blood-1951-bernhard-990-1001

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1951 6: 990-1001

WILLIAM G. BERNHARD, IRA GORE and RALPH A. KILBYCongenital Leukemia

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Congen ita l L eukem iaB y WILL IAM G . BERNHARD , M.D . , IRA GORE , MI) . AN D

RAL I H A . KILBY , I \ I .D .C ONGEN ITA L leukem ia is an exeed in g ly u ndom m on (lisea se , ye t th eie isa num ber o f w ell au th en tica ted cases in the lite ra tu !e ind !icatin g tha t the

fac to r o r fac to rs w h ich p ro duce the leu kem ic sta te m ay op era te in u te ro . P!csentday pa tho log is ts a re keen ly aw are of the ex trao rd !ina ry lab ility o f the in fan t sh em ato po ie tic system . A s a con seq uence , b u t som ewhat pa rado x ically , few ercase s o f th is d iso rde r are now - recog n ized than in th e past. Many of th e o lde rrep orts a re now m o re accura te ly c lass ified as e ry th rob lastos is fe ta lis , cong en ita lsyph ilis , o r sepsis . T ab le 1 lis ts the 1 4 cases in the lite ra tu re th at p re sen ted !accep tab le docum en ta tion as to the p re sence of a leu kem ic sta te at b i! th . T othese w e h av e add ed 4 cases from the file s o f th e A rm ed Forces Ins titu te ofPath o log y (tab le 2 ) . In add itio n to au top sy ex am ina tion and m ic rosco p ic s tudlyof th e tissues, aded lua t.e hem ato lo g ic s tud ies had 1 )een conduc ted du i ing life ineach of these cases .

T o fu lfill the c rite ria o f congen ita l leu kem ia , the re m ust 1 )e m an ifest a t b irthor shortly th ereafter, sym p tom s or s ign s w hich can be corre la ted w ith thech ara cte ris tic hem a tolo gic d istu rban ce . T he iecogn it ion o f the na tu re o f thela t ter , how eve r , m ay b e de lay ed as in C ase 4 (A F IP 234131 ). Sign if ican t phys-ical m an ife sta tions a re: spont aneous hem orrh ages o f sk in and! m u cou s m em bra ne,nodu lar sk in in f iltra tions , en la rgem en t o f sp leen and live i , ad !enop ath y , fev e rand pa llo r . T h e b lo od sho u ld ref lect an a lte ra tion of the m arrow by show in gan undue proportion o f po orly d ifferen t iated o i und if feien tia ted cells usu ally o fthe g ranu locy tic ser ie s; idea lly the re sho u ld b e confirm ato ry bo ne mai I Owstu d ie s . In m o st. cases cons ide rab le e leva tion of the w hite b loo d cell co un t andreduced num bers o f red ce lls and p la te le ts arc also o bse rv ed . N u clea ted redcells m ay be presen t. in va ry ing num ber . S in ce ch an ges easily confused l p at ho log-ic ally w ith leuk em ia occur in con gen ita l syph ilis an d e rv th rob la stos is feta lis ,iepo rts of se ro log ic stud ies on the m o the r sh ou ld he ava ilab le an d informationregaro ! ing th e possib ility o f b loo d g ro up or type incom patib ility be tw een m o the iand in fan t shou ld ! be ob tained .C ase Repo rts

Ca se 1 , A F IP Acces sion 2 80588 .* A w h ite , fu ll te rm m ale in fan t, w ho l ived for o!I ly 19hours, had been d elive red w ithou t inc iden t o n Augus t 18 , 1948 , at 2 :11 P .M . T h e m other,ag ed 37 , pa ra 3 , grav id a 4 , h ad been under observa tion fo r the las t five and a ha lf m o !lth s o fher p regn ancy and had experienced an uncom plica ted ges tation . S ero log ic tes ts fo r syph ilishad! been nega tiv e; the b lo od grou p w as 0 t ype , Rh 0 posi t ive . The ch ild a rrived from thede live ry room in a depre ssed sta te n ine teen m inu tes afte r b irth . H e w as le th arg ic an (lcya notic; h is sk i! i was m ottled ; h is fac ies m ongo lo id , i sis liv er palpab le 5 cm . be low thecos ta l m arg in , an tI the re were (lif fuse pu lm onary rho nch i. D esp ite stim u la!i ts and art i f ic ia l

F rom th e A rm ed Fo rc es In stitu te o f P atho log y , W ash ing ton , 1) . C .Subm itted Ja !iu ary 16 , 1951 ; accep ted fo r pub lica tio n A pril 3 , 1951 .8Case 1 (A ce . 280588) stud ied th rough th e co urtesy of D r. Paul Russoma! lno , Newa r k ,

N.J.99 0

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WILLIAM G. B ERNHARD , IRA GORE AND RALPH A . KILB Y 99 1

respirat iO t i 11 0 i!nI)ro velne! it svas !io te (l ; the temperature ro se an(I the infant died le ss thantw enty-four hours after birth.

