyro4ine treat+ent varia6les( Thyroid 200&:1&<11=:102B0&1( )0( Rovet M, Dane+an D( Congenital hypothyroidis+: a revie' of c*rrent diagnostic and treat+ent practices in relation to ne*ropsychologic o*tco+e( $aediatr Dr*gs 200&:)<&=:1210B( )1( #+erican #cade+y of $ediatrics ##$ %ection on Endocrinology and Co++ittee on Aenetics, and #+erican Thyroid #ssociation Co++ittee on $*6lic !ealth: -e'6orn screening for congenital hypothyroidis+: reco++ended g*idelines( $ediatrics 1BB&:B1</=:120&0B( )2( D*ssa*lt M!, Morissette M( !igher sensitivity of pri+ary thyrotropin in screening for congenital hypothyroidis+: a +ythY M Clin Endocrinol Meta6 1B1&:)/<2=:12B0)2( )&( La3ranchi %!, !anna CE, Krain; $L, %,eels MR, Miyahira R%, %esser DE( %creening for congenital hypothyroidis+ 'ith speci+en collection at t'o ti+e periods: res*lts of the -orth'est Regional %creening $rogra+( $ediatrics 1B1):5/<)=:5&2020( )2( Larson C, !er+os R, Delaney #, Daley D, Mitchell M( Ris, factors associated 'ith delayed thyrotropin elevations in congenital hypothyroidis+( M $ediatr 200&:12&<)=:)150B1( ))( $erry R, !einrichs C, "o*rdo*4 $, et al( Discordance of +ono;ygotic t'ins for thyroid dysgenesis: i+plications for screening and for +olec*lar pathophysiology( M Clin Endocrinol Meta6 2002:15<B=:205205( )/( Lanting C9, van Ti?n D#, Loe6er MA, N*ls+a T, de Ni?lder MM, Ner,er, $!( Clinical effectiveness and cost0effectiveness of the *se of the thyro4ine8thyro4ine06inding glo6*lin ratio to detect congenital hypothyroidis+ of thyroidal and central origin in a neonatal screening progra+( $ediatrics 200):11/<1=:1/105&( )5( van Ti?n D#, de Ni?lder MM, Ner6eeten ", Mr(, Ner,er, $!, N*ls+a T( -eonatal detection of congenital hypothyroidis+ of central origin( M Clin Endocrinol Meta6 200):B0</=:&&)00B( )56( -es6esio TD, McKenna M$, -a6han ZM et al( -e'6orn screening res*lts in children 'ith central hypothyroidis+( M $ediatr 2010:1)/:BB00&( )1( 3isher D#( Effectiveness of ne'6orn screening progra+s for congenital hypothyroidis+: prevalence of +issed cases( $ediatr Clin -orth #+ 1B15:&2<2=:1110B0( )B( #da+s LM, E+ery MR, Clar, %M, Carlton E9, -elson MC( Reference ranges for ne'er thyroid f*nction tests in pre+at*re infants( M $ediatr 1BB):12/<1=:12205( /0( %ie6ner R, Merlo6 $, Kaiser+an 9, %ac, M( Congenital ano+alies conco+itant 'ith persistent pri+ary congenital hypothyroidis+( #+ M Med Aenet 1BB2:22<1=:)50/0( /1( K*+ar M, Aordillo R, Kas,el 3M, Dr*schel CM, .oroniec,i R$( 9ncreased prevalence of renal and *rinary tract ano+alies in children 'ith congenital hypothyroidis+( M $ediatr 200B:1)2<2=:2/&0/( /2( 3ort $, Lifshit; 3, "ellisario R, et al( #6nor+alities of thyroid f*nction in infants 'ith Do'n syndro+e( M $ediatr 1B12:102<2=:)2)0B(

/&( Kr*de !, %ch*t; ", "ie6er+ann !, et al( Choreoathetosis, hypothyroidis+, and p*l+onary alterations d*e to h*+an -KQ201 haploins*fficiency( M Clin 9nvest 2002:10B<2=:25)010( /2( $erna MA, Civitareale D, De 3ilippis N, %acco M, Cisternino C, Tassi N( #6sence of +*tations in the gene encoding thyroid transcription factor01 <TT301= in patients 'ith thyroid dysgenesis( Thyroid 1BB5:5<&=:&55011( /)( Lapi $, Macchia $E, Chiovato L, et al( M*tations in the gene encoding thyroid transcription factor0 1 <TT301= are not a fre7*ent ca*se of congenital hypothyroidis+ <C!