Hypoproteinemia and edema in infants with cystic fibrosis of the pancreas

The Journal of P E D I A T R I C S

341

Hypoproteinemia and edema in infants with cysticfibrosis of the pancreas The histories o[ 4 in[ants with cystic fibrosis o[ the pancreas who developed hypoproteinemia and edema~are recordJ'cl. Twenty-two additional instances o[ this clinical pattern have been found in the literature. The majority of these patients had the onset o[ edema at about 2 months o[ age, and in the majority o[ instances their diet consisted either o[ human milk or a soybean milk preparation. The relationship between CFP and diet and the development of hypoproteinemic edema is discussed.

Daniel S. Fleisher, M.D., Angelo M. DiGeorge, M.D., ~ Lewis A. Barness, M.D., and David Cornfeld, M.D. PHILADELPHIA~

PA,

I N 1 9 3 6 , Garsche ~ first noted the occurrence of hypoproteinemia in a 5~2-year-old child with cystic fibrosis of the pancreas (CFP). Another instance was briefly noted by Menten and Middleton 2 in 1944. T h e first detailed report of hypoproteinemi a in an infant with C F P was that of Wissler and Zollinger a in 1945. Although a n u m b e r of additional cases have been reported from Europe, 4-1"~ only recently 'has the association From the Department of Pediatrics, Temple University School of Medicine, and St. Christopher's Hospital [or Children; and the Department o[ Pediatrics, University of Pennsylvania School o[ Medicine. This investigation was supported in part by Research Grants from the National Cystic Fibrosis Research Foundation and [rom the National Institutes o[ Health (AM-06469). eAddress, St. Christopher's Hospital ]or Children, 2600 N. Lawrence Street, Philadelphia 33, Pa.

of hypoproteinemia and C F P been noted in the United States? 4-17 T h e increasing use of soybean preparations as substitutes for cow's milk fotxnulas appears to have led to an increasing incidence of hypoproteinemia in infants with CFP. I n this paper are presented the clinical details on 4 infants with C F P who developed hypoproteinemia and edema. A subsequent paper presents the data derived from metabolic studies performed on patients with C F P to determine the relationship of soybean feedings to this symptom complex.

CASE REPORTS Case 1. L. M. (SCHC No. 583500). A 4-weekold female infant was admitted to St. Christopher's Hospital for Children on Aug. 1, 1958, with a history of diarrhea since birth. The birth weight was 6 pounds, 2 ounces. Despite many

342

AGE

(WE EKS]

Fleisher et al.

FORMULA MANY

[

WT.

(LBS,)

March 1964

SERUM EDEMA PROTEIN R E M A R K S GMS. =/~

VORACIOUS APPETITE

6,2

FORMULA

2

CHANGES

5

6A

4

s 0

5

Y

6

7

s

8

E

.u N

I0 II

N UTRAMIGEi',

12

8.5

5,2

HEMATEMESIS MELENA

2.0

6.5

.3.5 4,2

IV ALBUMIN =ARACENTESIS

4.0

PNEUMON(A

8.5

t5

MEAT

6.0

14

BASE

6.0

DEATH

L.M. WHITE FEMALE Fig. 1. Clinical and laboratory data of hypoproteinemia and edema in cystic fibrosis of the pancreas in Patient 1. formula changes, the diarrhea persisted, and she failed to regain her birth weight. She was noted to be an "excellent feeder." Other than signs of mild undernutrition, the physical examination was essentially within normal limits. She weighed 6 pounds, 1 89 ounces. She failed to gain weight while receiving an evaporated cow's milk formula for several days. This was then changed to a soybean preparation (Sobee) and though the diarrhea persisted she gained a few ounces of weight. She was discharged from the hospital after 10 days of soybean feedings with a presumptive diagnosis of allergy to cow's milk. Five weeks later (Sept. 18, I958) she was readmitted because of increasing anorexia and the onset of generalized edema (Fig. 1). Other than the presence of edema, the physical examination was normal. Laboratory results included: total serum protein 3.2, serum albumin 2.0, serum globulin 1.2, and hemoglobin 9.4 Gm. per 100 ml., respectively. The white blood cell count was 7,000 per cubic millimeter with 50 per cent polymorphonuclear leukocytes, 44 per cent lymphocytes, and 6 per cent eosinophils. Serum electrolyte values were within normal limits except for a total plasma carbon dioxide of 17 mEq. per liter. The blood urea nitrogen level was 11 mg. per 100 ml. Urinalyses were within normal limits.

