disorders of the thyroid gland in infancy childhood and adolescence

8/12/2019 Disorders of the Thyroid Gland in Infancy Childhood and Adolescence

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Disorders of the Thyroid Gland in Infancy,

Childhood and Adolescence

Last Updated: March 21, 2012

Authors

Rosalind S. Brown, M.D.

Director, Clinical Trials Research Division of Endocrinology, Childrens !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 )) Lae #ven*e-orth .orcester, M# 01/)) Tel: 1)0)/20 3a4: 1)0)/25

Thyroid hor+one is essential for the gro'th and +at*ration of +any target tiss*es, incl*ding the 6rain

and seleton( #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 effectson the gro'th and 8or +at*ration of these thyroid hor+onedependent tiss*es as 'ell( 9n +ost

instances, there are critical 'indo's of ti+e for thyroid hor+onedependent develop+ent and so the

specific clinical conse7*ence of thyroid dysf*nction depends on the age of the infant or child( 3ore4a+ple, ne'6orn infants 'ith congenital hypothyroidis+ fre7*ently have hyper6ilir*6ine+ia, and

delayed seletal +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 s o'n thyroid gland 6*t 6ythe 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 thyroidhor+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(
http://www.thyroidmanager.org/chapter/disorders-of-the-thyroid-gland-in-infancy-childhood-and-adolescence/http://www.thyroidmanager.org/chapter/disorders-of-the-thyroid-gland-in-infancy-childhood-and-adolescence/http://www.thyroidmanager.org/chapter/disorders-of-the-thyroid-gland-in-infancy-childhood-and-adolescence/http://www.thyroidmanager.org/chapter/disorders-of-the-thyroid-gland-in-infancy-childhood-and-adolescence/


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Ontogenesis of thyroid function in the fetus and

infantThe ontogeny of +at*re thyroid f*nction involves the organogenesis and +at*ration of thehypothala+*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 factorsother than T that i+pact on thyroid f*nction( 9n the first half of pregnancy, +aternal T provides an

i+portant so*rce of hor+one for the developing fet*s( M*ch of o*r no'ledge derives fro+ 'or inani+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*+anco*nterpart and significant +at*ration of the thyroid gland and of the hypothala+icpit*itarythyroid

a4is in this species occ*rs in the first 2 or & 'ees 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!ryogenesisThyroid 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 +edialo*tpo*ching fro+ the floor of the pri+itive pharyn4, the prec*rsor of the thyro4ine


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3ig*re 1) 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 'ees gestation #t this stage, tiny follicle

prec*rsors can 6e seen, iodine 6inding can 6e identified and thyroglo6*lin


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

The hy"othalaic#"ituitary a$is

T%! is detecta6le at levels of & to +U8L at gestational age 12 'ees and increases +oderately over

the last t'o tri+esters to levels of / to +U8L gestation


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3ig*re 1)2( 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


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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 T in the fetal thyroid econo+y 'as rea'aened 'ith therecognition that in infants 'ith the congenital a6sence of thyroid pero4idase, the cord ser*+

concentration of T is nonetheless 6et'een 2) and )0 of nor+al


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pregnancy o n fetal 6rain develop+ent( #t variance 'ith the afore+entioned st*dies, Li* et al , and+ore recently, Mo+ota+i et al failed to de+onstrate any 9 deficit in 6a6ies 6orn to hypothyroid

+others as long as the hypothyroidis+ 'as corrected 6y the end of the second tri+ester


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+ared increase in T& fro+ its lo' 6asal levels in cord ser*+ can 6e e4plained 6y the a6r*pt increasein T%!, the si+*ltaneo*s fall in reverse T& and T& s*lfate are consistent 'ith an increase in D1 activity

occ*rring at the sa+e ti+e( D2 has 6een identified in h*+an 6ro'n adipose tiss*e as 'ell as 6rain and

the ac*te increase in T& in adipose tiss*e at 6irth is re7*ired for opti+al *nco*pling protein synthesis

and ther+ogenesis < &), &/ =(

%reature infantsThyroid f*nction in the pre+at*re infant reflects, in part, the relative i++at*rity of the hypothala+icpit*itarythyroid a4is that is fo*nd in co+para6le gestational age infants in *tero( 3ollo'ing delivery,

there is a s*rge in T and T%! analogo*s to that o6served in ter+ infants, 6*t the +agnit*de of the

increase is less in pre+at*re neonates


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iodide stores


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hypothyroidis+ 'as de+onstrated convincingly( 9n a st*dy 6y Klein et al, 5 of infants 'ithcongenital hypothyroidis+ treated 6efore & +onths of age 6*t 0 treated after / +onths of age had an

intelligence 7*otient


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+U8L are +ost liely to have per+anent congenital hypothyroidis+ 'hile a T%! 6et'een 20 and B+U8L is fre7*ently a false positive, or represents transient hypothyroidis+, a pro6le+ that is

partic*larly co++on in pre+at*re infants in 6orderline iodine deficient areas of E*rope(

