Congenital Hipotiroid

8/12/2019 Congenital Hipotiroid

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1967;40;283PediatricsMARGARET H. MACGILLIVRAY, JOHN D. CRAWFORD and JOHN S. ROBEY

Congenital Hypothyroidism and Prolonged Neonatal Hyperbilirubinemia

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In M ed ic ine on e m ust p ay a tten tion n ot to p la usib le theo riz ing bu t to exp erienc e and re aso ntogether . . . . I ag ree th at th eo riz ing is to be app rov ed , p rov ide d tha t it is b ase d on facts, an dsystem atic ally m ak es its de duc tio ns from w hat is observ ed . . . . B ut co nc lusion s d raw n fromu naided reaso n c an h ard ly be serv icea b le ; on ly tho se draw n from o bse rve d fac t. H ipp ocrate s:Precep ts.

. . .Sh ort comm unica tions o f fac tua l mate r i a l are pub lished here . C omm en ts an d cr itic ism s appear

as Le tter s to th e Ed i tor .

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xperien ce and eason B rie fly R ecorded

ongen ita l ypo thy ro id ismand P ro longed N eonata l

yperbi l i rubinemiaIn tense neon ata l jaund ice of lo ng duration is

an un co m m o n and p uzz ling con com itan t o fcon gen ita l m y xedem a . T he assoc iatio n w aso rig inal ly do cu m e nted b y A kerren in 195 4an d con firm ed by C h ristensen in 19 56 .2

T h is repo rt d ocum ents th e d irec t causa l re -la tion sh ip be tw een co ngen ita l m y xedem a andhv perb il irub ine m ia in a pat ien t in i tia l ly p re-sen ting in the n ew b orn per iod . T he sub se que ntreco gnitio n o f m yx ede m a an d tre atm en t w ithtriio do thy ron ine (T ,) w as associated w ithp rom pt fall in b ili rub in leve ls an d a n im prove -m ent in thyro id sta tus. A cc id en ta l w ithd raw alo f trea tm en t w as fo llo w ed by an early recur-renc e of jau ndice and m yx ede m a . R ein stitu tio no f thy ro id rep lace m e nt led o nce aga in to n or-m a l b iliru b in lev els and e u th yro id ism .

CASE H ISTORYC . W ., an in fan t g irl, w as b orn of a fu l l-te rm ,

firs t p regn anc y w ith a 7-ho ur labo r and b reec hvag in a l d eliv er y . E xc ep t for frequ en t upper r es -pirato ry in fec tion s, the pregn anc y w a s w itho u tinciden t. A t b irth h er w eigh t w as 6 lb , 2 oz a ndshe m e asu red 1 9 in . in len g th . H ead circum fe r-en ce w a s d isp rop ort ion ately larg e, be lon g in g inthe 90 th pe rce n ti le . O n the sec ond d ay of life ,ja un(lic c w hic h c ould not be exp lain ed on th eba s is o f a m ate rn a l-feta l b loo d group incom pati-bil ity w a s re corded . P hy sio log ic jaun dic e w as a s-s u m e d the ca use o f the icteru s and n o fu rth ers tud ies w e re pe rform e d at tha t tim e. T ota l b ill -ru b in lev el on the fo urth day of li fe w a s 2 0 m gw ith 19 .4 m g/1 00 m l u nco nju ga ted . T h e infan t as d isc ha rg ed c lin ical ly w ell o n the fifth d ay w itha b iliruh in of 17 m g /10 0 m l.

In the fo llo w in g 3 w ee ks w hile at hom e, th erew a s inc rea sin g in ac tiv ity an d th e bab y w as de -scribed a s be ing to o goo d . Jaun dic e pe rsis ted ac -co m p anied b y s too ls of n orm al co lor , c ons istenc y ,and fre que ncy . U rine co lor w a s no rm a l. B re astm ilk fe ed ings , w hic h w ere beg un a t b irth , w erec ont inue d .

A surv ey of th e fa m ily h is to ry reve ale d bo th pa r-en ts w ere h eal thy , an d n o rela tive ha d be en ill w ithja un dice or thyro id d ise ase .

