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Prenatal influence in rickets
PRENATAL II.
INFLUENCE
IN RICKETS
EARLY POSTNATAL I%ICKETS AND FLORID ]~ICKETS WITI-I MULTIPLE FRACTURES
JOHN IKOTT RECTOR, M.D. SAN I~RANCISCO~ CALIF.
N A previous p a p e r a t t e n t i o n was directed to a n t e n a t a l influence in rickets a n d to the occurrence of f e t a l rickets. Some of the import a n t p r e n a t a l f a c t o r s we.re discussed a n d a case of fetal r i c k e t s was reported. 1 The p u r p o s e of this s t u d y is to ascertain the effect of m a t e r n a l influence on the d e v e l o p m e n t of certain other f o r m s of rickets in the infant. The s t u d y is based upon a s u r v e y of 400 cases of active rickets. A.
EARLY
POSTNATAL
RICKETS
IN
THE
INFANT
BORN
AT
TERM
Investigators have rather uniformly agreed that rickets is a rarity under three months of age, and yet the literature yields little as to the actual incidence in this age group. Hess 2 states that r i c k e t s begins a b o u t the t h i r d m o n t h a n d ends a b o u t the eighteenth month. H o l t and McIntosh ~ mentio.n the period from the fourth to the eighteenth m o n t h and go on to say t h a t the disease is r a r e before the t h i r d m o n t h a n d a f t e r the second year. S c h m o r P in 1909 conducted a pathologic s t u d y on 365 cases of rickets e x a m i n e d at a u t o p s y and f o u n d histologic evidence of the disease in t w e n t y i n f a n t s u n d e r three m o n t h s of age, an incidence of 5.5 per cent. F o u r of the p a t i e n t s were two months old, and the others were all b e t w e e n t w o and three months old. I t is well k n o w n t h a t p r e m a t u r e infants a n d t w i n s are susceptible to e a r l y a n d severe rickets. Ylppo 5 has o b s e r v e d rickets in a prem a t u r e i n f a n t at t h e age of six weeks. The y o u n g e s t p a t i e n t with rickets described in this c o u n t r y was an i n f a n t t h i r t y - f o u r d a y s old, r e p o r t e d b y D u n h a m , ~ a n d while this b a b y was a l l e g e d l y b o r n prem a t u r e l y , its b i r t h w e i g h t w a s 3,260 gin. Rickets in the Infant Born at Term.--In an a t t e m p t to d e t e r m i n e the actual incidence of early rickets, and to i n v e s t i g a t e possible etiologic f a c t o r s of significance, 400 cases of rickets seen in this clinic o v e r a period of the p a s t nine y e a r s h a v e been reviewed. All of these were in an active phase of the disease, and in each instance clinical diagnosis w a s c o r r o b o r a t e d b y r o e n t g e n o g r a p h i c e x a m i n a t i o n a n d chemiFrom the Department of Pediatrics, Harvard Medical School, and the Infants' and Children's I-Iospitals, Boston, lV[ass. 167
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cal analysis of the blood. Only patients with abnormally low phosphorus have been included in this survey. In this series of 400 it was f o u n d that thirty-two cases, or 8 p e r cent, were aged three months or younger. Of these, the youngest was a full-term infant of thirty-five days. F o u r t e e n of the t h i r t y - t w o were u n d e r two months of age, and eighteen infants were from two to three months old. W h e n ene considers the generally accepted r a r i t y of rickets in the first three months of life, it is surprising to find that 8 per cent of the cases of rickets developed in this age group. E x a c t l y half of the infants were the result either of p r e m a t u r e birth or of twin pregnancy. The other sixteen infants were all born at full term. Thus among 400 cases of rickets 4 per c e n t (sixteen cases) occurred in full-term infants u n d e r three months of age. Among these, 1.75 per cent were less than two months old, and 2.25 per cent were: in their second or third month of life. None of the sixteen had a birth weight of less t h a n 6 pounds and 12 ounces, which is well above the figure a r b i t r a r i l y accepted as one of the indices of p r e m a t u r i t y . The average weight at birth was 7 pounds. Comment.--With only three exceptions this group of full-term infants presented on admission an excellent state of n u t r i t i o n and had shown consistent gains in weight since birth. Most of them appeared healthy, and hospitalization was usually requested because of mild r e s p i r a t o r y infection or convulsions f r o m an associated tetany. The association of t e t a n y with rickets in these v e r y young infants is w o r t h y of note. A recent analysis b y Guild 7 of 293 cases of t e t a n y f r o m the H a r r i e t Lane Home disclosed an incidence of 7 ~ per cent in patients u n d e r three months. Since infantile t e t a n y almost always develops on the basis of a previous rickets, the close parallelism between this figure and the 8 per cent incidence of rickets found in this series for the same age group is of interest. The youngest case of t e t a n y in the recent l i t e r a t u r e was r e p o r t e d in a nine-day-old i n f a n t b y Small. s I t is k n o w n t h a t " r o e n t g e n o l o g i c r i c k e t s " indicates a f a i r l y advanced stage of the disease, f o r in 1928 W i m b e r g e r 9 demonstrated that the interval between the first histologic raehitic change and the first radiographic change is " c e r t a i n l y as long as several w e e k s . " When one recalls that almost h a l f of this full-term g r o u p showed roentgenologie evidence of the disease prior to the second month, it at once becomes evident t h a t in them the disorder must have had its incipiency in t h e v e r y early weeks a f t e r birth. T u r n i n g to an analysis of possible c o n t r i b u t o r y factors to the development of such an early rickets it i s seen that p r e n a t a l influence m a y be of importance (Table I). An investigation of m a t e r n a l health a/ld diet during p r e g n a n c y Was not quite as satisfactory as might be
TABLE I
MATERNAL DIET
Unknown Deficient Unknown Good Unknown Unknown Deficient Unknown Unknown Unknown Unknown Good Unknown Unknown Unknown Deficient
CASE
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Poor ~5or Unknown Good Unknown Unknown Poor Unknown Unknown Unknown Unknown Good Poor Unknown Unknown Poor
RIATERNAL HEALT]:t
ANTENATAL
8 9 Unknown 7 Unknown 9 5 17 6 Unknown 13 10 4 Unknown 8 2,5