= 'ith thyroid dysgenesis( Thyroid 1BB5:5<&=:&1&05( //( Clifton0"ligh RM, .ent'orth MM, !ein; $, et al( M*tation of the gene encoding h*+an TT302 associated 'ith thyroid agenesis, cleft palate and choanal atresia( -at Aenet 1BB1:1B<2=:&BB0201( /5( "ro'n R%, De++er L#( The etiology of thyroid dysgenesis0still an enig+a after all these years( M Clin Endocrinol Meta6 2002:15<B=:20/B051( /1( Kopp $( $endred>s syndro+e: identification of the genetic defect a cent*ry after its recognition( Thyroid 1BBB:B<1=:/)0B( /B( %*nthornthepvara,*i T, Aottschal, ME, !ayashi I, Refetoff %( "rief report: resistance to thyrotropin ca*sed 6y +*tations in the thyrotropin0receptor gene( - Engl M Med 1BB):&&2<&=:1))0/0( 50( "ie6er+ann !, %chone6erg T, Kr*de !, %ch*lt; A, A*der+ann T, Ar*ters #( M*tations of the h*+an thyrotropin receptor gene ca*sing thyroid hypoplasia and persistent congenital hypothyroidis+( M Clin Endocrinol Meta6 1BB5:12<10=:&251010( 51( Aagne -, $ar+a M, Deal C, Nassart A, Nan Nliet A( #pparent congenital athyreosis contrasting 'ith nor+al plas+a thyroglo6*lin levels and associated 'ith inactivating +*tations in the thyrotropin receptor gene: are athyreosis and ectopic thyroid distinct entitiesY M Clin Endocrinol Meta6 1BB1:1&<)=:15510)( 52( %tein %#, @ates EL, !all CR, et al( 9dentification of a point +*tation in the thyrotropin receptor of the hyt8hyt hypothyroid +o*se( Mol Endocrinol 1BB2:1<2=:12B0&1( 5&( Kr*de !, "ie6er+ann !, Aopel ., Ar*ters #( The gene for the thyrotropin receptor <T%!R= as a candidate gene for congenital hypothyroidis+ 'ith thyroid dysgenesis( E4p Clin Endocrinol Dia6etes 1BB/:102 %*ppl 2:115020( 52( #hl6o+ "D, Ia7oo6 M, Larsson #, 9lic,i #, #nneren A, .adeli*s C( Aenetic and lin,age analysis of fa+ilial congenital hypothyroidis+: e4cl*sion of lin,age to the T%! receptor gene( !*+ Aenet 1BB5:BB<2=:11/0B0( 5)( Mordan -, .illia+s -, Aregory M., Evans C, @'en M, L*dgate M( The .)2/Q +*tation of the thyrotropin receptor gene: potential +a?or contri6*tor to thyroid dysf*nction in a Ca*casian pop*lation( M Clin Endocrinol Meta6 200&:11<&=:10020)( 5/( Levine M#, Map T%, !*ng .( 9nfantile hypothyroidis+ in t'o si6s: an *n*s*al presentation of pse*dohypoparathyroidis+ type 9a( M $ediatr 1B1):105</=:B1B022( 55( Coll* R, Tang M, Castagne M, et al( # novel +echanis+ for isolated central hypothyroidis+: inactivating +*tations in the thyrotropin0releasing hor+one receptor gene( M Clin Endocrinol Meta6 1BB5:12<)=:1)/10)( 51( "ro'n R%, "hatia N, !ayes E( #n apparent cl*ster of congenital hypopit*itaris+ in central Massach*setts: +agnetic resonance i+aging and hor+onal st*dies( M Clin Endocrinol Meta6 1BB1:52<1=:1201(

5B( Dattani ML, Martine;0"ar6era M, Tho+as $D, et al( Molec*lar genetics of septo0optic dysplasia( !or+ Res 2000:)& %*ppl 1:2/0&&( 10( Machinis K, $antel M, -etchine 9, et al( %yndro+ic short stat*re in patients 'ith a ger+line +*tation in the L9M ho+eo6o4 L!Q2( #+ M !*+ Aenet 2001:/B<)=:B/101( 11( $ar,s M%, "ro'n MR( Transcription factors reg*lating pit*itary develop+ent( Aro'th !or+ 9A3 Res 1BBB:B %*ppl ":201: disc*ssion 011( 12( D*+itresc* #M, Liao Q!, "est T", "roc,+ann K, Refetoff %( # novel syndro+e co+6ining thyroid and ne*rological a6nor+alities is associated 'ith +*tations in a +onocar6o4ylate transporter gene( #+ M !*+ Aenet 2002:52<1=:1/105)( 1&( .eiss RE, "al;ano %, %cher6erg -!, Refetoff %( -eonatal detection of generali;ed resistance to thyroid hor+one( Ma+a 1BB0:2/2<15=:222)0)0( 1&6( "och*,ova E, %choen+a,ers -, #gostini E, et al( # +*tation in the thyroid hor+one receptor alpha gene( - Engl M Med 2012:&//:22&0B( 12( D*+itresc* #M, Liao Q!, #6d*llah M%, et al( M*tations in %EC9%"$2 res*lt in a6nor+al thyroid hor+one +eta6olis+( -at Aenet 200):&5<11=:12250)2( 1)( l>#lle+and D, Ar*ters #, "eyer $, .e6er "( 9odine in contrast agents and s,in disinfectants is the +a?or ca*se for hypothyroidis+ in pre+at*re infants d*ring intensive care( !or+ Res 1B15:21<1=:220B( 1/( "ro'n R%, "loo+field %, "ednare, 3M, Mitchell ML, "raver+an LE( Ro*tine s,in cleansing 'ith povidone0iodine is not a co++on ca*se of transient neonatal hypothyroidis+ in -orth #+erica: a prospective controlled st*dy( Thyroid 1BB5:5<&=:&B)0200( 15( Cheron RA, Kaplan MM, Larsen $R, %elen,o' !