A t 1 m onth of a ge bec ause o f pe rsis ting jaun dic e,in crea sin g leth arg y , an d p oor fee d in g , th e in fan tw as re adm itted for further e valuation . O n p hys ica le xam ina tio n she w as in ten sely ic ter ic and rath erod d in ap pe aran ce. H e r fa ce w as sm all re la tiv e tohe ad siz e an d th ere w as an e xce ss o f lon g , stra ig h t,fin e ha ir w h ich seem ed to s tan d o n end g iv ing a porcup ine a ppe ara nce . M arked in act iv i ty andg ene ral ize d hy po ton icity w ere e v id en t. R ep eate de xposure to lou d n oises fai led to elic it s ign s ofa ud ito ry pe rce p tion . T he liv er ed ge w as palpab le2 c m be low th e r igh t cos ta l m a rg in ; the sp leenw as not en larg ed . N e uro log ic ex am inat ion d isc losedg ene ral ize d br isk ref lex es, s low m u scle re lax atio n ,an d hyp oton icity . U r ine and stoo l co lor w e re nor-m l

B reas t m ilk feed ing s w ere co ntinue d thro ug hou tth is hosp ita l ad m is sio n and un til the in fan t w as 5m on ths of ag e.

L a bo rato ry stu d ies sh ow ed th e fo llo w in g : h em o-g lob in , 14 .6 g m /1 00 m l; W B C , 8 ,90 0; p o ly m o rph s,4 4 % ; lymphocytes, 46% . U rin aly sis w a s no rm al.T o tal b iliru b in leve ls o n thre e oc cas ion s w e re 12 ,1 0 , an d 9 .5 m g/1 00 m l w ith d ire ct b ilirub in valuesof 0 .2 , 1 .3 , a nd 1 .4 m g, re spe ctiv ely . A lk alin e p hos -p hatase w a s 23 .3 B o dan sky u nits; tra nsa m inase w a s65 u nits pe r 1 00 m l. C e reb rosp in al flu id w as ictericb u t o th erw ise n orm al . N o in trac ere bra l calc ific ationswere seen in sk u ll film s but the su tu res w ere w idelyse pa rate d . T ox oplasm os is dy e te st w as ne gative a ndthe ele ctroen cep ha log ram w as n orm al .

D uring th e fir st da ys of h osp ita liza tio n , the ob-P a ax m cs , V ol . 40 , N o . 2 , A ugust 1 967

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28 4 H Y P O T H Y R O ID IS M A N D H Y P E R B IL IR U B IN E M IAserv ers bec am e pro gre ssiv ely m ore im p res sed w iththe infa n ts le tha rgy , a fain tly c ret ino us fac ia l ap -p ea r an ce , an d co oi, m o ttle d sk in . B lood sub m ittedfo r P B I a t th is tim e sh ow ed very low va lues-1 .0a nd 1 .6 psg /10 0 m l w ith a to ta l io d in e o f 4 .5 & g/10 0 m l. T he elec tro ca rd iog ram w as abn orm a l inthat the vo ltage w as reduced . X -ray of the lo ngb one s sh ow ed n ot on ly absen ce of c alcifica tio n o fa ll the carp al ep iph yse al c en ters bu t o f the d ista lfem ora l and p rox im al tib ia l ep iphy ses w hich nor-m ally c alc ify p ren atal ly .

S inc e fu ll e ffec tiv ene ss o f U S P th yro id w ou ldn ot be at ta in ed u nti l 3 w ee ks af ter its in trod uct ion ,it w as dec ided to em ploy bo th U SP thy ro id andt r i iodo thyron ine ( T 3 ) to ge th er , th e la tter to insu ree arly retu rn to eu thyro id ism . It w a s also p lan ne dth at T 3 w ou ld be w ith dra w n gradu ally ov er th ein i tia l 3 -w e ek p erio d w hile c on tinu ing d esicca tedth yro id as dem on stra ted in F igure 1 . A ccord ing ly ,triiodo thy ron ine (T 3) w as begu n in a dose of 50g /m 2/d ay g ive n as 3 ev ery 8 h ours. W ith in4 8 hou rs there w as im p rov em ent in sk in w a rm th ,act iv i ty , and feed ing . Jaund ice appeared less s trik -in g and w ith in 2 da ys o f s tar ting T 3 the b ili rub inw as redu ced to 6 m g fro m a p re -treatm en t va lueof 1 m g /100 m l. T 3 ad m in istra t ion w as m o nito redb y an e valuat ion o f c ard iac rate p rio r to eac h do seof m ed ica tion and b y a da ily e lec trocard iogram .T he course o f th erapy w as uneven tfu l .

