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Skeletal changes associated with erythroblastosis fetalis
S K E L E T A L CHANGES ASSOCIATED W I T H EI~YTHROBLASTOSIS F E T A L I S RICHARD H . FOLLIS, JR., DEBORAH JACKSON, AND WILLIAM H . CARNES ~ BALTIMORE, ]V[D.
H E term erythroblastosis fetalis has been used to designate a group
T of clinical and pathologic manifestations occurring in the newborn infant. Clinically, one may find generalized edema (hydrops retails), jaundice (icterus gravis), or anemia with erythroblastemia (congenital anemia of t h e newborn infant). Post-mortem examination usually reveals enlargement of the liver and spleen with varying degrees Of extramedullary erythropoiesis. In addition, the placenta shows characteristic changes. 1 The close relationship of the clinical pictures has been established mainly because of its occurrence in succeeding pregnancies. Recently new and important light has been thrown on the etiology of erythroblastosis fetalis by the serologic observations of Levine and his co-workers. 2 It is the purpose of this report to present the clinical records and pathologic observations on five cases of erythroblastosis fetalis and to call attention especially to changes in the skeletal system which heretofore have not been described. CASE 1. ( 1 6 7 3 3 9 ) . - - T h i s baby was the third child born to a mentally deficient mother 2~1 years of age. The two previous children, by other men, are feeble-minded a n d one is a cripple. The mother went into labor at home two weeks before her expected date of confinement and delivered spontaneously about two and a half hours later. W h e n seen by the outside obstetric service, the child, a male, was breathing well t h o u g h crying only feebly. The baby on examination seemed normal and was l e f t with the mother. Next day, however, the child died quite unexpectedly. The m o t h e r ' s bloo,d W a s s e r m a n n as well as t h a t of the cord blood was negative. The placenta will be described below. A t autopsy (16327, H L I t 1456) the following findings were noted: The baby weighed 3,200 Gin. ExternMly he was normM. There was no jaundice or edema. The h e a r t weighed 30 Gin.; the right ventricle was hypertrophied. I n the interauricular sep~um there were numerous f e n e s t r a t i o n s ; the foramen ovale was widely open and only partially guarded by a valve. The l u n g s were incompletely expanded. The liver was enlarged, weighing 235 Gin. The spleen likewise was big, weighLag 40 Gin. The placenta weighed 880 Gin.; its surface was yellowish pink a a d the tissue was friable. ~r there was an extreme degree of blood formation in the liver. ~ y e l o l d tissue was found in the spleen and kidneys as well. Stains for iron showed this p i g m e n t in the liver cells and a small a m o u n t in the spleen; none was found in the renal tubular epithelium. The lungs showed fresh inflammatory exudate in the alveoli. From the Departments of Pathology, Pediatrics, and Obstetrics. The Johns Hopkins ~VIedieal School, and the Children's ]~ureau of the U. S. Department of Labor. *Present address, Department of Pathology, Stanford University School of Medicine, San
FranciSco,
Calif.
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X - r a y s o f t h e b o n e s showed t h e c a r t i l a g e s h a f t j u n c t i o n to be s t r a i g h t a n d normal. "Beneath t h i s w a s a dense s h a d o w e x t e n d i n g .down f o r a d i s t a n c e of a b o u t 2 ram. T h e n there w a s a m o r e rarefied zone e x t e n d i n g f o r a b o u t 1 ram. A second b a n d of i n c r e a s e d d e n s i t y was f o u n d b e n e a t h this, e x t e n d i n g f o r a b o u t a n o t h e r millimeter. T h e bone f r o m t h e n on seemed to be u n i f o r m l y denser t h a n n o r m a l . Sections o f the b o n e s revealed a s t r a i g t l t a n d r e g u l a r line of ossification at t h e c a r t i l a g e s h a f t j u n c t i o n . T h e m a t u r e c a r t i l a g e cells l a y i n orderly rows. 'Between t h e r a t h e r e w a s a n a b u n d a n c e of ealMfied m a t r i x s u b s t a n c e . I n v a s i o n of t h e Cartilage c o l u m n s b y blood vessels w a s regular. "Bone was b e i n g d e p o s i t e d on t h e m a t r i x subs t a n c e i n n o r m a l f a s h i o n . The lattice o f t h e m a t r i x With i t s c o a t i n g of bone, how-ever, w a s m u c h denser t h a n n o r m a l because a p p a r e n t l y n o n e w a s b e i n g destroyed. T h e r e was n e excess n u m b e r of osteoblasts, n o r were t h e r e a n y osteoclasts. T h i s d e n s i t y e x t e n d e d d o w n t h r o u g h o u t t h e entire s h a f t . I n t h e sections it w a s difficult to m a k e out t h e zone of r a r e f a c t i o n seen in the x-ray. D e e p in t h e s h a f t t h e r e was a a a b u n d a n c e of calcified m a t r i x s u b s t a n c e in all t h e t r a b e e u l a e . I t could be r e a d i l y d i s t i n g u i s h e d because it retalned-'%he blue s t a i n of h e m a t o x y l i n , w h e r e a s t h e n e w bone f o r m e d a r o u n d it took the p i n k o f t h e eosin. F r o m t h e a r r a n g e m e n t of t h e s e cores o f m a t r i x s u b s t a n c e one could perceive the original a r c h i t e c t u r a l p a t t e r n of t h e m a t r i x as a sort of honeycomb-like s y s t e m of h o r i z o n t a l l y a n d vertically disposed walls. Some of t h e t r a b e c u l a e h a d become very t h i c k b e c a u s e of h e a v y e n c a s e m e n t of t h e m a t r i x with bone as t h e result of a p p o s i t i o n a l a c t i v i t y on t h e par~ o f t h e osteoblasts. T h i s corresponded w i t h t h e second d e n s e zone seen b y x-ray. T h e bone t o w a r d the c e n t e r o f t h e s h a f t showed less calcified m a t r i x , a n d t h e t r a b e c n l a e were t h i n n e r a n d fewer. T h e cortex was thickened t h o u g h n o t m a r k e d l y so. The m a r r o w a p p e a r e d active. I r o n s t a i n w a s n e g a t i v e . I n t h e p l a c e n t a , whieli w a s s o m e w h a t i n c r e a s e d in size, t h e villi were m o d e r a t e l y larger than normal. 2~ f e w p e r s i s t i n g L a n g h a n s ' cells were f o u n d ; t h e r e were vacuoles in some. T h e s y n c y t i a l elements showed a r e t a r d a t i o n in d e g e n e r a t i o n . T h e s t r o m a w a s byperplastie. N o evidence of blood f o r m a t i o n w a s seen. I:[owever, t h e r e were occasional n u c l e a t e d red blood cells in t h e vessels. T h e s t r o m a w a s edematous in places. T h i s t h e n showed evidence of i m m a t u r i t y c o m p a t i b l e with t h e diagnosis of e r y t h r o b l a s t o s i s . I t is i n t e r e s t i n g to add t h a t a y e a r later, a f o u r t h child b y a n o t h e r m a n w a s born to this woman. This child is living a n d well at t h e p r e s e n t time.
Summary.--This baby, born to a feeble-minded mother, had a congenital malformation of the heart, and lobular pneumonia. There was no hydrops or jaundice. The liver and spleen were enlarged. Myeloid tissue was f o u n d in the liver, spleen, and kidneys. The bones showed alternating zones of increased density and rarefaction. A diagnosis of erythroblastosis was made on the presence os massive extramedullary blood formation and the appearance of the placenta. CASE 2 ( 1 6 1 9 3 4 ) . - - T h e m o t h e r of t h i s stillborn b a b y gave t h e following obstetric history. H e r first p r e g n a n c y , f o u r y e a r s before, w a s a n a b o r t i o n a t two m o n t h s . A y e a r later s h e delivered a f u l l - t e r m i n f a n t who developed a n e m i a a n d j a u n d i c e b u t s u r v i v e d a f t e r n u m e r o u s t r a n s f u s i o n s . A y e a r a f t e r t h i s she delivered at seven m o n t h s a s t i l l b o r n f e t u s which h a d a swollen face a n d a b d o m e n . The p l a c e n t a w a s said to h a v e b e e n large. The f o u r t h p r e g n a n c y , the p r e s e n t one, w a s u n e v e n t f u l u n t i l six weeks b e f o r e the expected date o f confinement w h e n a stillborn, s l i g h t l y m a c e r a t e d m a l e b a b y w a s delivered. "Blood W a s s e r m a n n s of t h e p a r e n t s were negative. A t a u t o p s y (]6299, tIL.It 1449) t h e b o d y w e i g h e d 2,500 Gm. T h e a b d o m e n w a s swollen; t h e f a c e w a s puffy. T h e t i s s u e s o f t h e head a n d t h o r a x were e d e m a t o u s .