#, Crigler M3, Mr( -eonatal thyroid f*nction after propylthio*racil therapy for +aternal Araves> disease( - Engl M Med 1B11:&02<B=:)2)01( 11( "ro'n R%, "ellisario RL, "otero D, et al( 9ncidence of transient congenital hypothyroidis+ d*e to +aternal thyrotropin receptor06loc,ing anti6odies in over one +illion 6a6ies( M Clin Endocrinol Meta6 1BB/:11<&=:11250)1( 1B( "ro'n R%, Keating $, Mitchell E( Maternal thyroid06loc,ing i++*noglo6*lins in congenital hypothyroidis+( M Clin Endocrinol Meta6 1BB0:50<)=:1&210/( B0( Connors M!, %tyne DM( Transient neonatal Jathyreosis> res*lting fro+ thyrotropin06inding inhi6itory i++*noglo6*lins( $ediatrics 1B1/:51<2=:2150B0( B1( Mits*da -, Ta+a,i !, #+ino -, !osono T, Miyai K, Tani;a'a @( Ris, factors for develop+ental disorders in infants 6orn to 'o+en 'ith Araves disease( @6stet Aynecol 1BB2:10<& $t 1=:&)B0/2( B2( Mandel %!, !anna CE, La3ranchi %!( Di+inished thyroid0sti+*lating hor+one secretion associated 'ith neonatal thyroto4icosis( M $ediatr 1B1/:10B<2=://20)( B&( De+ing DD, Ra6in C., !opper #@, $everini RL, Nyh+eister -R, -elson MC( Direct e7*ili6ri*+ dialysis co+pared 'ith t'o non0dialysis free T2 +ethods in pre+at*re infants( M $ediatr 2005:1)1<2=:20201( B2( .illia+s 3L, @gston %#, van Toor !, Nisser TM, !*+e R( %er*+ thyroid hor+ones in preter+ infants: associations 'ith postnatal illnesses and dr*g *sage( M Clin Endocrinol Meta6 200):B0<11=:)B)20/&( B)( Daliva #L, Linder ", DiMartino0-ardi M, %aenger $( Three0year follo'0*p of 6orderline congenital hypothyroidis+( M $ediatr 2000:1&/<1=:)&0/(

B/( Calaci*ra 3, Motta RM, Miscio A, et al( %*6clinical hypothyroidis+ in early childhood: a fre7*ent o*tco+e of transient neonatal hyperthyrotropine+ia( M Clin Endocrinol Meta6 2002:15<5=:&20B012( B5( Mi,i K, -ose @, Miyai K, Ia6**chi !, !arada T( Transient infantile hyperthyrotrophinae+ia( #rch Dis Child 1B1B:/2<1=:1155012( B1( C;ernicho' $, Nandale+ ML, !ennen A( Transient neonatal hyperthyrotropine+ia: a factitio*s syndro+e d*e to the presence of heterophilic anti6odies in the plas+a of infants and their +others( M Clin Endocrinol Meta6 1B11:)&<2=:&150B&( BB( %+ith D., Klein #M, !enderson MR, Myrianthopo*los -C( Congenital hypothyroidis+[signs and sy+pto+s in the ne'6orn period( M $ediatr 1B5):15</ $t 1=:B)10/2( 100( @hnishi !, %ato !, -oda !, 9no+ata !, %asa,i -( Color Doppler *ltrasonography: diagnosis of ectopic thyroid gland in patients 'ith congenital hypothyroidis+ ca*sed 6y thyroid dysgenesis( M Clin Endocrinol Meta6 200&:11<11=:)12)0B( 101( Mehta #, !ind+arsh $C, %tanhope RA, "rain CE, $reece M#, Dattani MT( 9s the thyrotropin0 releasing hor+one test necessary in the diagnosis of central hypothyroidis+ in children( M Clin Endocrinol Meta6 200&:11<12=:)/B/050&( 102( Mitchell ML, .alraven C, Ro?as D#, Mc9ntosh K3, !er+os RM( %creening very0lo'06irth'eight infants for congenital hypothyroidis+( Lancet 1BB2:&2&<1111=:/001( 10&( "ro'n R%, La3ranchi %, Rose %R( $atient infor+ation page fro+ the hor+one fo*ndation( Congenital hypothyroidis+( M Clin Endocrinol Meta6 200B:B2<)=:11&)0/( 102( %elva K#, Mandel %!, Rien L, et al( 9nitial treat+ent dose of L0thyro4ine in congenital hypothyroidis+( M $ediatr 2002:121</=:51/0B2( 10)( Tiosano D, Even L, %hen @rr Z, !och6erg Z( Reco+6inant thyrotropin in the diagnosis of congenital hypothyroidis+( M Clin Endocrinol Meta6 2005:B2<2=:12&205( 10/( .illia+s 3L, Nisser TM, !*+e R( Transient hypothyro4inae+ia in preter+ infants( Early !*+ Dev 200/:12<12=:5B50102( 105( van .assenaer #A, Ko, M!, de Ni?lder MM, et al( Effects of thyro4ine s*pple+entation on ne*rologic develop+ent in infants 6orn at less than &0 'ee,s> gestation( - Engl M Med 1BB5:&&/<1=:210 /( 101( van .assenaer #A, .estera M, !o*t;ager "#, Ko, M!