Pediatric Graves Disease + Author: Lyne Lipton Lewtshy, MD; Chef Estor Stophon Kemp, MD, PRD. mero Undates: oc 08, 2013 Background Graves ciate i the most common cause af hypertycidsm n pda paints. IRis1an mmonemedated daorer tat results fom the production of tyr mlaingimmunogltulins (TS) by imate B ymphactes. Toso immunegebulne bind tote thyo-imulating hormone (TSH) roapor to mimic (See Etiology) Sons and symptoms of thyotne Graves ease ine an enlarged hyo, pt hoat a, widened pul pressure, a hypertyro slare (frequent ink) or franc axahthaimes, ror, sweating, Paptstions, smooth mes skin, fequent bows movorents or dartea,sloplossnes,alleton probloms i soa ira, ond weight ss, (See Cla) Diagnosis requlres identfcaton of suppressed TSH (hyfettopin levels and lovated Iovls of tee thyroin (FT «) andor triodathyronine (rs. Measurement of TSI of teres ut eno oqsed for therapoic evaluation. Twat drt a ltevating symptoms and reducing tyrd harmane prosuchon. Symptoms may be improves by roatmant with bot loceg drugs. Roduction otha hormone sczompsned by use of dug erapy, surges subotl hyroidectomy, er eatmert ‘wih aseactve 'oato (RAD, Because relating TSI can cose Io placa, Infants bom to woman Wt 8 Nstoy ef Graves saase may Nave andl hecnatl Graves thytoxcosi and rqure raat. (See Workup eaters, ane Mogeatons) ‘Athaugh Peny was ett po" hypetyeiesm in Enis, the clase desertion, in 1835, by Grevos became most wily accented. Europeans ten pofr io ‘how below heart won yoni sacra ovale paecage of mtr hyretimalng ‘ne mast common assocaton wih chichood Graves #soase i hstry of other Family mmbore with tyro eisease, On the hor hand, concordance fr Graves Medscape Drugs, Diseases & Procedures‘4ssas in ional wins is oly 30-80%, nscating that gontc and envronmertal featos play a olein tus asease (See Elegy.) Complications Graves eisoass fs potently Ie threatening. The most sovre manifestation of Graves dacase i thyald stm, which carta a mrtalty rk appoacng 100% in Unteatad ads. Sotes conaucted with rower reatmert,ineduang bolaasrenergc blocking agent, show s reduced rok af death now! 20%. THs sucha fae dearer in chern that no comparable ure ae avaiable, (See Prognoss Treatment. ‘hd Medeatens) an eepay Inger consequences of this desde, clung pablo with Patient education Inst ptints woate wih aninyrld drug a to possible avers ffx and the need forces folowua "Patents eat wth surgery and RAl must. thes olowup. Foc patint education information, see the Tyrld and Metabolism Canter, as we Pathophysiology ‘The rasons forth development of Graves dissase are presently urkroan, Specteautoaninoaes areca spans vanou hyo agers and against, proline wih putatively star anigese tes nother sas. road the beta ase ted extraocular masses, The TSH receptor tha most nificant thy autoantigen i th deorder, However, chien win Grave. {d2aase aso rodsee mmunopladuina drated against nyoperodase(ant-TPO) and thyrencbutn, as wall as TSH rocaporlecng atbodos, as maybe ound in vant mphosyie Wyld (Hashim. yoda ‘neste conducted genome-wide assacton study in 1538 indians with Gravoscitoaso an further valated a group of associates sale mucosa palmer (SNP) ina second aa of 3984 caes. The dla cntimea Previously ropoted lod (TSHR, CTLAA, and FORLS) anders 2 noe isco on (RNASE TZ GFREIOP-CCRG region at 8927), aan largenie region at 4pi4. These rely assocated SNPs wero sssocatod wih in expres Towle of BNASET2 a 6927, of CHRNAS, and of» provouy unctaractorzed at 4314, respectaly. Stang assodations of TSH and major Msocompatbly omplex dats Ivars wih persistently TRAD-postve Graves dave wer also identi a hyetoe, However, thyexcol isthe hallmark of mast cases of Graves ‘snaea, In gener, tyotone Graves dcaao 'sconscered in atc. Once! of ‘Graves cease in suscepti indvuale hat varoualy been atrbuted to ate Infections ant physical and emtonal sre ‘The thyroid is enlarged boca of constant TSH recaptr simulation ar