Feedings were changed to Nutramigen and later to a meat-base formula. She developed hematemesis and melena on one occasion and had two episodes of pneumonitis. Treatment included intravenous infusions of concentrated human serum albumin, intramuscular injections of h u m a n gamma globulin, and several transfusions of whole blood. O n Oct. 10, 1958, she developed severe pneumonitis followed by anemia (hemoglobin 6.4 Gin. per 100 mI.) and shock. She died on Oct. 14, 1958. Microscopic e x a m i n a t i o n of the pancreas revealed a moderate increase Of connective tissue within and between the lobules. Numerous ducts and acini were dilated, some to cystic proportions, and contained acidophilic l~tmellated deposits. The liver showed severe fatty metamorphosis. Most of the hepatic cells contained large discrete vacuoles. Scattered brown pigmented granules, probably representing hemosiderin, were present in the residual cytoplasm of some of the hepatic cells. Sections of the gastrointestinal tract revealed two superficial cystic glands in the deeper mucosa of the duodenum filled with acidophilic material. Brunner's glands appeared normal. These changes were considered diagnostic of CFP. Case 2. T. W. ( S G H C No. 584699). A white male infant was admitted to a local hospital at 8 weeks of age because of edema of a few days duration. He weighed 7 pounds, 1 ounce at birth and was well until 3 days of age when he developed diarrhea. At 7 days of age gross tremors were noted. Subdural and lumbar punctures were performed; no abnormalities were noted. H u m a n milk and Similac were offered but he failed to gain weight. At 2 weeks of age he was discharged with a Nutramigen formula. Diarrhea persisted and at 5 ~ weeks of age the formula was changed to a soybean preparation (Mullsoy). His appetite was described as "voracious," but he failed to gain weight normally and subsequently became edematous (Fig. 2). Laboratory data at the local hospital revealed the following: Hemoglobin 9.2, total serum protein 2.2, serum albumin 1.4, and serum globulin 0.8 Gm. per 100 ml., respectively. His formula was changed to Probana, and he was given one transfusion of whole blood. The edema gradually subsided and after 3 weeks he was transferred to St. Christopher's Hospital for Children. On admission (Oct. 4, 1958) the edema was barely discernible. His total serum protein had risen to 4.7 Gm. with 3.5 Gm. per 100 ml. of serum albumin a n d 1.2 "Gm. per 100 ml. of

Volume 64 Number 3

Hypoproteinemia and edema in cystic fibrosis

serum globulin. Urinalysis was within normal limits. Feedings of a meat-base formula were initiated. Sweat chloride concentration was 223 mEq. per liter. He developed pneumonia at home at 13 weeks of age and died shortly thereafter. Microscopic examination of the pancreas revealed dilatation of numerous acini and ducts, many of which contained acidophilic lamellated secretion within their lumens. There was mildto-moderate inter- and intralobular fibrosis. Sections of the liver revealed large amounts of fine brown pigment in the hepatic cells, probably representing hemosiderin. There.. was no portal fibrosis. The hepatic sinusoids and the spaces of Disse were very slightly dilated in the intermediate zones compared with the centers and peripheries of the lobules. The hepatic cords in these intermediate zones were possibly slightly narrower than elsewhere in the lobules. These changes were consistent with the diagnosis of CFP. Case 3. C. S. ( S C H C No. 585805). An 8week-old male infant was admitted to St, Christopher's Hospital for Children on Dec. 14, 1958, with a history of increasing generalized edema of 4 days' duration. He weighed 7 pounds, 2 ounces at birth, and received Similac feedings for the first week of life. Because he was "colic," his feedings were then changed to an evaporated cow's milk preparation a n d at 4 weeks of age to a soybean formula (Sobee). Four days prior to admission edema was first noted in his periOrbital tissues and rapidly became generalized (Fig. 3). Two days prior to admission "blood tinged" diapers were noted on two occasions. This prompted the referring physician to make a presumptive diagnosis of nephritis. Except for the moderate generalized pitting edema, the physical e x a m i n a t i o n was within normal limits. H e weighed 9 pounds, 14 ounces on admission. Laboratory, data included: total serum protein 2.8, serum albumin 1.9, serum globulin 0.9, and hemoglobin 11,0 Gm. per 100 ml., respectively. The blood urea nitrogen was 8.5 rag. per 100 ml. T h e white blood cell count was 11,600 per cubic millimeters (24 per cent polymorphonuclear leukocytes, 69 per cent lymphocytes, and 6 per cent eosinophils). Serum electrolyte levels were within normal limits, as were several urinalyses. His parents had denied the presence of d i a r r h e a b u t in the hospital his stools were noted to be malodorous and large in volume. Further questioning revealed that his stools had been of this character since birth.