YEARS MARRIED
FACTORS
6 5 Unknown 5 Unknown 6 3 9 5 Unknown 6 8 2 Unknown 5 2
N U M B E R OlV CHILDREN
M F M M M F M F F M F M F F
F
SE~
irish Irish American Scotch American Irish Italian German Scotch Scotch American Irish Italian Irish American German
NATIONALITY FEEDING
Breast Breast Artificial Breast Breast Breast Artificial Breast Breast Artificial Breast Breast Breast Artificial Breast Breast
LIVER OIL
Adequate None None None None None Tnadequate None None None None None Adequate None None None
COD
P O S T N A T A L FACTORS
CASE ANALYSIS OF ETIOLOGIC FACTORS IN FULL-TERM INFANTS WITS ACTIVE RICKETS UNDEI% THREE MONTtIS
MONTH
August October February September November March September April January Nfareh October June January December ~ebruary May
m rj~
>
0
r4
0
9
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G. M., a f o u r - m o n t h - o l d f e m a l e i n f a n t f r o m a poor I t a l i a ~ f a m i l y , e n t e r e d t h e h o s p i t a l on Sept. 12~ 1933, with a complaint of " f a i l u r e to g a i n . " The m o t h e r was twenty-five y e a r s old; she h a d been m a r r i e d f o r 1fine years, a n d t h i s was t h e fifth child. I I e r h e a l t h h a d been poor f o r several years, a n d w i t h t h e onset of this pregna~ncy it b e c a m e m u c h worse. T h e r e w a s a c o n s t a n t n a u s e a p r e s e n t ; t h r o u g h o u t p r e g n a n c y she ate little except cooked vegetables, occasional s m a l l a m o u n t s of raw f r u i t s ( o r a n g e s a n d a p p l e s ) a n d soup. 1Vicars, milk, a n d e g g s were entirely excluded f r o m this self-imposed diet. A v a g i n a l d i s c h a r g e h a d b e e n p r e s e n t for some m o n t h s a n d d u r i n g t h e h e i g h t o f p r e g n a n c y she developed severe p a i n s in h e r legs a n d j o i n t s d i a g n o s e d as ~ ' g o n o r r h e a l a r t h r i t i s . " These b e c a m e of such severity t h a t d u r i n g the l a t t e r m o n t h s of confinement She was- "u n a b l e to descend s t a i r s and w a s f o r c e d to r e m a i n i n a room t h a t received l i t t l e s u n l i g h t . W e a k n e s s was a n outs t a n d i n g feature. Severe d e n t a l caries developed. Following a full-term~ difficult delivery, t h e r e was considerable s p o n t a n e o u s i m p r o v e m e n t of her pain, a n d subse~ q u e n t ultraviolet i r r a d i a t i o n created a p r o m p t remission. T h e f a m i l y h i s t o r y was o f f u r t h e r interest. T h r e e of t h e f o u r siblings were in good health, b u t the y o u n g e s t , a g e d two years, showed evidence of an a d v a n c e d rickets w~th a l a r g e square head, p r o m i n e n t f r o n t a l bosses, rachitic rosary, extensive b o w i n g of t h e legs~ a n d epiphyseal enlargement. T h e p a t i e n t w e i g h e d 6 p o u n d s a n d 4 ounces a t birth, a n d her i m m e d i a t e postn a t a l condition w a s good. She w a s placed o n a modification c o n t a i n i n g dextrimaltose, milk, a n d water. T h i s w a s t a k e n w i t h avidity, and, while t h e i n f a n t seemed in good condition, she was u n a b l e to g a i n consistently. O r a n g e juice was b e g u n a t one m o n t h a n d a d m i n i s t e r e d t h e r e a f t e r in a d e q u a t e a m o u n t s . D u r i n g t h e e n s u i n g weeks t h e i n f a n t continued in u n e v e n t f u l f a s h i o n a n t i ] she w a s two m o n t h s old. A t this t i m e t h e m o t h e r detected a swelling of t h e " f r o n t of the l e f t shin b o n e . " This w a s only slightly tender, seemed q u i t e h a r d , a n d in no w a y curtailed the b a b y ' s activities. A few d a y s later t h e r e occurred a single generalized convulsion. Cod liver oil was t h e n b e g u n i n d a i l y teaspoon a m o u n t s b u t a f t e r one m o n t h it w a s disc o n t i n u e d because of occasional a t t a c k s of d i a r r h e a . The b a b y still showed no t e n d e n c y to gain, a n d finally at t h e age of f o u r m o n t h s she was b r o u g h t to the hospital for investigation. On admission~ e x a m i n a t i o n disclosed a n u n d e r d e v e l o p e d 'and m a r k e d l y undern o u r i s h e d , h y p e r t o n i c f e m a l e i n f a n t who w e i g h e d 7 p o u n d s a n d 5 ounces. She app e a x e d chronically ill; color w a s a n a s h e n pallor, a n d skin t n r g o r was poor. The h e a d was of square c o n f i g u r a t i o n w i t h p r o m i n e n c e of s u p r a o r b i t a l bosses. There w a s no d e m o n s t r a b l e craniotabes. A r o s a r y o f raehitic t y p e was present, a n d a b e g i n n i n g H a r r i s o n ' s groove w a s detectable. T h e a b d o m e n w a s q u i t e p ~ o t u b e r a n t a n d t h e splenic edge could be p a l p a t e d 2 cm. below t h e costal m a r g i n . ]~piphyseal e n l a r g e m e n t was n o t evident, b u t over the a n t e r o l a t e r a l a s p e c t of t h e l e f t t i b i a a r a t h e r diffuse swelling could r e a d i l y be seen. Thi~ w a s h a r d i n consistency, seemed to b e c o n t i g u o u s w i t h t h e bone~ a n d Was n o t t e n d e r to m a n i p u l a t i o n . There was f r e q u e n t s p o n t a n e o u s m o v e m e n t of all e x t r e m i t i e s w i t h o u t a p p a r e n t discomfort. A n a n e m i a of h y p o c h r o m i e t y p e was f o u n d ; s e r u m calcium c o n t e n t was 7.7 rag. p e r 100 c.c., ~ a n d t h e i n o r g a n i c p h o s p h o r u s w a s 4.5 m g . p e r eent.t A p l a s m a phosp h a t a s e c o n t e n t of 1.3 u n i t s per cubic c e n t i m e t e r s was i n d i c a t i v e of a d v a n c e d active rickets.~7 Other d a t a , i n c l u d i n g s e r u m protein, n o n p r o t e i n nitrogen, a n d r e n a l f u n c t i o n tes~s~ were w i t h i n n o r m a l limits. Man%onx t u b e r c u l i n tests, r u n up *Calcium d e t e r m i n a t i o n by m e t h o d of Fiske---normal r a n g e d u r i n g first y e a r from 9 to 12mg. per cent. ~Phosphorus d e t e r m i n a t i o n by method of F i s k e a n d S u b b a r o w - - n o r m a l r a n g e d u r i n g first :fear, f r o m 4.5 to 5.5 rag. l~er cent. SPhosDhatase d e t e r m i n a t i o n bsr m e t h o d of K a y - - n o r m a l r a n g e for i n f a n t s under on.e y e a r from 0.10 to 0.27 units per cubic centimeter.
