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

$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. 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. have 6een detected in h*+an e+6ryonic coelo+ic fl*id as early as / 'ee.s <&0= ( These res*lts 'ere 'idely interpreted as s*pporting an i+portant role of +aternal thyr oid hor+one early in . 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.e the severe develop+ental delay associated 'ith *ntreated +aterno 0fetal hypothyroidis+ . 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. '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+. 'hen fetal thyroid hor+one levels are lo' <1B.e 6y the fet*s can also occ*r via fetal ingestion of a+niotic fl*id( . i+paired hearing. there is significant 6*l. 'hen the fet*s is hypothyro4ine+ic. s*ch as +aterno0fetal $@U131 deficiency <2/= and T%! receptor 6loc. significant develop+ental delay despite early and ade7*ate postnatal therapy has also 6een reported in other +odels of co+6ined +aternal0fetal hypothyroidis+.s gestation .hile the T2 concentrations in a+niotic fl*id appear +odest. tho*gh the difference fro+ nor+al 'as not statistically significant <2B= ( 9n s*pport of this o6servation. the net fl*4 of T2 fro+ +other to fet*s is relatively li+ited( !o'ever. pres*+a6ly of +aternal origin.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.e of thyroid hor+one fro+ the a+niotic fl*id thro*gh the i++at*re epider+is( T2 *pta. indicating that the +achinery to convert T2 to T& and to respond to T& is present( 9t see+s li. 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 prior to the onset of fetal thyroid f*nction( 3*rther+ore. a res*lt first noted 6y Man <21= ( Unli.ely that 'hen fetal thyroid f*nction is nor+al.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. 22= ( Lo' concentrations of T2. 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.s gestation and in fetal 6rain as early 10 'ee.ened 'ith the recognition that in infants 'ith the congenital a6sence of thyroid pero4idase.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.e T2.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. 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.

Li* et al . the placenta is freely per+ea6le to TR! and to iodide <1)= ( The placenta is also per+ea6le to certain dr*gs. the Infant. 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. hor+ones and to i++*noglo6*lins <9gs= of the 9gA class( Th*s.ing anti6odies <&1c= (Recently a large prospective rando+i. reaching concentrations as high as /0 to 50 +U8L <1= ( This ca*ses a +ar. indicating the a6sence of any transplacental passage of this large protein( Thyroid (unction in the )eonate. 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.ed controlled trial failed to de+onstrate any 6enefit of L0thyro4ine treat+ent given to hypothyroid +others fro+ the 1& th 'ee. the ad+inistration to the +other of e4cess iodide.ole=. decreasing thereafter( The T& concentration rises stri.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. Tg is *ndetecta6le in the ser*+ of athyreotic infants.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 . TS'.ingly at Day 5. and +ore recently. dr*gs <especially propylthio*racil or +ethi+a. free T2 and T"A re+ain elevated over cord levels at 5 days of postnatal life <3ig*re &=.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. 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. and to other #s noted. 'hile a significant portion of the . of gestation on the cognitive f*nction of the offspring at & years of age <&2= ( #nother large rando+i. 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+. &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. a position that has 6een endorsed 6y so+e 6*t not other professional societies %lacental "er ea!ility to factors aternal TR'. and During Childhood The full#ter neonate Mar.pregnancy o n fetal 6rain develop+ent( #t variance 'ith the afore+entioned st*dies.

the circ*lating T2 concentration +ay not increase and +ay even fall in the first 1 to 2 'ee. 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 < &). in 'ho+ the ser*+ T2 +ay occasionally 6e *ndetecta6le( 9n +ost cases. 6*t the +agnit*de of the increase is less in pre+at*re neonates <1= 9n infants E&1 'ee. 'hile rT& and T%! decline( The increase in T2 and free T2 is 6l*nted in infants E&) 'ee.s. there is a s*rge in T2 and T%! analogo*s to that o6served in ter+ infants.ed increase in T& fro+ its lo' 6asal levels in cord ser*+ can 6e e4plained 6y the a6r*pt increase in T%!. T"A. of life( T& also rises stri. free T2.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. free T2 and T"A in the f*ll ter+ infant in the first 'ee. rT& and T%! according to gestational age( -ote the increase in T2. 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.s of life <&5=<3ig*re 2=( This decrease in the T2 concentration is partic*larly significant in very pre+at*re infants.ingly. and not seen at all in very pre+at*re infants in 'ho+ thyroid hor+one levels +ay act*ally decline( <Redra'n fro+ . 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.+ar. the total T2 is +ore affected than the free T2 <&1=. preter+ 6a6ies have decreased thyroidal . T&.s. &/ =( %re ature infants Thyroid f*nction in the pre+at*re infant reflects. in part.

there is an increase in sensitivity to the thyroid0s*ppressive effects of e4cess iodide fo*nd in certain s. and they +ay 6e treated 6y dr*gs that affect neonatal thyroid f*nction <partic*larly dopa+ine and steroids=( 9n addition. given the relative i++at*rity of the thyroid gland. <1() . 'ith . et al fo*nd. partic*larly in those 'ho are sic.illia+s et al(10%ee te4t for details= %o+e'hat s*rprisingly. for e4a+ple. infants 'as 10fold higher and in lo' 6irth 'eight.g=. transient elevations in T%! are seen.er than their +ore +at*re co*nterparts. since the capacity of the i++at*re thyroid to adapt to e4ogeno*s iodide is red*ced. are less a6le to reg*late iodide 6alance.iodide stores <&B= <a pro6le+ of partic*lar significance in 6orderline iodine0deficient areas of the 'orld=. 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.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. T&.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%=. <E1() . T"A. <Redra'n fro+ . the finding of a T%! concentration F20 +U8L 6eing +ore fre7*ent the greater the degree of pre+at*rity( 3ran.g02() . i(e(. very pre+at*re.hereas in so+e cases. that the prevalence of a T%! concentration F20 +U8L in very lo' 6irth 'eight. the T%! concentration is not significantly elevated in +ost of these infants( 9n so+e 6a6ies. 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. they are fre7*ently sic. ser*+ Tg concentrations are higher in the pre+at*re than in the f*ll ter+ infant <21=. an elevated T%! concentration +ay reflect tr*e pri+ary hypothyroidis+.g= neonates 20fold higher than the prevalence in ter+ 6a6ies <20=( . 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.

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 . ' 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.g8day( The si.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.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. it is li. T& and T%! d*ring infancy and childhood <2&= ( Io*nger children tend to have slightly higher ser*+ concentrations of T& and T%!.respiratory distress syndro+e 9n vie' of the atten*ated postnatal T%! rise in the latter 6a6ies.)00= <22= ( . it 'as not *ntil the 1B50 > that the i+portance of early treat+ent in di+inishing the ne*ro0psychological a6nor+alities of congenital . free T2.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. the si. despite the de+onstration 6y M*rray in 11B1 that thyroid e4tract co*ld a+eliorate +any of the feat*res of *ntreated cretinis+. an incidence of 6et'een 1 in &000 and 1 in 2000 infants 'orld'ide 'as o6tained.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.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.g per day decreasing slo'ly over the first fe' years of life to a6o*t 2 to & +cg8.edly higher T2 t*rnover in this age gro*p relative to that in the ad*lt( 9n infants. 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.orld'ide. the c*rrent esti+ate is even higher < F1 in 2. and Tho+as C*rling first descri6ed sporadic nongoitro*s hypothyroidis+ in 11)0( !o'ever. T2 prod*ction rates are esti+ated to 6e on the order of ) to / +cg8.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. 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 .e of a6o*t 1) to 20 g( 9n general.

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. 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. 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.ely to have per+anent congenital hypothyroidis+ and are recalled i++ediately <)1= ( @n the other hand. prefera6ly 'ithin the first fe' days of life: &= at that age. the +ean 9D of the early treated gro*p 6eing 1B.hereas initially a c*toff of the &rd percentile <T2 E/ +cg8dL or 55 n+ol8L= 'as e+ployed. 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. 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. still favored in +*ch of -orth #+erica and the -etherlands.ed nations and are *nder develop+ent in +any other parts of the 'orld( 9t has 6een esti+ated that as of 1BBB.eton*ria for 'hich screening progra+s 'ere initially developed=: 2= to prevent +ental retardation. as s*++ari. 6a6ies 'hose initial T%! is F)0 . 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).ed on the sa+e 6lood spot in those speci+ens in 'hich the T2 concentration is lo'( . 6*t non0instit*tionali. 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. 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. cheap effective treat+ent are availa6le: and /= the 6enefit0cost ratio is highly favora6le <appro4i+ately 1081. T2 is +eas*red initially 'hile T%! is chec. the diagnosis +*st 6e +ade early. 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+.*p T%! +ethod. specific screening tests and )= si+ple. co+pared 'ith an 9D of )2 in those treated late <2)=( Unfort*nately. 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. +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+. 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. clinical recognition is diffic*lt if not i+possi6le: 2= sensitive.ed. ne'6orn screening progra+s have 6een introd*ced thro*gho*t the ind*striali. person= <25= ( %ince the develop+ent of the first pilot screening progra+ for the detection of congenital hypothyroidis+ in D*e6ec in 1B52. favored in +ost parts of E*rope and Mapan.*p T%! +ethod. the eradication of +ental retardation.hypothyroidis+ 'as de+onstrated convincingly( 9n a st*dy 6y Klein et al.ed 6y Delange.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. the +ain o6?ective of screening.

6a6ies 'ith a lo' ser*+ T2 level 6*t delayed rise in the T%! concentration.s of age <)&= ( 9n addition.eton*ria <1 in 11. in addition to a pri+ary T2 86ac. 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. ho'ever. 6*t 'ill +iss secondary or tertiary hypothyroidis+.000 =. 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.000= si+ilar to that of phenyl. of delayed T%! rise are 6a6ies 'ith cardiovasc*lar ano+alies. a delayed T%! rise. in so+e of these cases. or represents transient hypothyroidis+. 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( . 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. on the other hand. 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. secondary or tertiary hypothyroidis+. 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. patients 'ith Do'n syndro+e and +ono. 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. 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. T"A deficiency and hyperthyro4ine+ia: this approach +ay.*p T%! approach. +iss s*6clinical hypothyroidis+ ( # pri+ary T%! strategy. +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.*p T%! progra+ 'ill detect overt pri+ary hypothyroidis+. '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.ely to have per+anent congenital hypothyroidis+ 'hile a T%! 6et'een 20 and 2B +U8L is fre7*ently a false positive. the presence of congenital hypothyroidis+( # f*rther refine+ent in screening is one e+ployed 6y the -etherlands 'here.+U8L are +ost li.ygotic t'ins <))= ( 9n the latter gro*p of infants. of delayed T%! elevation. e*thyroid syndro+e( @ther gro*ps at high0ris. and i n vie' of an apparent fre7*ency <1 in 1/. 'ill detect 6oth overt and s*6clinical hypothyroidis+. 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. a disorder associated 'ith high +or6idity and +ortality for 'hich effective treat+ent e4ists <)5=. 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. fetal cord +i4ing +ay occ*r and initially +as.

d*e. 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. the screening strategy *tili. the infant sho*ld al'ays 6e tested <3ig*re )=( %i+ilarly. ho'ever. 12 = and nor+al ser*+ levels of free T2 and T%! in the first 'ee. 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+. free T2.ed( This can occ*r d*e to poor co++*nication. in part. depending on the specific assays *sed( . T&. 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. of receipt of re7*ested speci+ens. Canada and so+e states in the United %tates have s'itched to a pri+ary T%! progra+( 9n practice. reverse T&. lac.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. ad*lt nor+ative val*es. 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&. non0radioisotopic T%! assays. 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. early discharge increases the n*+6er of false positive res*lts( 9n California.Recently 'ith the develop+ent of +ore sensitive. T"A. 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. 'hichever screening progra+ is *tili. tho*gh it sho*ld 6e noted that precise val*es +ay vary so+e'hat. 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. of life <)B= have also 6een p*6lished. provided 6y +any general hospital la6oratories. the ratio of false positive to confir+ed congenital hypothyroidis+ has increased fro+ 2():1 to appro4i+ately ):1. as is o6vio*s fro+ the disc*ssion earlier in the chapter. 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. they increase the n*+6er of T2 assays in a pri+ary T%! progra+ 6y BC <20= ( %i+ilarly. 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.