The re (I 1)100(1 cell count several hours before death ss-as 4 ,200 ,00 0 and the hemoglobin15 .3 Gm. or 93 p cent . Color index w as I .1 , atid the red blood cells show ed anisocyto sis ,po ikilo cytosis, macrocy tos is and hyperchromia. White blo od cel l counts ranged betw een246 ,5 (X) aIi(I lS l,()0 (), uncorrecte(1 for nuc leated ret! blo od ce lls . The corrected w hite blood(c li c oulits w ere 1S1 ,()0 ( ) a!id 90 ,70 0 , w ith 65 ,000 and 63 ,000 nuc leated red blood ce lls . In( lifferential c ounts nw eloblasts niade U I) from 19 to 25 per cent; pro granulocytes 4 to 8 perce nt ; m yelo cy te s, 12 to 16 PC F ce nt ; m etam ve lo cy tes , 14 to 22 per cent ; and segmented forms,1 5 to 24 per cent.. There w ere numerous mature a! id immature eos inophilic forms. The in-fant.s re (! 1 )10 0(1 cells c ontaine(1 the Rh fac tor, Rh0 type .

A iolops!j. A full term, new i)o rn male, 5 2 cm. in length, w e ighing 3200 Gm ., presentedniottle(I ( \t t I iO S I S o f an o th er w ise u n m ar r ed skill surface . There wa s moderate caput sue -ce tianeum; the skull was brachycephalic; the facial features w ere typically mongolo id. Hy-I)e rtroPh o f the left buccal area tt! i( ! partial ag ene sis and de formity of the le ft ear w ere!iOte(I. Th e abdome ti w as l)rotul)eratit . In the slightly enlarged heart (2 5 Gm.) the interatrialseptum w as v irtually aI)se! it . The spleen and liv er w ere considerably enlarg ed, w eighing 35and 210 Gm., respectiv ely . The skull exhibite (I premature c losure of the fontane lles; theligaments o f the najor jo ints w ere u!iusuallv lax , atid there wa s shortening o f both humeri.Other f indlings inc luo ling a patent (iuctus arte riosus w ere considereo l w ithin no rmal l imits.

.Ificroscopic examination. The liv er, splee ti, lung s and pancreas w ere extens ive ly in-filtrated w ith i!lmature ce lls o f the granulo cy tic series. M aiiy of the ce lls contained eos ino-1)hilic granules, and a mo (Ie rate num i)e r o f megakaryocyte s w ere pre sent. in the liver andsI) lee li. The mo st. s triking change s had occurred it the liv er w here the intense leukem ic in-f iltrate seemed almo st. to have o l)literated the no rmal histo lo g ic components . The bonemarrow w as hyperplastic and! its cy to log ic pat te rn unduly homog eteous . Large numbers ofpoo rly differetitiated arid! undifferentiated! ce lls o f the granulocytic series formed the majo rportio !1 of the hematopoie tic tissue. Erythropoie sis w as reduced to a few i n con s p i cu ou sfoc i; m egakaryo cytes w ere sparse.

Case 2, AF IP Accession 205756 #{149} *A w hite female infant, w ho (lied at the ag e of 3 w eekswith acu te gr a t u loc y t i c leukem ia, prese !ite (! i)ilateral talipes v arus, congenital sho rteningof the neck (Klippe l-Feil sy ndrome), and! idiopathic enlargement of the heart. The mo therw as 25 y ears o f age, and pregnancy , w hich w as of normal duratio n, w as no tew orthy only forhydramnios during the term inal t.w o mo!it.hs . S ero log ic s tudies o f t.he maternal blo od w erenegative ; the mo t.hers 1 )10 0(1 cel ls contained the Rh f ac t or . D eliv e r y w as normal. The i n f a n tw eighed 4 ,196 Gm . at birth, J an u a r y 14, 1948; the abno rm a l i t ie s already mentio ned w ereapparent. o n physical ex am i!1atio n. The abdome!3 w as protuberant w ith a larg e round massit the le ft upper quadrant.. D ifficulty in breathing w as attributed to aspirated mucus andatelec tasis o f t.he le ft lung .