( Ten0year follo'0*p of children 6orn at E&0 'ee,s> gestational age s*pple+ented 'ith thyro4ine in the neonatal period in a rando+i;ed, controlled trial( $ediatrics 200):11/<)=:e/1&01( 10B( %i+onea*0Roy M, Marti %, Deal C, !*ot C, Ro6aey $, Nan Nliet A( Cognition and 6ehavior at school entry in children 'ith congenital hypothyroidis+ treated early 'ith high0dose levothyro4ine( M $ediatr 2002:122</=:5250)2( 110( Rovet M3( 9n search of the opti+al therapy for congenital hypothyroidis+( M $ediatr 2002:122</=:/B10500( 111( Di+itropo*los #, Molinari L, Etter K, et al( Children 'ith congenital hypothyroidis+: long0ter+ intellect*al o*tco+e after early high0dose treat+ent( $ediatr Res 200B:/)<2=:22201( 112( 3isher D#( The i+portance of early +anage+ent in opti+i;ing 9D in infants 'ith congenital hypothyroidis+( M $ediatr 2000:1&/<&=:25&02( 11&( Za,ari?a M, McKen;ie MM( $regnancy0associated changes in the thyroid0sti+*lating anti6ody of

Araves> disease and the relationship to neonatal hyperthyroidis+( M Clin Endocrinol Meta6 1B1&:)5<)=:10&/020( 112( %,*;a K#, %ills 9-, %tene M, Rapaport R( $rediction of neonatal hyperthyroidis+ in infants 6orn to +others 'ith Araves disease( M $ediatr 1BB/:121<2=:2/201( 11)( 3ort $, Lifshit; 3, $*gliese M, Klein 9( -eonatal thyroid disease: differential e4pression in three s*ccessive offspring( M Clin Endocrinol Meta6 1B11://<&=:/2)05( 11/( Za,ari?a M, McKen;ie MM, M*nro D%( 9++*noglo6*lin A inhi6itor of thyroid0sti+*lating anti6ody is a ca*se of delay in the onset of neonatal Araves> disease( M Clin 9nvest 1B1&:52<2=:1&)20/( 115( Kohn LD, %*;*,i K, !off+an .!, et al( Characteri;ation of +onoclonal thyroid0sti+*lating and thyrotropin 6inding0inhi6iting a*toanti6odies fro+ a !ashi+oto>s patient 'hose children had intra*terine and neonatal thyroid disease( M Clin Endocrinol Meta6 1BB5:12<12=:&BB10200B( 111( -eal $R, Mansen RD, Le+ons M#, Mir,in LD, %chreiner RL( Un*s*al +anifestations of neonatal hyperthyroidis+( #+ M $erinatol 1B1):2<&=:2&10)( 11B( Dane+an D, !o'ard -M( -eonatal thyroto4icosis: intellect*al i+pair+ent and craniosynostosis in later years( M $ediatr 1B10:B5<2=:2)50B( 120( Mats**ra -, Konishi M, 3*?ieda K, et al( T%!0receptor anti6odies in +others 'ith Araves > disease and o*tco+e in their offspring( Lancet 1B11:1<1)5)0/=:1205( 121( Ta+a,i !, #+ino -, #o;asa M, et al( Universal predictive criteria for neonatal overt thyroto4icosis re7*iring treat+ent( #+ M $erinatol 1B11:)<2=:1)201( 122( Mats**ra -, !arada %, @hya+a I, et al( The +echanis+s of transient hypothyro4ine+ia in infants 6orn to +others 'ith Araves > disease( $ediatr Res 1BB5:22<2=:21201( 12&( Cooper D%, Riv,ees %#( $*tting propylthio*racil in perspective( M Clin Endocrinol Meta6 200B:B2</=:111102( 122( de Ro*4 -, $ola, M, Co*et M, et al( # neo+*tation of the thyroid0sti+*lating hor+one receptor in a severe neonatal hyperthyroidis+( M Clin Endocrinol Meta6 1BB/:11</=:202&0/( 12)( !ol;apfel !$, .onero' $, von $etry,o's,i ., !enschen M, %cher6a*+ .#, $asch,e R( %poradic congenital hyperthyroidis+ d*e to a spontaneo*s ger+line +*tation in the thyrotropin receptor gene( M Clin Endocrinol Meta6 1BB5:12<11=:&15B012( 12/( %ch'a6 K@, Aerlich M, "roec,er M, %ohle+ann $, Der'ahl M, Lohse MM( Constit*tively active ger+line +*tation of the thyrotropin receptor gene as a ca*se of congenital hyperthyroidis+( M $ediatr 1BB5:1&1</=:1BB0B02( 125( Kopp $, M*irhead %, Mo*rdain -, A* .Q, Ma+eson ML, Rodd C( Congenital hyperthyroidis+ ca*sed 6y a solitary to4ic adeno+a har6oring a novel so+atic +*tation <serine211[Fisole*cine= in the e4tracell*lar do+ain of the thyrotropin receptor( M Clin 9nvest 1BB5:100</=:1/&20B( 121( Ar*ters #, %chone6erg T, "ie6er+ann !, et al( %evere congenital hyperthyroidis+ ca*sed 6y a ger+0line neo +*tation in the e4tracell*lar portion of the thyrotropin receptor( M Clin Endocrinol Meta6 1BB1:1&<)=:12&10/( 12B( Davies T3( Really significant genes for a*toi++*ne thyroid disease do not e4ist[so ho' can 'e predict diseaseY Thyroid 2005:15<11=:10250B( 1&0( "ro'n R%( #*toi++*ne thyroid disease: *nloc,ing a co+ple4 p*;;le( C*rr @pin $ediatr 200B:21<2=:)2&01(