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 .

l*ng.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. 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. and fore6rain develop+ent in +ice 'ith a targeted disr*ption of this gene </&= ( 9n contrast. 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. and develop+ental delay has 6een fo*nd in a n*+6er of patients 'ith genetic a6nor+alities of NKX 2(1. the syndro+e of congenital hypothyroidis+ associated 'ith *ne4plained neonatal respiratory distress. the +a?ority <1) to B0C= of cases of per+anent congenital hypothyroidis+ in -orth #+erica. analogo*s to the findings of a6nor+al thyroid. /) =( # si+ilar sit*ation has 6een fo*nd 'ith FOXE 1 < TTF 2=.es .( %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. <ectopy=( 3e+ales are affected t'ice as often as +ales( 9n the United %tates. a +*tation 'hich has 6een reported in 2 si6lings 'ith the co+6ination of thyroid agenesis. no ger+line +*tations in NKX 2(1 gene 'ere fo*nd in a total of 5/ patients 'ith isolated C! < /2. in +ost cases the ca*se is *n. epigenetic +odifications. 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=.1 % 1271& #DP TTF2$FOXE1 % B722 #RPP .no'n +olec*lar defects in transcription factors and other ca*ses of congenital hypothyroidis+( Ta!le . cleft palate. a6nor+alities in these genes have 6een fo*nd in only a s+all proportion of affected patients. thyroid dysgenesis. FOXE 1 < TTF 2= and PAX 1 'o*ld appear to 6e o6vio*s candidate genes in vie' of their i+portant role in thyroid organogenesis and in thyroid0specific gene e4pression( To date.of ne'6orn screening and +oved to the United %tates shortly thereafter( -ote the d*ll facies.gro*nd </5= ( #lternately. Aenetic ca*ses of per+anent congenital hypothyroidis+( A!nor ality Gene Gene locus Inheritance Abnormal thyroid land d!"!lo#m!nt$mi ration O TTF1$NKX2. *s*ally in association 'ith other develop+ental a6nor+alities( 3or e4a+ple.y hair and choanal atresia <//= ( 9n a different st*dy. early so+atic +*tations or stochastic develop+ental events +ay play a role( Ta6le 1( s*++ari. ata4ia. ho'ever. pit*itary.ard. spi. 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.e in iodine0deficient areas of the 'orld 'here ende+ic cretinis+ contin*es to 6e a +a?or health ha.no'n( The occasional fa+ilial occ*rrence. . . 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. perior6ital ede+a and large tong*e( Causes of %er anent Congenital 'y"othyroidis Thyroid Dysgenesis Unli.

and )= a6nor+al iodotyrosine deiodinase activity </1= ( The association of an organification defect 'ith sensorine*ral deafness is . that a +olec*lar 6asis has no' 6een identified in all of the+( .-2. &= defective organification of iodide d*e to an a6nor+ality in the pero4idase en.y+e or in the !2@2 generating syste+. P#D. consistent 'ith a single gene a6nor+ality( 9t is not s*rprising.no'n as $endred syndro+e( Tho*gh *s*ally incl*ded in ca*ses of congenital hypothyroidis+ 6eca*se it is ca*sed 6y a genetic defect.PAX8 Abnormal&thyroid&hormono !n!'i' Decreased T2 synthesis N(S TPO )*OX2 + TG )EHA.#D #R #R )7 &p11 B7&2(& 172) &p21(20p21(2 &p 127&1 1p1& 127&1 2071&(2 #R #R.ed SE-(SBP2 B722(2 #R O*s*ally sporadic.A/$P)S Decreased T%! synthesis @ther pit*itary hor+one deficits P0OP1 PO*1F1 . these in6orn errors of thyroid hor+onogenesis are co++only associated 'ith an a*toso+al recessive for+ of inheritance.HX/ HESX1 9solated decreasedT%! T0H T0H0 TSH 1 Decreased T%! response TSH0 G' 2 Abnormal&thyroid&hormon!&a3tion 2711(2 #D 1Bp1201&(2 2p2) 1)71)(& 1722 /72202) 57&1 #R #R #R #R. therefore. % 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. PP #R.e thyroid dysgenesis.#D #R #R. a*toso+al do+inant. a sporadic condition.#D #R. a*toso+al recessive. $endred syndro+e rarely presents in the ne'6orn period( Unli. 2= defective Tg synthesis or transport.HX3 .ed and incl*de: 1= decreased T%! responsiveness.1 S. 2= fail*re to concentrate iodide.#D #R #R #R #R #D T0 1 &p22(& #D 4-T8 Q71&(2 Q0lin.

T$@ . inactivating +*tations of the T%! receptor gene 'ere fo*nd in only 1 of 100 patients 'ith congenital hypothyroidis+.-2. 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. +ost 6a6ies 'ith T%! resistance have a nor+al or hypoplastic. 50 =: in rare cases no thyroid gland at all is discerni6le on thyroid i+aging.no'n( 9n one st*dy. analogo*s to the hyt8hyt +o*se <52= ( 9n a fe' affected infants. 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 .1 =( $endred syndro+e is no' .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. 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+. 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= . e*topic gland that +ay in so+e cases +i+ic an a6nor+ality of thyroid gland develop+ent < /B. have 6een sho'n to ca*se 6oth transient and per+anent for+s of congenital hypothyroidis+. the sodi*+0iodide sy+porter < N(S =. 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 .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. 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.or Tertiary 'y"othyroidis Central hypothyroidis+ 'as previo*sly tho*ght to occ*r in 1 in )0. 6*t. as noted previo*sly.000 to 1 in 100. depending *pon 'hether the +*tation is +onoallelic or 6iallelic( 9n6orn errors of thyroid hor+onogenesis are s*++ari. a recent st*dy s*ggests that +*tations in this gene +ay 6e +ore co++on. 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. 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. '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 . and iodotyrosine deiodinase < )EHA.e at 6irth and this feat*re for+s the 6asis for the clinical distinction fro+ thyroid dysgenesis( 9n contrast. no' called S.A 2=. d*al o4idase <DU@Q= 2. Tg.00 0 ne'6orn infants.no'n to 6e ca*sed 6y +*tations in the pendrin gene < P)S . a pict*re indisting*isha6le fro+ thyroid agenesis <51=( %i+ilar to the varia6ility o6served in thyroid gland si.These incl*de defects in the genes for the T%! receptor < TSH0 =. i+portant in hydrogen pero4ide generation.e in this condition.

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 . septo0optic dysplasia. a ho+eodo+ain protein that is e4pressed 6riefly in the e+6ryonic pit*itary.ygo*s nonsense +*tation in the gene encoding TR alpha has 6een descri6ed <1&6=( 9n this patient.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. e7*ivalent to appro4i+ately 10C of all cases of congenital . the original esti+ate 'as 1 in 20.000 infants.ygo*s +*tation in SE-(SBP 2. spastic 7*adriplegia. is *s*ally diagnosed later in life. 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.a6nor+al +idline facial and 6rain str*ct*res <partic*larly cleft lip and palate.HX3 < 10= . 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.e and hearing <12= ( !etero. adverse effects on gro'th and s. have attention deficit disorder. have 6een associated 'ith +ale0 li+ited hypothyroidis+ and severe ne*rological a6nor+alities. 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. 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 classical ca*se of inade7*ate T2 action. . 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. lactotrophs and so+atotrophs 'hile P0OP 1. located on the Q0chro+oso+e. incl*ding glo6al develop+ental delay.ed: inade7*ate intracell*lar T2 transport. central hypotonia.ed resistance to thyroid hor+one <ART!=.e into 6rain cells is a ne'ly recogni.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 fe+ales had a +ilder thyroid phenotype and no ne*rological defects( ii+ Thyroid 'or one Resistance Aenerali. rotary nystag+*s and i+paired ga.ed congenital a6nor+ality of thyroid hor+one action( 9n this syndro+e +*tations in the +onocar6o4ylate transporter 1 < 4-T 1 gene. the only .HX/7 PO*1F 1 <11= or P0OP 1 <11= ( PO*1F 1 <$it01 in +ice= is essential for the differentiation of 6oth thyrotrophs. 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. dystonia.

for e4a+ple. the hypothala+ic0pit*itary0thyroid a4is. incl*ding increased s. an iodine0s*fficient region < 25=( 9n "elgi*+. povidone0iodine= *sed for s. 6*t 6eca*se of i++at*rity in 6oth the capacity for thyroid hor+onogenesis. transient hypothyroidis+ 'as reported in 20C of pre+at*re infants. 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. iodine0ind*ced transient hypothyroidis+ has not 6een doc*+ented fre7*ently in -orth #+erica < 1/=( . in so+e cases the ca*se is *n. 'hether ad+inistered to the +other d*ring pregnancy. potassi*+ iodide. e*thyroid syndro+e Maln*trition T"A deficiency 9n addition to iodine deficiency. at least in part.in a6sorption are also li. pro6a6ly d*e. recovery fro+ the thyroid0 s*ppressive effect of iodine does not +at*re 6efore &/ 'ee.000= < 22=.hypothyroidis+( Recent data s*ggest that the condition is no' +ore than three0fold +ore co++on <1 in 11. radiocontrast agents and antiseptic sol*tions <e(g(. prior to the instit*tion of ro*tine iodine s*pple+entation in pre+at*re infants. in part 6eca*se.s gestation: ho'ever.000 to 1 in 12. 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. lactation or directly to the 6a6y < 1)=( This occ*rs. and in the a6ility to convert T2 to the +ore +eta6olically active T& ( 3*rther+ore.s gestation= Dr*gs Miscellaneous 9solated hyperthyrotropine+ia %ic.in cleansing or vaginal do*ches( 9n contrast to E*rope.ing anti6odies are the +ost co++on ca*ses of transient hypothyroidis+.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+ $re+at*rity <partic*larly E25 'ee. iodine e4cess.ely to play a role( Reported so*rces of iodine have incl*ded dr*gs <e(g(.no'n( i+ Iodine Deficiency or -$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. 6oth the fet*s and ne'6orn infant are sensitive to the thyroid0 s*ppressive effects of e4cess iodine. a+iodarone=. dr*gs and +aternal T%! receptor 6loc. other factors. as noted earlier. pre+at*re infants are in negative iodine 6alance for the first 1 or 2 'ee.