Roentgenoglog ic ex am i natio n confirmed the at elec tas is anti demons trated an enlargedheart shadow . l3 lo od counts w ere as fo llow s: January 17 , 19 48 : hemog lobin 1 04 p e r cen t ,ervthrocvtes 5 ,900 ,000 , to tal leukocv tes 32 ,70 0 segmented! forms 35 p er cen t , b a n d s 4 p cent, immature granulocy t.ic forms 3 per cent., lym phocyte s 57 p e r cen t , b asop h ils 1 p ercent. February 1 , 1948 : h emog lo b in 95 pea cent, ery thro cy tes, 5 ,2 00 ,00 0 , to tal leuko cytes1 0 ,3 00 , segmented! forms 21 per cent., bands 29 p e r cen t , im m a tu r e gr an u locy t ie f orm s 30per cent, lymphocytes 20 p er cen t .

The infant stea(hly lost w eight and a persistent pulmonary infec tion dev elope(l. N asalbleeding , w hich had been noted! at birth, s till occurred on cr y in g an d ex er t ion tw o weeksla t er a n d wa s associated w ith a purulent nasal in f ec t ion . D eat .h occu r r ed at t h r ee weeks .

Autopsy. A fem ale in f a t it , 52 cm . in length, w eighed 4025 G m . T h e n eck w as so abnormallyshort. as to be v irtually a1)sent; a larg e mass fil led the le ft side of a dis tended and tympaniticab d om en , a n t ! t h er e w a s b ila t er a l t a lip e s v ar u s. N um er ou s en la r ged h u t d isc r et e n od esw ere obse rved in the cerv ical, mediastinal, pe ril )ronchial, and mesente ric and re troperitoneal

* Case2 (A ce. 2 05756 ) contributed by I)r. H. 11 . Leff ler, Prov ide! lce Hospital, W ashingt.o n,D . C.


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99 6 CONGEN ITAL LEUKEMIAreg ions. The thymus as v is ibly e tilarged by hemorrhage . TIie,e w as co iss ide rable e lllarge -metit o f the live r, spleen (15 x 7 x 4 cm . and 10 x 4 x 2 cm ., respectiv e ly ; w eights no t g iven)2011(1 hear t . . C ardiac e nlarg em ent was entire ly muscular; the re w ere no a! iomalies, Pate !ic iesof bo th the foramen ovale and the d!uctus arteriosus beitg ( onsid!ered w ithin the li! liits o f!lor!nal for a 3 w eek o ld infant.

. ic ro scopic exa mina tion .. The bo tse niarrow w as st riking ly hyperplast ic :o! i(I i t S c v t o l og iccharacter uniform , cons isti tig of po orly (iif ferentiated! and prin tive ce lls of the graIn!-locytic series . Erythropo ies is w as considerably reduced and megakarvocvtes w ere veryfe w . Ixt.e !isive it i lt.rat.e s o f leukem ic ce lls in the hea,t , l i,pl bodIes . liv er :1 11(1 spleen toe -counted for enlarge!11ent o f these o rgans. Less ex tetisiv e (le l)o sits of sim ilar c ells w ere oh-se rved iti the other v isc era.

C a se 3 , AF IP Access ion 1 89 595 . A white male i!i fatit. l)orn February 19 , 194 7 , afte r a fullterm uncomplicated! pregnancy , w eighed! 4 ,082 Gm. at birth. A ! lu n3 be t o f c ut an eo us lumpsof various s izes w ere noted to t once . S ero log ic examinatio ti of the maternal blood w as isega-

FIG. 1 .-Case 1 . AFIP N eg . 2 80 588 -1 , 2 . Low (2 05 X ) and! high (435 X ) magnificatio tiso f the liver. S o intens ive is the leukemic infiltrate that it is dlifficult to ide titify the org a!Ihis to lo g ically . A fair deg ree of granulo cy tic dif ferentiatio !1 is to be o l)serve(I in the highermagnification.

tive . The mo thers blood cells contained the Rh fac tor, as did the i t i f a t i t s blood! whets teste(1subsequently . Tw enty- four hours af ter birth the infatit v om ited after feediing and it. w asnoteti that the v omitus contained appreciable quantitie s o f 1)1 00 (1 . Total leuko cy te (o utitat this time w as report.ed t.o be 280 ,0 00 .