RECTOR:
EARLY POSTNATAL ICICKETS
173
to 100 rag. of old tuberculin, p r o d u c e d no reaction. The W a s s e r m a n n , t I i n t o n , a n d K a h n reactions on b o t h p a r e n t s a n d b a b y were negative. R o e n t g e n o g r a m s (Sept. 13, 1933) showed m u l t i p l e f r a c t u r e s , i n c l u d i n g t h e l e f t clavicle, t h e s e v e n t h l e f t rib anteriorly, t h e left radius~ l e f t u l n a , a n d t h e r i g h t radius. T h e r e were also two f r a c t u r e s of t h e l e f t t i b i a a n d two o f the l e f t fibula. These were all s u r r o u n d e d by a m o d e r a t e a m o u n t o f callus f o r m a t i o n . T h e r e was a n extreme degree of generalized osteoporosis, a n d the m e t a p h y s e a l m a r g i n s were i r r e g u lar a n d defectively calcified (Fig. 1). T h e i n f a n t was i m m e d i a t e l y placed on a vigorous a n t i r a c h i t i c r e g i m e n c o n s i s t i n g of liberal a m o u n t s of a h a l i b u t liver oil p r e p a r a t i o n fortified w i t h viosterol. U l t r a violet i r r a d i a t i o n was given. R e e x a m i n a t i o n of t h e long bones two weeks a f t e r e n t r y (Sept. 26, 1933) showed definite i m p r o v e m e n t , c h a r a c t e r i z e d b y a n i n c r e a s e in the a m o u n t a n d d e n s i t y of t h e callus a r o u n d the f r a c t u r e s . Likewise, t h e osteoid a t
:Fig'. I.
~ i g . 2.
~ig. 1 . - - A film of t h e lower extremities t a k e n Sept. 13, 1933. Note the generalized osteoporosis, t h e i r r e g u l a r m e t a p h y s e a l margins, a n d multiple fractures. There a r e two f r a c t u r e s of the left tibia a n d two of the left fibula. l~tg. 2 . - - R o e n t g e n o g r a m a t time of discharge, Nov. 14, 1933. This illustrates complete healing of the infractions in good position with no r e m a i n i n g evidence of previous existence. Calcification h a s become a l m o s t normal, b u t slight rachitic c h a n g e s a r e still extant. the ends of t h e long bones showed i n c r e a s e d calcification. S e r u m calcium at t h i s t i m e h a d r i s e n to 12.4 rag. p e r cent a n d p h o s p h o r u s to 5.9 rag. A n o t h e r tilm t a k e n two weeks l a t e r (Oct. 11, 1933) disclosed well-calcified m e t a p h y s e s , a n d all of t h e f r a c t u r e s a l m o s t united. Six weeks a f t e r a d m i s s i o n t h e f r a c t u r e s were well healed, a n d t h e only evidence of t h e i r p r e v i o u s existence was a s m a l l a m o u n t of u n r e s o l v e d callus in t h e l e f t tibia. U p o n d i s c h a r g e two m o n t h s a f t e r e n t r y (Nov. 16, 1933) t h e r a d i o g r a p h d e m o n s t r a t e d complete e f f a c e m e n t o f all f r a c t u r e lines a l t h o u g h t h e r e were some slight raehitic c h a n g e s still p r e s e n t ( F i g . 2). S e r u m calcium w a s t h e n 10 rag. per 100 c.c., a n d p h o s p h o r u s , 5.7. A p l a s m a p h o s p h a t a s e of 0.51 u n i t s
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per cubic centimeter was f u r t h e r evidence t h a t healing was as yet not complete. T h r o u g h o u t her s t a y there was marked g e n e r a l i m p r o v e m e n t and a weight gain of almost five p o u n d s in two months.
That osteomalacia was present in the mother during the latter months of her pregnancy seems probable. A raehitogenie diet, frequent pregnancies, poor health, and an insufficient exposure to sunshine are all etiologic factors to the development of this disorder. The disease is f u r t h e r suggested by the extreme weakness and severe joint pain, which are outstanding symptoms of osteomalacia. At the time she was seen, however, this diagnosis could not be confirmed. A radiograph of her extremities taken six months postpartum (Nov. 16, 1933) showed nothing of note, although this is not surprising in view of the fact that her diet since delivery had been normal. She had also received over a month of intensive ultraviolet light therapy, which would contribute to f ur t her healing. A request f o r calcium and phosphorus determination on the mother was refused. This case, in several respects, resembles the one reported by Dunham. The mother of that baby had undergone seven pregnancies, had been exposed to very little sunlight, and her diet had been very deficient. During the latter months of pregnancy weakness and pain in the legs developed. X-rays disclosed considerable rarefaction of the bones; it was likely that she had osteomalacia. A SURVEY OF 400 CASES OF ACTIVE RICKETS W I T H AN ANALYSIS OF CASES W I T H FRACTURES
Of the four hundred cases of rickets surveyed by the author, fractures occurred in fourteen instances; an incidence of 3.5 per cent. Nine of the patients who developed fractures were full-term infants and the remainder were either premature infants or twins. The age incidence in this group closely followed t hat usually seen in rickets, with an average range of from six to fifteen months. The youngest was two months old, and the oldest, twenty-six months. 0nl y two cases were found in infants under three months of age. The patients with severe rickets associated with fractures entered the hospital with a chief complaint of " f a i l u r e to g a i n " or " c o u g h . " Almost without exception they presented extreme degrees of malnutrition and underdevelopment. Severe respiratory infections were frequent; and the mortality in the group was 29 per cent, death occurring from bronchopneumonia. COMMENT
The etiologic factor in the causation of severe rickets with fractures cannot be definitely stated. Postnatal factors did not seem t0 be outstanding. (Table II.) Sex, season, and nationality were hardly worthy of connotation. Five of the fourteen infants were breast fed;
1 2 3 4 5 6 7 8 9 10 11 12 13 14
CASE
Unknown Unknown Deficient Unknown Unknown Good Deficient Unknown Unknown Unknown Deficient Unknown Deficient Unknown Unknown Poor Poor Unknown Poor Good Poor Unknown Poor Unknown Poor Unknown Poor Unknown 6 9
4 11 5 8 ? 1 9 6 3 ? 13
YEARS MARRIED NUI~IBER OF /SEX CI-IILDP~EN i M M F M F F F M F M M F M
ANALYSIS OF ETIOLOGIC FACTORS
ANTENATAL PACTORS MATERNAL MATERNAL DIET ~EALTH
CASE
TABLE II
Irish Italian American Greek American Irish Italian Italian Scotch Greek Irish American Portuguese Italian
NATIONALITY Breast Artificial Artificial Breast Artificial Artificial Artificial Breast Artificial Artificial Breast Artificial Artificial Breast
None Adequate Adequate Inadequate None None Inadequate Adequate None Adequate Adequate Adequate None None
POSTNATAL FACTORS COD LIVEE FEEDING OiL
IN INFANTS WIT~I FRACTURES
December Oetober :February April July February September August July March April October March January
MONTH
CA
>
>
o
E~
>
..