1&1( 3oley T$, Mr(, #66assi N, Copeland KC, Dra;nin M"( "rief report: hypothyroidis+ ca*sed 6y chronic a*toi++*ne thyroiditis in very yo*ng infants( - Engl M Med 1BB2:&&0<5=:2//01( 1&2( Ailani "", MacAillivray M!, Noorhess ML, Mills "M, Riley .M, MacLaren -K( Thyroid hor+one a6nor+alities at diagnosis of ins*lin0dependent dia6etes +ellit*s in children( M $ediatr 1B12:10)<2=:211022( 1&&( -e*feld M, Maclaren -, "li;;ard R( #*toi++*ne polygland*lar syndro+es( $ediatr #nn 1B10:B<2=:1)20/2( 1&2( "etterle C, Areggio -#, Nolpato M( Clinical revie' B&: #*toi++*ne polygland*lar syndro+e type 1( M Clin Endocrinol Meta6 1BB1:1&<2=:102B0))( 1&)( %cott !%, !eino M, $eterson $, et al( Co++on +*tations in a*toi++*ne polyendocrinopathy0 candidiasis0ectoder+al dystrophy patients of different origins( Mol Endocrinol 1BB1:12<1=:11120B( 1&)6( .ildin R%, %+y,0$earson %, 3ilipovich #!( Clinical and +olec*lar feat*res of the i++*nodysreg*lation, polyendocrinopathy, enteropathy, Q0lin,ed <9$EQ= syndro+e( M Med genet 2002: &B:)&502)( 1&/( Le;noff #, Mosse RA, Den6*rg M, Dolovich M( #ssociation of chronic *rticaria and angioede+a 'ith thyroid a*toi++*nity( #rch Der+atol 1B1&:11B<1=:/&/020( 1&5( @>Regan %, 3ong M%, Kaplan "%, Chadarevian M$, Lapointe -, Dr*++ond K-( Thyroid antigen0 anti6ody nephritis( Clin 9++*nol 9++*nopathol 1B5/:/<&=:&210/( 1& 1( 3eingold %", %+ith M, !o*t; M, et al( $revalence and f*nctional significance of thyrotropin <T%!= receptor 6loc,ing anti6odies in children and adolescents 'ith chronic ly+phocytic thyroiditis( M Clin Endocrinol Meta6 200B:B2: 252201( 1&B( "ro'n R%( 9++*noglo6*lins affecting thyroid gro'th: a contin*ing controversy( M Clin Endocrinol Meta6 1BB):10<)=:1)0/01( 120( Rallison ML, Do6yns "M, Keating 3R, Rall ME, Tyler 3!( @cc*rrence and nat*ral history of chronic ly+phocytic thyroiditis in childhood( M $ediatr 1B5):1/<)=:/5)012( 121( Maenpaa M, Raati,,a M, Rasanen M, Tas,inen E, .ager @( -at*ral co*rse of ?*venile a*toi++*ne thyroiditis( M $ediatr 1B1):105</=:1B10B02( 122( Moore DC( -at*ral co*rse of Js*6clinical> hypothyroidis+ in childhood and adolescence( #rch $ediatr #dolesc Med 1BB/:1)0<&=:2B&05( 12&( La;ar L, 3r*+,in R", "attat E, Le6enthal I, $hillip M, Meyerovitch M( -at*ral history of thyroid f*nction tests over ) years in a large pediatric cohort( M Clin Endocrinol Meta6 200B:B2<)=:1/51012( 122( %*r,s M9, %ievert R( Dr*gs and thyroid f*nction( - Engl M Med 1BB):&&&<2)=:1/110B2( 12)( McCo'en KC, Aar6er MR, %par, R( Elevated ser*+ thyrotropin in thyro4ine0treated patients 'ith hypothyroidis+ given sertraline( - Engl M Med 1BB5:&&5<12=:101001( 12/( Delange 3M( 9odine Deficiency( 9n: "raver+an LE, Utiger,R(D(, ed( .erner \ 9ng6ar>s The Thyroid( 1th ed( $hiladelphia: Lippincott .illia+s \ .il,ins: 2000( 125( $aca*d D, Nan Nliet A, Delvin E, et al( # Third .orld endocrine disease in a /0year0old -orth #+erican 6oy( M Clin Endocrinol Meta6 1BB):10<B=:2)520/( 121( Donadie* M, Rolon M#, Tho+as C, et al( Endocrine involve+ent in pediatric0onset Langerhans > cell histiocytosis: a pop*lation06ased st*dy( M $ediatr 2002:122<&=:&220)0(