SERUM AGE FORMULA WT. EDEMA PROTEIN (WEEKS] (LBS. GMS. % I 2

SEVERAL FORMULA

343

REMARKS VORACLOUS APPETITE

7.1 6.5

3 4

CHANGES

5 6

7

6.75 7.0

SOY

BEAN

2.2

8

CHEST X-RAY NORMAL BLD. TRANS.

2..3

9 Io

PROBANA

Ii 12

6.5

4.7

SWEAT CI mEq,/L

22:5

MEAT BASE

DEATH

13 T.W. WHITE

MALE

Fig. 2. Clinical and laboratory data of hypoproteinemia and edema in CFP in Patient 2. I AGE FORMULAI WT. :WEEKS) (LBS.

I 2 3

SIMILAG

EDEMA SERUM PROTEIN

REMARKS

GMS. %

"ABDOMINAL CRAMPS"

7.1

VORACIOUS APPETITE

E.M.

4 5 6

soy BEAN

7

9,9

,

8

9.6 i 9.0 y 8.5

i

LOW No

9

'r SWEAT CI 1:57 mEq~/L

2,8 5.7

CHEST X-RAY NORMAL

I0

soy

8.5

II

BEAN

8.7

A

5.0

12 15

E.M. E.M. S

l

2.6 4.1

14

VIOKASE

I0 10.9 8.5

4.0

LOW No 15 16

soy BEAN

C.S. WHITE

8,0

5.3

7.6

5.3

PNEUMONIA

DEATH

MALE

Fig. 3. Clinical and laboratory data of hypoproteinemia and edema in CFP in Patient 3. Sweat chloride concentration was 137 mEq. per liter. There was no tryptic activity in a sample of duodenal fluid. Nitrogen balance studies performed on this infant are included in the following paper? 8 He became free of edema after receiving a lowsodium cow's milk preparation ~ for 8 days. Sobee feedings were reinstituted and edema re~Walker Gordon Dairies, Plainsboro,

N. J.

344

Fleisher et al.

Table

I.

Reported

March 1964

cases

of

hypoproteinemia

and

edema

in

infants

with

c y s t i c f i b r o s i s of t h e

Milk feeding

Case

Reference

Sex

Type

Duration (weeks)

Onset of edema (months)

L-living D-dead

1

Garsche 1

M

60

D

66

2

Menten and Middleton 2

~

15

D

15

3

Wissler a n d Zollinger 3

Y

2

D

3

4

Glanzmann ~

M

2

D

2

5

Glanzmann*

M

2

L

?

6

F a n c o n i a n d Botsztejn 5

F

Human

7

1.5

D

2

7

F a n c o n i a n d Botsztejn 5

M

Human

3

2

D

2.5

8

Odegard 6

M

3

D

3.5

9

Jones 7

M

2.5

D

4.5

Lumb and Beautyman s

1~

1

D

9

11

Bille a n d V a h l q u i s t 9

F

Human

4

L

12

12

H e n d e r s o n 1~

M

Human

8

2

L

14

13

M a r i e et al. 11

F

H u m a n , 2 weeks Half-skimmed and soybean

4

1.5

D

2

14

M a r i e et al. 11

lq"

Cow and human

6

2

D

4.5

15

M a r i e et al. 11

M

2

D

2

16

Present report 14

F

Soybean

5

2

D

3

10

Human

1

Human

Case 1 17

Case 2

M

Soybean

4

1.5

D

3

18

Case 3

M

Soybean

4

1.5

D

3.5

19

D e s b u q u o i s et al. 12

?