U pon e xam inatio n on the second day o f life the i!ifant tlid n o t . appeal to 1) e acu te l y ill.Hard m asse s, v ar v i!3g f r om 1 to 2 cm . i n d ia me te r, attached! to skits but not to u!!(lerly ingtissue , w ere palI)able its the subcutaneous tis sue . The ove r l y i ! i g skin v ar ied ! f r om reddish topurplish in co lor, the larg est masses hav ing a central area of purplish v io le t co lor surroundedby a thin ring of blue. There w ere many o ther disco lo red areas on t he s kin, appro xim ately 1mno. in diameter, w hich w ere deep blue w ith no underly itg mass . F:xantiat.io t o f head a!sdneck, thorax and lung s o as negativ e. The heart w as !so t e tilarg ed to percussion and! no mur-nours w ere heard!, although t.he heart soundis at the apex w ere o f a I)ecU lia! rough character;the r a t e w as 120 per m inute and the rhy thm regular. The liv er, w hich w as palpable 7 c !n.below the cos tal marg in amid! extended across t.he midline to the left midclav icular line, fi lled


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W ILL IAM G . BERNHARD , IRA GORE AND RALPh A . K ILBY 99 7

to larg e 1)art o f the to l)(ld)I f le!1 . 1 ho e spleen w as e!i larg e(I , bei! lg PalI )tib le 4 dl . be low t he co stal!i1ttrgiti . T he d d)!d l w as a ro x i!o oately 4 cm . lo tig tO !ld w to s dry a!i(I rio t O oz i!lg . N o ly nophit lO( le e tilto rgem etit o r f u rthe r I )h ly sical abnorm alities w ere rio ted .

T he i! If t t t lt w as l)lttced 0 !1 a forn ula o f an lig els a!id glu cose (5 cen t) in 1/1 ratio . oIos tof t lie f e edin gs w ere vO !f l ite(1 PrO tf lPtl th e v ono itu s, to t f irst cof f ee g round in appettra! lce ,late , Iscatsie st reak ed w ith brigh t red ! blo od. T he i!sf to!i t wt t s give! i to subcu tan eou s i!i fU S id)!Io f l6 n io lar so tIiu ts lac tate :01 (1 g lucose (2 .5 ie r cen t) in a phy s io logic so lu tion o f s O (! iu fl ocblo !id c. T he s too ls regu ltorly co!l tain ed brigh t red blood antI tarry toaterial . On th e af te r-t lOO ! l o f l bru to i 21 , t h e i! lf at it s ie spirtitions b ecttno e tn ore rttp id tt! i(I Itobored atl(I h e w as1) 1tI (e( I i t i ton ox ygen t e tit . A t 7 : 30 P . \1 . , Fe b rua ry 23 , re sp i rat i otis w e re so sI i gh t tos n o t t o 1en ot i cd a l)l e, a!ld to Sho rt t i! ile later t h e Pulse becatu e if l1 l)e!d el)t ib le . T he in f ttt it. t ts p ro-nou! lcp ( l ( let t(1 sev en day s tof ter l)irth.

J:r t h iroct yes !sun1l)e re(I 4 ,20(),() ()0 ; l euk ocy tes l9 8 ,(X .X ), w it h i b las ts I 5 l)CF de! it , progra!IulO-cy tes 16 p r cen t , no v elo cy tes 5 per ceti t, m etam y e locy te s 2 pe r cent, 1 )andS 2 pe r tetit , f i la-

Fw . 2 .-Case 2 . A FIP N e g . 205756-1 , 7 . L ow (205 X ) an d h igh (435 X ) magn i f ica t ionsof t h e bon e m arrow illu st rat it ig t h e hom oge! leous a! id u !,d if f ere!it iated cellu lar grow th .

m ents 4 p ce !it, ly m phocy tes S per cen t, sn oudge s 38 P# { 176 } e nt, e ry th ro blasts pe r cent,no rm oldast.s 5 p c ent a!s(I u ts ide tit if ied fo r!n s 1 er cent . B leed itig tim e w as fifteen m inutesand pro t.h rom bin tim e w as f iv e m inu tes. O ne o f the larg e sk its n odu les w as rem ov ed and1 o tu m arrow ln ,!lc t u re w as p erf orm ed t o oh ) t to i !l !nat e r ial f o r p to t ho l o g ic ex am i Illo t i o n.bent g e!lo grtom s of sk ull alit! lo!ig bo!ieS w ere n egativ e.