12B( !*ang %#, T* !M, !arney M., et al( %evere hypothyroidis+ ca*sed 6y type & iodothyronine deiodinase in infantile he+angio+as( - Engl M Med 2000:&2&<&=:11)0B( 1)0( !a*ser $, Za+et,in #M, Martine; $, et al( #ttention deficit0hyperactivity disorder in people 'ith generali;ed resistance to thyroid hor+one( - Engl M Med 1BB&:&21<12=:BB501001( 1)1( "erc* "", @rloff %, %ch*l+an MD( $it*itary resistance to thyroid hor+one in cystinosis( M Clin Endocrinol Meta6 1B10:)1</=:12/201( 1)2( -a??ar %%( M*sc*lar hypertrophy in hypothyroid children: the Kocher0De6re0%e+elaigne syndro+e( # revie' of 2& cases( M $ediatr 1B52:1)<2=:2&/0B( 1)&( !op'ood -M, Loc,hart L!, "ryan AT( #c7*ired hypothyroidis+ 'ith +*sc*lar hypertrophy and precocio*s testic*lar enlarge+ent( M $ediatr 1B52:1)<2=:2&&0/( 1)2( #nasti M-, 3lac, MR, 3roehlich M, -elson LM, -is*la "C( # potential novel +echanis+ for precocio*s p*6erty in ?*venile hypothyroidis+( M Clin Endocrinol Meta6 1BB):10<1=:25/0B( 1))( #los -, !*ot C, La+6ert R, Nan Nliet A( Thyroid scintigraphy in children and adolescents 'ith !ashi+oto disease( M $ediatr 1BB):125</=:B)10&( 1)/( Rovet M3, Dane+an D, "ailey MD( $sychologic and psychoed*cational conse7*ences of thyro4ine therapy for ?*venile ac7*ired hypothyroidis+( M $ediatr 1BB&:122<2=:)2&0B( 1)5( Nan Dop C, Conte 3#, Koch TK, Clar, %M, .ilson0Davis %L, Ar*+6ach MM( $se*dot*+or cere6ri associated 'ith initiation of levothyro4ine therapy for ?*venile hypothyroidis+( - Engl M Med 1B1&:&01<11=:105/010( 1)1( %*r,s M9, @rti; E, Daniels A!, et al( %*6clinical thyroid disease: scientific revie' and g*idelines for diagnosis and +anage+ent( Ma+a 2002:2B1<2=:2210&1( 1)B( Lo+enic, M$, El0%ayyid M, %+ith .M( Effect of levo0thyro4ine treat+ent on 'eight and 6ody +ass inde4 in children 'ith ac7*ired hypothyroidis+( M $ediatr 2001:1)2<1=:B/0100( 1/0( Riv,ees %#, "ode !!, Cra'ford MD( Long0ter+ gro'th in ?*venile ac7*ired hypothyroidis+: the fail*re to achieve nor+al ad*lt stat*re( - Engl M Med 1B11:&11<10=:)BB0/02( 1/1( van der Aaag RD, Dre4hage !#, .iersinga .M, et al( 3*rther st*dies on thyroid gro'th0 sti+*lating i++*noglo6*lins in e*thyroid nonende+ic goiter( M Clin Endocrinol Meta6 1B1):/0<)=:B520B( 1/2( Rother K9, Zi++er+an D, %ch'en, .3( Effect of thyroid hor+one treat+ent on thyro+egaly in children and adolescents 'ith !ashi+oto disease( M $ediatr 1BB2:122<2=:)BB0/01( 1/&( %vensson M, Ericsson U", -ilsson $, et al( Levothyro4ine treat+ent red*ces thyroid si;e in children and adolescents 'ith chronic a*toi++*ne thyroiditis( M Clin Endocrinol Meta6 200/:B1<)=:152B0&2( 1/2( Mali N$, $ra6ha,aran K( Rec*rrent ac*te thyroid s'ellings 6eca*se of pyrifor+ sin*s fist*la( M $ediatr %*rg 2001:2&<2=:e250&0( 1/)( %h*l+an D9, M*har 9, Morgensen EN, Dia+ond 3", "erc* "", Root #.( #*toi++*ne hyperthyroidis+ in prep*6ertal children and adolescents: co+parison of clinical and 6ioche+ical feat*res at diagnosis and responses to +edical therapy( Thyroid 1BB5:5<)=:5))0/0( 1/)6( Leger M, Ael'ane A, Kag*elido* 3 et al( $ositive i+pact of long0ter+ antithyroid dr*g treat+ent on the o*tco+e of children 'ith Araves disease: nat*ral long0ter+ cohort st*dy( M Clin Endocrinol Meta6( 2012: B5:1100B(

1/)c( Kag*elido* 3, #l6erti C, Castanet M, et al( $redictors of a*toi++*ne hyperthyroidis+ relapse in children after discontin*ation of antithyroid dr*g treat+ent( M Clin Endocrinol Meta6 2001: B&: &1150 2/( 1//( %egni M, Leonardi E, Ma;;oncini ", $*carelli 9, $as7*ino #M( %pecial feat*res of Araves > disease in early childhood( Thyroid 1BBB:B<B=:15105( 1/5( Aoday0#rno #, Cerda0Esteva M, 3lores0Le0Ro*4 M#, Chillaron0Mordan MM, Corretger MM, Cano0 $ere; M3( !yperthyroidis+ in a pop*lation 'ith Do'n syndro+e <D%=( Clin Endocrinol <@4f= 200B:51<1=:11002( 1/1( Rapoport ", Cha;en6al, AD, Ma*+e MC, McLachlan %M( The thyrotropin <T%!= receptor: interaction 'ith T%! and a*toanti6odies( Endocr Rev 1BB1:1B</=:/5&051/( 1/B( %+ith "R, %anders M, 3*r+ania, M( T%! receptor anti6odies( Thyroid 2005:15<10=:B2&0&1( 150( %anders M, Evans M, $re+a'ardhana LD, et al( !