the preence af aated TIymphocyles and plasma cls in pseusfalcus paler "Tho thyroid often has a frm, ruboryconistoney whon plpatd, andthe pyarial abe may be prominent. When overainuated by TS, the hyo becomes ta aes and an aula Brut snot uncommen, IF the nya Bocores very age, nay cause posture empioms and egns, clung dial allowing ane hoatsness: Rarely, cher may rat assocated pain Tryrié hormone excess, 25a result of thrid hyporstimaton affects all organ systems Patient wth ye hypertimuaion ae tale and ellen, Me poor Sloop habs, and often reper daytime trednass associated wi noctual insomnia poor handwrting, and deterorating school performance. Neuropeychitnc symptoms an mimi attention dic hyperactivity isrdor (ADHO), yt few hon wih ‘ADHD are actualy @szoverod tobe fetone. ADHO and ryetoccose aro usally ‘atydisingushad by thy examination ané mensuremo of pula and blood pressure Cardovascar simulation by thyroid homane leads to a rapid pulse ate an a ‘imam proconium, Patents sometimes sbjecsvely pot palpitations. The Pallet ype shows a widened pulse pesare Hypermetabcllam usualy lad to ‘Weight lose wth inerated appetite Heat flares is often sb, Muscle wasting i preset, wih deceased muscle stonath.Typcally,srophy of the thea’ and hypathanareminenoes may be doers. The ha becomes fe, eh tomporal hairless often occur. Rare gonetealy determined ndvduals may evap Vytcione pad prays. Daring of he en may oon, most Toicoably in daerscnnad india, and intense pnts may alee occur. The nie pict very ine and most. Swing sntease. Thekening othe Sin (localized mudora) Is almost nover dosed In chchood Graves asea50, In inviuals with sovremypormetabotim, abnormal ver function may be ‘huered th slovatons of serum glamicaaloaratie tensamise (SGOT) ana Serum slutamic pyruvic vansarinase (SGPT). Increases In gu at result In toloes of tone mineral decensed bone dena, and reeutant hypereacura. renal tubule lead o noctura, and. n soma susoaplta chlaren, Ilsa to roctural enuresis, Normal errs oraonaly is he ft dng noted in ‘hldran th Graves @sesneGroat in hight may be enhanced by hyperetabotsm, and bone age may be ‘stance Puberty may be afected. Gis wih Graves disease may have regular, parse menses, nd boys may have sioese estrogen effet bacauoe Of ncrenees ‘elation of slerids fo estogen. Symptoms of gynecomadlia and decreased Mido lr adolescent are ot uncarsman. Etiology raves santo is 3 humoraly mediate autoimmune disorder in wich Inert is nduoed by TSH recopor-sumulating enibedas,n most eeren and ats, theso abodes are ondoqoneus howove, ranepiacontal passage ot immunegcbuin & (4G) aniboses tm woman win Graves ease to ean ‘ay leas fo tne davelopmert of neonatal raves dssass. This sa selHtod ‘sore hat esokes when tn munca. are dared by the neo and ‘may be followed by tansen hypothyroidism fetal ptutary TSH remains ‘The prosanes of atong-ating thyroid stimulator (LATS) was postulated by Acame and Puvos in 1956 and was contra by to nifeation of ho stimultery ‘ecoptr and mimie TSH acon ° Almost ll patents producing TS also produce ater immunsglbulins more Fammoay astodated wih choniymprocye yids, sues ae ntibodos Siecte agains thyoperxcase and thyroglobulin, This suggests close relation bntwoen aves eaoase ad evoielmmphoete tyros Indeed Many Individuals nave thyretoxe components to nae ehrne lymphocytic tno, sna the natural try oF untested Graves naan i that prcorage of duals wh Graves eventually become hypathytd. Moreover yon ates smor To these of ernie phocytes are Found inthe thrid of pavers wh Immunoglbutn produced inthis dsrder may be measured by numerous in vito assay. Because theso assays may measure fort aspects of mmunoglobuln Tieton, reste in ferent assays may be Gscropent. For istanco, TSHeceptor Dining is measuod in assays of tryros-inding mmunegcbuls 7B), woereas "Toitrceplor acai op, ered avalon of adeny plas) eared by TSI or thyoiéstmulatng artboses (SAD) ‘Some