hereas a 6iallelic +*tation in DU@Q2 is associated 'ith per+anent congenital hypothyroidis+.ole.ed in their infants < 1B=( Unli. 'hen a +onoallelic +*tation is fo*nd the co*rse of the congenital hypothyroidis+ is transient( Ta!le 1.e T%! receptor sti+*lating anti6odies that +i+ic the action of T%!.ing #6 %everity of C! R to RRRR R to RRRR $alpa6le thyroid -o -o 12&9 *pta.ing anti6odies inhi6it 6oth the 6inding and action of T%! <see 6elo'=( "eca*se T%!0ind*ced gro'th is 6loc. a pop*lation of anti6odies closely related to the T%! receptor sti+*lating anti6odies in Araves disease.inganti6ody0ind*ced Congenital !ypothyroidis+( Dysgenesis "loc.ed. MM9= for the treat+ent of Araves > disease( Even +aternal $TU doses of 200 +g or less have 6een associated 'ith an effect on neonatal thyroid f*nction.e +ay res*lt in a +isdiagnosis of thyroid agenesis < B0=( Us*ally the hypothyroidis+ resolves in & or 2 +onths( "a6ies 'ith T%! receptor 6loc.ing anti6odies +ost often are fo*nd in +others 'ho have 6een treated previo*sly for Araves disease or 'ho have the non goitro*s for+ of chronic ly+phocytic thyroiditis <pri+ary +y4ede+a=( @ccasionally these +others are not a'are that they are hypothyroid and the diagnosis is +ade in the+ only after congenital hypothyroidis+ has 6een recogni. -o 8!' T$@ #6s Naria6le Naria6le T%! Receptor #6s #6sent Pot!nt .ii+ Maternal Antithyroid Medication Transient neonatal hypothyroidis+ +ay develop in 6a6ies 'hose +others are 6eing treated 'ith antithyroid +edication <either propylthio*racil. +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.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 / .000 < 11=( T%! receptor 6loc. 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.Clinical feat*res of thyroid dysgenesis vers*s T%! receptor 6loc. these 6a6ies do not have a goiter( %i+ilarly. 6a6ies 'ith +aternal 6loc.ing anti6odies. 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. inhi6ition of T%!0ind*ced radioactive iodine *pta. $TU or +ethi+a. 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.e -one to lo' -one to nor+al Clinical Co*rse $er+anent Tran'i!nt 3a+ilial ris. 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.

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 . 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=. 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 . 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. 6*t also a+inophylline. and +*tations in thyropero4idase and T%! receptor genes than do controls < B/=. 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. pre+at*re infants fre7*ently have T"A deficiency d*e to 6oth i++at*re liver f*nction and *ndern*trition.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. antithyroid anti6odies.$rognosis -or+al 4ay&b!&d!lay!d Transient Central 'y"othyroidis i+ Maternal hy"erthyroidis @ccasionally. a transient condition. 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. and the cold0ind*ced T%! s*rge o6served postnatally( %everal years ago. 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.no'n agents s*ch as steroids and dopa+ine. caffeine and dia+orphine. and they +ay have G sic.

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. +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. *s*ally 2) +cCi. 'hen present. is *s*ally preferred 6eca*se of the greater sensitivity and 6eca*se. of radiation e4pos*re.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. *ltrasonography has 6eco+e an . gestation longer than 22 'ee.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. delayed passage of stools. if diagnosis is delayed. *nli. 6a6ies 'ith athyreosis or a co+plete 6loc. partic*larly pre+at*re infants. 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.e( !o'ever.sit*ation of co+6ined +aternal0fetal hypothyroidis+( Many of the classic feat*res <large tong*e. are s*6tle and develop only 'ith the passage of ti+e( 9n addition to the afore+entioned findings. 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.e and trapping a6ility of the thyroid gland: ectopic thyroid glands. 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. feeding diffic*lties. in thyroid hor+onogenesis tend to have +ore signs and sy+pto+s at 6irth than infants 'ith an ectopic thyroid. hypother+ia or respiratory distress in an infant 'eighing over 2() . sho*ld 6e *sed( #dvantages of pertechnetate.no'n ris. hypotonia. 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. the e4tent of the clinical findings depends on the ca*se. if availa6le. *+6ilical hernia. 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. facial p*ffiness. si. nonspecific signs that sho*ld s*ggest the diagnosis of neonatal hypothyroidis+ incl*de: prolonged. on the other hand.e on scintiscan. and8or the ser*+ T%! concentration is F&0 +U8L( 9f there is no *pta.e ac7*ired hypothyroidis+. 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.e pertechnetate is organified( Therefore. +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 in centers 'here only 1&1 09 is *sed and relatively large doses of isotope are ad+inistered( $artly for this reason.s. cold hands and feet and lethargy=. *ncon?*gated hyper6ilir*6ine+ia. hoarse cry. +ottling. the +ost co++on ca*se of congenital hypothyroidis+( Unli. i+aging 'ith this isotope allo's 7*antitative *pta. 12&9. fre7*ently s*6ling*al. 6a6ies 'ith congenital hypothyroidis+ are of nor+al si.

ing activity is e4tre+ely potent. or 6orderline res*lt sho*ld ca*se a reconsideration of this diagnosis( %i+ilarly. the 6loc. apparent thyroid agenesis is d*e to the presence of +aternal T%! receptor 6loc. if present in a s*fficiently high titer. half0+a4i+al T%! 6inding0inhi6ition 6eing reported 'ith as little as a 1820 to 18)0 dil*tion of ser*+: a 'ea. Tg is *ndetecta6le in +ost patients 'ith thyroid agenesis.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+. and so.ing anti6odies.e and location of the thyroid gland 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=( . 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.increasingly pop*lar alternative to thyroid scintigraphy to provide infor+ation a6o*t the si. color Doppler *ltrasonography 'as al+ost as good as scintiscan. 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. so interpretation of the res*lts needs to 6e co+6ined 'ith other infor+ation. or an iodide concentrating a6nor+ality( $otential cl*es to the diagnosis of a loss of f*nction +*tation of the T%! receptor incl*de a nor+al Tg and8or evidence of a thyroid gland on *ltraso*nd e4a+ination despite the fail*re to vis*ali.no'n and sho*ld not 6e relied *pon( # radio0receptor or EL9%# assay is appropriate for screening: a co++ercial 6ioassay for 6loc. T$@ anti6odies. 'hich. a finding that needs to 6e confir+ed < 100=( @ccasionally. 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 . thyroid *ltraso*nd reveals the presence of a nor+al or s+all. altho*gh fre7*ently detecta6le in 6a6ies 'ith 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+. co+pletely inhi6it T%!0ind*ced thyroidal *pta.e of radioisotope <B0= ( 9n these cases. iodine e4cess. 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. e(g(.ing anti6ody0ind*ced 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. the ser*+ Tg concentration( 9n one report. 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.

fre7*ently is not as lo' as the total T2( 9n the latter infants T2 <and8or free T2=. 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+. has 6een 7*estioned < 101=( 9n any case.9n 6a6ies in 'ho+ hypothyro4ine+ia *nacco+panied 6y T%! elevation is fo*nd.g is generally reco++ended so as to nor+ali. a free T2 sho*ld 6e +eas*red. 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.s *ntil the T2 nor+ali. the free T2 'hen +eas*red 6y a direct dialysis +ethod. TR! is no longer availa6le for testing in the U%( 9n pre+at*re. therapy sho*ld 6e 6eg*n i++ediately 'itho*t 'aiting for the res*lts of the confir+atory ser*+( #s noted a6ove. *sed for +any years to disting*ish 6et'een a hypothala+ic or pit*itary defect. and T%! sho*ld 6e repeated every 2 to 2 'ee. lo' 6irth 'eight or sic. 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+( Thera"y 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(.g. e7*ivalent to )0 +cg in a f*ll ter+ 6a6y= +ay 6e even 6etter < 102=( "a6ies 'ith +ild . 6a6ies in 'ho+ a lo' T2 and a J nor+al > T%! are fo*nd. T2 E) +cg8dL /2 n+ol8L= and8or T%! F)0 +U8L=. 102 =( %i+ilarly.es 6eca*se of the rare occ*rrence of delayed T%! rise < )&. 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.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.

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 a ca*sal relationship co*ld not 6e deter+ined since the ser*+ T2 in pre+at*re infants. a trial off replace+ent therapy can 6e initiated after the age of & years 'hen +ost thyro4ine0dependent 6rain +at*ration has occ*rred( #lternatively. s*ch as those 'ith thyroid agenesis. 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.e the T2 as soon as possi6le. the T2 'ill nor+ali. 'hich has the advantage that therapy need not 6e discontin*ed. 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. reco+6inant hT%!. has 6een sho'n to reflect the severity of illness and ris.ation is even faster <& days and 1 'ee. s*ch as iron. 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. do*6le 6lind trial of L0thyro4ine treat+ent..g per day for / 'ee. 6*t care sho*ld 6e ta. 'hile those 'ith severe congenital hypothyroidis+ <e(g(.s in 200 infants less than &0 'ee. to avoid hyperthyroidis+ 'here possi6le. 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. every 20& +onths 6et'een 1 and & years of age.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. and to pro+ote nor+al gro'th and develop+ent( . 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%.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( . or 6y giving an e4tra ta6let once a 'ee. every 102 +onths d*ring the first year of life. 1 +cg 8.e 'ithin 1 +onth( .( %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. sho*ld 6e started on the higher dosage( Thyroid hor+one +ay 6e cr*shed and ad+inistered 'ith ?*ice or for+*la. Nan . and the T%! 'ill nor+ali.e in +ost infants 'ithin 1 'ee. of death < 10/=( 9n the +ost thoro*gh st*dy to date. 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.s gestation < 105=( #ltho*gh overall no difference in cognitive o*tco+e 'as fo*nd. 6y giving an alternating dosage on s*6se7*ent days. altho*gh they have 6een *sed s*ccessf*lly in E*rope( The ai+s of therapy are to nor+ali. affected infants are not sy+pto+atic.g8dL </2 n+ol8L==. as in ad*lts.assenaer et al carried o*t a place6o0controlled. soy. +ay 6eco+e the preferred +ethod in the f*t*re < 10)=( .hen an initial dosage of 1001) +cg8. 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. T2 E) +cg8. 6ony +at*ration. at a dosage of 1 +c0 .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.hen a higher dosage is *sed <12015 +c g8. 6*t nonco+pliance sho*ld al'ays 6e e4cl*ded( 9n these cases.hen the cohort 'as reeval*ated at 10 years of age the difference in 9D 'as no longer significant. and availa6le infor+ation s*ggests that these short0ter+ T2 elevations are not associated 'ith any adverse effects on gro'th.g is *sed.g= nor+ali.hypothyroidis+ sho*ld 6e started on the lo'er dosage.s after the initiation of L0thyro4ine treat+ent.