F o llow ing d ischa rg e from th e hosp ital the in -fan ts m oth er m isu nd erstood ins tru ctio ns an d U S Pthy ro id w as no t adm in iste red w h ile T 3 w as grad -u ally tap ere d a nd d isco n tin ued . F igure 1 show stha t fa ilu re to g iv e ex ogenou s thy ro id w as accom -pa nie d by a n e arly re cur ren ce o f hy perb ili rub ine m iaand du rin g th is p eriod the i n f a n t a ga in m an ife ste dle tha rg y an d co o l e x t r e m i t i e s Thyro id rep lacemen tw as p rom pf ly res tarted w he n th e e rror w as d is-cov e red and aga in th ere w as a re tu rn to n orm alserum bil irub in va lues . T he pa tie n t ha s rem ain edfree o f jau nd ice and c lin ica lly eu thy ro id on treat-m e n t with 12 0 m g/m /day of US P thy ro id th ro ug h-o u t th e obse rva t ion p erio d ex ten d in g to ag e 16m o nth s. O n ex am inat ion at 6 m o nth s it w as fo un dth at she re spo nd ed to au dito ry s tim uli. H e r w eig h tw as 16 .5 lb a nd h er le ng th 23 % in . H er he ad cir-cumference w as 18 3 in . and ch est c ircu m feren cew as 16 in . H er b od y p rop ort ion s w e re norm a l forag e (upp er segm en t/lo w e r se gm ent , 1 : 1 .6 ) . S e ruman tith y ro g lob u lin an tib ody tite r w as e leva ted to1 :4 0 in the pa tie n ts m o the r a nd 1 :8 0 in th e in-fan t at 6 m o n ths .

R e-exa m inat ion a t 16 m on ths o f ag e rev ealedthat th e p atien t w a s eu thy ro id an d tha t m o tor de -v elop m ent w as w ith in n orm al lim its . She had b eenw alk in g fro m 13 m on ths of ag e a nd w a s sa y in gtw o sin g le w ord s an d m u ch no nse nse v oca bu lary .H er w e igh t w as 21 lb and le ng th w as 3 0 in . H ea dc irc um fe renc e w as 20 in . T h e da ily dose of thy ro idw as 75 m g a t th is t im e .

C O M M E N TT h e case desc ribed con firm s the asso cia tio n

of co ngen ita l hypo thy ro id ism and pro longedneo na tal h yp erb ilirub in em ia. F urthe rm ore, thecausa l re latio nsh ip b etw een m y xedem a an djaun d ice w as d ocum en ted b y th e fall in se rumbilirub in w hen exo geno us thy ro id w as in itiallyin trod uced , by th e recu rren ce o f h ype rb iliru -b in em ia w h en thy ro id rep lacem en t w as acc i-d entally w ithdraw n, a nd by th e sec ond dec lin ein se rum b ilirub in w hen th y ro id w as re -in sti-tu ted .