.1 ulops!/. A w ell dev elo ped , n ew bo rn w hite m ale o f 7 day s , w e igh ed 3600 Gm . totid n eas-U re(I 51 .5 ( t il. in le! ig th . N u !s1 erous sup erf icito l f irtn nodu lar elev at iO ! IS of t lie sk its , v ary ingits S IZP f ro s I ens . to 4 .5 cm .. a!sd i!i co lor f rom gray to purp le a!sd hem orrhagic , w e re tio tedov er t he I t ire I )ody su rf ace . A x i II a ry atid i !igui !ial Isode s w ere e nl to rg ed .

L iv e r :u!( I sp leeti w e re greatly e!ilarg ed, w e igh ing 300 a!1d 37.5 Gm ., resp ectiv ely . T heheart, w hich w e igh ed 27.7 Gn s., p rese!s ted sev e ral g rtty -y e llow , poo rly circum sc rib ed ,!Iod ular cle vatio tis of the epicardium . S im ilar ! isc rete les io lis w e re p rese tit in the sm alli nt est i tie and bladd er, a!sd i n v o lv em e !st o f t lie f irs t po rt io n o f t l ie toscetid in g colo n w asdifT use. I Ienorrhages w ere l) re se !it in the itite st i!,al m uco sa, t he re iial Pelv es a!1d the lept.o-!lie !ii! !ge s ov e r t he le f t ce reb rum . L x cep t f or discrete e!i ltorgenoen t. o f th e ly m ph tiod es andl :o t ( b y c o!is olid at iO!5 o f t l ie lungs, t h ere w ere !iO o t h er po sit iv e f in din gs. W ith the ex cep t iono f 1 ) ronchop! ieumonia , :ol 1 g ross cha!lg es could be re l cd l to a leuk em ic Pro cess.


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99 8 C O N G E N I T A L L E UK E M I A

. icr o sco p ic e.r a in in a tio n . The boIse nottrro w as occupied by a uts ifo rm grow th o f pri no i-tive and poorly dif ferentiated ce lls o f the g ranulo cy tic series. Ery thropo iesis w as consider-ably reduced and megakaryo cytes w ere few . Liv er sec tio ns w ere scarcely recognizable , SOintense w as the leukemic c ellular infil tration. The splee ti an(! lymph tiodes w ere diffuse lyinvo lve t! and the nodulmor le sio ns of skin, heart, intes tine tond blto( ide r pro ved to be cel lularmasses identical in character w ith the bone marrow . Le ss intens ive dleposits w ere l.)rese!s tin to ll tis sue s.

An incidental finding as a smto ll (m icro scopic ) to drenal rest in the epidlid!vm is.C ase 4, -IF IP Acce ssion 23 41 51 . A w hite male infant, w ho w eighed 3005 Gm. at birth,,

presente t! dex trocardia tonti bilaterto lly tobsent. radii, as w ell as ev idence of hemttto lo g icdisturbance. Pe techiae of the skin, the mucous membrtone, to n(I the conjunc tiv tte w ereobse rved on the f irst day o f l ife . The spleen w as palpably eis larg ed. lv idence of g astro-intes tinal ble eding w as fount! in bo th the sto o l and vomitus . l)ut the episode o f b le edi !s gwa s apparently trtonsitory . Ots the tenth day c ircumcis ion w as accomplished w ithoutdifficulty . B lo od count wa s reported as tsormal tmnd the infatst was re leased from the Iso spit to lon the seventee!s th day .

On the forty -secono! day of life the child, w ho exhibited only a slig ht g aits iii weight,wa s admitted to the hospital because o f considerable ble eding from the rec tum fo r thep r eced in g three days. There w as mtorked pallor; petechiae w ere observeo! oto the ptolate,and the child appeared! moribund. The liver w as enlarged but the sple eti w as no t palpable .B lo od count w as: erythrocv tes 1 ,500 ,000 ; to tal leuko cy tes 1 2 ,0 00 to 17 ,00 0; platelets 80 ,00 0 .B leeding and c lotting tim es w ere reported normal. Rec tal ble ediisg contitsued afte r tw otransfusio ns. On the six ty-e ighth day o f life the child w as transferred to tonot her hospital,w here extens ive skin pe techiae and ecchymo ses w ere noted. Spleen atsd liver w ere foundto be enlarg ed and intes tinal ble eding continued. D espite multiple trto tss fusions , the i n f t o n tdied.