hile the cognitive o*tco+e data of these 6a6ies is not yet . to a nor+al infant.hether or not these infants sho*ld 6e treated 'ith T2 and at 'hat dosage re+ains to 6e deter+ined( %rognosis #ltho*gh all are agreed that the +ental retardation associated 'ith *ntreated congenital hypothyroidis+ has 6een eradicated 6y ne'6orn screening. steroids. +*ltiple T%! receptor sti+*lating and 6loc. the onset of hyperthyroidis+ did not 6eco+e apparent *ntil 102 +onths postpart*+ 'hen the higher affinity 6loc.s= are i+portant( Ti+e to nor+ali. caffeine and dia+orphine= that have 6een sho'n to s*ppress T%! < 10/=. lang*age.no'n . the relative proportion of 'hich +ay change over ti+e( -ot s*rprisingly. 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.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. s*ggesting that this dose +ight 6e e4cessive( . or 1 in )0.g= and early onset of treat+ent <6efore 2 'ee. 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.dopa+ine. a+inophylline.ing anti6odies had 6een cleared fro+ the neonatal circ*lation < 11/=( 9n the latter case. and one 'ith transient hypothyroidis+ < 11)=( 9n another neonate.ing anti6odies 'ere isolated fro+ the +aternal peripheral ly+phocytes( Each +onoclonal anti6ody recogni. 112 =( This corresponds to 102C of +others 'ith Araves disease. if possi6le.000 ne'6orns.s of postnatal life 'as associated 'ith s*ppression of T%! and an increased incidence of necroti.g8day co*pled 'ith T& for the first 2 'ee. socioecono+ic and ethnic stat*s have also 6een related to o*tco+e < 21. 2B.g8. 'ith close follo' *p of circ*lating thyroid hor+one levels *ntil they nor+ali.e.ing enterocolitis. one affected +other gave 6irth. 112 =( The long ter+ pro6le+s for these 6a6ies appear to 6e in the areas of +e+ory. 110.ing anti6odies( %o+e +others have +i4t*res of sti+*lating and 6loc.ing anti6odies in their circ*lation.e( . ass*rance of co+pliance and caref*l longter+ +onitoring are essential for an opti+al develop+ental o*tco+e( 'y"erthyroidis Causes of Transient )eonatal 'y"erthyroidis Unli. s*rgery or 6y . fine +otor. partic*larly in the +ost severely affected infants < 21. 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&. the initial free T2 concentration.e congenital hypothyroidis+ 'hich *s*ally is per+anent. treat the pri+ary illness and to avoid. controversy persists as to 'hether s*6tle cognitive and 6ehavioral deficits re+ain.ation of circ*lating thyroid hor+one levels. it is clear that +ore data are needed( 9n the +eanti+e. 10B0112 =( "oth the initial treat+ent dose <at least 10 +cg01) +cg8. the +aternal thyroid has 6een destroyed either 6y prior radioa6lation. dr*gs <e(g(. 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. in t*rn. a 6a6y 'ith transient hyperthyroidis+. 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. +aternal 9D.

r*6ella. as noted earlier. a pict*re that +ay 6e conf*sed 'ith congenital infections s*ch as to4oplas+osis. +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. and pro+inent eyes <3ig*re 5=( Aoiter. irrita6ility. +ethi+a. 'hen present. are silent in contrast to the neonate 'hose thyroid gland is nor+al < 115=( Clinical anifestations #ltho*gh +aternal T%! receptor anti6ody0+ediated hyperthyroidis+ +ay present in *tero.ole or car6i+a. 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. arrhyth+ias and cardiac fail*re +ay develop and +ay ca*se death. or cyto+egalovir*s < 111=( 9n addition. and hypoprothro+6ine+ia.coincident destr*ctive a*toi++*ne processes so that potent thyroid sti+*lating anti6odies. present in the +aternal circ*lation. ?a*ndice. infants 'ith neonatal Araves disease present 'ith thro+6ocytopenia. poor 'eight gain. $TU. hepatospleno+egaly. the father 'as *naffected( Rarely. +ost often the onset is d*ring the first 'ee.ins disease( 9n contrast. characteristic signs and sy+pto+s incl*de tachycardia.ole= fro+ the infant > s circ*lation and to the increased conversion of T2 to the +ore +eta6olically active T& after 6irth( Rarely. incl*ding pre+at*re .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. *ntreated fetal and neonatal hyperthyroidis+ is associated 'ith deleterio*s long0ter+ conse7*ences. of life( This is d*e 6oth to the clearance of +aternally0ad+inistered antithyroid dr*g <propylthio*racil. the onset of neonatal hyperthyroidis+ +ay 6e delayed *ntil later if higher affinity 6loc.

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. 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. hyper6ilir*6ine+ia. 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. indicate the degree to 'hich the 6a6y is at ris. if T%! receptor anti6ody potency is inter+ediate. 6a6ies li. depending on the relative contri6*tion of +aternal hyperthyroidis+ vers*s the effects of +aternal antithyroid +edication. it is li. fail*re to thrive. the radioreceptor assay or EL9%# is a cost0effective. 'o+en 'ith persistently elevated T%! receptor anti6odies and 'ith a high re7*ire+ent for antithyroid +edication are at an increased ris. a f*nction of anti6ody potency and the rate of their +eta6olic clearance. 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.ely to 6eco+e hyperthyroid have the highest T%! receptor anti6ody titer 'hereas if T%! receptor anti6odies are not detecta6le. have transient hypothala+ic0pit*itary s*ppression or have a transiently elevated T%!.clos*re of the cranial s*t*res <cranial synostosis=. %it*ations That %ho*ld $ro+pt Consideration of -eonatal !yperthyroidis+ • Une4plained tachycardia. ideally.ely that the 6a6y 'ill 6e e*thyroid. 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. goiter or stare • Une4plained petechiae. the 6a6y is +ost *nli. in 6a6ies 'hose thyroid f*nction testing is nor+al initially.s( The d*ration of neonatal hyperthyroidis+. rapid and technically feasi6le approach( 9f desired. and T&. fet*ses and infants at ris. specific val*es that are reco++ended in the literat*re sho*ld 6e interpreted 'ith ca*tion and. 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.ely to 6eco+e hyperthyroid < 11B0121=( 9n the latter case. 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. and develop+ental delay < 11B=( The half0life of T%! receptor anti6odies is 1 to 2 'ee. 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. 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( .ing anti6ody0ind*ced congenital hypothyroidis+.( Ta!le &. it can 6e anticipated that the 6a6y 'ill 6e e*thyroid.

1 drop every 1 ho*rs= is added to 6loc. close s*pervision of the infant is advisa6le( %er anent neonatal hy"erthyroidis Rarely. aggressive therapy 'ith either thyroidecto+y or even radioa6lation has 6een reco++ended( . depending on the response( $ropranolol <2 +g8. 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. treat+ent 'ith digo4in sho*ld 6e initiated. 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. 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=. a conse7*ence of p! differences and increased protein 6inding.e the fetal heart rate and render the +other e*thyroid or slightly hyperthyroid( 9n the neonate. 6elo'=( The goals of therapy are to *tili. a conse7*ence of decreased intrathyroidal thyroid hor+one storage( Therapy 'ith 6oth antithyroid dr*g and iodine is ad?*sted s*6se7*ently. respectively( The +il. 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. irreversi6le se7*elae. 6*t concerns a6o*t potential $TU to4icity need to 6e considered( #t higher dosages of antithyroid +edication.g8day= has 6een *sed initially in & divided doses( 9f the hyperthyroidis+ is severe.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.e the +ini+al dosage necessary to nor+ali.Thera"y 9n the fet*s.g8day in 2 or & divided doses= is added if sy+pathetic oversti+*lation is severe. 'hen diagnosis and therapy is delayed. prednisone <2 +g8. a strong iodine sol*tion <L*gols sol*tion or %%K9. s*ch as cranial synostosis and develop+ental delay +ay res*lt < 125=( 3or this reason early. treat+ent is e4pectant( Either $TU <) to10 +g8. a +e+6er of the A protein co*pled receptor s*perfa+ily < 1220125=( Less fre7*ently.8ser*+ ratio of $TU is 1810 that of MM9. and propranolol sho*ld 6e discontin*ed( Rarely. so one +ight anticipate less trans+ission to the infant. and. 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. partic*larly in the presence of prono*nced tachycardia( 9f cardiac fail*re develops. 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.g8day= or MM9 <0() to 1(0 +g8.

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

as indicated a6ove. s*ggesting that the presence of potent T%! receptor 6loc. 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. car6i+a. 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. 'ater poll*tants. e4ternal irradiation of nonthyroid t*+ors = 0%*rgery Aoiter. partic*larly in those 'ith initial co+pensated hypothyroidis+ < 120012&=( @n the other hand. ca66age.e in ad*lts. 'hen present at a high concentration. a+inosalicylic acid. 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 . appeared to persist indefinitely. and. close follo' *p is necessary( Thyroid Dysgenesis and In!orn -rrors of Thyroid 'or onogenesis @ccasionally. 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. soya 6eans= Miscellaneous 0C ystinosis 0Langerhans Cell !istiocytosis 09rradiation of the Thyroid < radioactive iodine . or +ay have s*6clinical or overt hypothyroidis+( @ccasionally. spontaneo*s recovery of thyroid f*nction +ay occ*r.ole= 0 #nticonv*lsants 0 @ther <lithi*+. s'eet potatoes.hypothyroidis+ <defined as a ser*+ T%! concentration F20 +U8L=( Unli. 6roccoli. thiona+ides. MM9. ca*liflo'er. children +ay e4perience an initial thyroto4ic phase d*e to the discharge of prefor+ed T2 and T& fro+ the da+aged gland( #lternatively. 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. they 'ere fo*nd in goitro*s as 'ell as nongoitro*s patients . so+e initially e*thyroid patients 'ill 6eco+e hypothyroid 'ith o6servation( Therefore. a+inogl*tethi+ide= 0 Aoitrogens <cassava.ing #6s in adolescent fe+ales +ight identify patients at ris.

e of thiocyanate0containing foods that 6loc. children 'ith in6orn errors of thyroid hor+onogesis +ay only 6e recogni. 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. iodine deficiency contin*es to 6e an i+portant ca*se of hypothyroidis+. <Langerhans cell histiocytosis= < 121=( #lternatively.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(. 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. soya 6eans. 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. in the radiation field( Rarely. a+inosalicylic acid. affecting at least 100 +illion people living largely in developing co*ntries( 9n addition. incl*ding certain anticonv*lsants. gran*lo+ato*s disease. 12) =( %i+ilarly. lithi*+. a+inogl*tethi+ide and sertraline < 122. even in certain parts of E*rope. secondary or tertiary hypothyroidis+ +ay develop as a res*lt of ac7*ired da+age to the pit*itary or hypothala+*s. +ay 6e recogni. hypothyroidis+ has 6een reported in infants 'ith large he+angio+as < 12B=( 9n these cases. a large n*+6er of nat*rally occ*rring goitrogens <6roccoli.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.ed organification of iodine( Miscellaneous Causes of Ac4uired 'y"othyroidis Rarely.ed only later in childhood( #lternatively. 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=( . ca*liflo'er. infection <+eningitis=.orld'ide. hyperactivity. s*rgery or tra*+a( Us*ally other trophic hor+ones are affected. head irradiation. e(g(.or along the co*rse of the thyroglossal d*ct( %i+ilarly. the child cons*+ed a large inta. 6y t*+ors <partic*larly craniopharyngio+a=.ed later in childhood 6eca*se of the detection of a goiter( Drugs or Goitrogens 9n addition to antithyroid +edication. partic*larly gro'th hor+one( Thyroid 'or one Resistance 9n contrast to the neonatal period. hypothyroidis+ +ay 6e a long ter+ co+plication of +antle irradiation for !odg. occasionally *sed in childhood for the definitive treat+ent of Araves disease. fre7*ently ca*se per+anent hypothyroidis+( . an iodine s*fficient area. s'eet potatoes. cassava and 'ater poll*tants= have 6een identified( "oth radioiodine therapy and thyroidecto+y. 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. a+iodarone. ca66age. the thyroid gland +ay 6e involved in generali. a n*+6er of dr*gs *sed in childhood +ay affect thyroid f*nction.