20

G o l d m a n et al. 15, 13

M

Soybean

19

21

G o I d m a n et al. 15, zo

F

Soybean

5

22

C.P.C.

F

Cow

23

S h a h i d i et al. 1~

M

Soybean

24

S h a h i d i et al. 17

M

Soybean

25

L a u n a y et al. a~

F

26

Present report

M

~6

Soybean

< 12

D

< 12

6

D

24

2.5

L

14

5

1.5

D

2

3

2

L

40

6

3

L

40

1.5

D

2

L

3

3.5 57

Case 4 J

Volume 64 Number 3

Hypoproteinemia and edema in cystic fibrosis

345

~creaS

Total Serum urn I Serum sertein I atbumin globulin Hemoglobin or RBC pro ~ l(Gm.% ) (Gin.%) 3.8 X 10~ RBC/mm. 3

3.8

5,5 4,6 3.2 4.5

3.0

1.6

Post mortem

2.0

2.5

3.3

1.6

Post mortem

8.0 Gin.%

Sibling of Patient 5 Additional family history of CFP

9.1 Gm.%

Sibling of Patient 4 Additional family history of CFP Post mo,rtem

4.7

Post mortem

4.6 3,5

1.3

2.2

3.0 4,1

2.4

1.7

510

2.7

2.3

3.6

1.2

2.4

Post mortem "36%"

Post mortem Post mortem

7.1 Gm.%

Duodenal drainage

Improved on pancreatin

Duodenal drainage

Edema cleared spontaneously in several weeks

2.9

1.5

1.4

"90%"

4,5 5.5

2.6

2.9

2.5 x 106 RBC/mm. s

Post mortem

5,0

3.0

2.0

3.3 x 10 6 RBC/mm. s

Post mortem

2.0

2.5 x 10 6 RBC/mm. 3

Sibling of case 14 Died of heat stroke

5,0 3,2 1.9

2.0 0.8

1.2 1.1

7.3 G m . %

Post mortem

2,2

1.4

0.8

9.1 G m . %

High sweat chloride Post mortem

2,8

1.9

0.9

8.1 Gin.%

High sweat chloride Post mortem

3,6

2.0

1.6

10.4 G m . %

High sweat chloride Post mortem

3.6

2.1

1.5

10.7 Gm.%

High sweat chloride

3.8

2.9

0,9

96 . 7

I~]OWll

~low~

,

Gin.%

1.5

1.7

7.2 Gm.%

3,9

1.6

2.3

7.7 Gin.%

High sweat chloride Duodenal drainage

2.5 x 10 6 RBC/mm. a

High sweat chloride

7.2 Gin.%

High sweat chloride Duodenal drainage Family history

1.1

1.5

Improved on addition of pancreatic granules

Post mortem

3,2

3,5

Serum protein did not rise on high protein diet

Post mortem

High sweat chloride Duodenal drainage

2.6

Miscellaneous

Post mortem

4,0 4,9

Evidence [or diagnosis

Improved on cow's milk and pancreatic granules Improved on cow's milk and Viokase

Improved on Similac and pancreatic granules

3 46

Fleisher et al.