I Per ip h e r a l B lood C ou n t s o f t h e L ast T en I )ay sD a t e ______ -

(Millions) H gb W B C P L I M E B B le eding Clo tting P la te l e t s

4 /12 /48 2 .47 5 0% 13 ,50 0 42 51 1 6 I 2 30 4lO N one7 .8 Gm. . I I see ,,

4 /13 /48 3 .75 7 8% 9,8 00 1 415 34 0 No ! l e12 .2 Gm . I se e,,

4 /14 /48 14 /15 /48 3 .6 6 8% 21 ,80 0 35 64 1 I 630 53 5 N one

9 .8 Gm. I seen4 /16 /48 2 .9 59% 5 ,600 30 55 1 14

9 .2 Gm.4 /22 /18 5 .36 95% I 18 ,750 21 74 3 1 1 2SS 3 ,40 16 ,05 0

14 .8Gm.

Tests o f the maternal blo od fo r syphilis (luring preg tsancy had been negtitive . The B hifacto r had not been ascertaits ed in e ithe r the mo ther or the i ! l f t o t s t .

Autopsy . D ex tro ctirdia tond bilate ral abse isc e o f the rtodii had to lready beds note (I 0!!phy sical examinatio ts . Petechiae and ecchymo tic hemorrhtoges w ere foulsd! in the ski!s,intes tinal tract and o ther serous and mucous surfaces . B ody w eight wa s 3500 Gm.; t.hto t ofthe liver, 15 0 Gm.; of the spleen, 1 3 Gm. The lymph nodes of the cerv ical and med l i to s t i l i a lr eg ion s w er e lar g e and pro mi ne ls t.

Micr o sco pic exa min a tion . There wa s co tssiderahle though uts iforno hyperplasia of tlsemarrow . N early all o f the ce lls w ere of the g ranulo cytic series and many w ere poo rly dif-ferentiated. There w to s to fairly rich component o f eo sinophilic myelocytes ; erythropo iesisw as c ons ide rabl y reduced, and megakaryocytes w ere exceedi tig ly sc to rce . G ranulocyt i cmetaplasia w as conspicuous in the spleen atsd in the lymph tsodes, and topparent in thel iver. The v isce ra show ed small intrav ascular foc i o f ervthropoie sis.


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D I S C U S S I O NIt seem s mote than a co inc idence that 3 of our 4 cases o f cong enital leukemia

j ) l esent .ed multiple deve lopmental anomalie s . Farber4 has 0 l)se lved exampleso f cong enital leukem ia assoc iated w ith mongo lism , and there is, therefo re , abasis f or sp ecu la t in g that the f a ct o r s r esp on sib le f or the latter may also havel)een influential in caus ing the blood (!ys (raS ia. A ((o ldhng to Ingalls7 t he cruc ialdev e lopmental pe l iOdl for the production o f mongo lism is the six th to the ninthw eek of fe tal life . It is his opinion that occas ionally (luring this period, and le ssf!equently than other structures, the bone mar ow sustains an i n j u r y which(u lm in at e s in leukemia. A lthough there w as only 1 case (Case I ) o f m on go li sm ,i t is interesting that all o f the other anomalie s no ted entailed damage at appio x -imate ly the same p er iod ! o f em br y on ic dev elopment (table 3 ). O f the 14 caseso f cong enital leukemia recorded in the literature only one presented an assoc iatedanomaly , hut the (ursory reports o f the postmortem examinatio ns in 11 in-S ttui(es led to the suspicio n that a malformation might have gone unreco rded.A t any rate such ob ious grow th disturbances lead! to speculation regarding theire sence of the leukemid process 0! som e m t e f u n d lam en ta l d isor d er d u r in g themorphog enesis o f the various struc tures . From the a(cd)unt o f (latw orthy and

TA BL E 3. - ( ongeni ta l Leukem ia : ()b ser r ed .1 no ma lies 00 (1 C r uc ia l I)e ie lopm en ta l P er iod1olotig o l ism 6t h-9 t Is week ( .ose 1Int.e ratrial S ept.al 1 )efect I Sth-7 ths w eek Case 1A getses is o f Ear I lOth-l4 tls w eek Case 1Klippe l-Fe il S yndlrorne 9th w eek Case 2I)ex tro cardia 5th week Coo se 4A bsence of Radii 6 t1 ,-8 th w eek Case 4Pat ent I n t er v en t r icu l a r Sept urn .... 5t hs-7t I, week Cro ss3 (Case 1)