immunoglobulins may bina to the TSH ecepor who stimulating and ‘ay sla block he ation of TSH (o-alos ose abodes). Thewe may be proses in ndicuae with Graves disease or chon hmphooyt thy, Graves esoasa I nat entirely underatod, ana competing typatreses have rat ye, Nonetheless, histoconpatiiy antigen haplotypes commonly ssacted wth he ‘ulommune dsorcers (88, DRS) hae also besn lea to Gteves doase, ‘An infectious etiology of thystocose has bean postulated based on eccurenoe Frequency unelates family members, An assceation wih Yara enor Infection has been dese but hee not been fly confmed case-control sues nave suggested an assocatin wth rece: Ife sess. The fomtal occurence of hyotocons sx wall ath autoimmune hyo iors, Sggests gonattelink that may be mote powerful than that othe histocompateiiy angen assoatin. Epidemiology Occurrence in the United States once of Graves disease in cilood inthe Usted States has not been "An ncience of ©2-0.4% has been opecustd but a obeys ‘reostimaton. Approximately 10% of infants bom fo wemon with Graves cscas6 fave elevation of tyrold homone levels bony Y-2%have dives ptm ot Uhyotoezose, ‘Danish study identifies» national incidence deny for thrtosicsis of 0.79 ‘aes por 100,000 peconsear in cron ages 014 yar “linddence dons Increases dung ienooa, wih a eax neience of O48 cases po 10,000 porsons for boys and 3.01 cases per 100,000 persons fr gis, ape 10-14 years Racer, sex, and age-related demographics No race predeton for Graves daeage' apparent. thas been reported In every population sucod In whos, Graves dsoaa ie associated win cartain Ftocompatttyantgune fe, DR. DR) tat have prevousy bean ink to ther ‘utsmmune disrces, The Ink between histocampatsiy antigen subtypes and Proponderanco hasbeen estimates to bo 47 gis fr every boy aectod ‘The incdence of Graves cseat increases wih age, reaching a chishood peal ding adelesconce. Graves disease Is avery rare caus a yflencosi in elon younger than age 8 years. Prognosisraves sinate i 9 cronies without tue cut. None of he management oplios for this sore actual remove tba undering inmunoogie dart tho prognosts of he sloror greatly dopends on ts form of therapy ‘Antithyroid drug therapy In one roviow, 48.8% of patients had 3 pormanertromsson flowing dug leatment or vaate numb f yaar, and 29% hada flaps6. O's popdation of 651 cnleron, cule frm a umber of epors, 6.6% of patents dveloped ‘ancoyopona 23% had ari, 9% ha Iver ease, and 8 aoveoped @ $e ash The lklinood of rmission fs greater tho nad gland is smaller, he Fadsctve line uptake (RAIL rally low, snd TSI leva ae lower ‘statistical anata of ieren who had longterm drug eaten sugested that ‘pproimately 25% of cern have remision every 2 years. This romlason rate Senos, and iis loner than ie mason ale obeared i Sa Subtotal thyroidectomy ‘A revi of outomas in $55 children, taken from saveral large aria, suageeted that 42% of patios cderging sustal hyo bacome hypothyr and that 10% nave recur, Inthe combined sven, 2% of paints naa hypoparathyecem. 12% had vocal cor paralysis, 0.2% had Boadg, 1.7% had alold formation, and.S% were dscoverad to have papllay cancer by tly. Radioactive iodine therapy Ina roew of outcomes of 855 ceren, taken fom several lage sais, 69% of hilbren ho underwent asaacve ane therapy became hypalhyta, 8% ‘iperionced cre of hypernyoim, 12% requed erent, 27d 4.4% Nad Fistalogiay benign neds The pra today most conte eto am for hypothyr, which would change these fue, Complications Hypnos lea to hperaloaia an lst of Bone mineral ding childhood fd adcleecenc, In saver thyotonc naidua. asaszomant of bone mineral by ‘ial evra raciograghic absorptiometry (ORA) may be ade ‘Try storm is he most sovere fom of thyrotoxicosis an can be provoked by surgical or mecca sess an unaiagrosed thot hada, ther autoimmune disorders con be asscited wih Graves disease including type ‘aiaoetes malts, Adizon dna, wig, alopeca, and