P ro lo nged neona ta l u ncon ju ga ted hyp erb il-i rub inemia of the so rt d isp lay ed b y th e p res-en t case is ind ica tive of a d efect in g lucuro n idefo rmation . G lucuron y l transfe rase ac tiv ity upo nw hich co n jug atio n d ep en ds m ay be absen t a sin th e perm an en t ic te rus o f th e C rig ie r-N a jja rsynd ro m e3 o r it m ay be b loc ked as in the tran -sien t ic terus due to the p regn an ed io l b reastm ilk fac to r . P re sum ab ly icte rus in th e p re s-en t case w as no t d ete rm ined by pregnaned io lin ge stio n s inc e breas t feed in g w as con tinuedth ro ugh ou t and fluc tua tion s in the b ilirub inleve l w ere c lose ly co rrela ted w ith th y ro idtreatm en t. T he m ost co m m o n and ev anescen ttype o f n eo na ta l hy pe rb ilirub inem ia , so -calledp hys io log ic jau nd ice , is a ttr ibu ted to im m a-turity of the co n jug atio n m echan ism . T hep ro long ed n eona ta l jaun d ice o f the h ypo thy -ro id in fan t has b een co nsid ered an exagg era tedv arian t o f th is la st ty pe ,5 althou gh a recen t ex -pe rim en tal a ttem pt to dem o nstra te dep res siono f g lucu ron y l tran sfe rase ac tiv ity in liv er m i-c roso m es of o ffsp ring o f p rop y lth io u rac il treat-ed rats w as unrew ard ing .6 In th is rega rd , ho w -ev e r , it m ay be pertinen t to n o te th at th e ex -p erim en ta l d es ign fa iled to te st fo r hum oralin h ib ito rs o f con juga tion . T h at the se m ay bere spo nsib le fo r the b lo ck in b ilirub in m etabo-lism in con gen ita l h ypo thy ro id ism is sugg ested th e g lucu rony l tran sfe rase inh ib ito ry capa -b ility o f a va riety o f s tero ids k now n to be p re s-en t a t h ig h leve ls in the neon a te7 as w e ll as thein flu en ce o f th y ro id h orm on es in in c rea singgen era tion of T P N H and the reby acce lera tings te ro id d eg ra da tio n.8O f add itio nal in terest in th e p resen t ca se w asthe p re sence of dea fn ess n o ted a t 1 m on th o fage w h en the pa tien t w as m ax im a lly hvp o thy -ro id and its sub sequen t d isapp ea ran ce by 6m on th s w hen the pa tien t w as eu thy ro id . T he as-soc ia tion of dea fn es s and hyp o thy ro id ism has re -cen tly been d iscussed b y H o w a rth a nd L lov dan d by d e V os1 {1 76}ho a ttribu ted revers ib le hear-



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E X PE R IE N C E A N D R E A S O N -B R IE F L Y R E C O R D E D 28 5

T O T A L 5B IL l R U B INm g / lO O m I)

0

5 IPBI 1 6

I I

u . s . p T H Y R O ID 5 m gT 3 g J 6 3 i _ _ _ _ _ _ _ _ _ _L 3 V //A i A 5 _ __ __ __ __ __ __ __ __ _ I I I I ,

0 5 3 0 4 5 60 7 5 90D A Y SF I G 1 . In flu enc e of thy ro id trea tm ent on seru m bil irub in in an in fan t w ithco nge nita l hy po thy ro id ism . N o te sh arp d ecl ine w ith b eg inn ing of tre at-m e nt, recrude sce nce of h yp erb iliru b in em ia w hen th yro id w as acc ide n ta lly( l i sc ont inue d , an d seco nda ry fall to no rm al lev els w ith resum ptio n of m ed i-

cat ion .

ing los s in acq uire d m yx ede m a to de fec tiv e c on-d uct ion ca used by ed em a of th e eus tach ian tub e.E dem a of the m ucosa o f th e u ppe r airw ay m aybe a pro m in en t find in g in con gen ital hyp o thy-ro id ism ; in so m e ca ses it is th e ch ief clue todiagnosis.

T h is case em phasizes tha t p ro lon ged neona-ta l jau nd ice sho u ld b e consid ered as a p ossib lemanifesta t ion o f con gen ital h ypo thy ro id ism .W hen cre tin ism does und erlie the h ype rb iliru -b in em ia, the la tter pro m p tly sub sid es on a p-pro pria te trea tm en t w ith thyro id horm on e . It iso f no te , ho w e ver , th at t he h yp er bi lir ub in em iaof th e eu thyro id prem atu re in fan t app ears no tto be sim ilar ly rap id ly am e lio rated , if a t allin flu enc ed , b y trea tm ent w ith thyroac tiv e

1 1 1 2

S U MM A R YA cre tinou s in fan t exh ib ited p ro lon ged neo-

na tal ja un dic e w h ich sub sid ed on thyro id re-p lacem en t the rapy . A cciden ta l w ithd raw al o ftreatm e nt w ith rec rud esc en ce of jau nd ice anda secon d d rop in b ilirub in o n re sto ra tion of thy -ro id trea tm en t se rv ed to docum en t th e c loseassociat ion of thyro id insu ffic iency and u ncon-ju gate d h yp erb iliru bin em ia.