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FOLLIS, JR.~ ET AL. :
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The limbs were less conspicuously affected, but the scrotum was very swollen. There wds early maceration as evidenced by peeling of the epidermis. There was no jaundice. The peritoneal cavity contained 100 c.c. of fluid; the pleural and pericardial cavities contained some excess fluid. The heart was normal. The lungs were collapsed. The liver was a little enlarged, weighing 135 @m. The spleen was definitely enlarged, weighing 30 Gm. The other tissues were not remarkable except that the shafts of the long bones were decidedly denser than normal. Microscopically, there was much erythropoiesis in the liver, spleen, and' kidneys. There was a good deal of iron pigment in the ~periportal cells of the liver lobules. Pigment was found in the spleen and in the epithelium of the convoluted tubules in the kidneys. In the placenta, which weighed 1,390 Gin., the villi were large with hyperplastic as well as edematous stroma. There was only slight degeneration of the syncytial cells. Many of the cells of the L a n g h a n s ' layer were persisting. There was marked vacuolization in some. Many nucleated red blood cells Were seen in the vessels, and there were scattered foci of red blood cell formation. Post-mortem x-ray examination of the bones showed ~ cartilage. The cartilage shaft junction was straight and regular. The bone bene~.th was uniformly increased in density. This was an entirely regular process which extended throughout the entire shaft. The cartilage shaft junction in the bones was sharp. The cartilage was entirely normal in appearance; i t s cells were arranged in orderly rows, and the blood vessels were invading in a regular manner. Between the cartilage cell rows tl{ere was a normal amount of calcified cartilaginous matrix substance and this extended down as a heavy lattice on which osteoid borders and borders of true bone were being d e p o s i t e d . However, a little below this, in the zone where normally the structure becomes more rarefied due to a destruction of matrix a~d the encasing bone, it remained extremely dense and this change extended down into the shaft so that there were thick trabeculae~ composed of calcified matrix substance covered by bone throughout the shaft. There were no changes in the osteoblasts or marrow save that the latter appeared hyperplastic. Iron stain was negative. No periosteal changes were found nor were there any focal inflammatory lesions.
Summary.--There is a familial history of erythroblastosis fetalis. The present case was a premature stillborn macerated child with hydrops and an enlarged liver and spleen. There was no jaundice. There was blood formation in the liver, spleen , and kidneys. The placenta showed large villi, with persistence of the Langhans' cells and erythropoiesis. The bones showed an increase in density which were interpreted as being due to a lack of destruction or resorption of the calcified matrix substance and bone. X - r a y examination confirmed the increased density of the bones. The diagnosis of erythroblastosis was based on the familial history, hydrops, extensive extramedullary blood formation together with evidence of blood destruction, and the appearance of the placenta. C~SE 3 (124822).--The b a b y ' s mother was a 30:year-old white secundigrav~a with a normal pelvis and negative Wassermann. She was admitted to the obstetric service about ten weeks before her expected date of confinement, complaining o f exertional dyspnea, vomiting, ankle edema, and pain in the right upper quadrant of the abdomen. She was found to have marked hydramnios (McDonald measurement , 37 cm.; circumference of abdomen at umbilicus, ]02.5 cm.). There was no evidence of toxemia. She was discharged but returned two weeks later, having had
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c o n s t a n t l u m b a r backache. B y t h i s t i m e t h e M c D o n a l d m e a s u r e m e n t w a s 47 cm. a n d t h e c i r c u m f e r e n c e of t h e a b d o m e n was 109 era. T h e f e t a l h e a r t could n o t be heard. T h e cervix was 2 cm. dilated. I n two d a y s ' t i m e the cervix w a s 5 cm. in diameter, a n d it w a s decided to r u p t u r e t h e m e m b r a n e s artificially. T w e n t y - f o u r h u n d r e d gfibic c e n t i m e t e r s o f yellowish ~tuid were m e a s u r e d w h e n t h i s w a s done. F o l l o w i n g this the f e t a l h e a r t was heard, a l t h o u g h i t s r h y t h m w a s i r r e g u l a r . T h e p a t i e n t p r o m p t l y w e n t i n t o labor a n d delivered a stillborn mule child, w e i g h i n g 3,580 Gm. The p l a c e n t a , which s e p a r a t e d spontaffe~usly, w e i g h e d 1,195 Gin. T h e W a s s e r m a n n on t h e cord blood w a s negative. T h e m o t h e r ' s course w a s u n e v e n t f u l . A t a u t o p s y (16214, H L H :[433) t h e a p p e a r a n c e of t h e i n f a n t was remurkaSle, d u e to m a s s i v e swelling of the h e a d , especially t h e face. The scalp was fully 1.5 em: t h i c k e r t h a n n o r m a l . The a b d o m e n was swollen a n d p r o t u b e r a n t . I n c o n t r a s t , the e x t r e m i t i e s a p p e a r e d n o t m u c h e n l a r g e d a n d were n o r m a l l y proportioned. The s c r o t m n w a s swollen. T h e r e w a s n o j a u n d i c e . T h e p e r i t o n e a l c a v i t y contained 575 c.c. o f c l e a r yellow fluid. T h e h e a r t w e i g h e d 20 Gin. a n d was normal. B o t h l u n g s were completely collapsed. T h e spleen w e i g h e d 5 Gin. a n d showed n o t h i n g a b n o r m a l . The liver w e i g h e d 100 Gin. a n d g r o s s l y showed no change. U p o n o p e n i n g t h e c r a n i a l cavity, a t e a r wds f o u n d i n the l e f t c r u s o f t h e t e n t o r i u m cerebelli, a n d t h e r e w a s h e m o r r h a g e over t h e cerebellum. A f e w s c a t t e r e d h e m o r r h a g e s were seen i n t h e white m a t t e r o f t h e brain. T h e s h a f t s of t h e b o n e s were denser t h a n normal. Microscopic e x a m i n a t i o n showed loci of h e m a t o p o i e s i s in t h e liver. I n t h e perip o r t a l cells of t h e liver lobules t h e r e was i r o n p i g m e n t . The spleen a n d k i d n e y s showed no blood f o r m a t i o n n o r w a s t h e r e a n y i r o n p i g m e n t i n t h e m either. There w a s a n e o g e n i c zone in t h e k i d n e y s i n d i c a t i n g some degree of p r e m a t u r i t y . X - r a y s o f the l o n g bones were tureen p o s t m o r t e m . The c a r t i l a g e was n o r m a l except t h a t t h e c a r t i l a g e s h a f t j u n c t i o n w a s s l i g h t l y i r r e g u l a r ; t h i s i r r e g u l a r i t y looked as t h o u g h it were due to calcification o f t h e walls of t h e c a r t i l a g e canals. ( T h e s e were n o t seen i n t h e sections, however.) J u s t b e n e a t h the j u n c t i o ~ there w a s a zone o f i n c r e a s e d density, a b r i g h t e r zone t h a n is u s u a l l y seen ( a n d which is due to t h e l a t t i c e ) . ]~eneath it t h e r e w a s a zone o f r a r e f a c t i o n which w a s a b o u t 1 m m . i n ws The bone b e n e a t h t h i s in t u r n w a s denser t h a n n o r m a l , a n d this dense f o r m a t i o n e x t e n d e d down into t h e s h a f t , b e c o m i n g less as t h e c e n t r a l p a r t w a s n e a r e d . However, even here t h e bone w a s definitely denser t h a n n o r m a l . There w a s no periosteal new bone f o r m a t i o n n o r a n y focal u r e a s of destruction. S e c t i o n s o f t h e bones showed n o r m a l c a r t i l a g e . The c a r t i l a g e c a n a l s were n o t conspicuous. T h e h y p e r t r o p h i c cells l a y i n orderly rows. T h e r e was a n a b u n d a n c e o f calcified m a t r i x s u b s t a n c e b o t h i n t h e v e r t i c a l p a r t i t i o n s e p a r a t i n g t h e rows of c a r t i l a g e cells a n d in t h e cross p a r t i t i o n s s e p a r a t i n g i n d i v i d u a l cells. T h i s m a t r i x did n o t seem i n c r e a s e d in a m o u n t . I n v a s i o n of t h e c a r t i l a g e a p p e a r e d to be p r o c e e d i n g n o r m a l l y . B e n e a t h t h e c a r t i l a g e t h e lattice of m a t r i x w a s denser t h a n non,real; t h a t is, t h e r e were m o r e spicules p e r field t h a n a r e u s u a l l y seen. I t app a r e n t l y w a s n o t b e i n g d e s t r o y e d i n n o r m a l f a s h i o n . N u m e r o u s osteoblasts l a y in t h e spaces b e t w e e n the lattice w h i c h w a s b e i n g covered w i t h bone. A s one proceeded d o w n into t h e s h a f t , t h e lattice) covered b y bone, did become less d e n s e f o r a dist a n c e o f a b o u t h a l f a low-power field. However, below this level t h e calcified m a t r i x s u b s t a n c e i n c r e a s e d in a m o u n t a n d was covered b y a h e a v y m a n t l e of bone. I n such t r a b e c u l a e one could see the original s t r u c t u r e of the calcified m a t r i x h o r i z o n t a l a n d vertical b l u e - s t a i n i n g linear m a s s e s completely encased in p i n k - s t a i n i n g bone. The bone on t h e m a t r i x seemed i n c r e a s e d in a~nount; t h e n u m b e r of bone ceils p e r u n i t a r e a s e e m e d n o r m a l , a n d t h e n u m b e r o f o s t e o b l a s t s a b o u t t h e t r a b e c u l a e did n o t seem increased. P r a c t i c a l l y no osteoid was seen. The cortex was thicker t h a n norm a l , b u t t h e r e w a s no evidence of excessive periosteal new bone f o r m a t i o n . The m a r r o w i n t h e i n t e r t r a b c c u l a r spaces was h y p e r p l a s t i c . N o iron could be s t a i n e d in t h e trabeculae.