curred within 15 days. The diet was then successively changed to evaporated milk, evaporated milk with Viokase, and low-sodium milk. Balance studies were performed during each of these periods. Edema did not subside until the low sodium milk was instituted. Another balance period was then started with the use of a soybean formula. However, he developed severe pneumonitis and died 4 days later. At 13 weeks of age, while still edematous, the hemoglobin concentration was 8.i Gm. per 100 ml. Microscopic examination of the pancreas revealed moderate interstitial fibrosis and dilatation of a number of ducts and acini, some of which contained lamellated acidophilic material. The liver revealed considerable deposits of brown pigment, probably representing hemosiderin, within the hepatic cells. There was no portal fibrosis nor atrophy of the hepatic cords. The gastrointestina! tract revealed multiple superficial erosions of the esophagus, a prominent covering of cuboidal mesothelial cells (occasionally including elongated cystic spaces) in the stomach, a deep duodenal ulcer in the pylorus, and a small amount of acidophilic secretions in a number of the mucosal glands of the duodenum. Brunner's glands appeared normal with the exception of a few dilated ones in the duodenum, one of which contained acidophilic secretions. The small bowel revealed acidophilic deposits in a number of the mucosal glands. The colon appeared normal. These changes confirmed the diagnosis of CFP. Case 4. G. B. (Hospital of the University of Pennsylvania No. 120905). An 11-week-old white male was admitted to the Hospital of the University of Pennsylvania on Nov. 19, 1957, with a history of having had generalized edema for 3 weeks. He weighed 6 pounds, 3 ounces at birth and remained well until 3 weeks of age when he developed a "cold" and diarrhea, both of which persisted for 2 weeks. After the second week of diarrhea he was admitted to another hospital, where it was thought that he might have an allergy to cow's milk and the formula was changed to a soybean product (Sobee). The diarrhea subsided and he was discharged from the hospital after 10 days, weighing 7 pounds, 3 ounces. At 8 weeks of age his weight was 9 pounds, i ounce; edema was generalized. He was readmitted to the same hospital and after 5 days was transferred to the Hospital of the University of Pennsylvania. On admission, physical examination w a s within normal limits except for generalized

March 1964

pitting edema, involving his face, head, extremi. ties, abdomen, back, and scrotum. Laboratory results included: hemoglobin 8.1 Gin. per 100 ml., total serum protein 2.6 Gin. per 100 ml., serum calcium 8.5 mg. per 100 ml., and serum phosphorus 5.1 mg. per 100 ral. Serum alkaline phosphatase was 12.3 Bodansky units. Urinalyses were within normal limits. Stools were noted to be well formed but of adult size. Sweat chloride concentration was l l 1 mEq. per liter. Fluid obtained by duodenal intubation had no trypsin, amylase, or lipase activity. Small transfusions of whole blood and concentrated human serum albumin were administered. Over a period of 5 days his weight decreased from 9 pounds, 12 ounces, to 7 pounds, 8 ounces, and he lost all traces of edema. Feedings were begun with Similac and Viokase (pancreatic granules). One month after admission, studies were performed with the use of SMA formula (protein 1.5 per cent, carbohydrate 7.0 per cent, and fat 3.5 per cent). On a daily intake of 136 calories per kilogram of body weight and a protein intake of 3.37 Gm. per kilogram of body weight, he retained 0.96 Gm. of nitrogen per day. During the subsequent week the balance study was repeated by means of Varamel formula (protein 3.1 per cent, carbohydrates 5.2 per cent, and fat 3.6 per cent). On a daily intake of 136 calories per kilogram of body weight and 6.12 Gm. of protein per kilogram of body weight, he retained 0.59 Gm. of nitrogen per day. The protein content of the SMA and Varamel were obtained by direct analysis of nitrogen content. Several attempts to perform a similar balance study by employing a soybean preparation were unsuccessful because of intermittent vomiting and diarrhea. After 2 months, the patient was discharged. Subsequently, he developed several mild pulmonary infections and when last seen at 57 months of age he had radiographic and clinical evidence of severe pulmonary disease. DISCUSSION E d e m a as a result of hypoproteinemia is a rare occurrence i n patients with cystic fibrosis of the: pancreas. I n the past three decades only 22 other instances of hypoprot e i n e m i a a n d edema have been reported in patients with C F P (Table I ) . O f the total of 26 cases, all b u t 2 were u n d e r 6 months of age at the time of a p p e a r a n c e of edema.