o
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the others all had adequate artificial f o r m u l a s w i t h but three exceptions. F o r t y - t h r e e per cent of these babies received cod liver oil or a substitute in a m o u n t s o r d i n a r i l y mlfficient to p r e v e n t rickets. Infection was a p r o m i n e n t f e a t u r e in the m a j o r i t y of cases b u t m a y have been the result r a t h e r t h a n a predisposing cause of the development of rickets. A c c u r a t e m a t e r n a l history could be obtained in eleven of the fourt e e n cases. Fifty-five p e r cent, or six cases, had a history of five or m o r e p r e g n a n c i e s in r a p i d succession. D a t a concerning the m o t h e r ' s heal.th and d i e t a r y were ascertained in eight instances. Only one m o t h e r was definitely k n o w n to h a v e h a d b o t h an a d e q u a t e diet and good health. I n this case the infant was b o r n p r e m a t u r e l y and was a twin so that the florid rickets a n d multiple f r a c t u r e s seen in this b a b y are more r e a d i l y understood. F o u r m o t h e r s h a d v e r y poor h e a l t h a n d diets t h a t were definitely deficient, while in three others health was i m p a i r e d b u t no details of the diets could be elicited. I n t w o cases in which the m a t e r n a l health a n d diet were exceptionally bad, the infants, in addition to multiple f r a c t u r e s , h a d thoracic and spinal deformities. These cases w e r e somewhas similar to those rep o r t e d b y P a r k and H o w l a n d . TM G r a n t is describes cases in y o u n g r a t s b o r n of mothers w i t h p a r t i c u l a r l y defective diets, who developed extensive osteoporosis, multiple fractures, thoracic deformities, and kyphosis. Calcium and phosphorus d e t e r m i n a t i o n s in these cases with multiple f r a c t u r e s differed in no essentials f r o m the figures obtained in usual cases of rickets. B y r o e n t g e n o g r a m all cases showed m e t a p h y s e a l irr e g u l a r i t y and cupping, b u t the o u t s t a n d i n g f e a t u r e in each case was a generalized osteoporosis of e x t r e m e degree. This characteristic is of interest in r e g a r d to an observation made b y T o v e r u d and Toverud. 1~ T h e y h a d placed p r e g n a n t r a t s on a diet m a r k e d l y deficient in calcium, b u t otherwise adequate, a n d f o u n d t h a t the y o u n g of these m o t h e r s showed an extensive osteoporosis w i t h multiple f r a c t u r e s but relatively little actual rachitic change in the m e t a p h y s e s . One cannot postulate t h a t the same m e c h a n i s m p r e v a i l e d in these i n f a n t s with multiple f r a c t u r e s . H o w e v e r , there w e r e a n t e n a t a l f a c t o r s p r e s e n t in a large n u m b e r which were capable of e x e r t i n g an influence on fetal metabolism. I t would be m o s t interesting if one could know the age at which rickets first developed in these babies who s u b s e q u e n t l y p r o g r e s s e d to the stage of multiple fractures. I t seems likely t h a t a considerable p o r t i o n would have shown rickets in the e a r l y months of life. SUMMARY
A review of l i t e r a t u r e on early p o s t n a t a l rickets and rickets with m u l t i p l e fractures, t o g e t h e r with a s u r v e y of 400 cases of active rickets a n d the d e t e r m i n a t i o n of the incidence of ear.ly rickets and of rickets
RECTOR:
EARLY POSTNATAL RICKETS
177
with multiple fractures, permits an analysis of possible factors cont r i but or y to the development of these two forms of the disease. It is suggested that early postnatal rickets and florid rickets with multiple fractures may result from an insufficiency of stored skeletal calcium at the time of birth incident to nutritional and metabolic defects on the part of the maternal organism. A case of early infantile rickets with multiple fractures is reported. 2EFEEENCES 1. l:~c~;or, J . M . : J. PED~AT. 6; 161~ 1935. 2. Hess, A. :F.: ~ickets Including Osteomalacia and Tetany~ Philadelphia, 1929, Lea and Febiger, pp. 253-257. 3. Holt, L. E , and 1VfeIntosh, R.: t t o l t and Howland's Diseases of I n f a n c y and Childhood, ed. 10, New York, 1933, D. Appleton-Century Co., p. 237. 4. Schmorl, G.: Ergebn. d. inn. ~r u. ]Kinderh. 4: 403, 1909. 5. Ylppo, A.: Ztschr. f. Kiuderh. 24: 1, 1920. 6. Dunham, E . C . : Am. J. Dis. Child. 26: 155, 1923. 7. Guild: Quoted by Holt and McIntosh,8 p. 259. 8. Small, A. S.: J. PEDIAT. 2: 681, 1933. 9. Wimberger, H.: Quoted b y Hess.~ 10. Hess, A. 1% and Matzner, M . J . : Am. J. Dis. Child. 26: 285~ 1923. 11. Toverud, ]K. U., a n 4 Toverud, G.: Aeta paediat. (supp. 2) 12: 1, 1931. 12. Park, E. A., and ttowland, J.: Bull. Johns Hopkins Hosp. 32-' 101, 1921. 13. Lereboullet, P., and Chabun, J . : Bull. Soc. de p6diat, de Paris 9.9: 151, 1931. 14. Steiner, B.: 0rvosi hetil. 73: 733, 1929. 15. J u n g w i r t h : Wien. reed. Wchnschr. 77: 654~ 1927. 16. Hutchison, H. S., and Stapleton, G.: Brit. J. Child. Dis. 12: 18, 1924. 17. Smith, J., and Maizels, 1Vf.: Arch. Dis. Child. 7: 149, 1932. 1 8 . Grant, A . H . : Am. J. I-Iyg. 6: 228, 1926. 2000 VAN NESS AvE~trz
INFLUENCE
IN RICKETS
EARLY POSTNATAL I%ICKETS AND FLORID ]~ICKETS WITI-I MULTIPLE FRACTURES
JOHN IKOTT RECTOR, M.D. SAN I~RANCISCO~ CALIF.