Each screening strategy has its advantages and disadvantages, 6*t the t'o approaches appear to 6e

e7*ivalent in the detection of 6a6ies 'ith per+anent for+s of congenital hypothyroidis+


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Recently 'ith the develop+ent of +ore sensitive, nonradioisotopic T%! assays, Canada and so+estates in the United %tates have s'itched to a pri+ary T%! progra+( 9n practice, the screening strategy

*tili;ed is chosen 6y the screening progra+(

-e'6orn screening 'as perfor+ed initially at 6et'een & and 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'isehealthy f*ll ter+ infants has res*lted in a greater proportion of 6a6ies 6eing tested 6efore this ti+e( 3or

e4a+ple, it has 6een esti+ated that in -orth #+erica 2) or +ore of ne'6orns are no' discharged'ithin 2 ho*rs of delivery and 0 in the second 2 ho*rs of life


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3ig*re 1)) ( Three +onth old +ale infant 'ho 'as diagnosed clinically 'hen he presented 'ith ahistory of poor feeding at & +onths of age( The child 'as 6orn in $*erto Rico prior to the develop+ent
http://www.thyroidmanager.org/wp-content/uploads/2011/06/25-5.jpg


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of ne'6orn screening and +oved to the United %tates shortly thereafter( -ote the d*ll facies, perior6italede+a and large tong*e(

Causes of %eranent Congenital 'y"othyroidis

Thyroid DysgenesisUnlie in iodinedeficient areas of the 'orld 'here ende+ic cretinis+ contin*es to 6e a +a?or health

ha;ard, the +a?ority


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PAX8 2711(2 #D

Abnormal thyroid hormono!n!'i'

Decreased T synthesis

N(S 1Bp121&(2 #R

TPO 2p2) #R

)*OX2+ 1)71)(& #R TG 72 #R,#D

)EHA,1 /722) #R

S,-2A/$P)S 57&1 #R

Decreased T%! synthesis

@ther pit*itary hor+one deficits

POP1 )7 #R

PO*1F1 &p11 #R,#D

,HX3 B7&(& #R

,HX/ 172) #R,#D

HESX1 &p21(2p21(2 #R,#D

9solated decreasedT%!

TH &p #R

TH 17&1 #R

TSH 1p1& #R

Decreased T%! response

TSH 17&1 #R

G' 2071&(2 #D

Abnormal thyroid hormon! ation

T &p2(& #D

4-T8 Q71&(2 Qlined

SE-(SBP2 B722(2 #R

O*s*ally sporadic, P#D, a*toso+al do+inant, PP #R, a*toso+al recessive, %5'5ally'yndromi+#!rman!nt6h!nbiall!li7tran'i!nt6h!nmonoall!li7

In!orn -rrors of Thyroid 'oronogenesis

9n6orn errors of thyroid hor+onogenesis are responsi6le for +ost of the re+aining cases


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These incl*de defects in the genes for the T%! receptor < TSH=, the sodi*+iodide sy+porter


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a6nor+al +idline facial and 6rain str*ct*res 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, theoriginal esti+ate 'as 1 in 0,000 infants, e7*ivalent to appro4i+ately 10 of all cases of congenital


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hypothyroidis+( Recent data s*ggest that the condition is no' +ore than threefold +ore co++on


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ii+ Maternal Antithyroid Medication

Transient neonatal hypothyroidis+ +ay develop in 6a6ies 'hose +others are 6eing treated 'ithantithyroid +edication disease( Even +aternal $TU doses of 200 +g or less have 6een associated 'ith an effect on neonatal

thyroid f*nction, ill*strating the increased fetal sensitivity to these dr*gs < 5=( "a6ies 'ith $TU orMM9ind*ced hypothyroidis+ characteristically develop an enlarged thyroid gland and if the dose is

s*fficiently large, respiratory e+6arrass+ent +ay occ*r( "oth the hypothyroidis+ and goiter resolvespontaneo*sly 'ith clearance of the dr*g fro+ the 6a6y > s circ*lation( Us*ally replace+ent therapy isnot re7*ired(

iii+ Maternal TS' Rece"tor Anti!odies

Maternal T%! receptor 6locing anti6odies, a pop*lation of anti6odies closely related to the T%!receptor sti+*lating anti6odies in Araves disease, +ay 6e trans+itted to the fet*s in s*fficient titer to

ca*se transient neonatal hypothyroidis+( The incidence of this disorder has 6een esti+ated to 6e 1 in