Volume 64 Number 3

Hypoproteinemia and edema in cystic fibrosis

Some striking similarities are evident in these cases. A typical clinical course of an infant in the United States with CFP who develops edema and hypoproteinemia is as follows: Characteristically, the infant is normal at birth but gains weight poorly during the first month of life in spite of an excellent appetite. Diarrhea may or may not be noted, but close questioning usually reveals that the stools are volumino.us. Often the infant draws up his legs on his abdomen as if experiencing abdominal pain. This usually leads to a diagnosis of allergy to. e~w's milk and a soybean formula is prescribed. After maintenance on this'diet for 2 weeks or more, edema secondary to hypoproteinemia becomes manifest. The average: duration for this clinical course is 2 months. A change, of feeding to a cow's milk formula or the addition of pancreatic enzymes to the feeding regimen usually results in subsidence of the edema. In spite of clinical improvement, the majority of infants quickly develop pulmonary infections and anemia and die suddenly between 8 and 16 weeks of age. Postmortem findings do not differ from those in other infants with CFP. In neither our patients nor the other patients with this syndrome on whom autopsies were perfo.rmed have there been pathologic changes in the liver of suffiCient magnitude to. explain satisfactorily the hypoproteinemia. In the cases reported from Europe, the infants have been predominantly breast fed. Bille and Vahlquist 9 noted that human milk was the only source o.f dietary protein in their patient as well as in the 6 o~ the 8 cases they found in the European literature up to 1955 fo.r whom a dietary history was available. They stated, however, that "what part is played by the diet in the genesis of the hypoproteinemia must for the present be left open." It is noteworthy that of the patients whose d i e t a r y history was available to us, only one patient was fed a cow's milk preparation alone. All other infants were fed human milk or a soybean preparation. In the following paper an attempt is made to. evaluate the role of the; soybean feedings in the production of the hypoproteinemia and

347

edema in patients with C F P ? s Evidence to be presented indicates that soybean preparations are a relatively poor source of protein for infants with CFP. When soybean is the sole dietary protein, infants with CFP excrete a higher proportion of the ingested nitrogen in the stools than with other diets. Under such circumstances hypoproteinemia would not be unexpected. When a newborn baby with CFP was fed a soybean preparation for the first 25 days of life, the serum protein level decreased from 6.8 Gm. at birth to 4.1 Gm. per 100 ml. at 25 days of age. 17 Because human milk has a low-protein content when compared to. cow's milk, it too may be more apt to. lead to. hypoproteinemia if it is the sole source of protein for infants with CFP. Presently, the diagnosis of CFP is established most readily by demonstration of an elevated chloride concentration in the sweat. Hence, it should be noted that two infants with CFP had normal chloride concentrations in their sweat while they were. edematous and hypopro.teinemic, la Subsequently, when edema was no longer present, the chloride concentration of the: sweat was elevated to diagnostic levels. On the other hand, 3 of our patients who were tested while edematous were found to. have markedly elevated concentrations of sweat chloride. However, if one has an edematous infant suspected of having CFP and the sweat chloride concentration is within the normal range, it would be judicious to repeat the test after the edema has subsided. Marie and co-workers1. were the first to suggest that anemia may be. a part of the symptom complex of the hypoproteinemic form of cystic fibrosis of the pancreas. Subsequent studies by Shahidi, Diamond, and Schwachman 17 demonstrated a definite relationship between the anemia and inadequate protein intake of two. infants with cystic fibrosis of the pancreas and hypoproteinemia. As may be seen from Table I, anemia is a frequent finding in-these children. It is not surprising that protein deficiency leads to anemia as well as to decreases in both serum albumin and globulin levels.

348

Fleisher et al.

S e r u m protein deficiency a n d a n e m i a are easily ascertained. However, one can only surmise that other intracellular proteins (enzymes) with relatively short half-lives are probably also diminished. T h e early a n d often sudden d e a t h o.f these infants may in p a r t be attributable to poor nitrogen retention a n d deficient protein synthesis. Soybean feedings have p r o d u c e d satisfactory growth a n d nitrogen retention in large groups of n o r m a l infants. 2~ ~ IKowe~zer, in the absence of no.rmal pancreatic exocrine secretion, soyb e a n feeding is a poor source of protein a n d potentially hazardous. SUMMARY

T h e case histories are presented of 4 infants with cystic fibrosis of the pancreas who developed e d e m a and hypoproteinemia shortly after the institution of soybean feedings. T w e n t y - t w o other examples of this association have been f o u n d in the literature. H u m a n milk or soybean milk feedings have been implicated as the factors responsible for h y p o p r o t e i n e m i a in infants with cystic fibrosis of the pancreas.