N A previous p a p e r a t t e n t i o n was directed to a n t e n a t a l influence in rickets a n d to the occurrence of f e t a l rickets. Some of the import a n t p r e n a t a l f a c t o r s we.re discussed a n d a case of fetal r i c k e t s was reported. 1 The p u r p o s e of this s t u d y is to ascertain the effect of m a t e r n a l influence on the d e v e l o p m e n t of certain other f o r m s of rickets in the infant. The s t u d y is based upon a s u r v e y of 400 cases of active rickets. A.
EARLY
POSTNATAL
RICKETS
IN
THE
INFANT
BORN
AT
TERM
Investigators have rather uniformly agreed that rickets is a rarity under three months of age, and yet the literature yields little as to the actual incidence in this age group. Hess 2 states that r i c k e t s begins a b o u t the t h i r d m o n t h a n d ends a b o u t the eighteenth month. H o l t and McIntosh ~ mentio.n the period from the fourth to the eighteenth m o n t h and go on to say t h a t the disease is r a r e before the t h i r d m o n t h a n d a f t e r the second year. S c h m o r P in 1909 conducted a pathologic s t u d y on 365 cases of rickets e x a m i n e d at a u t o p s y and f o u n d histologic evidence of the disease in t w e n t y i n f a n t s u n d e r three m o n t h s of age, an incidence of 5.5 per cent. F o u r of the p a t i e n t s were two months old, and the others were all b e t w e e n t w o and three months old. I t is well k n o w n t h a t p r e m a t u r e infants a n d t w i n s are susceptible to e a r l y a n d severe rickets. Ylppo 5 has o b s e r v e d rickets in a prem a t u r e i n f a n t at t h e age of six weeks. The y o u n g e s t p a t i e n t with rickets described in this c o u n t r y was an i n f a n t t h i r t y - f o u r d a y s old, r e p o r t e d b y D u n h a m , ~ a n d while this b a b y was a l l e g e d l y b o r n prem a t u r e l y , its b i r t h w e i g h t w a s 3,260 gin. Rickets in the Infant Born at Term.--In an a t t e m p t to d e t e r m i n e the actual incidence of early rickets, and to i n v e s t i g a t e possible etiologic f a c t o r s of significance, 400 cases of rickets seen in this clinic o v e r a period of the p a s t nine y e a r s h a v e been reviewed. All of these were in an active phase of the disease, and in each instance clinical diagnosis w a s c o r r o b o r a t e d b y r o e n t g e n o g r a p h i c e x a m i n a t i o n a n d chemiFrom the Department of Pediatrics, Harvard Medical School, and the Infants' and Children's I-Iospitals, Boston, lV[ass. 167
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cal analysis of the blood. Only patients with abnormally low phosphorus have been included in this survey. In this series of 400 it was f o u n d that thirty-two cases, or 8 p e r cent, were aged three months or younger. Of these, the youngest was a full-term infant of thirty-five days. F o u r t e e n of the t h i r t y - t w o were u n d e r two months of age, and eighteen infants were from two to three months old. W h e n ene considers the generally accepted r a r i t y of rickets in the first three months of life, it is surprising to find that 8 per cent of the cases of rickets developed in this age group. E x a c t l y half of the infants were the result either of p r e m a t u r e birth or of twin pregnancy. The other sixteen infants were all born at full term. Thus among 400 cases of rickets 4 per c e n t (sixteen cases) occurred in full-term infants u n d e r three months of age. Among these, 1.75 per cent were less than two months old, and 2.25 per cent were: in their second or third month of life. None of the sixteen had a birth weight of less t h a n 6 pounds and 12 ounces, which is well above the figure a r b i t r a r i l y accepted as one of the indices of p r e m a t u r i t y . The average weight at birth was 7 pounds. Comment.--With only three exceptions this group of full-term infants presented on admission an excellent state of n u t r i t i o n and had shown consistent gains in weight since birth. Most of them appeared healthy, and hospitalization was usually requested because of mild r e s p i r a t o r y infection or convulsions f r o m an associated tetany. The association of t e t a n y with rickets in these v e r y young infants is w o r t h y of note. A recent analysis b y Guild 7 of 293 cases of t e t a n y f r o m the H a r r i e t Lane Home disclosed an incidence of 7 ~ per cent in patients u n d e r three months. Since infantile t e t a n y almost always develops on the basis of a previous rickets, the close parallelism between this figure and the 8 per cent incidence of rickets found in this series for the same age group is of interest. The youngest case of t e t a n y in the recent l i t e r a t u r e was r e p o r t e d in a nine-day-old i n f a n t b y Small. s I t is k n o w n t h a t " r o e n t g e n o l o g i c r i c k e t s " indicates a f a i r l y advanced stage of the disease, f o r in 1928 W i m b e r g e r 9 demonstrated that the interval between the first histologic raehitic change and the first radiographic change is " c e r t a i n l y as long as several w e e k s . " When one recalls that almost h a l f of this full-term g r o u p showed roentgenologie evidence of the disease prior to the second month, it at once becomes evident t h a t in them the disorder must have had its incipiency in t h e v e r y early weeks a f t e r birth. T u r n i n g to an analysis of possible c o n t r i b u t o r y factors to the development of such an early rickets it i s seen that p r e n a t a l influence m a y be of importance (Table I). An investigation of m a t e r n a l health a/ld diet during p r e g n a n c y Was not quite as satisfactory as might be
TABLE I
MATERNAL DIET
Unknown Deficient Unknown Good Unknown Unknown Deficient Unknown Unknown Unknown Unknown Good Unknown Unknown Unknown Deficient
CASE
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Poor ~5or Unknown Good Unknown Unknown Poor Unknown Unknown Unknown Unknown Good Poor Unknown Unknown Poor
RIATERNAL HEALT]:t
ANTENATAL
8 9 Unknown 7 Unknown 9 5 17 6 Unknown 13 10 4 Unknown 8 2,5
YEARS MARRIED
FACTORS
6 5 Unknown 5 Unknown 6 3 9 5 Unknown 6 8 2 Unknown 5 2
N U M B E R OlV CHILDREN