*+an +onoclonal thyroid sti+*lating a*toanti6ody( Lancet 200&:&/2<B&51=:12/01( 151( %anders M, Mig*el R-, "olton M, et al( Molec*lar interactions 6et'een the T%! receptor and a Thyroid0sti+*lating +onoclonal a*toanti6ody( Thyroid 2005:15<1=:/BB050/( 152( Rapoport ", McLachlan %M( The thyrotropin receptor in Araves> disease( Thyroid 2005:15<10=:B11022( 15&( .illia+s RC, Mr(, Marshall -M, Kilpatric, K, et al( Kappa8la+6da i++*noglo6*lin distri6*tion in Araves> thyroid0sti+*lating anti6odies( %i+*ltaneo*s analysis of C la+6da gene poly+orphis+s( M Clin 9nvest 1B11:12<2=:1&0/012( 152( Misra M, Levits,y LL, Lee MM( Transient hyperthyroidis+ in an adolescent 'ith hydatidifor+ +ole( M $ediatr 2002:120<&=:&/20/( 15)( R*i; M, Ra?atanavin R, Io*ng R#, et al( 3a+ilial dysal6*+ine+ic hyperthyro4ine+ia: a syndro+e that can 6e conf*sed 'ith thyroto4icosis( - Engl M Med 1B12:&0/<11=:/&)0B( 15/( Mariotti %, Martino E, C*pini C, et al( Lo' ser*+ thyroglo6*lin as a cl*e to the diagnosis of thyroto4icosis factitia( - Engl M Med 1B12:&05<5=:21002( 155( Costagliola %, Morgenthaler -A, !oer+ann R, et al( %econd generation assay for thyrotropin receptor anti6odies has s*perior diagnostic sensitivity for Araves> disease( M Clin Endocrinol Meta6 1BBB:12<1=:B005( 151( "olton M, %anders M, @da I, et al( Meas*re+ent of thyroid0sti+*lating hor+one receptor a*toanti6odies 6y EL9%#( Clin Che+ 1BBB:2)<12=:221)05( 15B( %+ith "R, "olton M, Io*ng %, et al( # ne' assay for thyrotropin receptor a*toanti6odies( Thyroid 2002:12<10=:1&00)( 110( "otero D, "ro'n R%( "ioassay of thyrotropin receptor anti6odies 'ith Chinese ha+ster ovary cells transfected 'ith reco+6inant h*+an thyrotropin receptor: clinical *tility in children and adolescents 'ith Araves disease( M $ediatr 1BB1:1&2<2=:/1201( 111( Alaser -%, %tyne DM( $redicting the li,elihood of re+ission in children 'ith Araves> disease: a prospective, +*lticenter st*dy( $ediatrics 2001:121<&=:e21101( 112( Rahhal %-, E*gster E#( Thyroid sti+*lating i++*noglo6*lin is often negative in children 'ith Araves> disease( M $ediatr Endocrinol Meta6 2001:21<11=:101)01( 1126( Lytton %D, Kahaly AM( "ioassays for T%!0receptor a*toanti6odies: an *pdate( #*toi++*n Rev

2010: 10:11/022( 11&( 9chi,i I, #,ahoshi M, Ia+ashita -, et al( $ropylthio*racil0ind*ced severe hepatitis: a case report and revie' of the literat*re( M Aastroenterol 1BB1:&&<)=:5250)0( 112( R*sso M., Aalan,o M#, %hrestha R, 3ried M., .at,ins $( Liver transplantation for ac*te liver fail*re fro+ dr*g ind*ced liver in?*ry in the United %tates( Liver Transpl 2002:10<1=:101102&( 11)( Riv,ees %#, Mattison DR( Ending propylthio*racil0ind*ced liver fail*re in children( - Engl M Med 200B:&/0<1)=:1)520)( 11/( %+ith M, "ro'n R%( $ersistence of thyrotropin <T%!= receptor anti6odies in children and adolescents 'ith Araves> disease treated *sing antithyroid +edication( Thyroid 2005:15<11=:110&05( 115( 3en;i A, !ashi;*+e K, Ro*de6*sh C$, DeAroot LM( Changes in thyroid0sti+*lating i++*noglo6*lins d*ring antithyroid therapy( M Clin Endocrinol Meta6 1B5B:21<2=:)520/( 111( Teng C%, Ie*ng RT( Changes in thyroid0sti+*lating anti6ody activity in Araves> disease treated 'ith antithyroid dr*g and its relationship to relapse: a prospective st*dy( M Clin Endocrinol Meta6 1B10:)0<1=:12205( 11B( "liddal !, Kir,egaard C, %iers6ae,0-ielsen K, 3riis T( $rognostic val*e of thyrotrophin 6inding inhi6iting i++*noglo6*lins <T"99= in longter+ antithyroid treat+ent, 1&19 therapy given in co+6ination 'ith car6i+a;ole and in e*thyroid ophthal+opathy( #cta Endocrinol <Copenh= 1B11:B1<&=:&/20B( 1B0( Collen RM, Landa' EM, Kaplan %#, Lippe "M( Re+ission rates of children and adolescents 'ith thyroto4icosis treated 'ith antithyroid