these children are relatively over'eight for their height.no'n. altho*gh they rarely are significantly o6ese <3ig*re 1=( 9f the hypothyroidis+ is severe and longstanding.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. 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. in6orn errors of thyroid hor+onogenesis. and 6reast develop+ent 6*t relatively little se4*al hair( M*lticystic ovaries. 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.Clinical Manifestations The onset of hypothyroidis+ in childhood is insidio*s( #ffected children often are recogni. and perior6ital ede+a( %chool perfor+ance is not *s*ally affected. 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. cold intolerance. tho*gh they often are not the presenting co+plaints( These incl*de lethargy. 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 . +ay 6e de+onstrated on *ltrasonography( 9n other cases. thyroid dysgenesis. the etiology of 'hich is *n. on the other hand. 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. se4*al precocity has 6een descri6ed( 3e+ales 'ith se4*al precocity have +enstr*ation. 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.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.eletal +at*ration are delayed. testic*lar enlarge+ent +ay 6e fo*nd < 1)&=( #n elevation in ser*+ prolactin. constipation. altho*gh in longstanding severe hypothyroidis+.in or hair te4t*re. the latter possi6ly d*e to elevated TR! 'hich is . in thyroid hor+one synthetic defects. 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. dry s. galactorrhea or severe +enses have 6een the presenting feat*res( 9n 6oys. thyroid hor+one resistance= sho*ld 6e disting*ished fro+ non goitro*s ca*ses <pri+ary +y4ede+a.

hyperactivity. 6*t gonadotropin levels are not consistently elevated( 9t has 6een hypothesi.ation +ay res*lt in *n'anted side effects <deterioration in school perfor+ance.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. of adverse conse7*ences in children 'ith +ild hypothyroidis+( .g= 'as so+eti+es *tili. and therefore.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.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. 6*t not l*teini.no'n to sti+*late prolactin as 'ell as T%!. 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%#.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. ho'ever( 3*rther+ore.ing anti6odies sho*ld 6e considered in adolescent patients 'ith severe hypothyroidis+ 6eca*se of the potential ris. and 6ehavior diffic*lties= < 1)/=( 9n these children it is prefera6le to increase the replace+ent dose slo'ly over several 'ee. has 6een descri6ed in so+e cases.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. 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. severe thyroid *nderactivity in 'ho+ rapid nor+ali.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. on the other hand. and a large gland on scan( @ther etiologies of hypothyroidis+ *s*ally are evident on history( Thera"y 9n contrast to neonatal hypothyroidis+. short attention span. 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. f*ll replace+ent can 6e initiated at once 'itho*t +*ch ris. rapid replace+ent is not essential in the older child( This is partic*larly tr*e in children 'ith long standing. of 6loc.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%!. inso+nia.e and scan= +ay 6e perfor+ed if thyroid anti6ody tests are negative or if a nod*le is palpa6le..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. 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+. i+aging st*dies are helpf*l in identifying the presence and location of thyroid tiss*e. the typical pict*re of spotty *pta. there is little increase in ser*+ testosterone as +ight 6e e4pected if the 3%!. then eval*ation of the free T2 or free T2 inde4 <total T2 +*ltiplied 6y the T& resin *pta. 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. 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.

availa6le data s*ggests a significant li. at least for several years( Conse7*ently. elevated T%!= is controversial( 9n ad*lts in 'ho+ the ris. 6*t not colloid goiter( .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. if there is not a strong fa+ily history of hypothyroidis+ and the patient is not sy+pto+atic. too. of progression to overt hypothyroidis+ is significant.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 . & to 2 +c g8. others appear to *ndergo periods of gro'th . 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. occ*rs in 1(2C of school children in -orth #+erica < 120=( Li. the +ost co++on thyroid disorder in pediatrics. hypothyroid or hyperthyroid. 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.ing the i+portance of early diagnosis and treat+ent( Treat+ent is *s*ally contin*ed indefinitely( Asy "to atic goiter Causes Chronic ly "hocytic thyroiditis Aoiter. 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.no'n( -ot infre7*ently there is a fa+ily history 6oth of goiter. +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=.hereas +any colloid goiters regress spontaneo*sly. and there6y +ini+i. of developing hypothyroidis+ in patients 'ith chronic ly+phocytic thyroiditis.elihood of re+ission.eep the T%! in the lo' nor+al range <0(& to 1(0 +U8L in an *ltrasensitive assay=.Treat+ent of children and adolescents 'ith s*6clinical hypothyroidis+ <nor+al free T2. leading to the s*ggestion that colloid goiter. 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. the fe+ale: +ale ratio 6eing 2 to &:1( $atients 'ith goiter +ay 6e e*thyroid. *nless the hypothyroidis+ is severe < 1)B=( %o+e children 'ith severe. partic*larly if they are over the age of /0 years.g for children 1 to ) years of age. there is a fe+ale preponderance. chronic ly+phocytic thyroiditis and Araves disease. and 2 to & +cg8. disc*ssed a6ove( Ca*ses of goiter that are associated 'ith a6nor+al thyroid f*nction are disc*ssed else'here in this chapter( Colloid or Si "le *)onto$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. e+phasi. 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. long standing hypothyroidis+ at diagnosis +ay not achieve their ad*lt height potential even 'ith opti+al therapy < 1/0=.g for those ages / to 10 years.e thyroid disease in general.s( @nce a e*thyroid state has 6een achieved.

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. 1/& =( # significant decrease in goiter si. progression to a6scess for+ation +ay occ*r rapidly so pro+pt recognition and anti6iotic therapy are essential( Rec*rrent attac. it is +ost co++on in adolescence( $rep*6ertal children tend to have +ore severe disease. the +ost co++on sit*ation. the a6sol*te difference 7*antitatively 'as not reported and so. 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.and regression. is disc*ssed else'here( 'y"erthyroidis Causes Gra0es Disease More than B)C of cases are d*e to Araves disease.e chronic ly+phocytic thyroiditis. an a*toi++*ne disorder that. 'hether or not this difference 'as signicant clinically re+ains *nclear( Aiven the varia6ility in response in different patients. 6oth endocrine and non . 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. 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.s( %*6ac*te 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. it 'o*ld 6e reasona6le to atte+pt a therape*tic trial in patients 'hose goiter is large( %ainful thyroid $ainf*l thyroid enlarge+ent is rare in pediatrics and s*ggests the pro6a6ility of either ac*te <s*pp*rative= or s*6ac*te thyroiditis( Rarely chronic ly+phocytic thyroiditis +ay 6e associated 'ith inter+ittent pain and 6e conf*sed 'ith the latter disorders( 9n ac*te thyroiditis. rare in childhood.e in patients 'ith chronic ly+phocytic thyroiditis as assessed 6y standard deviation score on *ltrasonography has 6een de+onstrated recently in patients treated for & years < 1/&=( !o'ever. the distinction is dependent *pon the presence of elevated titers of T$@ 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( Thera"y Thyroid s*ppression in children 'ith a e*thyroid goiter is controversial < 1/2. s*rgical e4tirpation of the pyrifor+ sin*s 'ill fre7*ently prevent f*rther attac. 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 . li.

ing anti6odies. 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. a pict*re has e+erged of distinct 6*t overlapping 6inding sites of 6oth sti+*lating and 6loc.endocrine( These incl*de dia6etes +ellit*s. and e+otional la6ility +ay lead to 6ehavioral and school diffic*lties( %o+e patients co+plain of poly*ria and of noct*ria. T"A e4cess. heat intolerance and tachycardia( @ften the onset is insidio*s( %hortened attention span.ing T%! receptor anti6odies 6ind to the e4tracell*lar do+ain of the receptor and appear to recogni. often acco+panied 6y advance+ent in s. 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. periodic paralysis. +yasthenia gravis. hyperthyroidis+ +ay 6e ca*sed 6y a f*nctioning thyroid adeno+a. strongly s*ggesting that they are +onoclonal or pa*ciclonal < 15&=( "loc. s*ch as tre+ors. +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. pro4i+al +*scle 'ea. rhe*+atoid arthritis.hen a high total T2 concentration is associated 'ith a nor+al free T2 and T%! level. inhi6it T%!0ind*ced sti+*lation of adenyl cyclase( "oth sti+*latory and 6loc. the patient +ay co+plain of fatig*e( . p*6erty +ay 6e delayed( 9f +enarche has occ*rred. vitiligo. the res*lt of an increased glo+er*lar filtration rate( #cceleration in linear gro'th +ay occ*r. 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. are not si+ilarly restricted( Rarer causes of hy"erthyroidis Rarely.eletal +at*ration <6one age=( #d*lt height is not affected( 9n the adolescent child.e chronic ly+phocytic thyroiditis in 'hich thyrocyte da+age is predo+inant.1/B=( #s noted earlier. pregnancy +ay 6e associated 'ith an elevation in circ*lating T2 and a lo'0nor+al or s*ppressed ser*+ T%! concentration( . and +ost have sy+pto+s and signs of e4cessive thyroid activity. either genetic or ac7*ired <e(g(. secondary a+enorrhea is a co++on conco+itant( 9f sleep is dist*r6ed. on the other hand. ina6ility to fall asleep.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. T%! receptor 6loc. syste+ic l*p*s erythe+atosis. 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. 'eight loss despite an increased appetite. #ddison > s disease. in contrast.ing anti6odies. 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.ness.en together.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.