A ndlerson- it appears that the dlis turbance must hav e occurred early in fe tallife , be tw een the fifth and fourteenth w eeks . Tabulated abov e are some of theobserv ed anomalies corre lated w ith the period of fe tal life (luring w hich theyw e!c presumably initiated.5

S in ce q u an t it a t iv ely sig n if ica n t gr an u locy to p oiesis (1005 n o t a p p ear until thefourth month of intrauterine life (W introbe20), it. does n o t seem like ly that l e u -k e m i a could ex ist before that time . How ev er, the re lative abundance o f recog -nizable differentiatio n in the leukemic ce lls fo und in the tissues at autopsyindicate s that the process must certainly have been present. during an apprec iableportion of fe tal life . Histo log ically , at. least. in this re spec t, the granulocyticleukemic process in mo st o f these cases o f the congenital v arie ty resembles thethto nic counterpart. in the adult. The acute clinical course is a. measure onlyof the observ able pait o f the disease . S ince Farber4 found that 98 per cent o f theleukemias of children under ten years o f ag e w ere o f the acu t e v a r iet y (19 6 o f200 ), it w ould! appear fruitful to compare the process in new bo rns hav ing con-genital anomalies w ith that. in normally form ed infants. The reports in thelit e r a t u r e a r e in ad leq u at e f or such a study ant! the 4 cases in this study are to ofew to pe rm it c onc lusio ns.

Most cases seem to have o ffered little diagnos tic difficulty . The prevalent us e


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of sero lo g ic te sts fo r syphilis and the current alertness to the facto ls p r odu c in gerythroblastosis have minim ized the problem that confronted earlier patho l-og ists . In these (OnditionS an(l also in sepsis a considerable amount o f e xtra-medullary hematopo ie sis is to be observed. W hen the ie is app!ec itohle asSO(iate(!pro liferatio n o f !eticulo -endothehal ce lls , distinc tio n from leukem ia may not beeasy . In g eneral, how ever, the piocess in the forme! (onfo !ms to the normalarchitecture of s uc h s tru ct. ui e s as liver, spleen an(l lymph nodes , and though thisma y also he true in leukem ia, ac tual tumorlike agg regate s and! (o lonies may,and often (10 , comple tely e fface normal his to log ic structures. In Case 4 (A FIPAcce s s i o n 234151) a diagnosis o f congenital thrombocy topenic purpura w asentertained during life but. coultl no t he subs tantiated by po stmortem observa-t ion s. H em atop oiesis w as v iitually all o f poorly differentiated! granulocy ticcharactei. Ery thropo ie sis w as considerably reduced! and mega kaiy ocyte s w erealmo st absent, contrary to w hat. w ould be expec ted in thrombopenic purpura.14

It is o f academic interest that all but 2 of the repo ited cases of congenitalleukemia w e ie o f the granulocyt.ic varie ty . That. o f W hite and! B ulns is ques-tionable an(! although incomplete ly studied possibly represents lymphocyticleukemia. Later in childhood, c lassif ication o f the usually acute leukemia ishandicapped by the v irtual absence o f ce llular differentiatio n. Zuelzer,2 for thatm at t er , q u e st ion s the v alidity o f a t t em p t s t o distinguish the ce ll type in thea cu t e d isease. N ev erthe le ss , it w ould seem ap p r op r ia t e t o en t er t a in som e r e ser v a-t ion s r ega r d in g the frequently stated generalizatio n that the majority o f len-kem ias in infants and children are lymphocy tic.

Maternal influences w hich might have contributed to the onset o f the leukemicprocess w ere not. apparent in this material. N one of the mothels w ere leukemic ,and since there are many repo rted cases o f normal children 1)orn to franklyleukem ic w omen, the presence o f a blo od dy scrasia in the mo t h e r does notappear to he of e tio log ic s ignificance.