M F M M M F M F F M F M F F
F
SE~
irish Irish American Scotch American Irish Italian German Scotch Scotch American Irish Italian Irish American German
NATIONALITY FEEDING
Breast Breast Artificial Breast Breast Breast Artificial Breast Breast Artificial Breast Breast Breast Artificial Breast Breast
LIVER OIL
Adequate None None None None None Tnadequate None None None None None Adequate None None None
COD
P O S T N A T A L FACTORS
CASE ANALYSIS OF ETIOLOGIC FACTORS IN FULL-TERM INFANTS WITS ACTIVE RICKETS UNDEI% THREE MONTtIS
MONTH
August October February September November March September April January Nfareh October June January December ~ebruary May
m rj~
>
0
r4
0
9
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G. M., a f o u r - m o n t h - o l d f e m a l e i n f a n t f r o m a poor I t a l i a ~ f a m i l y , e n t e r e d t h e h o s p i t a l on Sept. 12~ 1933, with a complaint of " f a i l u r e to g a i n . " The m o t h e r was twenty-five y e a r s old; she h a d been m a r r i e d f o r 1fine years, a n d t h i s was t h e fifth child. I I e r h e a l t h h a d been poor f o r several years, a n d w i t h t h e onset of this pregna~ncy it b e c a m e m u c h worse. T h e r e w a s a c o n s t a n t n a u s e a p r e s e n t ; t h r o u g h o u t p r e g n a n c y she ate little except cooked vegetables, occasional s m a l l a m o u n t s of raw f r u i t s ( o r a n g e s a n d a p p l e s ) a n d soup. 1Vicars, milk, a n d e g g s were entirely excluded f r o m this self-imposed diet. A v a g i n a l d i s c h a r g e h a d b e e n p r e s e n t for some m o n t h s a n d d u r i n g t h e h e i g h t o f p r e g n a n c y she developed severe p a i n s in h e r legs a n d j o i n t s d i a g n o s e d as ~ ' g o n o r r h e a l a r t h r i t i s . " These b e c a m e of such severity t h a t d u r i n g the l a t t e r m o n t h s of confinement She was- "u n a b l e to descend s t a i r s and w a s f o r c e d to r e m a i n i n a room t h a t received l i t t l e s u n l i g h t . W e a k n e s s was a n outs t a n d i n g feature. Severe d e n t a l caries developed. Following a full-term~ difficult delivery, t h e r e was considerable s p o n t a n e o u s i m p r o v e m e n t of her pain, a n d subse~ q u e n t ultraviolet i r r a d i a t i o n created a p r o m p t remission. T h e f a m i l y h i s t o r y was o f f u r t h e r interest. T h r e e of t h e f o u r siblings were in good health, b u t the y o u n g e s t , a g e d two years, showed evidence of an a d v a n c e d rickets w~th a l a r g e square head, p r o m i n e n t f r o n t a l bosses, rachitic rosary, extensive b o w i n g of t h e legs~ a n d epiphyseal enlargement. T h e p a t i e n t w e i g h e d 6 p o u n d s a n d 4 ounces a t birth, a n d her i m m e d i a t e postn a t a l condition w a s good. She w a s placed o n a modification c o n t a i n i n g dextrimaltose, milk, a n d water. T h i s w a s t a k e n w i t h avidity, and, while t h e i n f a n t seemed in good condition, she was u n a b l e to g a i n consistently. O r a n g e juice was b e g u n a t one m o n t h a n d a d m i n i s t e r e d t h e r e a f t e r in a d e q u a t e a m o u n t s . D u r i n g t h e e n s u i n g weeks t h e i n f a n t continued in u n e v e n t f u l f a s h i o n a n t i ] she w a s two m o n t h s old. A t this t i m e t h e m o t h e r detected a swelling of t h e " f r o n t of the l e f t shin b o n e . " This w a s only slightly tender, seemed q u i t e h a r d , a n d in no w a y curtailed the b a b y ' s activities. A few d a y s later t h e r e occurred a single generalized convulsion. Cod liver oil was t h e n b e g u n i n d a i l y teaspoon a m o u n t s b u t a f t e r one m o n t h it w a s disc o n t i n u e d because of occasional a t t a c k s of d i a r r h e a . The b a b y still showed no t e n d e n c y to gain, a n d finally at t h e age of f o u r m o n t h s she was b r o u g h t to the hospital for investigation. On admission~ e x a m i n a t i o n disclosed a n u n d e r d e v e l o p e d 'and m a r k e d l y undern o u r i s h e d , h y p e r t o n i c f e m a l e i n f a n t who w e i g h e d 7 p o u n d s a n d 5 ounces. She app e a x e d chronically ill; color w a s a n a s h e n pallor, a n d skin t n r g o r was poor. The h e a d was of square c o n f i g u r a t i o n w i t h p r o m i n e n c e of s u p r a o r b i t a l bosses. There w a s no d e m o n s t r a b l e craniotabes. A r o s a r y o f raehitic t y p e was present, a n d a b e g i n n i n g H a r r i s o n ' s groove w a s detectable. T h e a b d o m e n w a s q u i t e p ~ o t u b e r a n t a n d t h e splenic edge could be p a l p a t e d 2 cm. below t h e costal m a r g i n . ]~piphyseal e n l a r g e m e n t was n o t evident, b u t over the a n t e r o l a t e r a l a s p e c t of t h e l e f t t i b i a a r a t h e r diffuse swelling could r e a d i l y be seen. Thi~ w a s h a r d i n consistency, seemed to b e c o n t i g u o u s w i t h t h e bone~ a n d Was n o t t e n d e r to m a n i p u l a t i o n . There was f r e q u e n t s p o n t a n e o u s m o v e m e n t of all e x t r e m i t i e s w i t h o u t a p p a r e n t discomfort. A n a n e m i a of h y p o c h r o m i e t y p e was f o u n d ; s e r u m calcium c o n t e n t was 7.7 rag. p e r 100 c.c., ~ a n d t h e i n o r g a n i c p h o s p h o r u s w a s 4.5 m g . p e r eent.t A p l a s m a phosp h a t a s e c o n t e n t of 1.3 u n i t s per cubic c e n t i m e t e r s was i n d i c a t i v e of a d v a n c e d active rickets.~7 Other d a t a , i n c l u d i n g s e r u m protein, n o n p r o t e i n nitrogen, a n d r e n a l f u n c t i o n tes~s~ were w i t h i n n o r m a l limits. Man%onx t u b e r c u l i n tests, r u n up *Calcium d e t e r m i n a t i o n by m e t h o d of Fiske---normal r a n g e d u r i n g first y e a r from 9 to 12mg. per cent. ~Phosphorus d e t e r m i n a t i o n by method of F i s k e a n d S u b b a r o w - - n o r m a l r a n g e d u r i n g first :fear, f r o m 4.5 to 5.5 rag. l~er cent. SPhosDhatase d e t e r m i n a t i o n bsr m e t h o d of K a y - - n o r m a l r a n g e for i n f a n t s under on.e y e a r from 0.10 to 0.27 units per cubic centimeter.