10,000 < =( T%! receptor 6locing anti6odies +ost often are fo*nd in +others 'ho have 6eentreated previo*sly for Araves disease or 'ho have the non goitro*s for+ of chronic ly+phocytic

thyroiditis


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$rognosis -or+al 4ay b! d!lay!d

Transient Central 'y"othyroidis

i+ Maternal hy"erthyroidis

@ccasionally, 6a6ies 6orn to +others 'ho 'ere hyperthyroid d*ring pregnancy develop transienthypothala+icpit*itary s*ppression < B1=( This hypothyro4ine+ia is *s*ally selfli+ited, 6*t in so+e

cases it +ay last for last years and re7*ire replace+ent therapy < B2=( 9n general the titer of T%!

receptor sti+*lating anti6odies in this pop*lation of infants is lo'er than in those 'ho developtransient neonatal hyperthyroidis+


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sit*ation of co+6ined +aternalfetal hypothyroidis+( Many of the classic feat*res


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increasingly pop*lar alternative to thyroid scintigraphy to provide infor+ation a6o*t the si;e andlocation of the thyroid gland and so, disting*ish a6nor+alities of thyroid develop+ent


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9n 6a6ies in 'ho+ hypothyro4ine+ia *nacco+panied 6y T%! elevation is fo*nd, a free T sho*ld 6e

+eas*red, prefera6ly 6y a n e7*ili6ri*+ dialysis +ethod and the T"A concentration sho*ld 6e

eval*ated as 'ell( The finding of a lo' free T 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 6eperfor+ed in these infants( The *tility of TR! testing, *sed for +any years to disting*ish 6et'een a

hypothala+ic or pit*itary defect, has 6een 7*estioned < 101=( 9n any case, TR! is no longer availa6le

for testing in the U%( 9n pre+at*re, lo' 6irth 'eight or sic 6a6ies in 'ho+ a lo' T and a J nor+al >T%! are fo*nd, the free T 'hen +eas*red 6y a direct dialysis +ethod, fre7*ently is not as lo' as the

total T( 9n the latter infants T


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hypothyroidis+ sho*ld 6e started on the lo'er dosage, 'hile those 'ith severe congenitalhypothyroidis+


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g8g8day co*pled 'ith T& for the first 2 'ees of postnatal life 'as associated 'ith s*ppression of T%!and an increased incidence of necroti;ing enterocolitis, s*ggesting that this dose +ight 6e e4cessive(

.hile the cognitive o*tco+e data of these 6a6ies is not yet no'n , it is clear that +ore data are

needed( 9n the +eanti+e, it 'o*ld see+ reasona6le to treat only pre+at*re infants 'ith

hypothyro4ine+ia and a nor+al T%! only in the conte4t of a clinical trial( 9n all pre+at*re every effortsho*ld 6e +ade to ass*re ade7*ate iodine intae, treat the pri+ary illness and to avoid, if possi6le,

dr*gs


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

Clinical anifestations

#ltho*gh +aternal T%! receptor anti6ody+ediated hyperthyroidis+ +ay present in *tero, +ost often

the onset is d*ring the first 'ee of life( This is d*e 6oth to the clearance of +aternallyad+inisteredantithyroid dr*g s circ*lation

and to the increased conversion of T to the +ore +eta6olically active T& after 6irth( Rarely, as notedearlier, the onset of neonatal hyperthyroidis+ +ay 6e delayed *ntil later if higher affinity 6locing

anti6odies are also present( 3etal hyperthyroidis+ is s*spected in the presence of fetal tachycardia


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clos*re of the cranial s*t*res


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Thera"y

9n the fet*s, treat+ent is acco+plished 6y +aternal ad+inistration of antithyroid +edication( Untilrecently $TU 'as the preferred dr*g for pregnant 'o+en in -orth #+erica, 6*t c*rrent

reco++endations s*ggest the *se of MM9 rather than $TU after the first tri+ester 6eca*se of concerns

a6o*t potential $TUind*ced hepatoto4icity < 12&=


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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, lie Araves disease is a co+ple4 genetic disorder in 'hich as +any as20/0 i++*nos*scepti6ility genes, each 'ith s+all effect, have 6een post*lated < 12B= and in 'hich the

trigger is *nno'n( "oth thyroidspecific 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 topredo+inate only in Araves disease( .hereas in chronic ly+phocytic thyroiditis, ly+phocyte and

cytoine+ediated thyroid destr*ction predo+inates, in Araves disease anti6ody+ediated thyroid

sti+*lation occ*rs, 6*t overlap +ay occ*r in so+e patients(

"oth a goitro*s

striing predilection for fe+ales and a fa+ily history of a*toi++*ne thyroid disease