S U M M A R YFour new cases o f congenital leukemia reported he ie may be added to the 14

acceptable cases in the literature. In all ex cept 1 of t h e se (ases ce lls o f the granu-lo cy t ic ser ies w er e inv o lved; males predominat.ed ov er f em ale s in a r at io of m o r ethan 2 to 1 . C ongenital anomalies w ere present in 3 of the 4 cases w e havereported, indicating a grow th dis turbance early in fe tal life . Contrary to theu s ua l f inding in childhood leukemia, ce lls o f the g ranulocytic series in the 4 casesr ep o r t ed h er e exhibited a fair degree of differentiation anti in this r esp ec t a t esim ilar t o t h ose w hich characterize the chronic form of the disease . It seemslike ly , therefore , that the leukemia ex isted during a sig n if ica n t p or t ion d )f intra-uterine life .

REFERENCES1 I 3 U N GE L E R , W.: A ngeborene Leuk# { 228 } m ie . Ztschr. f. Path. 41 : 257-264 , 1931 .2 C L A T W O R T H Y , H. W ., JR . A ND A ND ERSON , R. G .: Development . and g row th of the human

embryo and fetus. Am. J. D is . Child. 67: 167 -175 , 1944 .Co ss, F. S .: Cong enital le u cem ia , a r ep or t o f tw o case s. J. Pediat. 24: 191 -194 , 1944 .F A R B E R , S .: Personal communicatio n.G IB U N , J.: A case of mvelogenous leukemia occurring us ais infaiit f ive w eeks o ld. A r(hs.

Peditot. 50 : 662 -6 65 , 19 33 .


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W ILL IAM G . B ER NH ARD , IR A GO RE AND RALPH A . K ILBY 10016 I I A MME , B .: Em Fall v on k o !sge !s itale r m velo ischer leuk #{ 228} mie . A ct to padito t . 31 : 330-339,

1944 .INGALLS , T . II.: Pathogetses i s of i so ( )ngo l i sm. A i s s . J. 1)is. Child. 73 : 279 -292, 1947.

8 -: Persotsal comtsou!s icatio! i .I s .E ITH , H . N I.: C hsron ic !so y elogenous l e u k em i a in its f to ncy . A m. J. I)is . (hsild . 69 : 366 -368 ,

1945 . 1 \ELSEY , W . N I. A N !) AN DERS oN , 1). II .: (o !ig em sital leuk em ia. A m . J. l)is. Child . 58 :

1268-1277, 1939. hocit, M . I .: T togun g tIe r su dw es tdeu tscher Ptttho log en its M ann he im , 21 to M to i 19 22 .

Z e lstralf il. f . to llg . p tith . u . p to th . A nat. 33 : 7-8 , 1 922 . XORNMANN , V .: B eit rag z u r f r# { 252 } hk ind lichen u tsd ang eborenem s !so y e lo ischen leuk #{ 228} mie .

Z tsch r. f . Kinderhs . 56 : 440-448, 1934 .13 1 ORR I s oN , M ., SAMwDK . A . A . A Nt) R UB IN ST EiN , H . I. : Co tigenital leu k em ito w ith chlo r-

om a. A m . J. D is . C hild . 58 : 332 -3 38 , 193 9 .- AN! ) -: C onge !s ital e sse ts titil th s rom b ope tsic pu rpurto . A m . ,J. D is. C hsild l. 70 : 115-118,

1945 .lb PA T T EN , B . N I.: Ilu noan Emb r yo l o g y , Ph ilade lph ia, B lak is ton , 19 46 .!6 PONCHER , H . G ., WEIR , H . F. AND L IM ARz !, L . H .: C hrom s ic m y e lo gem sou s leuk em ia in

etor ly in fan cy . C a se R epor t. J. Ped iat. 21 : 73-79, 1942 .17 SM I TH , L . W .: A case o f acu te leuk em ia its an in fa ts t . Am . J. Dis . Chi ld . 21 : 163-166,1921 .8 STRANSKY , E .: B e itr# { 228} g e z ur k lin ische,s H #{ 228} m atologie im S f lugling salter. M o !satschr. f .

Kitsderh . 29 : 654-659, 1925 .!9 WH ! T E , P. J. AN D B UR N , E . L .: Fto tal acute ly m phoblastic leuk em ia w ith great em slarg e-

m en t o f the k idn ey s its ats iisf ant 3 w eek s old . A m . J. D is. Ch ild . 41 : 866-870, 1931 .20 WINTROBE , M . M .: C lin ical Hem atolo gy , ed . 2 , Ph ilad elp h ia, L ea & Fehig er, 1946.2! ZU ELZER , W . \V .: N orm al and path o log ic phy s io logy of the hon e m arrow . A m . J. Dis .

Ch ild !. 77 : 48 2 -50 2 , 1 949 .


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