FOLLIS,
JR., ET AL. :
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The plaeenta~ which was enlarged (],195 Gin.), showed large villi whose stroma was very hyperplastic. There was slight syncytial cell degeneration; very few persistent Langhans' cells were found. The endothelial eells were immature looking. No nucleated red cells were seen in the vessels nor was there any evidence of blood formation.
Summary.--In this case there was hydrar~nios. The baby showed hydrops. The liver was not enlarged but showed blood formation. This was not abnormal, however, since, the child was premature, as evidenced by the neogenic zone in the kidneys. The bones showed a band of rarefaction at the growing ends beneath the lattice. Beneath this the structure was The diagnosis and
increased in density. of erythroblastosis was
characteristic
changes
:X-ray confirmed these findings. made on the presence of hydrops
in the placenta.
CASE 4 (224571).--The pregnancy of this baby's mother, a 14-year-old primigravida, was uneventful until two weeks before the expected date of confinement. At this time she was found to have a blood pressure of 165/95 and a trace of albumin in the urine. Labor was induced by artificial rupture of the membranes, and about severt hours later she was delivered of ~ stillborn male infant, weighing 4,000 Gin. The fetal heart was heard until about an hour before delivery. The placenta weighed 800 Gin. At autopsy (17280, IILII 1610) there was marked edema of the entire body, especially prominent in the scalp. There was no jaundice. There were 200 c.e. of fluid in the peritoneal cavity and 50 c.e. in each thoracic cavity. The pericardial sac contained 25 c.e. The heart was normal in size and showed small hemorrhages beneath the epiear.dium. The lungs were collapsed. The liver was enlarged, weighing 225 Gin. The spleen was likewise enlarged, weighing 28 Gin. The other tissues were n o t g r o s s l y r e m a r k a b l e except the bones which were i n a r e a s e d in density. Microscopically t h e r e was extensive blood f o r m a t i o n i n t h e liver a n d spleen a n d to a lesser e x t e n t in the kidney. T h e r e was a g r e a t deal o f iron p i g m e n t in t h e liver; t h i s p i g m e n t w a s also f o u n d in t h e t r a b e c u l a e a n d c o a t i n g t h e r e t i e u l u m o f t h e spleen, t h o u g h none was seen in the pulp. T h e r e w a s also h e m o s i d e r i n i n t h e convoluted t u b u l e s o f t h e kidneys. The p l a c e n t a , which was s o m e w h a t e n l a r g e d (800 Gin.), showed s l i g h t b u t definite e n l a r g e m e n t of t h e villi. There was little d e g e n e r a t i o n of t h e s y n c y t i a l e l e m e n t s and t h e L a n g h a n s ' cell l a y e r was very well preserved. N u m e r o u s H o f b a u e r ceils were f o u n d . The s t r o m a w a s h y p e r p l a s t i e . There were m a n y foci of blood f o r m a t i o n , a n d n u m e r o u s n u c l e a t e d cells were seen in t h e vessels. X - r a y e x a m i n a t i o n of the bones showed a s t r a i g h t line b o u n d a r y b e t w e e n t h e c a r t i l a g e a n d s h a f t . B e n e a t h this the bone was i n c r e a s e d in d e n s i t y for a d i s t a n c e of several m i l l i m e t e r s . F r o m t h e r e on t h e bone was less dense t h a n above, b u t t h e f o r m a t i o n r e m a i n e d still denser t h a n normal. N o periosteal c h a n g e s were seen. I n t h e bones t h e c a r t i l a g e s h a f t j u n c t i o n w a s s t r a i g h t . The c a r t i l a g e cells were n o r m a l T h e a m o u n t of calcified c a r t i l a g e m a t r i x was n o t a b n o r m a l . The lattice of calcified m a t r i x b e n e a t h t h e c a r t i l a g e was p r o m i n e n t al~d was b e i n g encased i n bone. However, a little f u r t h e r down, i n s t e a d o f b e c o m i n g decreased i n a m o u n t , the calcified m a t r i x p e r s i s t e d a n d a p p e a r e d to be covered bY increased a m o u n t s o f n o r m a l looking bone. T h e t r a b e c u l a e , c o n s i s t i n g of calcified m a t r i x encased in bone, e x t e n d e d down into t h e center o f t h e s h a f t . T h e r e was no increase in t h e n u m b e r of osteoblasts. T h e m a r r o w a p p e a r e d h y p e r p l a s t i e . The cortex o f t h e bone w a s definitely thickened. I r o n s t a i n o f t h e bone w a s n e g a t i v e .
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T H E J O U R N A L OF P E D I A T R I C S
F i g . 2 . - - 5 ( C a s e 3), i R . o e n t g e n o g r a m of f e m u r , tibia, a n d fibula, ' s h o w i n g z o n e of d e c r e a s e d d e n s i t y a t c a r t i l a g e s h a f t j u n c t i o n . B o n e b e n e a t h this is a b n o r m a l l y d e n s e . 6 ( C a s e 4 ) , R o e n t g e n o g r a m of f e m u r , tibia, a n d fibula, s h o w i n g diffuse i n c r e a s e d d e n s i t y . 7 ( C a s e 3), P h o t o m i c r o g r a p h of l o n g b o n e , s h o w i n g r a r e f i e d zone w i t h d e n s e r b o n e b e n e a t h . 8 ( C a s e 4), P h o t o m i c r o g r a p h of l o n g bone, s h o w i n g i n c r e a s e d a m o u n t of b o n e ; e a c h t r a b e c u l a c o n t a i n s a n a b n o r m a l a m o u n t of calcified c a r t i l a g e m a t r i x substance.
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Summary.--In this child there was hydrops with extensive evidence of extramedullary blood formation as well as extreme blood destruction. The bones were uniformly denser than normal. The placenta showed characteristic changes. The diagnosis of erythroblastosis was made on the hydrops, signs of blood formation, and destruction and changes in the placenta. CASE 5 (HL.tt 61446).--This 10-day-old white male was admitted to the tIarriet Lane Home with the following history. The father, aged 51 years~ was living and well; the, mother, aged 35 years, was living and well. There were six other siblings, all well. The course of pregnancy was uneventful and delivery was easy. The child appeared well at birth except for slight jaundice which the parents thought was fading. The child was brought to the hospital because of profuse bleeding from the umbilical cord. On examination he showed extreme icterus, subcutaneous hemorrhages, pallor, and a bleeding umbilicus. Adrenalin was applied to the latter and the bleeding teraporari]y became less but soon increased and could not be controlled again. Twenty cubic centimeters of blood from a professional donor were given into the longitudinal sinus and the child seemed to improve. About three hours later respirations became irregular and the general appearance alarming. Before another transfusion could be performed, the baby expired. Blood obtained by cardiac puncture showed 1,560,000 red blood cells; 45,000 white blood cells; and 14 norraoblasts while counting 100 white cells. Clotting time was thirty-five minutes. Wassermann reaction on this blood was negative. Van den B e r g h ' s test, 11.1 rag. per cent was read as a direct reaction. A t autopsy (10813, t t L H ]77) the following findings were described: The body weighed 1,600 Gin.; the skin was intensely jaundiced. The heart and lungs showed nothing abnormal save for hemorrhages beneath the pleura of the latter. The spleen weighed 20 Gin. and was enlarged. The liver was not enlarged; it weighed 74 Gin. There was hemorrhage beneath the dura over b o t h cerebral hemispheres. A puncture hole in the dura was demonstrated as the origin Of t~is hemorrhage. Microscopically, there was extraraedullary blood forraation in the liver, spleen, and kidneys. There was hemoss in the liver cells and in the convoluted tubules of the kidneys but none in the spleen. F a t stain of the lung revealed maerophages filled with lipoid droplets in many of the pulmonary alveo]i. The placenta was not available for microscopic study. X-rays of the long bones revealed normal cartilage. Beneath this there was a thin bright line corresponding to the lattice. Under this the bones were uniformly rarefied for a distance as great as 30 ram. at the head of the humerus. From there on the shafts became much denser than normal ; this was fairly uniform throughout the rest of the shaft. No periosteal changes were seen nor were there any areas of destruction. I n the bones the cartilage was normal ; the cells were arranged in or.derly fashion. The matrix between the rows of cells was calcified. The lattice was somewhat stubby and not as plentiful as normal. I t was well covered with bone. There were numerous osteoblasts about the trabeculae thus formed. The marrow was hyperplastic. Beneath the cartilage shaft junction the structure seemed normal. Bone was being destroyed in the usual fashion. However, at a distance of about 5 lowpower microscopic fields from the cartilage shaft junction the trabeeulae in the shaft became extraordinarily dense. The amount of calcified matrix in their centers was definitely excessive, and the bone enclosing this blue-staining material was much thicker than normal. There was no increase in osteoblasts. The marrow here was hyperplastic. 1~o periosteM changes were seen.