MARG ARE T H . M AC G I L L I V R A Y M . D .F orm erly , D epa rtm ent o f P ed iatricsH arvard M edical S c ho ol

an dC lin ica l an d R esearch F ellowC hild ren s S erv iceM assach use tts G en era l H o sp ita lP re sen t A ddress:C h ild ren s H osp ita l

Buffalo New York 4222J O l I N D . CRAWFORD M . D .

an dJou r S . ROBEY M . D .D epa rtm en t o f P ed ia tric sH arvard M ed ica l S choo l

an dC hild ren s S e rv iceM assachuse tts G enera l H osp ital

Boston M assachusettsT his w ork w a s supp orted in par t b y gra n ts o f

th e U .S . P u blic H e alth S erv ice , T I-H D -0 00 33 .H D -00 243 , an d K 3-H D -14 , 8 24 .

REFERENCES1 . A k erren , Y . : P ro long ed ja und ice in th e ne w -

born asso cia ted w ith co ngen ital m yxed em a.A c ta P aed ia t. (S tockh o lm ), 43 :411 , 1 9 5 4 .



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28 6 C H IL D -R E S IS T A N T C O N T A IN E R2 . C hr is te ns en , J. F . : P ro lo nge d icte rus ne ona -

to ru m and co ng enita l m yx ed em a. A c taP aed iat ., 4 5 :3 67 , 19 56 .

3 . S chm id , R . : H yp erb iiru b in em ia. in Stanbury ,J. B ., W y ng aa rd en , J. B ., a nd F re de ri ck so n,D . S ., ed . : T he M etabo lic B asis o f Inhe ritedD isease. N ew Y ork : M cG raw -H ill B oo k C o rn -p a n y I n c p 2 2 6 1 9 6 0 .

4. A rias, I. M ., G arth e r, L . M ., S e if te r, S ., an dF u rm an , M . : P ro lon ged neon ata l un co n-ju gated h yp erb ilirub inern ia w ith breas t fe ed-ing an d a ste ro id , p reg nane 3 (alp ha) , 2 0(be ta ) -d io l in m atern al m ilk that in h ib its g lu -curon id e fo rm atio n in v i tro . J . C lin . Inv es t.,43 :20 37 , 1 964 .

5. L ees , M . H ., an d R u thv en , C . R . J. : T he e ffec to f t ri io do th yr on in e in neona ta l h yperb ilim -b in em ia . L an c et, 2 :371 1959 .

6 . W erd er, E . A ., a nd Y affe , S . J. : Glucurony lt ran sferase ac tiv ity in e xpe rim en tal neo na talhypothyro id ism. Bio l . Neonat . , 6 :8 , 1964 . Jones , B. : G lucu ron yl tran sferase inh ib i tio nby stero id s. J . P ed ia t. , 64 :81 5 , 1 96 4 .

8 . M cG uire , J. S ., and T o m k ins , G . M . : E ffe cts ofthy rox in adm in istra tion on the enzymatic re -duct ion o f 4 - 3- k et o st er o id s . J . B io l. C he rn .,234:791 , 1 9 5 9

9 . H ow arth , A . E ., an d L loyd , H . E . D .: Percep-tiv e d ea fne ss in hy po thy ro id ism . B ri t. M ed .J. , 1 :431 , 195 6 .

10 . D e V o s, J . A . : Deafness i n h yp o th y ro id is m . J.L aryng ., 77 :3 90 , 1963 .

11 . N ajje r, S . : R esp irato ry m an ife sta t ion s in in -fan ts w ith h yp oth yro id ism . A rch . D is . C h ild .,37 :603 , 1962 .

1 2 . S hrand , H ., and R uth ven , C . R . J. : E ffec t o ftriiodo thy ron ine on se rum-b i l i rub in leve l an dneona ta l deve lop m en t o f th e p rem a tu re in -fan t. L ance t, 2:1 274 , 19 60 .