RECTOR:
EARLY POSTNATAL ICICKETS
173
to 100 rag. of old tuberculin, p r o d u c e d no reaction. The W a s s e r m a n n , t I i n t o n , a n d K a h n reactions on b o t h p a r e n t s a n d b a b y were negative. R o e n t g e n o g r a m s (Sept. 13, 1933) showed m u l t i p l e f r a c t u r e s , i n c l u d i n g t h e l e f t clavicle, t h e s e v e n t h l e f t rib anteriorly, t h e left radius~ l e f t u l n a , a n d t h e r i g h t radius. T h e r e were also two f r a c t u r e s of t h e l e f t t i b i a a n d two o f the l e f t fibula. These were all s u r r o u n d e d by a m o d e r a t e a m o u n t o f callus f o r m a t i o n . T h e r e was a n extreme degree of generalized osteoporosis, a n d the m e t a p h y s e a l m a r g i n s were i r r e g u lar a n d defectively calcified (Fig. 1). T h e i n f a n t was i m m e d i a t e l y placed on a vigorous a n t i r a c h i t i c r e g i m e n c o n s i s t i n g of liberal a m o u n t s of a h a l i b u t liver oil p r e p a r a t i o n fortified w i t h viosterol. U l t r a violet i r r a d i a t i o n was given. R e e x a m i n a t i o n of t h e long bones two weeks a f t e r e n t r y (Sept. 26, 1933) showed definite i m p r o v e m e n t , c h a r a c t e r i z e d b y a n i n c r e a s e in the a m o u n t a n d d e n s i t y of t h e callus a r o u n d the f r a c t u r e s . Likewise, t h e osteoid a t
:Fig'. I.
~ i g . 2.
~ig. 1 . - - A film of t h e lower extremities t a k e n Sept. 13, 1933. Note the generalized osteoporosis, t h e i r r e g u l a r m e t a p h y s e a l margins, a n d multiple fractures. There a r e two f r a c t u r e s of the left tibia a n d two of the left fibula. l~tg. 2 . - - R o e n t g e n o g r a m a t time of discharge, Nov. 14, 1933. This illustrates complete healing of the infractions in good position with no r e m a i n i n g evidence of previous existence. Calcification h a s become a l m o s t normal, b u t slight rachitic c h a n g e s a r e still extant. the ends of t h e long bones showed i n c r e a s e d calcification. S e r u m calcium at t h i s t i m e h a d r i s e n to 12.4 rag. p e r cent a n d p h o s p h o r u s to 5.9 rag. A n o t h e r tilm t a k e n two weeks l a t e r (Oct. 11, 1933) disclosed well-calcified m e t a p h y s e s , a n d all of t h e f r a c t u r e s a l m o s t united. Six weeks a f t e r a d m i s s i o n t h e f r a c t u r e s were well healed, a n d t h e only evidence of t h e i r p r e v i o u s existence was a s m a l l a m o u n t of u n r e s o l v e d callus in t h e l e f t tibia. U p o n d i s c h a r g e two m o n t h s a f t e r e n t r y (Nov. 16, 1933) t h e r a d i o g r a p h d e m o n s t r a t e d complete e f f a c e m e n t o f all f r a c t u r e lines a l t h o u g h t h e r e were some slight raehitic c h a n g e s still p r e s e n t ( F i g . 2). S e r u m calcium w a s t h e n 10 rag. per 100 c.c., a n d p h o s p h o r u s , 5.7. A p l a s m a p h o s p h a t a s e of 0.51 u n i t s
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per cubic centimeter was f u r t h e r evidence t h a t healing was as yet not complete. T h r o u g h o u t her s t a y there was marked g e n e r a l i m p r o v e m e n t and a weight gain of almost five p o u n d s in two months.
That osteomalacia was present in the mother during the latter months of her pregnancy seems probable. A raehitogenie diet, frequent pregnancies, poor health, and an insufficient exposure to sunshine are all etiologic factors to the development of this disorder. The disease is f u r t h e r suggested by the extreme weakness and severe joint pain, which are outstanding symptoms of osteomalacia. At the time she was seen, however, this diagnosis could not be confirmed. A radiograph of her extremities taken six months postpartum (Nov. 16, 1933) showed nothing of note, although this is not surprising in view of the fact that her diet since delivery had been normal. She had also received over a month of intensive ultraviolet light therapy, which would contribute to f ur t her healing. A request f o r calcium and phosphorus determination on the mother was refused. This case, in several respects, resembles the one reported by Dunham. The mother of that baby had undergone seven pregnancies, had been exposed to very little sunlight, and her diet had been very deficient. During the latter months of pregnancy weakness and pain in the legs developed. X-rays disclosed considerable rarefaction of the bones; it was likely that she had osteomalacia. A SURVEY OF 400 CASES OF ACTIVE RICKETS W I T H AN ANALYSIS OF CASES W I T H FRACTURES
Of the four hundred cases of rickets surveyed by the author, fractures occurred in fourteen instances; an incidence of 3.5 per cent. Nine of the patients who developed fractures were full-term infants and the remainder were either premature infants or twins. The age incidence in this group closely followed t hat usually seen in rickets, with an average range of from six to fifteen months. The youngest was two months old, and the oldest, twenty-six months. 0nl y two cases were found in infants under three months of age. The patients with severe rickets associated with fractures entered the hospital with a chief complaint of " f a i l u r e to g a i n " or " c o u g h . " Almost without exception they presented extreme degrees of malnutrition and underdevelopment. Severe respiratory infections were frequent; and the mortality in the group was 29 per cent, death occurring from bronchopneumonia. COMMENT
The etiologic factor in the causation of severe rickets with fractures cannot be definitely stated. Postnatal factors did not seem t0 be outstanding. (Table II.) Sex, season, and nationality were hardly worthy of connotation. Five of the fourteen infants were breast fed;
1 2 3 4 5 6 7 8 9 10 11 12 13 14
CASE
Unknown Unknown Deficient Unknown Unknown Good Deficient Unknown Unknown Unknown Deficient Unknown Deficient Unknown Unknown Poor Poor Unknown Poor Good Poor Unknown Poor Unknown Poor Unknown Poor Unknown 6 9
4 11 5 8 ? 1 9 6 3 ? 13
YEARS MARRIED NUI~IBER OF /SEX CI-IILDP~EN i M M F M F F F M F M M F M
ANALYSIS OF ETIOLOGIC FACTORS
ANTENATAL PACTORS MATERNAL MATERNAL DIET ~EALTH
CASE
TABLE II
Irish Italian American Greek American Irish Italian Italian Scotch Greek Irish American Portuguese Italian
NATIONALITY Breast Artificial Artificial Breast Artificial Artificial Artificial Breast Artificial Artificial Breast Artificial Artificial Breast
None Adequate Adequate Inadequate None None Inadequate Adequate None Adequate Adequate Adequate None None
POSTNATAL FACTORS COD LIVEE FEEDING OiL
IN INFANTS WIT~I FRACTURES
December Oetober :February April July February September August July March April October March January
MONTH
CA
>
>
o
E~
>
..