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FOLLIS, Ji~., E~ AL. :
SKELETAL ~HANGES
89
Summary.--This 10-day-old jaundiced white male was admitted because of bleeding. Family history was negative. Despite transfusions he died and at a u t o p s y was found to have an enlarged spleen. There was blood formation in the liver, spleen, and kidneys. Iron pigment was found in the renal epithelium. The diagnosis of erythroblastosis was founded on the jaundice, enlarged spleen, and extramedullary blood formation with evidence of red ceil destruction. The diagnosis by the clinicians was h e m o r r h a g e disease. DISCUSSION
We have presented the clinical and pathologic records of five cases of erythroblastosis fetalis. In three instances there was hydrops, in one, icterus with hemorrhagic manifestations, while in another, although clinically the child appeared normal, at autopsy the liver and spleen were enlarged and there was blood formation in these organs and in the kidneys. There was also a fresh lobular pneumonia. I n all, the cord blood and that of the mother gave negative serologic tests for syphilis. We were f o r t u n a t e in being able to review sections of the placentas with Dr. Louis Hellman who has described characteristic changes in this organ associated with erythroblastosis. 1 In Dr. H e l l m a n ' s opinion the f o u r placentas available f o r Study showed changes pathognomonie of erythroblastosis. I n two the changes were more marked than in the others. One could correlate the degree of blood formation in the placenta with that f o u n d in the other tissues. We have described in some detail changes in the skeletal systems of these five infants. The most striking alteration was a marked increase in density of the bones:, seen both in microscopic sections and in x-rays taken post mortem. This change consisted of an increase in the number and thickness of the trabeeulae, due apparently to a lack of destruction of the calcified cartilaginous matrix substance which was then covered with a thick layer of bone. In two instances this increase in density was uniform throughout the entire shaft, while in the other three eases there were zones of decreased density of varying width a short distance below beneath the lattice at the cartilage shaft junction. In one there was a band of increased density beneath the zone of rarefaction. The cartilage showed no change nor were there any indications of periosteal new bone formation. The cause f o r the zones of decreased density is not clear nor can we explain the band of increased density seen beneath this in one of the cases. Transverse lines of increased density are more common than zones of rarefaction in infants' bones and have been interpreted as due to effects produced by a retardation in the growth of the cartilage with continuation of osteoblastie activities2 T h e zones of rarefaction are probably due to an acceleration of the destructive forces, but why this should be present in these eases is difficult to explain. The most con-
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spicuous change, however, and the one common to all five of these cases, is the increase in density of the shafts of the bones. The exact mechanism for this increase in density is obscure. Several explanations n a t u r a l l y come to mind. Could these changes be due to the influence of some substance elaborated by the m a t e r n a l organism or placenta ? The placenta in erythroblastosis is frequently enlarged and h a s been reported to contain more chorionic hormone than is normal. 4 The relationship of estrogenic hormone to an increase in density of the bones of birds is well established2 I n experiments on rats to which large amounts of estrogenic hormone h a d been administered, we have o b s e r v e d increased density at the ends of the growing bones of young animals. 6 Estrogen had less m a r k e d effect in adult animals and had no influence on the bones of old animals. This increased density was i n t e r p r e t e d as a decrease in the rate of normal destruction. One wonders, then, whether the changes we have described could have been produced by some such mechanism as this. We know of no observations on animals whose mothers had received large amounts of estrogen during their pregnancy. A n o t h e r factor which must be considered is that some material liberated in the breakdown of red cells m a y play a role. We are familiar with an increase in osseous density produced by an excess of certain specific elements in the body. In lead poisoning in childhood one finds an increase in the a m o u n t of cartilaginous m a t r i x substance beneath the cartilage shaft junction. This is because lead as well as calcium is deposited in the matrix and seems to render the m a t r i x more resistant to destruction. Bone is then deposited on i t J Bismuth produces a zone of increased density in the growing bones of infants whose mothers have been injected with this element d u r i n g p r e g n a n c y 2 E l e m e n t a r y phosphorus likewise has been shown to produce an extremely dense deposition of calcified m a t r i x a n d bone at the growing ends of the long bones. ~ One wonders then whether excessive iron m a y have had a n y effect in producing the changes we have described. None could be stained in the sections. Analyses of the bone have not been made. I t is interesting, however, to point out t h a t MaeCallum 1~ has called attention to the possible role of iron in n o r m a l calcification. One thinks, too, of the changes in the skeleton associated with the chronic hemolytic anemias seen in childhood; namely, sickle cell anemia, Cootey's anemia, and congenital hemolytic jaundice. I n these eases, however, there is rarefaction of the long bones which is a p p a r e n t l y due to destruction of the trabeculae because of the extreme h y p e r p l a s i a of the m a r r o w cells. 11 Similar changes are seen in leucemia. The thickening which has been described in the skull in eases of chronic hemolytic anemia is more difficult to explain. B u t it is a p p a r e n t l y d u e to hyperplasia of the m a r r o w and a pushing" up of the periosteum covering the
FOLLIS,
JR.,
ET AL. :
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outer table of the skull. Thus, the picture in these cases is different f r o m the one which we have described. However, it m u s t be pointed out that in utero blood f o r m a t i o n takes place in the e x t r a m e d u l l a r y tissues with great ease a n d the effect of hyperplastic m a r r o w is not felt by the bone in the same way as one sees it in postuterine life. I n congenital syphilis one frequently encounters changes in x-rays of the skeleton which are similar to those we have described in Cases 1, 2 and 5. I n all our cases, as was pointed out above, serologic tests for s y p h i l i s were negative; nor were there any focal inflammatory lesions seen in the microscopic sections or localized areas of destruction in the x-rays. The nonspecifieity of m a n y of the x-ray changes f o r m e r l y thought to be associated with congenital syphilis is ~becoming more and more a p p a r e n t . This has been brought out most clearly in a recent study o2 Caffey 12 who f o u n d changes indistinguishable f r o m syphilitic osteochondritis, osteoperiostitis, and osteomyelitis in the roentgenograms o2 nonsyphilitic children that he examined. I t is interesting to note that Caffey 12 includes two cases of erythroblastosis in his series. The first (Case 2) was an in~ant 50 days old who had had persistent jaundice; on examination the spleen was enlarged and there was p i t t i n g edema of the lower abdominal wall and groin. The e r y t h r o c y t e count was 1.2 million p e r cubic millimeter of which 5,100 were nucleated. The child died but there was no autopsy. X - r a y s showed heavy transverse bands across the ends of the shafts of the long bones. There was no increased density ,in the shaft such as was found in our cases. Caffey's second case of erythroblastosis (Case 6) lived only f o u r hours and had h y d r o p s and e n l a r g e m e n t - o f the liver and spleen. The diagnosis of erythroblastosis was confirmed at autopsy. I n the roentgenograms there were " d e e p bands of increased density across the ends o2 the shafts with n a r r o w e r zones of diminished density lying parallel along the sha~tward m a r g i n s . " I n the reproductions of the x-ray, the shafts of this case do seem denser t h a n normal, although Caffey ~2 did not comment on this point. T h a t the bands seen in our cases are due to nonspecific factors is not unlikely. The change common to all, however, is: the increased density of the shafts. The disease p a r excellence in which there is a persistence of calcified cartilaginous m a t r i x substance upon which bone deposits is osteosclerosis 2ragilis generalisata (Albers-SchSnberg disease). Deep down in the shaft one finds large amounts of blue-staining calcified m a t r i x substance encased in bone, and in osteoid in those cases in which rickets is present. The anemia a c c o m p a n y i n g this disease is usually a s c r i b e 4 to the reduction in m a r r o w space. B u t the possibility t h a t there is some more fundamental disturbance affecting both hemopoiesis and bone f o r m a t i o n has also been advanced,
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W e h a v e d e s c r i b e d osseous c h a n g e s b o t h b y x - r a y a n d on m i c r o s c o p i c e x a m i n a t i o n in five cases of e r y t h r o b l a s t o s i s . The alteration Common to a l l w a s a n i n c r e a s e i n d e n s i t y . I n a d d i t i o n , i n t h r e e t h e r e w e r e b a n d s of decreased density which were probably nonspecific in origin. REFERENCES 1. Hellman, L. M, and ttertig, A . T . : Am. J. Path. 14: 111, 1938. 2. Levine, P., Burnham, L., Katzin, E. M , and Vogel, P. : Am. J. Obst. & Gynec. 42: 925, 1941. 3. Eliot, M. M., Souther, S. P., and Park, E. A. : Bull. Johns Hopkins IIosp. 41: 364, 1927. 4. Herrnberger, K.: Arch. f. Gyn~k. 170: 287, 1940. 5. Pfeiffer, C. A , and Gardner~ W . U . : Endocrino]ogy 23: 485, 1938. 6. Day, tI. G., and ]~011is, 1~. It., Jr. : Endocrinology 28: 83, 1941. 7. Park, E. A., Jackson, D., and Kajdi, L.: Am. J. Dis. Child. 41: 485~ 1931. 8. Whitridge, J., Jr.: Am. J. Syph., Gonor. & Ven. Dis. 24: 223, 1940. 9. Phemister, D. ]3.: J . A . 3s A. 70: 1737, 1918. 10. MacCallum, W. G.: A Text-Book of Pathology, Philadelphia, 1940, W. B. Saunders Co., p. 116. 11. Caffey, J.: Am. J. ~oentgenol. 37: 293, 1937. 12. Caffey, J.: Am. J. R oentgeno].'42: 637, 1939.