dr*gs( $ediatrics 1B10:/)<&=:))00/( 1B1( !ashi;*+e K, 9chi,a'a K, %a,*rai #, et al( #d+inistration of thyro4ine in treated Araves> disease( Effects on the level of anti6odies to thyroid0sti+*lating hor+one receptors and on the ris, of rec*rrence of hyperthyroidis+( - Engl M Med 1BB1:&22<12=:B250)&( 1B2( Mc9ver ", Rae $, "ec,ett A, .il,inson E, Aold #, Toft #( Lac, of effect of thyro4ine in patients 'ith Araves> hyperthyroidis+ 'ho are treated 'ith an antithyroid dr*g( - Engl M Med 1BB/:&&2<2=:22002( 1B&( Ta?iri M, -og*chi %, M*ra,a+i T, M*ra,a+i -( #ntithyroid dr*g0ind*ced agran*locytosis( The *sef*lness of ro*tine 'hite 6lood cell co*nt +onitoring( #rch 9ntern Med 1BB0:1)0<&=:/2102( 1B2( Riv,ees %#, %,lar C, 3ree+ar, M( Clinical revie' BB: The +anage+ent of Araves> disease in children, 'ith special e+phasis on radioiodine treat+ent( M Clin Endocrinol Meta6 1BB1:1&<11=:&5/50 5/( 1B)( -i,iforov I, Anepp DR, 3agin M#( Thyroid lesions in children and adolescents after the Cherno6yl disaster: i+plications for the st*dy of radiation t*+origenesis( M Clin Endocrinol Meta6 1BB/:11<1=:B012( 1B/( %her+an M, Tho+pson A", Lteif #, et al( %*rgical +anage+ent of Araves disease in childhood and adolescence: an instit*tional e4perience( %*rgery 200/:120</=:10)/0/1: disc*ssion /102( 1B5( !*ng ., #nderson KD, Chandra R%, et al( %olitary thyroid nod*les in 51 children and adolescents( M $ediatr %*rg 1BB2:25<11=:12050B( 1B1( %chl*+6erger M, De Nathaire 3, Travagli M$, et al( Differentiated thyroid carcino+a in childhood: long ter+ follo'0*p of 52 patients( M Clin Endocrinol Meta6 1B15:/)</=:10110B2( 1BB( 3lannery TK, Kir,land ML, Copeland KC, "ert*ch ##, Karaviti L$, "randt ML( $apillary thyroid

cancer: a pediatric perspective( $ediatrics 1BB/:B1<& $t 1=:2/20/( 200( Lair+ore TC, 3risella MM, .ells %#, Mr( Aenetic testing and early thyroidecto+y for inherited +ed*llary thyroid carcino+a( #nn Med 1BB/:21<)=:2010/( 201( %arne D, %chneider #"( E4ternal radiation and thyroid neoplasia( Endocrinol Meta6 Clin -orth #+ 1BB/:2)<1=:1110B)( 202( !ealy MC, %hafford E#, Re;ne, R!, et al( %onographic a6nor+alities of the thyroid gland follo'ing radiotherapy in s*rvivors of childhood !odg,in>s disease( "r M Radiol 1BB/:/B<12&=:/1502&( 20&( %o6er+an -, Leonidas MC, Cherric, 9, %chiff R, Karayalcin A( %onographic a6nor+alities of the thyroid gland in longter+ s*rvivors of !odg,in disease( $ediatr Radiol 1BB1:21<2=:2)00&( 202( Dina*er C#, "re*er C, Riv,ees %#( Differentiated thyroid cancer in children: diagnosis and +anage+ent( C*rr @pin @ncol 2001:20<1=:)B0/)( 2026( .ag*espac, %A, 3rancis A( 9nitial +anage+ent and follo' *p of differentiated thyroid cancer in children( M -atl Co+pr Canc -et' 2010: 1:121B0&00( 20)( Ahari6 !, Aoellner MR( 3ine0needle aspiration 6iopsy of thyroid nod*les( Endocr $ract 1BB):1</=:21005( 20/( Zi++er+an D, !ay 9D, Ao*gh 9R, et al( $apillary thyroid carcino+a in children and ad*lts: long0 ter+ follo'0*p of 10&B patients conservatively treated at one instit*tion d*ring three decades( %*rgery 1B11:102</=:11)50//( 205( Ladenson $., "raver+an LE, Ma;;aferri EL, et al( Co+parison of ad+inistration of reco+6inant h*+an thyrotropin 'ith 'ithdra'al of thyroid hor+one for radioactive iodine scanning in patients 'ith thyroid carcino+a( - Engl M Med 1BB5:&&5<1&=:1110B/( 201( .ohll, -, Cote AM, Evans D", Aoepfert !, @rdone; -A, Aagel R3( #pplication of genetic screening infor+ation to the +anage+ent of +ed*llary thyroid carcino+a and +*ltiple endocrine neoplasia type 2( Endocrinol Meta6 Clin -orth #+ 1BB/:2)<1=:102)( 20B( 3ogelfeld L, .iviott M", %hore03reed+an E, et al( Rec*rrence of thyroid nod*les after s*rgical re+oval in patients irradiated in childhood for 6enign conditions( - Engl M Med 1B1B:&20<1&=:1&)020(