o
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the others all had adequate artificial f o r m u l a s w i t h but three exceptions. F o r t y - t h r e e per cent of these babies received cod liver oil or a substitute in a m o u n t s o r d i n a r i l y mlfficient to p r e v e n t rickets. Infection was a p r o m i n e n t f e a t u r e in the m a j o r i t y of cases b u t m a y have been the result r a t h e r t h a n a predisposing cause of the development of rickets. A c c u r a t e m a t e r n a l history could be obtained in eleven of the fourt e e n cases. Fifty-five p e r cent, or six cases, had a history of five or m o r e p r e g n a n c i e s in r a p i d succession. D a t a concerning the m o t h e r ' s heal.th and d i e t a r y were ascertained in eight instances. Only one m o t h e r was definitely k n o w n to h a v e h a d b o t h an a d e q u a t e diet and good health. I n this case the infant was b o r n p r e m a t u r e l y and was a twin so that the florid rickets a n d multiple f r a c t u r e s seen in this b a b y are more r e a d i l y understood. F o u r m o t h e r s h a d v e r y poor h e a l t h a n d diets t h a t were definitely deficient, while in three others health was i m p a i r e d b u t no details of the diets could be elicited. I n t w o cases in which the m a t e r n a l health a n d diet were exceptionally bad, the infants, in addition to multiple f r a c t u r e s , h a d thoracic and spinal deformities. These cases w e r e somewhas similar to those rep o r t e d b y P a r k and H o w l a n d . TM G r a n t is describes cases in y o u n g r a t s b o r n of mothers w i t h p a r t i c u l a r l y defective diets, who developed extensive osteoporosis, multiple fractures, thoracic deformities, and kyphosis. Calcium and phosphorus d e t e r m i n a t i o n s in these cases with multiple f r a c t u r e s differed in no essentials f r o m the figures obtained in usual cases of rickets. B y r o e n t g e n o g r a m all cases showed m e t a p h y s e a l irr e g u l a r i t y and cupping, b u t the o u t s t a n d i n g f e a t u r e in each case was a generalized osteoporosis of e x t r e m e degree. This characteristic is of interest in r e g a r d to an observation made b y T o v e r u d and Toverud. 1~ T h e y h a d placed p r e g n a n t r a t s on a diet m a r k e d l y deficient in calcium, b u t otherwise adequate, a n d f o u n d t h a t the y o u n g of these m o t h e r s showed an extensive osteoporosis w i t h multiple f r a c t u r e s but relatively little actual rachitic change in the m e t a p h y s e s . One cannot postulate t h a t the same m e c h a n i s m p r e v a i l e d in these i n f a n t s with multiple f r a c t u r e s . H o w e v e r , there w e r e a n t e n a t a l f a c t o r s p r e s e n t in a large n u m b e r which were capable of e x e r t i n g an influence on fetal metabolism. I t would be m o s t interesting if one could know the age at which rickets first developed in these babies who s u b s e q u e n t l y p r o g r e s s e d to the stage of multiple fractures. I t seems likely t h a t a considerable p o r t i o n would have shown rickets in the e a r l y months of life. SUMMARY
A review of l i t e r a t u r e on early p o s t n a t a l rickets and rickets with m u l t i p l e fractures, t o g e t h e r with a s u r v e y of 400 cases of active rickets a n d the d e t e r m i n a t i o n of the incidence of ear.ly rickets and of rickets
RECTOR:
EARLY POSTNATAL RICKETS
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with multiple fractures, permits an analysis of possible factors cont r i but or y to the development of these two forms of the disease. It is suggested that early postnatal rickets and florid rickets with multiple fractures may result from an insufficiency of stored skeletal calcium at the time of birth incident to nutritional and metabolic defects on the part of the maternal organism. A case of early infantile rickets with multiple fractures is reported. 2EFEEENCES 1. l:~c~;or, J . M . : J. PED~AT. 6; 161~ 1935. 2. Hess, A. :F.: ~ickets Including Osteomalacia and Tetany~ Philadelphia, 1929, Lea and Febiger, pp. 253-257. 3. Holt, L. E , and 1VfeIntosh, R.: t t o l t and Howland's Diseases of I n f a n c y and Childhood, ed. 10, New York, 1933, D. Appleton-Century Co., p. 237. 4. Schmorl, G.: Ergebn. d. inn. ~r u. ]Kinderh. 4: 403, 1909. 5. Ylppo, A.: Ztschr. f. Kiuderh. 24: 1, 1920. 6. Dunham, E . C . : Am. J. Dis. Child. 26: 155, 1923. 7. Guild: Quoted by Holt and McIntosh,8 p. 259. 8. Small, A. S.: J. PEDIAT. 2: 681, 1933. 9. Wimberger, H.: Quoted b y Hess.~ 10. Hess, A. 1% and Matzner, M . J . : Am. J. Dis. Child. 26: 285~ 1923. 11. Toverud, ]K. U., a n 4 Toverud, G.: Aeta paediat. (supp. 2) 12: 1, 1931. 12. Park, E. A., and ttowland, J.: Bull. Johns Hopkins Hosp. 32-' 101, 1921. 13. Lereboullet, P., and Chabun, J . : Bull. Soc. de p6diat, de Paris 9.9: 151, 1931. 14. Steiner, B.: 0rvosi hetil. 73: 733, 1929. 15. J u n g w i r t h : Wien. reed. Wchnschr. 77: 654~ 1927. 16. Hutchison, H. S., and Stapleton, G.: Brit. J. Child. Dis. 12: 18, 1924. 17. Smith, J., and Maizels, 1Vf.: Arch. Dis. Child. 7: 149, 1932. 1 8 . Grant, A . H . : Am. J. I-Iyg. 6: 228, 1926. 2000 VAN NESS AvE~trz