H E term erythroblastosis fetalis has been used to designate a group
T of clinical and pathologic manifestations occurring in the newborn infant. Clinically, one may find generalized edema (hydrops retails), jaundice (icterus gravis), or anemia with erythroblastemia (congenital anemia of t h e newborn infant). Post-mortem examination usually reveals enlargement of the liver and spleen with varying degrees Of extramedullary erythropoiesis. In addition, the placenta shows characteristic changes. 1 The close relationship of the clinical pictures has been established mainly because of its occurrence in succeeding pregnancies. Recently new and important light has been thrown on the etiology of erythroblastosis fetalis by the serologic observations of Levine and his co-workers. 2 It is the purpose of this report to present the clinical records and pathologic observations on five cases of erythroblastosis fetalis and to call attention especially to changes in the skeletal system which heretofore have not been described. CASE 1. ( 1 6 7 3 3 9 ) . - - T h i s baby was the third child born to a mentally deficient mother 2~1 years of age. The two previous children, by other men, are feeble-minded a n d one is a cripple. The mother went into labor at home two weeks before her expected date of confinement and delivered spontaneously about two and a half hours later. W h e n seen by the outside obstetric service, the child, a male, was breathing well t h o u g h crying only feebly. The baby on examination seemed normal and was l e f t with the mother. Next day, however, the child died quite unexpectedly. The m o t h e r ' s bloo,d W a s s e r m a n n as well as t h a t of the cord blood was negative. The placenta will be described below. A t autopsy (16327, H L I t 1456) the following findings were noted: The baby weighed 3,200 Gin. ExternMly he was normM. There was no jaundice or edema. The h e a r t weighed 30 Gin.; the right ventricle was hypertrophied. I n the interauricular sep~um there were numerous f e n e s t r a t i o n s ; the foramen ovale was widely open and only partially guarded by a valve. The l u n g s were incompletely expanded. The liver was enlarged, weighing 235 Gin. The spleen likewise was big, weighLag 40 Gin. The placenta weighed 880 Gin.; its surface was yellowish pink a a d the tissue was friable. ~r there was an extreme degree of blood formation in the liver. ~ y e l o l d tissue was found in the spleen and kidneys as well. Stains for iron showed this p i g m e n t in the liver cells and a small a m o u n t in the spleen; none was found in the renal tubular epithelium. The lungs showed fresh inflammatory exudate in the alveoli. From the Departments of Pathology, Pediatrics, and Obstetrics. The Johns Hopkins ~VIedieal School, and the Children's ]~ureau of the U. S. Department of Labor. *Present address, Department of Pathology, Stanford University School of Medicine, San
FranciSco,
Calif.
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X - r a y s o f t h e b o n e s showed t h e c a r t i l a g e s h a f t j u n c t i o n to be s t r a i g h t a n d normal. "Beneath t h i s w a s a dense s h a d o w e x t e n d i n g .down f o r a d i s t a n c e of a b o u t 2 ram. T h e n there w a s a m o r e rarefied zone e x t e n d i n g f o r a b o u t 1 ram. A second b a n d of i n c r e a s e d d e n s i t y was f o u n d b e n e a t h this, e x t e n d i n g f o r a b o u t a n o t h e r millimeter. T h e bone f r o m t h e n on seemed to be u n i f o r m l y denser t h a n n o r m a l . Sections o f the b o n e s revealed a s t r a i g t l t a n d r e g u l a r line of ossification at t h e c a r t i l a g e s h a f t j u n c t i o n . T h e m a t u r e c a r t i l a g e cells l a y i n orderly rows. 'Between t h e r a t h e r e w a s a n a b u n d a n c e of ealMfied m a t r i x s u b s t a n c e . I n v a s i o n of t h e Cartilage c o l u m n s b y blood vessels w a s regular. "Bone was b e i n g d e p o s i t e d on t h e m a t r i x subs t a n c e i n n o r m a l f a s h i o n . The lattice o f t h e m a t r i x With i t s c o a t i n g of bone, how-ever, w a s m u c h denser t h a n n o r m a l because a p p a r e n t l y n o n e w a s b e i n g destroyed. T h e r e was n e excess n u m b e r of osteoblasts, n o r were t h e r e a n y osteoclasts. T h i s d e n s i t y e x t e n d e d d o w n t h r o u g h o u t t h e entire s h a f t . I n t h e sections it w a s difficult to m a k e out t h e zone of r a r e f a c t i o n seen in the x-ray. D e e p in t h e s h a f t t h e r e was a a a b u n d a n c e of calcified m a t r i x s u b s t a n c e in all t h e t r a b e e u l a e . I t could be r e a d i l y d i s t i n g u i s h e d because it retalned-'%he blue s t a i n of h e m a t o x y l i n , w h e r e a s t h e n e w bone f o r m e d a r o u n d it took the p i n k o f t h e eosin. F r o m t h e a r r a n g e m e n t of t h e s e cores o f m a t r i x s u b s t a n c e one could perceive the original a r c h i t e c t u r a l p a t t e r n of t h e m a t r i x as a sort of honeycomb-like s y s t e m of h o r i z o n t a l l y a n d vertically disposed walls. Some of t h e t r a b e c u l a e h a d become very t h i c k b e c a u s e of h e a v y e n c a s e m e n t of t h e m a t r i x with bone as t h e result of a p p o s i t i o n a l a c t i v i t y on t h e par~ o f t h e osteoblasts. T h i s corresponded w i t h t h e second d e n s e zone seen b y x-ray. T h e bone t o w a r d the c e n t e r o f t h e s h a f t showed less calcified m a t r i x , a n d t h e t r a b e c n l a e were t h i n n e r a n d fewer. T h e cortex was thickened t h o u g h n o t m a r k e d l y so. The m a r r o w a p p e a r e d active. I r o n s t a i n w a s n e g a t i v e . I n t h e p l a c e n t a , whieli w a s s o m e w h a t i n c r e a s e d in size, t h e villi were m o d e r a t e l y larger than normal. 2~ f e w p e r s i s t i n g L a n g h a n s ' cells were f o u n d ; t h e r e were vacuoles in some. T h e s y n c y t i a l elements showed a r e t a r d a t i o n in d e g e n e r a t i o n . T h e s t r o m a w a s byperplastie. N o evidence of blood f o r m a t i o n w a s seen. I:[owever, t h e r e were occasional n u c l e a t e d red blood cells in t h e vessels. T h e s t r o m a w a s edematous in places. T h i s t h e n showed evidence of i m m a t u r i t y c o m p a t i b l e with t h e diagnosis of e r y t h r o b l a s t o s i s . I t is i n t e r e s t i n g to add t h a t a y e a r later, a f o u r t h child b y a n o t h e r m a n w a s born to this woman. This child is living a n d well at t h e p r e s e n t time.
Summary.--This baby, born to a feeble-minded mother, had a congenital malformation of the heart, and lobular pneumonia. There was no hydrops or jaundice. The liver and spleen were enlarged. Myeloid tissue was f o u n d in the liver, spleen, and kidneys. The bones showed alternating zones of increased density and rarefaction. A diagnosis of erythroblastosis was made on the presence os massive extramedullary blood formation and the appearance of the placenta. CASE 2 ( 1 6 1 9 3 4 ) . - - T h e m o t h e r of t h i s stillborn b a b y gave t h e following obstetric history. H e r first p r e g n a n c y , f o u r y e a r s before, w a s a n a b o r t i o n a t two m o n t h s . A y e a r later s h e delivered a f u l l - t e r m i n f a n t who developed a n e m i a a n d j a u n d i c e b u t s u r v i v e d a f t e r n u m e r o u s t r a n s f u s i o n s . A y e a r a f t e r t h i s she delivered at seven m o n t h s a s t i l l b o r n f e t u s which h a d a swollen face a n d a b d o m e n . The p l a c e n t a w a s said to h a v e b e e n large. The f o u r t h p r e g n a n c y , the p r e s e n t one, w a s u n e v e n t f u l u n t i l six weeks b e f o r e the expected date o f confinement w h e n a stillborn, s l i g h t l y m a c e r a t e d m a l e b a b y w a s delivered. "Blood W a s s e r m a n n s of t h e p a r e n t s were negative. A t a u t o p s y (]6299, tIL.It 1449) t h e b o d y w e i g h e d 2,500 Gm. T h e a b d o m e n w a s swollen; t h e f a c e w a s puffy. T h e t i s s u e s o f t h e head a n d t h o r a x were e d e m a t o u s .