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. partic*larly in association 'ith precocio*s p*6erty. on the other hand. the finding of a thyroid nod*le s*ggests the possi6ility of a to4ic adeno+a( The hands are often 'ar+ and +oist( Tachycardia. and a hyperactive precordi*+ are co++on( CafT a* lait spots. prefera6ly. 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. free alpha s*6*nit sho*ld 6e +eas*red( #lternatively. 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.in and fine hair te4t*re. the circ*lating T& concentration fre7*ently is elevated o*t of proportion to the T2 6eca*se. for e4a+ple a res*lt of oral contraceptive *se= or rarer 6inding .e T%!. thyroto4icosis factitia sho*ld 6e considered( The ophthal+opathy characteristic of Araves disease in ad*lts is considera6ly less co++on in children. soft or G fleshy H thyroid gland. free T2 <or free T2 inde4= and T&=( 9n hyperthyroidis+. s+ooth s. e4cessive activity. and a fine tre+or of the tong*e and fingers( # thyroid 6r*it +ay 6e a*di6le( 9n contrast. li. a 'ide p*lse press*re. 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. 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*ggests a possi6le diagnosis of McC*ne #l6right syndro+e 'hile if a goiter is a6sent.

alternately.ed that in these patients.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. 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 .ing anti6odies inhi6it T%! 6inding to the receptor.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. sho*ld 6e +eas*red( 9f pregnancy or an hCA0secreting t*+or are s*spected. 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. if +eas*re+ent of T%! receptor anti6odies is negative. 6eco+e positive several 'ee.ed i++*nosor6ent assay UEL9%#V. strongly s*ggesting that li+ited assay sensitivity is the +ost li.y+e0lin. 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. TR#6s or T%! 6inding0inhi6itory 9gAs. that T%! receptor anti6odies escape detection 6eca*se of 6inding 6y sol*6le T%! receptor circ*lating in ser*+( !o'ever.y+e0lin. +ore recently. and the develop+ent of 6oth +olec*larly0engineered cells. or. 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.s later < 110=( 9t has 6een hypothesi. ser*+ T"A concentration or electrophoresis of T2 6inding proteins.protein a6nor+alities <for e4a+ple. 6ioassays are the +ost definitive and sensitive +ethod to doc*+ent that the hyperthyroidis+ is d*e to sti+*latory T%! receptor # 6s. or if a f*nctioning thyroid nod*le is s*spected=( . T"99= 'hereas those +eas*red 6y 6ioassay are *s*ally referred to as thyroid0 sti+*lating i++*noglo6*lins. 155015B =( Res*lts in 6ioassays are +ore varia6le( #ltho*gh 6ioassays are highly sensitive in a research setting < 110=.its. en. respectively. 6*t the ne'er. ta. initially reported to 6e negative in the radioreceptor assay.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. the proportion of patients 'ho are T%! receptor anti6ody positive has increased 'ith the introd*ction of 2nd generation and no' &rd generation assays. fa+ilial dysal6*+ine+ic hyperthyro4ine+ia= < 15)=( 9n the latter cases. 112 =( Recently.e and scan are *sed to confir+ the diagnosis of Araves disease only in atypical cases <for e4a+ple. partic*larly 'hen en. T%9. 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. T%! receptor anti6ody synthesis is restricted at first to 'ithin the thyroid gland itself. 9t +*st al'ays 6e . 6eing positive in *p to BBC of ad*lts and children 'ith Araves disease < 1/B. they are +ore fastidio*s and so res*lts fro+ so+e clinical la6oratories appear to 6e less sensitive < 111.ed +onoclonal T%! receptor anti6ody is s*6stit*ted for T%! as ligand < 15B=( %ince 6oth sti+*latory and 6loc. 151 =.

ed. MM9 and car6i+a. sho*ld 6e individ*ali. 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. partic*larly prep*6ertal ones.er <atenolol. and the re7*ire+ent for co+pliance( 9n general. s*rgery.ed 6*t not initially( @nce the T2 and T& have nor+ali.ole <MM9= is the initial choice of +ost pediatricians altho*gh radioiodine is gaining increasing acceptance.g8day given every 12 ho*rs and of $TU is ) +g8. a 6eta0adrenergic 6loc. 'ait *ntil the T%! 6egins to rise and add a s+all. and in those a6o*t to leave ho+e <for e4a+ple. &5C after / years and 2)C after 1 years( <1/)6=( The +edian d*ration of .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. 1 +g8.g8day given every 1 ho*rs( 9n severe cases. one can either decrease the dosage of thioa+ide dr*g 6y &0C to )0C or. or s*rgery= to *se.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. radioactive iodine. to go to college=( #lternately.es( 9t sho*ld 6e noted that the T%! concentration +ay not ret*rn to nor+al *ntil several +onths later( Therefore. 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. alternatively. $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. the ti+e re7*ired to control the hyperthyroidis+. leading to the reco++endation that $TU 6e *sed only in pediatric patients 'ho are allergic to MM9.e 6y / to 12 +onths <115011B=( 9n another st*dy. in children 'ho are develop+entally delayed. re7*ires less fre7*ent +edication= and 6eca*se it has a +ore favora6le safety profile( Recent reports have s*ggested that the ris. circ*lating thyroid hor+one levels can 6e nor+ali. 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&. +edical therapy 'ith +ethi+a. the oldest for+ of therapy. 6oth short and long ter+ co+plications. 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.ed and disc*ssed 'ith the patient and his8her fa+ily( Each approach has its advantages and disadvantages 'ith respect to efficacy.s *ntil the ser*+ concentration of T2 <or free T2 and total T&= nor+ali. +eas*re+ent of T%! is *sef*l as a g*ide to therapy only after it has 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. +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. partic*larly in non co+pliant adolescents.Thera"y The choice of 'hich of the three therape*tic options <+edical therapy.ed( 9n +ost children and adolescents. 20C of children re+itted after 2 years of therapy. s*pple+entary dose of l0thyro4ine <e(g(.ole .ing fe'er ta6lets. of hepatoto4icity 'ith $TU +ay 6e greater in the yo*ng < 11&011)=. 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. it has a longer half0life <and so.

ed( 9n patients treated 'ith antithyroid dr*gs alone. 'ho are proponents of *se of R#9 for therapy in yo*ng children((The ris.e $TU. 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&=. a s+all dr*g re7*ire+ent.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. 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. indicates a high li. s+all goiter.ees et al advise treat+ent 'ith doses of R#9 greater then 1/0 *Ci8gra+ thyroid. radioactive iodine is 6eing favored increasingly.e syndro+e. 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. or are nonco+pliant( 9n recent years.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. MM9 is rarely associated 'ith hepatocell*lar in?*ry( #ppro4i+ately 10C of children treated +edically 'ill develop long ter+ hypothyroidis+. 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. the red*ced need for +edical follo' *p and the lac. the higher dosage is reco++ended.ees et al <1B2=. 6*t therapy sho*ld 6e individ*ali. 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. 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= . a conse7*ence of coincident cell and cyto.ine0+ediated destr*ction and8or the develop+ent of T%! receptor 6loc.e of the thyroid gland is esti+ated. <E1)00 gran*locytes8++&=. a l*p*s li. even as the initial approach to therapy < 1B2=( The advantages are the relative ease of ad+inistration. 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. *rticaria.therapy in +ost st*dies is & to 2 years years. +ore severe se7*elae. to achieve a thyroidal radiation dose of at least 1)0Ay<a6o*t 1)000 rads=( . +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. transient gran*locytopenia. developed a to4ic dr*g reaction.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. s*ch as hepatitis. have 6een reported in )C to 12C of children( Rarely. partic*larly in yo*nger children. on the other hand. for ind*ction of cancer *sing the data presented 6y Riv. 6*t +ost a*thors do not consider the lo' ris. or gingival sores or ?a*ndice( Unli. and agran*locytosis. 6ased on the ass*+ption that the nor+al gland is 0()01(0 g+s8year of age. 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.elihood of relapse( 9nitial st*dies s*ggesting that co+6ined therapy <i(e(. sore throat. <E)00 gran*locytes8++&= +ay occ*r( Most reactions are +ild and do not contraindicate contin*ed *se( The ris. ho'ever. arthralgias. in order to co+pletely a6late the thyroid gland and there6y red*ce the ris. thro+6ocytopenia. 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. of f*t*re neoplasia( The si. to 6e 'orth the cost of close +onitoring( Many clinicians prefer to chec.

does not appear to 6e co++on in childhood( !o'ever.e the ris. they are +ore li. of rec*rrence( %*rgery *s*ally is reserved for patients 'ho have failed +edical +anage+ent.edly enlarged thyroid. the ad+inistered dose 'o*ld 6e 20<g+= 4 1/0*Ci8g+ 4 2 <to acco*nt for )0C *pta. and 1C at age 1)( .orsening of ophthal+opathy. if therapy is inade7*ate.e of 20 g+. '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. 6*t 'hen fo*nd.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. this 'o*ld see+ to +any persons to constit*te a significant ris.hether or not accepting a specific incre+ental 20)C ris. the third therape*tic +odality. 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.#ss*+ing a reasona6le R#9U of )0C and gland si. 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. s'elling= are rare( @ne *s*ally sees a therape*tic effect 'ithin / 'ee. the +ost co++on for+ of thyroid cancer in childhood and adolescence is papillary thyroid carcino+a. significant nec. 2 to 10 drops daily or -a ipodate.e in ad*lts. and. 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. if it is fi4ed . 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. 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. a of cancer +ortality 'o*ld 6e 2C at age ). 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.ers +ay 6e *sef*l d*ring this ti+e period( %i+ilarly. hypoparathyroidis+ <2C=.ing( Surgery %*rgery. long ter+ follo' *p data in a larger cohort are still lac. 2C at age 10. there does not appear to 6e any increased rate of congenital ano+alies in offspring nor in thyroid cancer( !o'ever. rarely <0(01C=. 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. of fir+ or hard consistency.eloid for+ation <2(1C=. s*ch as intrathyroidal thyroglossal d*ct cysts or *nilateral thyroid agenesis( Li. less co++on potential co+plications are . 'ho ref*se radioactive iodine therapy. 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.s to & +onths( . ) to 10 drops tid or potasi*+ iodide. 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. 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. 'ho have a +ar.e= S12(1 +Ci( Th*s the long ter+ cancer death ris. rec*rrent laryngeal nerve paralysis <2C=. 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. 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. descri6ed in ad*lts after R#9.

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. 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. *s*ally indicates the presence of *nderlying chronic ly+phocytic thyroiditis. a thyroid follic*lar cell0specific protein. hoarseness or dysphagia( Even the findings of a cystic co+ponent or a f*nctioning nod*le. on the other hand. a . pop*lar in the investigation of thyroid carcino+a in ad*lts. co++only *sed as favora6le signs in ad*lt patients. thyroid cancer presents in childhood as *ne4plained cervical adenopathy.ins and is also seen 'ith increased fre7*ency in le*. of thyroid cancer is related to the dose of e4ternal irradiation and.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. 20& =( Thyroid cancer is no' . children e4posed to high levels of radioactive iodine in the first decade of life or in *tero. s*ch as papillary or follic*lar carcino+a( This is 6est perfor+ed after a period <*s*ally / 'ee. is 'ell . associated cervical adenopathy. 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. 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. do not co+pletely e4cl*de the possi6ility of neoplasia < 1BB=( @ccasionally. the average latent period in s*rvivors of !odg. there appears to 6e a higher prevalence of gene rearrange+ents in children 'ith differentiated thyroid cancer.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. the latency 'as only 2 years < 1B)=( #s co+pared 'ith ad*lts. is *sed to detect evidence of +etastatic disease in differentiated for+s of thyroid cancer.no'n < 201=( The increased incidence of 6oth 6enign and carcino+ato*s nod*les in patients 'ith !odg. the long ter+ cancer specific +ortality rate is no greater in children than in ad*lts E20 years of age < 20/=( Th*s.e+ia s*rvivors < 202=( %i+ilarly.e the 1B year average latency after lo' dose irradiation. gro*p( The increased ris. '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. 2026 =( Meas*re+ent of circ*lating calcitonin is *sed as a t*+or +ar. are at a +ar. 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. of developing papillary thyroid cancer < 1B)=( The ris. 6*t in so+e cases. and 'hether it is single or +*ltifocal 3ine0needle aspiration 6iopsy.in disease appears to 6e only B years < 20&=( 9n Cherno6yl victi+s. *nli.edly increased ris. the dose of thyro4ine is ad?*sted to . findings s*ggestive of +*ltiple endocrine neoplasia <ME-= types 2# and8or 2" < 200=( Children e4posed previo*sly to thyroid irradiation co+prise a high0ris. d*ring childhood is also 6eing doc*+ented increasingly < 202.er for +ed*llary thyroid cancer <MTC=.e. 'hich can 6e confir+ed 'ith a radion*clide scan( The finding of positive anti6odies.no'n to 6e the +ost co++on second +alignancy in childhood s*rvivors of !odg.in disease 'ho had received radiotherapy to the nec. 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 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. a conse7*ence of the Cherno6yl disaster.