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hypothyroidis+


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or along the co*rse of the thyroglossal d*ct( %i+ilarly, children 'ith in6orn errors of thyroidhor+onogesis +ay only 6e recogni;ed later in childhood 6eca*se of the detection of a goiter(

Drugs or Goitrogens

9n addition to antithyroid +edication, a n*+6er of dr*gs *sed in childhood +ay affect thyroid f*nction,incl*ding certain anticonv*lsants, lithi*+, a+iodarone, a+inosalicylic acid, a+inogl*tethi+ide and

sertraline < 1, 1) =( %i+ilarly, a large n*+6er of nat*rally occ*rring goitrogens


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Clinical Manifestations

The onset of hypothyroidis+ in childhood is insidio*s( #ffected children often are recogni;ed either6eca*se of the detection of a goiter on ro*tine e4a+ination or 6eca*se of a poor interval gro'th rate

present for several years prior to diagnosis( "eca*se the deceleration in linear gro'th tends to 6e +ore

affected than 'eight gain, these children are relatively over'eight for their height, altho*gh they rarelyare significantly o6ese !erc*lean > appearance is no'n as the KocherDe6re%e+elaign e syndro+e < 1)2=(

$*6erty tends to 6e delayed in hypothyroid children in proportion to the retardation in the 6one age,

altho*gh in longstanding severe hypothyroidis+, se4*al precocity has 6een descri6ed( 3e+ales 'ith

se4*al precocity have +enstr*ation, and 6reast develop+ent 6*t relatively little se4*al hair( M*lticysticovaries, the etiology of 'hich is *nno'n, +ay 6e de+onstrated on *ltrasonography( 9n other cases,

galactorrhea or severe +enses have 6een the presenting feat*res( 9n 6oys, testic*lar enlarge+ent +ay

6e fo*nd < 1)&=( #n elevation in ser*+ prolactin, the latter possi6ly d*e to elevated TR! 'hich is
http://www.thyroidmanager.org/wp-content/uploads/2011/06/25-8.jpg


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no'n to sti+*late prolactin as 'ell as T%!, has 6een descri6ed in so+e cases, 6*t gonadotropin levelsare not consistently elevated( 9t has 6een hypothesi;ed that this syndro+e of pse*dop*6erty in

hypothyroid patients is d*e to cross interaction of the e4tre+ely elevated ser*+ T%! 'ith the 3%!

receptor < 1)=( Consistent 'ith the latter hypothesis, there is little increase in ser*+ testosterone as

+ight 6e e4pected if the 3%!, 6*t not l*teini;ing hor+one


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Treat+ent of children and adolescents 'ith s*6clinical hypothyroidis+


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

Clinical Manifestations and 2a!oratory In0estigation

Eval*ation of thyroid f*nction 6y +eas*re+ent of the ser*+ T%! concentration is the initial approach

to diagnosis( 9n e*thyroid patients, the +ost co++on sit*ation, chronic ly+phocytic thyroiditis sho*ld

6e disting*ished fro+ colloid goiter( Clinical e4a+ination in 6oth instances reveals a diff*sely enlargedthyroid gland( Therefore, the distinction is dependent *pon the presence of elevated titers of T$@ and

Tg anti6odies in chronic ly+phocytic thyroiditis 6*t not colloid goiter( #ll patients 'ith negativethyroid 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, 1/& =( # significant

decrease in goiter si;e in patients 'ith chronic ly+phocytic thyroiditis as assessed 6y standard

deviation score on *ltrasonography has 6een de+onstrated recently in patients treated for & years

< 1/&=( !o'ever, the a6sol*te difference 7*antitatively 'as not reported and so, 'hether or not thisdifference 'as signicant clinically re+ains *nclear( Aiven the varia6ility in response in different

patients, it 'o*ld 6e reasona6le to atte+pt a therape*tic trial in patients 'hose goiter is large(

%ainful thyroid$ainf*l thyroid enlarge+ent is rare in pediatrics and s*ggests the pro6a6ility of either ac*te