We wish to thank Norman D. Kendall, M.D., and Edwin Abrahamsen, M.D., for referring Cases 1 and 2, respectively, and James B. Arey, M.D., Ph.D., for making available the autopsy protocols.

REFERENCES

t. Garshe, R.: Zur Klinik und Pathogenese der Pankreasinsuffizienz im Kindesalter, Ztschr. Kinderh. 58: 434, 1936. 2. Menten, L., and Middleton, T. O.: Cystic fibrosis of the pancreas, Am. Dis. Child. 67: 355, 1944. 3. Wissler, 1-[., and Zollinger, H. U.: Die familiS,re kongenitale zystisehe Pankreasfibrose mit Bronchiektasien, Helvet. paediat, acta (suppl 1) 3: 88, 1945. 4. Glanzmann, E.: Dysporia entero-bronchopancreatica congenital familiaris cystische Pankreasfibrose, Ann. paediat. 166: 289, 1946.

March 1964

5. Fanconi, G., and Botsztejn, A.: Einige beson. dere Verlaufsformen der Pankreasfibrose rnit Bronchiektasien, Helvet. paediat, acta 2: 279, 1947. 6. Odegard, A.: t0demer, Hypoproteinemi og Fettlever Hos to Spebarn, Nord. Med. 40: 2003, 1948. 7. Jones, G. C.: Fibrocystie disease of the pancreas in an infant, Lancet 1: 651, 1949. 8. Lumb, G., and Beautyman, W.: Hypoplasia of the exocrine tissue of the pancreas, j. Path. Bact. 64: 679, 1952. 9. Bille, B. S., and Vahlquist, B.: Idiopathic hypoproteinemia versus hypoproteinemia due to pancreatic dysfunction, Acta paediat. 44: 435, 1955. 10. Henderson, W.: Fibrocystic disease of the pancreas with hypoproteinemic oedema in early infancy, Proc. Roy. Soc. Med. 48. 1107, 1955. 11. Marie, J., Salet, J., Debris, P., Hebert, S., Corbin, J. L., and Bezri, A.: Les Formes oedemateuses avec hypoproteinemie et anemic de la fibrose kystique due Pancreas, Semaine d. h6p. Paris (Ann. Pediatric) 35: 2140, 1959. 12. Desbuquois, G., Bqnlard, P., and Grenier, B.: Observations cliniques et constatations anatomiques de 16 fibroses kystiques due pancreas, Semaine d. h6p. Paris 36: 910, 1960. 13. Launay, C., Thiriez, H., Lacroix, A., and Lafaix, C.: Anemie avee hypoprotidemie revelatrlce d'une mucoviscidose, Arch. fran~. pddiat. 19: 982, 1962. 14. Fleisher, D. S., DiGeorge, A. M., and Huang, N. W.: Hypoproteinemia and edema as early manifestations of fibrocystic disease of the pancreas, A. M. A. J. Dis. Child. 98: 504, 1959. 15. Goldman, A. S., Travis, L. B., Dodge, W. F., and Daeschner, C. W.: Falsely negative skin tests in children with cystic fibrosis complicated by hypoproteinemic edema, J. PEDIAT. 59: 301, 1961 (Letter to the Editor). i6. Clinical Pathological Conference, J. PEDIAT. 59: 451, 1961. 17. Shahidi, N, T., Diamond, L. K., and Schwachman, H.: Anemia associated with protein deficiency, J. PEmAT. 59: 533, 1961. 18. Fleisher, D. S., DiGeorge, A. M., Auerbach, V. H., Huang, N. N., and Barness, L. A.: Protein metabolism in cystic fibrosis of the pancreas, J. PEDIAT. 64: 349, 1964. 19. Travis, L. B., Personal commflnication. 20. Fomon, S. J., and May, C. D.: The adequacy of soya bean protein in promoting nitrogen retention in infancy, A. M, A. J. Dis. Child. 98: 6, 1959. 21_ Fomon, S~ J.: Comparative study of human milk and a soya bean formula in promoting growth and nitrogen retention by infants, Pediatrics 24: 577, 1959.