%halho*6 N. Co*lter %. et al( %er*+ thyroglo6*lin levels in preter+ neonates( . 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. is of val*e in screening fa+ily +e+6ers < 200. detecta6le in nearly all fa+ilial for+s of MTC. Eds6agge M. %i+pson M. %i+pson M.illia+s 3L. 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%. 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. Nandersch*eren M. %e+6 !. Liao M. -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-. Aritli0Linde #.e and positioning( !*+ Mol Aenet 2005:1/<&=:25/01)( /( 3ag+an !.no'n( References 1( Missero C. -ilsson M( The 22711 deletion syndro+e candidate gene T641 deter+ines thyroid si. 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. 201 =( 9n fa+ilies affected 'ith +*ltiple endocrine neoplasia type 2. 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. 3isher D#. Morro' "E. -icolaides K!. Co6ellis A. McAregor #M( 3etal thyroid f*nction( Thyroid 1BB2:2<&=:2050 15( 10( . 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 $. Di La*ro R( Thyroid develop+ent and its disorders: genetics and +olec*lar +echanis+s( Endocr Rev 2002:2)<)=:52202/( &( Manley -R.esterl*nd M. Cornette C. -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 !. . Delah*nty C. 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. Arande M. Delah*nty C. De 3elice M. Larsen $R( Maternal and fetal thyroid f*nction( .C0cell derived +alignancy < 201=( M*tations of the RET protooncogene.Engl M Med 1BB2:&&1<1/=:105201( 1( 3isher D#. 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. 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. reg*lar assess+ent of thyroid f*nction <T%! and. #ndersson L.

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 !. 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.i AE. !olden R!. Mones . 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 -.. @6regon MM. Aons M!. 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". Kaptein E.el K. An*di #. D*denha*sen M. de Ni?lder MM( Maternal0fetal transfer of thyro4ine in congenital hypothyroidis+ d*e to a total organification defect or thyroid agenesis( . et al( Characteri.%. . 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 ".. "raver+an LE( The placental transport.al. et al( Maternal thyroid deficiency d*ring pregnancy and s*6se7*ent ne*ropsychological develop+ent of the child( . Ehrlich R( Long0ter+ se7*elae of hearing i+pair+ent in congenital hypothyroidis+( M $ediatr 1BB/:121</=:55/01&( 2/( de Zegher 3. $alo+a. Aere6en ".&X.)X0tri0 iodothyronine <reverse T&=. Nan den "erghe A. "liss ". $ernasetti 3. "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. M*no. Esco6ar del Rey 3. et al( Thyroglo6*lin reference val*es in a pediatric infant pop*lation( Thyroid 2005:15<11=:102B0)2( 1)( Roti E. "a.Engl M Med 1B1B:&21<1=:1&0 /( 22( Calvo RM. 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. Devlieger !. "*chanan L.C.. 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. C!. %egers 9. synthesis and +eta6olis+ of hor+ones and dr*gs 'hich affect thyroid f*nction( Endocr Rev 1B1&:2<2=:1&102B( 1/( Kester M!.). Aoodyer CA. .&X0di0iodothyronine. @6regon MM.er . #llan . &. &. A*l6is ". %aling E( #+niotic fl*id concentrations of &.Clin Endocrinol <@4f= 1B12:21<2=:12B0)&( 12( %o6rero A. "ernal M. Nan Di?.ara L.&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. de @na C. L.en.Engl M Med 1BBB:&21<1=:)2B0))( . Nanhole C.ation of iodothyronine s*lfatase activities in h*+an and rat liver and placenta( Endocrinology 2002:12&<&=:1120B( 15( Nan der Aeyten %.. Ma*nia*4 E.

et al( -eonatal hypothyro4ine+ia: effects of iodine inta. 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. %ni?ders RM.e. triiodothyronine. !alpern L. Aro*pPThe increased incidence of congenital hypothyroidis+: fact or fancyY Clin Endocrinol 2011:5):10/010( 2)( Klein #!. 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. . . %tinson D#. 3rancis 9.or.i D. "est'ic. Ma?. 9nderneel %ahai and the Massach*setts $ediatric Endocrine . et al( $revalence of thyroid deficiency in pregnant 'o+en( Clin Endocrinol <@4f= 1BB1:&)<1=:210/( &2( #6*id M. 3elton CN.er %.io M.e and pre+at*re 6irth( M Clin Endocrinol Meta6 1BB5:12</=:1502012( 20( 3ran. Mo+otani -. McAregor #M( Thyroid f*nction in s+all for gestational age fet*ses( @6stet Aynecol 1BB1:55<)=:5010/( 2&( Z*ra. Aold !( Thyroid f*nction in very preter+ infants( Early ! *+ Dev 1B11:1/<20&=:1&1021( &1( -elson MC. I* NI. 9shi. %evere early +aternal hypothyroidis+ prior to the third tri+ester associated 'ith nor+al cognitive o*tco+e in the offspring( Thyroid. . Esco6ar0Morreale !3. 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. thyrotropin. Ta. M. 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. Tegelaers . van "aar #L. Cars'ell M et al.y+ono'ic. !o0. $avel. M$. 9'a+a %. M!. !er+os RM. 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. %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. in press( & 2( L 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. Ni.!.a'a -. 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 . Di Can.o*6 M#( $ediatric reference intervals for ser*+ thyro4ine. -oh MI.a %. 3ai4 ME. 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.eiss RM. . !addo' ME. 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* !. in press( &1 c( Do'ning %D..ar*s M!. D*ero M. Channon % et al( #ntenatal thyroid screening and childhood cognitive f*nction( .en !s*.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 %. K*i?pens ML. -icolaides K!.&0( $op NM. %. Melt. 3ai4 MD.o's.Engl M Med 2012:&//:2B&0)01( &&( Klein RZ. ME.e6e K. K.

%. "( Congenital hypothyroidis+: develop+ental o*tco+e in relation to levothyro4ine treat+ent varia6les( Thyroid 200&:1&<11=:102B0&1( )0( Rovet M. Kei. Delaney #. Daley D. N*ls+a T( -eonatal detection of congenital hypothyroidis+ of central origin( M Clin Endocrinol Meta6 200):B0</=:&&)00B( )56( -es6esio TD. -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. Ner. N*ls+a T.er. Kaiser+an 9. 3.er0%chra+a %M( 9nfl*ence of ti+ing and dose of thyroid hor+one replace+ent on +ental.oroniec. 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. !er+os R. Krain. @er6ec. et al( Discordance of +ono. Clar. Mitchell M( Ris.er. Dr*schel CM. $L. Aordillo R.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. Kas. and 6ehavioral develop+ent in children 'ith congenital hypothyroidis+( M $ediatr 200):125</=:5/1052( 2B( !eyerdahl %. de Ni?lder MM. -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. psycho+otor.ing MM. van Ti?n D#. "ellisario R.eels MR. %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. "o*rdo*4 $.. !einrichs C. Morissette M( !igher sensitivity of pri+ary thyrotropin in screening for congenital hypothyroidis+: a +ythY M Clin Endocrinol Meta6 1B1&:)/<2=:12B0)2( )&( La3ranchi %!.ygotic t'ins for thyroid dysgenesis: i+plications for screening and for +olec*lar pathophysiology( M Clin Endocrinol Meta6 2002:15<B=:205205( )/( Lanting C9. Loe6er MA. Mr(. Miyahira R%. McKenna M$. Merlo6 $. E+ery MR. $!. Carlton E9. %M. %ac. factors associated 'ith delayed thyrotropin elevations in congenital hypothyroidis+( M $ediatr 200&:12&<)=:)150B1( ))( $erry R. de M*inc. 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!. $!( 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+( $ediatrics 200):11/<1=:1/105&( )5( van Ti?n D#. M( Congenital ano+alies conco+itant 'ith persistent pri+ary congenital hypothyroidis+( #+ M Med Aenet 1BB2:22<1=:)50/0( /1( K*+ar M.i R$( 9ncreased prevalence of renal and *rinary tract ano+alies in children 'ith congenital hypothyroidis+( M $ediatr 200B:1)2<2=:2/&0/( /2( 3ort $. . !anna CE. de Ni?lder MM. Lifshit. Ner6eeten ". et al( #6nor+alities of thyroid f*nction in infants 'ith Do'n syndro+e( M $ediatr 1B12:102<2=:)2)0B( .el 3M. Ner.

"hatia N. and p*l+onary alterations d*e to h*+an -KQ201 haploins*fficiency( M Clin 9nvest 2002:10B<2=:25)010( /2( $erna MA. !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( . Cisternino C. Castagne M.. %ch*t. 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. @'en M. cleft palate and choanal atresia( -at Aenet 1BB1:1B<2=:&BB0201( /5( "ro'n R%.Engl M Med 1BB):&&2<&=:1))0/0( 50( "ie6er+ann !.. Aregory M. A. 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%. Kr*de !. !all CR. Macchia $E.( 9nfantile hypothyroidis+ in t'o si6s: an *n*s*al presentation of pse*dohypoparathyroidis+ type 9a( M $ediatr 1B1):105</=:B1B022( 55( Coll* R.)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#. $ar+a M. Nassart A. ". @ates EL. !ayashi I./&( Kr*de !. L*dgate M( The .ent'orth MM. ME. 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 -. De 3ilippis N. et al( Choreoathetosis. Refetoff %( "rief report: resistance to thyrotropin ca*sed 6y +*tations in the thyrotropin0receptor gene( . 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.adeli*s C( Aenetic and lin. 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 %#. "ie6er+ann !.illia+s -.age to the T%! receptor gene( !*+ Aenet 1BB5:BB<2=:11/0B0( 5)( Mordan -.i #. Aopel .age analysis of fa+ilial congenital hypothyroidis+: e4cl*sion of lin. 9lic. . . Tassi N( #6sence of +*tations in the gene encoding thyroid transcription factor01 <TT301= in patients 'ith thyroid dysgenesis( Thyroid 1BB5:5<&=:&55011( /)( Lapi $. Tang M. Ia7oo6 M. 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 !. Deal C. %acco M. Map T%. Evans C. Larsson #. %chone6erg T. Aottschal. hypothyroidis+.*i T. 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. $. . "ie6er+ann !. !*ng . #nneren A. %ch*lt. Civitareale D. !ein. A*der+ann T. et al( M*tation of the gene encoding h*+an TT302 associated 'ith thyroid agenesis.