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FOLLIS, JR.~ ET AL. :
SKELETAL CHANGES
83
The limbs were less conspicuously affected, but the scrotum was very swollen. There wds early maceration as evidenced by peeling of the epidermis. There was no jaundice. The peritoneal cavity contained 100 c.c. of fluid; the pleural and pericardial cavities contained some excess fluid. The heart was normal. The lungs were collapsed. The liver was a little enlarged, weighing 135 @m. The spleen was definitely enlarged, weighing 30 Gm. The other tissues were not remarkable except that the shafts of the long bones were decidedly denser than normal. Microscopically, there was much erythropoiesis in the liver, spleen, and' kidneys. There was a good deal of iron pigment in the ~periportal cells of the liver lobules. Pigment was found in the spleen and in the epithelium of the convoluted tubules in the kidneys. In the placenta, which weighed 1,390 Gin., the villi were large with hyperplastic as well as edematous stroma. There was only slight degeneration of the syncytial cells. Many of the cells of the L a n g h a n s ' layer were persisting. There was marked vacuolization in some. Many nucleated red blood cells Were seen in the vessels, and there were scattered foci of red blood cell formation. Post-mortem x-ray examination of the bones showed ~ cartilage. The cartilage shaft junction was straight and regular. The bone bene~.th was uniformly increased in density. This was an entirely regular process which extended throughout the entire shaft. The cartilage shaft junction in the bones was sharp. The cartilage was entirely normal in appearance; i t s cells were arranged in orderly rows, and the blood vessels were invading in a regular manner. Between the cartilage cell rows tl{ere was a normal amount of calcified cartilaginous matrix substance and this extended down as a heavy lattice on which osteoid borders and borders of true bone were being d e p o s i t e d . However, a little below this, in the zone where normally the structure becomes more rarefied due to a destruction of matrix a~d the encasing bone, it remained extremely dense and this change extended down into the shaft so that there were thick trabeculae~ composed of calcified matrix substance covered by bone throughout the shaft. There were no changes in the osteoblasts or marrow save that the latter appeared hyperplastic. Iron stain was negative. No periosteal changes were found nor were there any focal inflammatory lesions.
Summary.--There is a familial history of erythroblastosis fetalis. The present case was a premature stillborn macerated child with hydrops and an enlarged liver and spleen. There was no jaundice. There was blood formation in the liver, spleen , and kidneys. The placenta showed large villi, with persistence of the Langhans' cells and erythropoiesis. The bones showed an increase in density which were interpreted as being due to a lack of destruction or resorption of the calcified matrix substance and bone. X - r a y examination confirmed the increased density of the bones. The diagnosis of erythroblastosis was based on the familial history, hydrops, extensive extramedullary blood formation together with evidence of blood destruction, and the appearance of the placenta. C~SE 3 (124822).--The b a b y ' s mother was a 30:year-old white secundigrav~a with a normal pelvis and negative Wassermann. She was admitted to the obstetric service about ten weeks before her expected date of confinement, complaining o f exertional dyspnea, vomiting, ankle edema, and pain in the right upper quadrant of the abdomen. She was found to have marked hydramnios (McDonald measurement , 37 cm.; circumference of abdomen at umbilicus, ]02.5 cm.). There was no evidence of toxemia. She was discharged but returned two weeks later, having had
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c o n s t a n t l u m b a r backache. B y t h i s t i m e t h e M c D o n a l d m e a s u r e m e n t w a s 47 cm. a n d t h e c i r c u m f e r e n c e of t h e a b d o m e n was 109 era. T h e f e t a l h e a r t could n o t be heard. T h e cervix was 2 cm. dilated. I n two d a y s ' t i m e the cervix w a s 5 cm. in diameter, a n d it w a s decided to r u p t u r e t h e m e m b r a n e s artificially. T w e n t y - f o u r h u n d r e d gfibic c e n t i m e t e r s o f yellowish ~tuid were m e a s u r e d w h e n t h i s w a s done. F o l l o w i n g this the f e t a l h e a r t was heard, a l t h o u g h i t s r h y t h m w a s i r r e g u l a r . T h e p a t i e n t p r o m p t l y w e n t i n t o labor a n d delivered a stillborn mule child, w e i g h i n g 3,580 Gm. The p l a c e n t a , which s e p a r a t e d spontaffe~usly, w e i g h e d 1,195 Gin. T h e W a s s e r m a n n on t h e cord blood w a s negative. T h e m o t h e r ' s course w a s u n e v e n t f u l . A t a u t o p s y (16214, H L H :[433) t h e a p p e a r a n c e of t h e i n f a n t was remurkaSle, d u e to m a s s i v e swelling of the h e a d , especially t h e face. The scalp was fully 1.5 em: t h i c k e r t h a n n o r m a l . The a b d o m e n was swollen a n d p r o t u b e r a n t . I n c o n t r a s t , the e x t r e m i t i e s a p p e a r e d n o t m u c h e n l a r g e d a n d were n o r m a l l y proportioned. The s c r o t m n w a s swollen. T h e r e w a s n o j a u n d i c e . T h e p e r i t o n e a l c a v i t y contained 575 c.c. o f c l e a r yellow fluid. T h e h e a r t w e i g h e d 20 Gin. a n d was normal. B o t h l u n g s were completely collapsed. T h e spleen w e i g h e d 5 Gin. a n d showed n o t h i n g a b n o r m a l . The liver w e i g h e d 100 Gin. a n d g r o s s l y showed no change. U p o n o p e n i n g t h e c r a n i a l cavity, a t e a r wds f o u n d i n the l e f t c r u s o f t h e t e n t o r i u m cerebelli, a n d t h e r e w a s h e m o r r h a g e over t h e cerebellum. A f e w s c a t t e r e d h e m o r r h a g e s were seen i n t h e white m a t t e r o f t h e brain. T h e s h a f t s of t h e b o n e s were denser t h a n normal. Microscopic e x a m i n a t i o n showed loci of h e m a t o p o i e s i s in t h e liver. I n t h e perip o r t a l cells of t h e liver lobules t h e r e was i r o n p i g m e n t . The spleen a n d k i d n e y s showed no blood f o r m a t i o n n o r w a s t h e r e a n y i r o n p i g m e n t i n t h e m either. There w a s a n e o g e n i c zone in t h e k i d n e y s i n d i c a t i n g some degree of p r e m a t u r i t y . X - r a y s o f the l o n g bones were tureen p o s t m o r t e m . The c a r t i l a g e was n o r m a l except t h a t t h e c a r t i l a g e s h a f t j u n c t i o n w a s s l i g h t l y i r r e g u l a r ; t h i s i r r e g u l a r i t y looked as t h o u g h it were due to calcification o f t h e walls of t h e c a r t i l a g e canals. ( T h e s e were n o t seen i n t h e sections, however.) J u s t b e n e a t h the j u n c t i o ~ there w a s a zone o f i n c r e a s e d density, a b r i g h t e r zone t h a n is u s u a l l y seen ( a n d which is due to t h e l a t t i c e ) . ]~eneath it t h e r e w a s a zone o f r a r e f a c t i o n which w a s a b o u t 1 m m . i n ws The bone b e n e a t h t h i s in t u r n w a s denser t h a n n o r m a l , a n d this dense f o r m a t i o n e x t e n d e d down into t h e s h a f t , b e c o m i n g less as t h e c e n t r a l p a r t w a s n e a r e d . However, even here t h e bone w a s definitely denser t h a n n o r m a l . There w a s no periosteal new bone f o r m a t i o n n o r a n y focal u r e a s of destruction. S e c t i o n s o f t h e bones showed n o r m a l c a r t i l a g e . The c a r t i l a g e c a n a l s were n o t conspicuous. T h e h y p e r t r o p h i c cells l a y i n orderly rows. T h e r e was a n a b u n d a n c e o f calcified m a t r i x s u b s t a n c e b o t h i n t h e v e r t i c a l p a r t i t i o n s e p a r a t i n g t h e rows of c a r t i l a g e cells a n d in t h e cross p a r t i t i o n s s e p a r a t i n g i n d i v i d u a l cells. T h i s m a t r i x did n o t seem i n c r e a s e d in a m o u n t . I n v a s i o n of t h e c a r t i l a g e a p p e a r e d to be p r o c e e d i n g n o r m a l l y . B e n e a t h t h e c a r t i l a g e t h e lattice of m a t r i x w a s denser t h a n non,real; t h a t is, t h e r e were m o r e spicules p e r field t h a n a r e u s u a l l y seen. I t app a r e n t l y w a s n o t b e i n g d e s t r o y e d i n n o r m a l f a s h i o n . N u m e r o u s osteoblasts l a y in t h e spaces b e t w e e n the lattice w h i c h w a s b e i n g covered w i t h bone. A s one proceeded d o w n into t h e s h a f t , t h e lattice) covered b y bone, did become less d e n s e f o r a dist a n c e o f a b o u t h a l f a low-power field. However, below this level t h e calcified m a t r i x s u b s t a n c e i n c r e a s e d in a m o u n t a n d was covered b y a h e a v y m a n t l e of bone. I n such t r a b e c u l a e one could see the original s t r u c t u r e of the calcified m a t r i x h o r i z o n t a l a n d vertical b l u e - s t a i n i n g linear m a s s e s completely encased in p i n k - s t a i n i n g bone. The bone on t h e m a t r i x seemed i n c r e a s e d in a~nount; t h e n u m b e r of bone ceils p e r u n i t a r e a s e e m e d n o r m a l , a n d t h e n u m b e r o f o s t e o b l a s t s a b o u t t h e t r a b e c u l a e did n o t seem increased. P r a c t i c a l l y no osteoid was seen. The cortex was thicker t h a n norm a l , b u t t h e r e w a s no evidence of excessive periosteal new bone f o r m a t i o n . The m a r r o w i n t h e i n t e r t r a b c c u l a r spaces was h y p e r p l a s t i c . N o iron could be s t a i n e d in t h e trabeculae.
FOLLIS,
JR., ET AL. :
SKELETAL
CHANGES
~5
The plaeenta~ which was enlarged (],195 Gin.), showed large villi whose stroma was very hyperplastic. There was slight syncytial cell degeneration; very few persistent Langhans' cells were found. The endothelial eells were immature looking. No nucleated red cells were seen in the vessels nor was there any evidence of blood formation.