lips “Treatment complication inde the flowin + Severe drug reaction to methimazole or propylvowacl PTU) ndusing liver esas pus, ana agranaloctoss + Surical complications, nding hypopaatnytidsm or ecurent lange owe damage + Rare incuation of hypoparainyoiim post-RAI therapy anda questonable gh inerose ne ik of Vy cane: «Feu wi hyo ablation i woman Wate with RAI cuting progeny Clncal Presentation Contributor information and Disclosures Autor {Lynne Lipton Levitsky, MD Chie, Pediat Endocsino Unit, Massachuslts Goneral Hostal, Associls Drotasort Pesatns, Harvard Madea Schoo! Lyme Lipton Leisy, MD Isa member of he flowing meal sodas: Alps Omege Alpha, American ‘Atademy of Peaatits, American Daotes Assocation, American Pedatie Sodety, Endocine Society, Pedatc Dladosure: Receive eranteseardh unde from El Lily or pi Received grantesoach fund tom Nowak fori: Rocolved consulting fos fort NovoNorsk for consul, Parner rated cansuting fo fom Onyx Hoar Vale fo conan. coauthors) Sun! Sinha, MD Assistant Profesor, Divison of Pelatic Endocrinology and Metals, Department of Peale, Unersy of Tennesse Heath Scones Cater Sunt Sinha, MO is a member of he foloang modal soitos:Amrian Academy of Patti, American [Assooatlon of Cn Enaconnaogist, Enasoina Sooaly, Pasa Endocine Sooty Dlstosure: Netting to asctose cet Ector ‘Stephen Kemp, MD, PhO Profesor, Deparment of Peciatcs, Section of Pediatr Endocnoogy, Univers of ‘ArNansas for Medial Scencss Colege of Medina, Ananaas Chiwrens Hospital ‘Sepen Komp, MD, PRD is 2 member ofthe folowing maeal socses: American Academy af Pesatcs, [Amerean Assocation of Cal Endocnelogiss, Aran Pedatre Soda, Endocine Soity, Ph Bota ‘appa, Southern Medica! Atsodatan, Souham Soaty for Pela Resear Disctosure: Nothing to dstose Aeoowlesgements ‘George P Chrouses, MD, FAAP, MACP, MACE, FRCP{London) Prcfssor and Cha, Fst Deparment of Pests, Athens University Meszal Sehel, Aghia Sophia Chron Hospta, Grosse; UNESCO Chal on ‘Adoloscan Heath Care, Unieraty of Athens, Grosce‘George P Orautas, MD, FAAP, MAGP, MACE, FRCP{Lonéon) isa member of the fing medial sci ‘Amercan Academy of Podatncs, Amencan Callege of Endociclogy. Ameican Calle af Physicans, Amerean Podiate Sorily, American Sods for ClricalInvesigation, Assocation o American Physcians, Endocrine Society, Pediatr Endocrine Sodky, and Soaly fr Pediatrie Research issue: Nothing to asctose ‘Robert J Ferry Jr, MDL Bonheur Cha of Exalane n Endcernlagy, Profesor and Chie, ivilon of Poste Endocinology and Welabalsm, Doparimon: of Pedals, Unvorty of TennessooHoath Sconco enter ‘Robert J Fry J, MD is 2 member of he flowing medial societies: Amarin Academy of Peas, ‘Amorcan Dibotos Associaton, Amicon Medal Assocation, Ensoorne Sosy, Posatc Ensoosne Seay, Soda for Pedic Reser, and Teras Peale Sodely Dlsdoaute: EU Lily & Co Graniesearch funds Investigator; MacroGercs, ne Grantesearch funds Ivestigatr, Ipson. Sk (formery Tocca, Ine] Graniesearct fund Investigator NowNordek SA Gretrooarch fund Irveagatr Diary Grantees unde Investig, BrstaAyers-Squbb Grareearch funds Other, Amylin ‘Ott Pear Graresearch funds Other, Takeda Gratresearch funds Other ‘Thomas A Wilson, MD Profestor of Cincal Peat, Chi and Program Director. Division of Padiaic Endostnalogy, Deparment of Pees The Sehoa ol Medne a Stony Brook Univeraly Medial Cee ‘Thomas A Wilson, MD isa member af the fling medical socio: Endouine Sodaly, Peale Ensocine Society, ana ®m deta Kaspa Disclosure: Nothing to esctse Mary L Windle, PharmD Adjunct Associate Profesor, Univers of Nebraska Medical Center Cale of Pharmacy, Estorin-chel, Medscape Drug Reterence Diode. Nothing to ssse “The auors and eco of Medscape Referancagalfuly ackronladge ta contrbutions of previous thor Lyme L. Lovialy, MD othe erga wring and development of ts arta. References 1. OnyoH, Minagawa A. Noh JY, MukasaK, Kun, Watanabe N, otal. 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