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endocrine( These incl*de dia6etes +ellit*s, #ddison > s disease, vitiligo, syste+ic l*p*s erythe+atosis,rhe*+atoid arthritis, +yasthenia gravis, periodic paralysis, idiopathic thro+6ocytopenia p*rp*ra and

pernicio*s ane+ia( There is an increased ris of Araves disease in children 'ith Do'n syndro+e


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Ta!le5( Differential diagnosis of thyroto4icosis in childhood(

'y"erthyroidis

Diff*se to4ic goiter nor+al > or slightly elevated( 9f the latter

diseases are s*spected, free alpha s*6*nit sho*ld 6e +eas*red( #lternatively, an elevated T level in

association 'ith an inappropriately J nor+al > T%! +ay 6e d*e to an e4cess of thyro4ine6inding

glo6*lins


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protein a6nor+alities


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therapy in +ost st*dies is & to years years, 6*t therapy sho*ld 6e individ*ali;ed( 9n patients treated'ith antithyroid dr*gs alone, a s+all dr*g re7*ire+ent, s+all goiter, and lac of or6itopathy are

favora6le indicators that dr*g therapy can 6e tapered grad*ally and 'ithdra'n( Lo'er initial degree of

hyperthyro4ine+ia


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#ss*+ing a reasona6le R#9U of )0 and gland si;e of 0 g+, the ad+inistered dose 'o*ld 6e 0


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to s*rro*nding tiss*es or if there is a fa+ily history of thyroid cancer( @ther 'orriso+e findings incl*dea history of rapid increase in si;e, associated cervical adenopathy, hoarseness or dysphagia( Even the

findings of a cystic co+ponent or a f*nctioning nod*le, co++only *sed as favora6le signs in ad*lt

patients, do not co+pletely e4cl*de the possi6ility of neoplasia < 1BB=( @ccasionally, thyroid cancer

presents in childhood as *ne4plained cervical adenopathy, or neoplasia is fo*nd in patients 'ho alsohave chronic ly+phocytic thyroiditis < 1BB=( The possi6ility of a rare +ed*llary thyroid carcino+a

sho*ld 6e considered if there is a fa+ily history of thyroid cancer or pheochro+ocyto+a or if the child

has +*ltiple +*cosal ne*ro+as and a +arfanoid ha6it*s, findings s*ggestive of +*ltiple endocrineneoplasia


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Ccell derived +alignancy < 20=( M*tations of the RET protooncogene, detecta6le in nearly allfa+ilial for+s of MTC, is of val*e in screening fa+ily +e+6ers < 200, 20 =( 9n fa+ilies affected 'ith

+*ltiple endocrine neoplasia type 2, screening of children as yo*ng as ) years follo'ed 6y total

thyroidecto+y has 6een s*ccessf*l in c*ring patients 'ith +icroscopic MTC, an other'ise highly

+alignant neoplas+ 'ith a poor prognosis < 200=(

@pti+al +onitoring of patients 'ith a history of thyroid irradiation d*ring childhood re+ains

controversial( "eca*se of the insensitivity of clinical palpation, reg*lar assess+ent of thyroid f*nction


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Clin Endocrinol


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Meta6 1BBB


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/&( Kr*de !, %ch*t; ", "ie6er+ann !, et al( Choreoathetosis, hypothyroidis+, and p*l+onaryalterations d*e to h*+an -KQ21 haploins*fficiency( Clin 9nvest 200210B


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5B( Dattani ML, Martine;"ar6era , Tho+as $, et al( Molec*lar genetics of septooptic dysplasia(!or+ Res 2000)& %*ppl 1:2/&&(

0( Machinis K, $antel , -etchine 9, et al( %yndro+ic short stat*re in patients 'ith a ger+line +*tation

in the L9M ho+eo6o4 L!Q( #+ !*+ Aenet 2001/B disease( - Engl Med 1B1&0


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B/( Calaci*ra 3, Motta RM, Miscio A, et al( %*6clinical hypothyroidis+ in early childhood: a fre7*ento*tco+e of transient neonatal hyperthyrotropine+ia( Clin Endocrinol Meta6 20025


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Araves> disease and the relationship to neonatal hyperthyroidis+( Clin Endocrinol Meta61B&)5 diseaseand o*tco+e in their offspring( Lancet 1B1


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1&1( 3oley T$, r(, #66assi N, Copeland KC, Dra;nin M"( "rief report: hypothyroidis+ ca*sed 6ychronic a*toi++*ne thyroiditis in very yo*ng infants( - Engl Med 1BB&&0s The

Thyroid( th ed( $hiladelphia: Lippincott .illia+s \ .ilins 2000(

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