Summary.--In this case there was hydrar~nios. The baby showed hydrops. The liver was not enlarged but showed blood formation. This was not abnormal, however, since, the child was premature, as evidenced by the neogenic zone in the kidneys. The bones showed a band of rarefaction at the growing ends beneath the lattice. Beneath this the structure was The diagnosis and
increased in density. of erythroblastosis was
characteristic
changes
:X-ray confirmed these findings. made on the presence of hydrops
in the placenta.
CASE 4 (224571).--The pregnancy of this baby's mother, a 14-year-old primigravida, was uneventful until two weeks before the expected date of confinement. At this time she was found to have a blood pressure of 165/95 and a trace of albumin in the urine. Labor was induced by artificial rupture of the membranes, and about severt hours later she was delivered of ~ stillborn male infant, weighing 4,000 Gin. The fetal heart was heard until about an hour before delivery. The placenta weighed 800 Gin. At autopsy (17280, IILII 1610) there was marked edema of the entire body, especially prominent in the scalp. There was no jaundice. There were 200 c.e. of fluid in the peritoneal cavity and 50 c.e. in each thoracic cavity. The pericardial sac contained 25 c.e. The heart was normal in size and showed small hemorrhages beneath the epiear.dium. The lungs were collapsed. The liver was enlarged, weighing 225 Gin. The spleen was likewise enlarged, weighing 28 Gin. The other tissues were n o t g r o s s l y r e m a r k a b l e except the bones which were i n a r e a s e d in density. Microscopically t h e r e was extensive blood f o r m a t i o n i n t h e liver a n d spleen a n d to a lesser e x t e n t in the kidney. T h e r e was a g r e a t deal o f iron p i g m e n t in t h e liver; t h i s p i g m e n t w a s also f o u n d in t h e t r a b e c u l a e a n d c o a t i n g t h e r e t i e u l u m o f t h e spleen, t h o u g h none was seen in the pulp. T h e r e w a s also h e m o s i d e r i n i n t h e convoluted t u b u l e s o f t h e kidneys. The p l a c e n t a , which was s o m e w h a t e n l a r g e d (800 Gin.), showed s l i g h t b u t definite e n l a r g e m e n t of t h e villi. There was little d e g e n e r a t i o n of t h e s y n c y t i a l e l e m e n t s and t h e L a n g h a n s ' cell l a y e r was very well preserved. N u m e r o u s H o f b a u e r ceils were f o u n d . The s t r o m a w a s h y p e r p l a s t i e . There were m a n y foci of blood f o r m a t i o n , a n d n u m e r o u s n u c l e a t e d cells were seen in t h e vessels. X - r a y e x a m i n a t i o n of the bones showed a s t r a i g h t line b o u n d a r y b e t w e e n t h e c a r t i l a g e a n d s h a f t . B e n e a t h this the bone was i n c r e a s e d in d e n s i t y for a d i s t a n c e of several m i l l i m e t e r s . F r o m t h e r e on t h e bone was less dense t h a n above, b u t t h e f o r m a t i o n r e m a i n e d still denser t h a n normal. N o periosteal c h a n g e s were seen. I n t h e bones t h e c a r t i l a g e s h a f t j u n c t i o n w a s s t r a i g h t . The c a r t i l a g e cells were n o r m a l T h e a m o u n t of calcified c a r t i l a g e m a t r i x was n o t a b n o r m a l . The lattice of calcified m a t r i x b e n e a t h t h e c a r t i l a g e was p r o m i n e n t al~d was b e i n g encased i n bone. However, a little f u r t h e r down, i n s t e a d o f b e c o m i n g decreased i n a m o u n t , the calcified m a t r i x p e r s i s t e d a n d a p p e a r e d to be covered bY increased a m o u n t s o f n o r m a l looking bone. T h e t r a b e c u l a e , c o n s i s t i n g of calcified m a t r i x encased in bone, e x t e n d e d down into t h e center o f t h e s h a f t . T h e r e was no increase in t h e n u m b e r of osteoblasts. T h e m a r r o w a p p e a r e d h y p e r p l a s t i e . The cortex o f t h e bone w a s definitely thickened. I r o n s t a i n o f t h e bone w a s n e g a t i v e .
86
T H E J O U R N A L OF P E D I A T R I C S
F i g . 2 . - - 5 ( C a s e 3), i R . o e n t g e n o g r a m of f e m u r , tibia, a n d fibula, ' s h o w i n g z o n e of d e c r e a s e d d e n s i t y a t c a r t i l a g e s h a f t j u n c t i o n . B o n e b e n e a t h this is a b n o r m a l l y d e n s e . 6 ( C a s e 4 ) , R o e n t g e n o g r a m of f e m u r , tibia, a n d fibula, s h o w i n g diffuse i n c r e a s e d d e n s i t y . 7 ( C a s e 3), P h o t o m i c r o g r a p h of l o n g b o n e , s h o w i n g r a r e f i e d zone w i t h d e n s e r b o n e b e n e a t h . 8 ( C a s e 4), P h o t o m i c r o g r a p h of l o n g bone, s h o w i n g i n c r e a s e d a m o u n t of b o n e ; e a c h t r a b e c u l a c o n t a i n s a n a b n o r m a l a m o u n t of calcified c a r t i l a g e m a t r i x substance.
FOLLIS, J R . , ET AL. :
SKELETAL CHANGES
87
Summary.--In this child there was hydrops with extensive evidence of extramedullary blood formation as well as extreme blood destruction. The bones were uniformly denser than normal. The placenta showed characteristic changes. The diagnosis of erythroblastosis was made on the hydrops, signs of blood formation, and destruction and changes in the placenta. CASE 5 (HL.tt 61446).--This 10-day-old white male was admitted to the tIarriet Lane Home with the following history. The father, aged 51 years~ was living and well; the, mother, aged 35 years, was living and well. There were six other siblings, all well. The course of pregnancy was uneventful and delivery was easy. The child appeared well at birth except for slight jaundice which the parents thought was fading. The child was brought to the hospital because of profuse bleeding from the umbilical cord. On examination he showed extreme icterus, subcutaneous hemorrhages, pallor, and a bleeding umbilicus. Adrenalin was applied to the latter and the bleeding teraporari]y became less but soon increased and could not be controlled again. Twenty cubic centimeters of blood from a professional donor were given into the longitudinal sinus and the child seemed to improve. About three hours later respirations became irregular and the general appearance alarming. Before another transfusion could be performed, the baby expired. Blood obtained by cardiac puncture showed 1,560,000 red blood cells; 45,000 white blood cells; and 14 norraoblasts while counting 100 white cells. Clotting time was thirty-five minutes. Wassermann reaction on this blood was negative. Van den B e r g h ' s test, 11.1 rag. per cent was read as a direct reaction. A t autopsy (10813, t t L H ]77) the following findings were described: The body weighed 1,600 Gin.; the skin was intensely jaundiced. The heart and lungs showed nothing abnormal save for hemorrhages beneath the pleura of the latter. The spleen weighed 20 Gin. and was enlarged. The liver was not enlarged; it weighed 74 Gin. There was hemorrhage beneath the dura over b o t h cerebral hemispheres. A puncture hole in the dura was demonstrated as the origin Of t~is hemorrhage. Microscopically, there was extraraedullary blood forraation in the liver, spleen, and kidneys. There was hemoss in the liver cells and in the convoluted tubules of the kidneys but none in the spleen. F a t stain of the lung revealed maerophages filled with lipoid droplets in many of the pulmonary alveo]i. The placenta was not available for microscopic study. X-rays of the long bones revealed normal cartilage. Beneath this there was a thin bright line corresponding to the lattice. Under this the bones were uniformly rarefied for a distance as great as 30 ram. at the head of the humerus. From there on the shafts became much denser than normal ; this was fairly uniform throughout the rest of the shaft. No periosteal changes were seen nor were there any areas of destruction. I n the bones the cartilage was normal ; the cells were arranged in or.derly fashion. The matrix between the rows of cells was calcified. The lattice was somewhat stubby and not as plentiful as normal. I t was well covered with bone. There were numerous osteoblasts about the trabeculae thus formed. The marrow was hyperplastic. Beneath the cartilage shaft junction the structure seemed normal. Bone was being destroyed in the usual fashion. However, at a distance of about 5 lowpower microscopic fields from the cartilage shaft junction the trabeeulae in the shaft became extraordinarily dense. The amount of calcified matrix in their centers was definitely excessive, and the bone enclosing this blue-staining material was much thicker than normal. There was no increase in osteoblasts. The marrow here was hyperplastic. 1~o periosteM changes were seen.