$everini RL. et al( 9ncidence of transient congenital hypothyroidis+ d*e to +aternal thyrotropin receptor06loc.0"ar6era M. %aenger $( Three0year follo'0*p of 6orderline congenital hypothyroidis+( M $ediatr 2000:1&/<1=:)&0/( . -etchine 9. Liao Q!. Linder ".s M%. 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. %cher6erg -!. "est T". "loo+field %.o' !#.ano %. "al. Martine. Liao Q!.e6er "( 9odine in contrast agents and s.ing anti6odies in over one +illion 6a6ies( M Clin Endocrinol Meta6 1BB/:11<&=:11250)1( 1B( "ro'n R%. %choen+a. Mitchell E( Maternal thyroid06loc. Larsen $R.i !. !*+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. $antel M. DiMartino0-ardi M. #+ino -. 3M. Ra6in C.5B( Dattani ML. Ta+a. "ellisario RL.+ann K. Nyh+eister -R.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. Ar*ters #.ed resistance to thyroid hor+one( Ma+a 1BB0:2/2<15=:222)0)0( 1&6( "och*. @gston %#. "raver+an LE( Ro*tine s.illia+s 3L. %tyne DM( Transient neonatal Jathyreosis> res*lting fro+ thyrotropin06inding inhi6itory i++*noglo6*lins( $ediatrics 1B1/:51<2=:2150B0( B1( Mits*da -. Mr( -eonatal thyroid f*nction after propylthio*racil therapy for +aternal Araves> disease( . Tani.ers -.Engl M Med 1B11:&02<B=:)2)01( 11( "ro'n R%. Tho+as $D.a'a @( Ris. "eyer $. %elen. Nisser TM. et al( # +*tation in the thyroid hor+one receptor alpha gene( . 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&( . . et al( Molec*lar genetics of septo0optic dysplasia( !or+ Res 2000:)& %*ppl 1:2/0&&( 10( Machinis K. "roc. factors for develop+ental disorders in infants 6orn to 'o+en 'ith Araves disease( @6stet Aynecol 1BB2:10<& $t 1=:&)B0/2( B2( Mandel %!. #gostini E.ova E. !opper #@. Crigler M3. van Toor !. !osono T.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%.. "ednare. Kaplan MM. Miyai K. #6d*llah M%. "otero D. Refetoff %( -eonatal detection of generali.Engl M Med 2012:&//:22&0B( 12( D*+itresc* #M. !anna CE. 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. Mitchell ML.ing i++*noglo6*lins in congenital hypothyroidis+( M Clin Endocrinol Meta6 1BB0:50<)=:1&210/( B0( Connors 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. -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( .eiss RE. La3ranchi %!( Di+inished thyroid0sti+*lating hor+one secretion associated 'ith neonatal thyroto4icosis( M $ediatr 1B1/:10B<2=://20)( B&( De+ing DD. Keating $.

Engl M Med 1BB5:&&/<1=:210 /( 101( van . Molinari L. 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.. Ko.assenaer #A.ernicho' $. La3ranchi %. %hen @rr Z. 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. Ro6aey $.ari?a M.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 #.ed.estera M. M!. Rien L. %tanhope RA. -oda !. Deal C. et al( 9nitial treat+ent dose of L0thyro4ine in congenital hypothyroidis+( M $ediatr 2002:121</=:51/0B2( 10)( Tiosano D. 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. Etter K.ager "#. -ose @. Nisser TM. Mandel %!. controlled trial( $ediatrics 200):11/<)=:e/1&01( 10B( %i+onea*0Roy M. 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 #. .s> gestational age s*pple+ented 'ith thyro4ine in the neonatal period in a rando+i. !ind+arsh $C. Klein #M. !och6erg Z( Reco+6inant thyrotropin in the diagnosis of congenital hypothyroidis+( M Clin Endocrinol Meta6 2005:B2<2=:12&205( 10/( . Mc9ntosh K3.s> gestation( .alraven C. .assenaer #A. Miyai K.ie MM( $regnancy0associated changes in the thyroid0sti+*lating anti6ody of . !*+e R( Transient hypothyro4inae+ia in preter+ infants( Early !*+ Dev 200/:12<12=:5B50102( 105( van . 9no+ata !. Even L. 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 !.illia+s 3L. M!( Ten0year follo'0*p of children 6orn at E&0 'ee.ing 9D in infants 'ith congenital hypothyroidis+( M $ediatr 2000:1&/<&=:25&02( 11&( Za. Marti %. Ro?as D#. $reece M#. !o*t. !enderson MR. Miscio A. Ia6**chi !. %asa. "rain CE. Ko.i K. !er+os RM( %creening very0lo'06irth'eight infants for congenital hypothyroidis+( Lancet 1BB2:&2&<1111=:/001( 10&( "ro'n R%.B/( Calaci*ra 3. !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. de Ni?lder MM. !*ot C. McKen. 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#. Motta RM. Nandale+ ML. %ato !. !arada T( Transient infantile hyperthyrotrophinae+ia( #rch Dis Child 1B1B:/2<1=:1155012( B1( C. et al( Effects of thyro4ine s*pple+entation on ne*rologic develop+ent in infants 6orn at less than &0 'ee.

A* . !arada %. #+ino -. %ills 9-. Mansen RD. Aerlich M. Konishi M.Araves> disease and the relationship to neonatal hyperthyroidis+( M Clin Endocrinol Meta6 1B1&:)5<)=:10&/020( 112( %. Der'ahl M. 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. et al( Universal predictive criteria for neonatal overt thyroto4icosis re7*iring treat+ent( #+ M $erinatol 1B11:)<2=:1)201( 122( Mats**ra -. $ola.apfel !$. Riv.in LD. !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 -. $*gliese M. 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 $. %chone6erg T. 3. Klein 9( -eonatal thyroid disease: differential e4pression in three s*ccessive offspring( M Clin Endocrinol Meta6 1B11://<&=:/2)05( 11/( Za. Ma+eson ML. Lifshit. Mir. Co*et M. 3*?ieda K. %chreiner RL( Un*s*al +anifestations of neonatal hyperthyroidis+( #+ M $erinatol 1B1):2<&=:2&10)( 11B( Dane+an D.o's.le( C*rr @pin $ediatr 200B:21<2=:)2&01( . Le+ons M#. %tene M.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.ari?a M.i .*.ie MM. #o. 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.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%. et al( Characteri. $asch. 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 #. . @hya+a I.#. !off+an ..*.. Rapaport R( $rediction of neonatal hyperthyroidis+ in infants 6orn to +others 'ith Araves disease( M $ediatr 1BB/:121<2=:2/201( 11)( 3ort $. %cher6a*+ .ing a co+ple4 p*. %*. 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. M*irhead %. %ohle+ann $.Q.er M. "roec.asa M.onero' $. Mo*rdain -. von $etry. McKen.!.a K#.ees %#( $*tting propylthio*racil in perspective( M Clin Endocrinol Meta6 200B:B2</=:111102( 122( de Ro*4 -. "ie6er+ann !.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@.i K. !enschen M. 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.

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

Dre4hage !#. .ees %#.Engl M Med 1B11:&11<10=:)BB0/02( 1/1( van der Aaag RD. "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-. @rti.iersinga . Morgensen EN. T* !M.ed resistance to thyroid hor+one( . Ericsson U".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. $ra6ha.. La+6ert R. MR. El0%ayyid M. !*ot C. Loc.hart L!. Ael'ane A. Root #. -ilsson $. "ode !!. Ar*+6ach MM( $se*dot*+or cere6ri associated 'ith initiation of levothyro4ine therapy for ?*venile hypothyroidis+( . et al( Levothyro4ine treat+ent red*ces thyroid si. @rloff %. "erc* "". 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. Daniels A!.12B( !*ang %#. Dia+ond 3". et al( #ttention deficit0hyperactivity disorder in people 'ith generali.Engl M Med 1B1&:&01<11=:105/010( 1)1( %*r. Zi++er+an D. Martine. "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.in #M.Engl M Med 2000:&2&<&=:11)0B( 1)0( !a*ser $. %+ith . Nan Nliet A( Thyroid scintigraphy in children and adolescents 'ith !ashi+oto disease( M $ediatr 1BB):125</=:B)10&( 1)/( Rovet M3.M. E.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. Koch TK. -elson LM.( #*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.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. Kag*elido* 3 et al( $ositive i+pact of long0ter+ antithyroid dr*g treat+ent on the o*tco+e of children 'ith Araves disease: nat*ral long0ter+ cohort st*dy( M Clin Endocrinol Meta6( 2012: B5:1100B( . %M. Conte 3#. et al( 3*rther st*dies on thyroid gro'th0 sti+*lating i++*noglo6*lins in e*thyroid nonende+ic goiter( M Clin Endocrinol Meta6 1B1):/0<)=:B520B( 1/2( Rother K9.e in children and adolescents 'ith chronic a*toi++*ne thyroiditis( M Clin Endocrinol Meta6 200/:B1<)=:152B0&2( 1/2( Mali N$. 3roehlich M. M$. .s M9. . et al( %evere hypothyroidis+ ca*sed 6y type & iodothyronine deiodinase in infantile he+angio+as( . %ch'en. -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 -. Za+et. 3lac. !arney M. 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 1BB&:&21<12=:BB501001( 1)1( "erc* "".ilson0Davis %L. M*har 9. $. Clar. %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. Dane+an D.

Castanet M.1/)c( Kag*elido* 3.illia+s RC. M( T%! receptor anti6odies( Thyroid 2005:15<10=:B2&0&1( 150( %anders M. 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. M3( !yperthyroidis+ in a pop*lation 'ith Do'n syndro+e <D%=( Clin Endocrinol <@4f= 200B:51<1=:11002( 1/1( Rapoport ". !oer+ann R. M. Leonardi E. 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.. McLachlan %M( The thyrotropin <T%!= receptor: interaction 'ith T%! and a*toanti6odies( Endocr Rev 1BB1:1B</=:/5&051/( 1/B( %+ith "R. $re+a'ardhana LD.Engl M Med 1B12:&0/<11=:/&)0B( 15/( Mariotti %. Levits.elihood of re+ission in children 'ith Araves> disease: a prospective. 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 %. @da I. Ma. 3*r+ania. "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 -%. Ma*+e MC. Marshall -M. Io*ng R#. K. et al( Molec*lar interactions 6et'een the T%! receptor and a Thyroid0sti+*lating +onoclonal a*toanti6ody( Thyroid 2005:15<1=:/BB050/( 152( Rapoport ". Cha. Evans M. %tyne DM( $redicting the li. Lee MM( Transient hyperthyroidis+ in an adolescent 'ith hydatidifor+ +ole( M $ediatr 2002:120<&=:&/20/( 15)( R*i. Kilpatric. Chillaron0Mordan MM. et al( 3a+ilial dysal6*+ine+ic hyperthyro4ine+ia: a syndro+e that can 6e conf*sed 'ith thyroto4icosis( . Cerda0Esteva M. Mig*el R-.y LL. Morgenthaler -A. Io*ng %. "olton M. %anders M. Cano0 $ere. McLachlan %M( The thyrotropin receptor in Araves> disease( Thyroid 2005:15<10=:B11022( 15&( . #l6erti C.oncini ". AD. Kahaly AM( "ioassays for T%!0receptor a*toanti6odies: an *pdate( #*toi++*n Rev . $*carelli 9. et al( !*+an +onoclonal thyroid sti+*lating a*toanti6ody( Lancet 200&:&/2<B&51=:12/01( 151( %anders M. et al( # ne' assay for thyrotropin receptor a*toanti6odies( Thyroid 2002:12<10=:1&00)( 110( "otero D. Martino E. C*pini C. Mr(. 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. 3lores0Le0Ro*4 M#. 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. +*lticenter st*dy( $ediatrics 2001:121<&=:e21101( 112( Rahhal %-. 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. Corretger MM. Ra?atanavin R.en6al. $as7*ino #M( %pecial feat*res of Araves > disease in early childhood( Thyroid 1BBB:B<B=:15105( 1/5( Aoday0#rno #. %anders M. "olton M.

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

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