R es u l t s o f T e s t i n g a C h i l d r es i s t an tM e d ic in e C o n ta in e r

A cc iden ta l po ison in g o f y oun g ch ild ren w ithits attend an t m orb id ity and m o rta lity con tin uesto attract the a tten tion o f p ed ia tric ians co n-c ern ed w ith th e p reven ta tive aspec ts o f theprob lem . D esp ite edu ca tion al and leg isla tiveprograms, the ov era ll m o rta lity h as sca rce lyd ecreased since 1 954 . A frequ en t cause o f ac-c iden ta l po iso n ing resu lts fro m th e ingestion ofm ed ic ines . R ea lizing th is , a C anad ian pharm a-ceu tical as soc ia tion he ld a con te st in 19 64 tofind an eff icien tly d esig ned , inexp en sive , ch ild -res istan t con ta ine r. T h is b rie f rep ort desc ribesthe resu lts o f tes tin g th e ab ility o f ch ild ren toop en th e con tes t-w inn ing con ta ine r.

METHOD S AN D MATERIALSA to ta l o f 420 ch ild ren fro m th e p ed ia tr ic

cl in ic , p ed ia tric w ards , nurse ries , an d nurse rysch oo ls at M adigan G enera l H osp ita l w eretested . A con tro l g roup of 120 ch ild ren ran gedfrom 9 m on ths to 1 1 years , w ith m ost be ing 3years of ag e o r you nge r . A te st g ro up cons istedo f 300 ch ild ren rang ing in age fro m 1 to 11years. O ne hun dred six ty -e igh t o f the 3 00 ch il-d ren w ho w ere te sted w ere und er th e age o f 5years .

T he tw o con ta in e rs tes ted are show n in F ig -u re 1 . T he con tro l w as a snap-top , p la sticm edicine con ta ine r in genera l use by ou r phar-m acy . T h e test item w as a p las tic con ta ine rw ith a ch i ld - resista n t top , w h ich m ay beo pened by em p loy in g tw o d istin ct an d coo rd i-na ted m aneuv ers: 1 depres sion of th e capag ain st a re sis tan t fo rce o f ap prox im ate ly 5 k gan d (2 ) a coun ter-c lo ck w ise tu rn o f 4 5 degrees.T h e ch ild ren w ere g iv en a clo sed con ta ine r inw hich w as p laced a rew ard ( sa ltw ate r ta ffyw ra pp ed in b rig h tly co lo red pap er) an d w ereasked to op en th e con ta ine r . A ll age g ro upsan d sub jec ts re sp ond ed to the stim u lu s. If thech ild g av e u p , o r w as un ab le to o pen th e con -tam er in 3 m in u te s, a fa ilu re w as reco rded .T h e ex am ine r then v isua lly d em ons tra ted tothe ch ild the co rrec t m e thod of op en ing th eco n ta ine r. T h is w as don e to ap pro x im a te aco m m o n situa tion w hich occurs a t h om e , i.e .,the ch ild w ho im ita te s th e pa ren tal actio n . T hech ild w as aga in a llo w ed 3 m inu te s. If he fa iled ,a secon d dem o nstra tion w as g iv en , and th ech ild w as aga in encou raged to o pen th e co n-t am er .

T he te st w as d iscon tin ued if the ch ild (1 )opened th e con ta ine r du ring the tes t pe r iod , o r(2 ) fa iled to op en it a fte r th e in itia l tr ia l and

t wo d em o ns tr at io ns .RESULTS

CONTROL GROUP : O n e hun dred n ine teen of12 0 ch ild ren stud ied w ere ab le to op en the con-tro l con tain er w ith in 3 m in u te s w ith ou t ad em onstra tion . T he on e ch ild w ho failed (age2 6 m o nths) ea sily op en ed the con ta in er a f tero ne d em on str atio n.

TEST GROUP: O f the 300 ch ild ren tested ,2 92 w ere un ab le to o pe n the c ontain er w ith ou ta dem on stra tio n (T ab le I) . S e ven of the eig h tsu cce ssfu l ch ild ren w ere 8 y ears of a ge or o lde r.O nly on e 5 -y ea r-o ld ch ild (1 o f 55 ) succeed edw ith ou t d em o nstra tion w ith in th e 3-m inu te tes tpe riod . W ith e ithe r o ne or tw o dem o nstratio ns,



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1967;40;283PediatricsMARGARET H. MACGILLIVRAY, JOHN D. CRAWFORD and JOHN S. ROBEY

Congenital Hypothyroidism and Prolonged Neonatal Hyperbilirubinemia

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