rD
9
9
oo
o,.~
~4a
P
~~=
e
~o}
0,I~ 0 r
0 ~,-Cl
,'~ ~ . ~
FOLLIS, Ji~., E~ AL. :
SKELETAL ~HANGES
89
Summary.--This 10-day-old jaundiced white male was admitted because of bleeding. Family history was negative. Despite transfusions he died and at a u t o p s y was found to have an enlarged spleen. There was blood formation in the liver, spleen, and kidneys. Iron pigment was found in the renal epithelium. The diagnosis of erythroblastosis was founded on the jaundice, enlarged spleen, and extramedullary blood formation with evidence of red ceil destruction. The diagnosis by the clinicians was h e m o r r h a g e disease. DISCUSSION
We have presented the clinical and pathologic records of five cases of erythroblastosis fetalis. In three instances there was hydrops, in one, icterus with hemorrhagic manifestations, while in another, although clinically the child appeared normal, at autopsy the liver and spleen were enlarged and there was blood formation in these organs and in the kidneys. There was also a fresh lobular pneumonia. I n all, the cord blood and that of the mother gave negative serologic tests for syphilis. We were f o r t u n a t e in being able to review sections of the placentas with Dr. Louis Hellman who has described characteristic changes in this organ associated with erythroblastosis. 1 In Dr. H e l l m a n ' s opinion the f o u r placentas available f o r Study showed changes pathognomonie of erythroblastosis. I n two the changes were more marked than in the others. One could correlate the degree of blood formation in the placenta with that f o u n d in the other tissues. We have described in some detail changes in the skeletal systems of these five infants. The most striking alteration was a marked increase in density of the bones:, seen both in microscopic sections and in x-rays taken post mortem. This change consisted of an increase in the number and thickness of the trabeeulae, due apparently to a lack of destruction of the calcified cartilaginous matrix substance which was then covered with a thick layer of bone. In two instances this increase in density was uniform throughout the entire shaft, while in the other three eases there were zones of decreased density of varying width a short distance below beneath the lattice at the cartilage shaft junction. In one there was a band of increased density beneath the zone of rarefaction. The cartilage showed no change nor were there any indications of periosteal new bone formation. The cause f o r the zones of decreased density is not clear nor can we explain the band of increased density seen beneath this in one of the cases. Transverse lines of increased density are more common than zones of rarefaction in infants' bones and have been interpreted as due to effects produced by a retardation in the growth of the cartilage with continuation of osteoblastie activities2 T h e zones of rarefaction are probably due to an acceleration of the destructive forces, but why this should be present in these eases is difficult to explain. The most con-
90
THE JOURNAL OF PEDIATRICS
spicuous change, however, and the one common to all five of these cases, is the increase in density of the shafts of the bones. The exact mechanism for this increase in density is obscure. Several explanations n a t u r a l l y come to mind. Could these changes be due to the influence of some substance elaborated by the m a t e r n a l organism or placenta ? The placenta in erythroblastosis is frequently enlarged and h a s been reported to contain more chorionic hormone than is normal. 4 The relationship of estrogenic hormone to an increase in density of the bones of birds is well established2 I n experiments on rats to which large amounts of estrogenic hormone h a d been administered, we have o b s e r v e d increased density at the ends of the growing bones of young animals. 6 Estrogen had less m a r k e d effect in adult animals and had no influence on the bones of old animals. This increased density was i n t e r p r e t e d as a decrease in the rate of normal destruction. One wonders, then, whether the changes we have described could have been produced by some such mechanism as this. We know of no observations on animals whose mothers had received large amounts of estrogen during their pregnancy. A n o t h e r factor which must be considered is that some material liberated in the breakdown of red cells m a y play a role. We are familiar with an increase in osseous density produced by an excess of certain specific elements in the body. In lead poisoning in childhood one finds an increase in the a m o u n t of cartilaginous m a t r i x substance beneath the cartilage shaft junction. This is because lead as well as calcium is deposited in the matrix and seems to render the m a t r i x more resistant to destruction. Bone is then deposited on i t J Bismuth produces a zone of increased density in the growing bones of infants whose mothers have been injected with this element d u r i n g p r e g n a n c y 2 E l e m e n t a r y phosphorus likewise has been shown to produce an extremely dense deposition of calcified m a t r i x a n d bone at the growing ends of the long bones. ~ One wonders then whether excessive iron m a y have had a n y effect in producing the changes we have described. None could be stained in the sections. Analyses of the bone have not been made. I t is interesting, however, to point out t h a t MaeCallum 1~ has called attention to the possible role of iron in n o r m a l calcification. One thinks, too, of the changes in the skeleton associated with the chronic hemolytic anemias seen in childhood; namely, sickle cell anemia, Cootey's anemia, and congenital hemolytic jaundice. I n these eases, however, there is rarefaction of the long bones which is a p p a r e n t l y due to destruction of the trabeculae because of the extreme h y p e r p l a s i a of the m a r r o w cells. 11 Similar changes are seen in leucemia. The thickening which has been described in the skull in eases of chronic hemolytic anemia is more difficult to explain. B u t it is a p p a r e n t l y d u e to hyperplasia of the m a r r o w and a pushing" up of the periosteum covering the
FOLLIS,
JR.,
ET AL. :
SKELETAL CHANGES
91
outer table of the skull. Thus, the picture in these cases is different f r o m the one which we have described. However, it m u s t be pointed out that in utero blood f o r m a t i o n takes place in the e x t r a m e d u l l a r y tissues with great ease a n d the effect of hyperplastic m a r r o w is not felt by the bone in the same way as one sees it in postuterine life. I n congenital syphilis one frequently encounters changes in x-rays of the skeleton which are similar to those we have described in Cases 1, 2 and 5. I n all our cases, as was pointed out above, serologic tests for s y p h i l i s were negative; nor were there any focal inflammatory lesions seen in the microscopic sections or localized areas of destruction in the x-rays. The nonspecifieity of m a n y of the x-ray changes f o r m e r l y thought to be associated with congenital syphilis is ~becoming more and more a p p a r e n t . This has been brought out most clearly in a recent study o2 Caffey 12 who f o u n d changes indistinguishable f r o m syphilitic osteochondritis, osteoperiostitis, and osteomyelitis in the roentgenograms o2 nonsyphilitic children that he examined. I t is interesting to note that Caffey 12 includes two cases of erythroblastosis in his series. The first (Case 2) was an in~ant 50 days old who had had persistent jaundice; on examination the spleen was enlarged and there was p i t t i n g edema of the lower abdominal wall and groin. The e r y t h r o c y t e count was 1.2 million p e r cubic millimeter of which 5,100 were nucleated. The child died but there was no autopsy. X - r a y s showed heavy transverse bands across the ends of the shafts of the long bones. There was no increased density ,in the shaft such as was found in our cases. Caffey's second case of erythroblastosis (Case 6) lived only f o u r hours and had h y d r o p s and e n l a r g e m e n t - o f the liver and spleen. The diagnosis of erythroblastosis was confirmed at autopsy. I n the roentgenograms there were " d e e p bands of increased density across the ends o2 the shafts with n a r r o w e r zones of diminished density lying parallel along the sha~tward m a r g i n s . " I n the reproductions of the x-ray, the shafts of this case do seem denser t h a n normal, although Caffey ~2 did not comment on this point. T h a t the bands seen in our cases are due to nonspecific factors is not unlikely. The change common to all, however, is: the increased density of the shafts. The disease p a r excellence in which there is a persistence of calcified cartilaginous m a t r i x substance upon which bone deposits is osteosclerosis 2ragilis generalisata (Albers-SchSnberg disease). Deep down in the shaft one finds large amounts of blue-staining calcified m a t r i x substance encased in bone, and in osteoid in those cases in which rickets is present. The anemia a c c o m p a n y i n g this disease is usually a s c r i b e 4 to the reduction in m a r r o w space. B u t the possibility t h a t there is some more fundamental disturbance affecting both hemopoiesis and bone f o r m a t i o n has also been advanced,
92
THE JOURNAL OF PEDIATRICS SUMMARY
W e h a v e d e s c r i b e d osseous c h a n g e s b o t h b y x - r a y a n d on m i c r o s c o p i c e x a m i n a t i o n in five cases of e r y t h r o b l a s t o s i s . The alteration Common to a l l w a s a n i n c r e a s e i n d e n s i t y . I n a d d i t i o n , i n t h r e e t h e r e w e r e b a n d s of decreased density which were probably nonspecific in origin. REFERENCES 1. Hellman, L. M, and ttertig, A . T . : Am. J. Path. 14: 111, 1938. 2. Levine, P., Burnham, L., Katzin, E. M , and Vogel, P. : Am. J. Obst. & Gynec. 42: 925, 1941. 3. Eliot, M. M., Souther, S. P., and Park, E. A. : Bull. Johns Hopkins IIosp. 41: 364, 1927. 4. Herrnberger, K.: Arch. f. Gyn~k. 170: 287, 1940. 5. Pfeiffer, C. A , and Gardner~ W . U . : Endocrino]ogy 23: 485, 1938. 6. Day, tI. G., and ]~011is, 1~. It., Jr. : Endocrinology 28: 83, 1941. 7. Park, E. A., Jackson, D., and Kajdi, L.: Am. J. Dis. Child. 41: 485~ 1931. 8. Whitridge, J., Jr.: Am. J. Syph., Gonor. & Ven. Dis. 24: 223, 1940. 9. Phemister, D. ]3.: J . A . 3s A. 70: 1737, 1918. 10. MacCallum, W. G.: A Text-Book of Pathology, Philadelphia, 1940, W. B. Saunders Co., p. 116. 11. Caffey, J.: Am. J. ~oentgenol. 37: 293, 1937. 12. Caffey, J.: Am. J. R oentgeno].'42: 637, 1939.