Volume 87 Number 2
Brief clinical and laboratory observations
Pancreatic insufficiency and the congenital rubella syndrome Mark Donowitz, M.D., and J o y c e D. Gryboski, M.D.,*
New Haven, Conn.
A L T H O U G H ACUTE PANCREATIC DISEASE has b e e n associated with such viral infections as infectious m o n o nucleosis, infectious hepatitis, Coxsackie B infection, a n d mumps, 1'~ it is u n c e r t a i n w h e t h e r viral infections c a n cause chronic pancreatic disease in m a n . I n d i r e c t evidence suggesting such a n association is p r o v i d e d b y the occurrence of diabetes mellitus within days to weeks after m u m p s a n d within several years after Coxsackie B or rubella infections. 3-6 A l t h o u g h the r u b e l l a virus has b e e n isolated from pancreatic tissue o f infants with the congenital rubella syndrome, interstitial pancreatitis has b e e n described in only one i n f a n t a n d n o n e has h a d clinically d o c u m e n t e d acute or chronic pancreatitis. 7, 8 It is therefore the purpose o f this report to describe a n i n f a n t with congenital rubella w h o h a d b o t h clinical a n d l a b o r a t o r y d o c u m e n t a t i o n o f chronic p a n c r e a t i c insufficiency.
CASE REPORT Patient P. S., a white male, was born November 18, 1964 after a 40-week gestation. His mother was exposed to rubella late in the first trimester of the pregnancy and was treated with gamma globulin. Several weeks later one of her children developed rubella and she herself experienced myalgia but had no exanthem. The infant's birth weight was 2,895 gm (tenth percentile); length, 48.2 cm (tenth percentile), head circumference, 32.8 cm (less than third percentile), and Apgar score, 8. Rubella virus was isolated from a throat culture taken at delivery, but complement fixation and indirect neutralization tests in green monkey kidney wire negative. He had a partial cleft palate and developed hyperbilirubinemia to 23 mg/dl on the third day of life. The jaundice subsided gradually and he seemed well until 3 weeks of age when he developed greasy, foul-smelling stools, vomiting, and pain after feedings. Viral studies during the first three weeks of life on two occasions were positive for rubella virus in throat cultures though serum titers were negative. By 12 weeks he was extremely malnourished and was admitted to the hospital.
From the Department of Pediatrics, Yale University School of Medicine. Supported by a grant from the National Institutes of Health, RR0012510. *Reprint address: Department of Pediatrics, Yale University School of Medicine, 333 Cedar St., New Haven, Conn. 06510.
24 1
He appeared markedly emaciated with loss of subcutaneous tissue and wasting of musculature. The abdomen was scaphoid, bowel sounds were hyperactive, the liver was palpable 2 cm below the right costal margin, and all measurements were below the third percentile for age. Labol"atory data included a normal hematocrit value and hemoglobin concentration and a white blood cell count of 8,100/ mm 8 with 31% polymorphonuclear cells, 49% lymphocytes, and 17% monocytes. The stools contained no ova, parasites, bacterial pathogens, or trypsin on three occasions. Measurements of concentrations of serum electrolytes, proteins, immunoglobulins, fasting blood sugar, and measurements of renal, hepatic, and thyroid function were normal. The serum carotene concentration was 78 /~g/dl and an oral xylose absorption test showed 3.5% excretion of the sugar. Stool PH determinations ranged from 5.5 to 6.5, but mono- and disaccharide tolerance tests were normal. Concentrations of sweat electrolytes (CI-) measured 18 and 21 mEq/1. A 72-hour stool collection contained 1.9 gm fat/24 hours (83% absorption of ingested fat). Radiologic examinations of the gastrointestinal and urinary tracts were normal. A jejunal biopsy showed normal morphology and the duodenal fluid contained no lipase or trypsin and less than 20 units of amylase. He remained irritable and failed to gain wright while taking 120 cal/kg of Enfamil and later of Nutramigen. At 16 weeks he was given pancreatic enzyme supplementation as Cotazym and within two weeks his stools appeared normal and he gained 500 gm. Vomiting decreased and the quantitative determinations of stool fat decreased to 0.5 gm/24 hours and fat absorption increased to 98%. By one year body measurements reached the tenth percentile and by 18 months, the twenty-fifth percentile for his age. He remained well except for episodes of diarrhea whenever pancreatic enzymes were omitted or if he had an intercurrent respiratory infection. At 35 months he was readmitted for evaluation of pancreatic function and for a new complaint, epigastric pain. Radiologic studies remained normal and measurements of urinary and serum enzymes were normal except for one occasion when the sert~m lipase concentration was 1.9 ~/ml. Secretin stimulation of pancreatic enzymes resulted in a normal amylase response (1,100 i~/kg/50 min) but the lipase (4.6/~/kg/50 min), bicarbonate (0.3 mEq/kg/50 min), and volume (1.09 ml/kg/50 min) responses were depressed. By 87 months the pancreatic response to secretin stimulation was essentially unchanged except for an increase in lipase to 40/z/ kg/50 min. Enzyme therapy was gradually decreased over the next year and fat absorption remained normal without necessitating supplementation. At 10 years of age he remains in the twenty-fifth percentiles for height and weight and has an IQ of 90. He complains only occasionally of abdominal pain. Glucose tolerance tests stool fat concentrations, serum and urinary amylase, and serum lipase values remain normal. Studies of T and B cell lymphocyte functions are normal. DISCUSSION A l t h o u g h histologic changes are described for the heart, eye, liver s kidney, a n d bone, pathologic changes in the pancreas are usually n o t i n c l u d e d in surveys o f c o n g e n i t a l
242
Brief clinical and laboratory observations
rubella lesions. Chronic interstitial pancreatitis with extensive lymphocytic infiltration of both interstitial and periglandular tissue has been reported in only one infant who died of pneumonia and heart failure at 3 months of age? The development of diabetes or d!abetic-type glucose tolerance curves in 20% of older patients with congenital rubella certainly indicates that the virus affects islet cell function? Until more data are available, however, we can only speculate about the pathogenesis of the disease in our patient. Experimentally, acute pancreatic necrosis has followed picornavirus infection in the animal model, and pancreatic insufficiency has followed Coxsackie infection in adult mice. 9 It is known that the rubella virus causes both decreased cell formation and increased cell destruction in affected organs. Furthermore, incubation of the virus with fibroblasts in tissue culture leads to an inhibition of mitosis which appears to be mediated through a protein, the "rubella virus-inhibiting protein," which is released into the medium by the virus. 1~ The early impairment of enzyme as well as bicarbonate and volume response in our patient suggests involvement of both acinar and ductular cells. Since intrauterine viral infections are now implicated as etiologic agents in causing biliary atresia, such agents may work similarly to affect the pancreatic ducts and give rise to both cellular dysfunction and repeated bouts of pancreatitis. Such an hypothesis would then explain the development Of recurrent bouts of abdominal pain in the symptom-complex of rubella "pancreatic insufficiency." There is no doubt that this infant had congenital rubella because he was one of a group first reported by Horstman and associates11 in the 1965 rubella symposium. The disease was documented by a positive history of maternal exposure to the virus, recovery of the virus at birth and again during the first few weeks of life, cleft palate, and microcephaly. Neonatal hyperbilirubinemia may well have represented neonatal hepatitis, but laboratory measurements of liver function were not obtained. Failure-tothrive and malabsorption were present from the early neonatal period and the diagnosis of pancreatic insufficiency was confirmed by the absence of stool trypsin, impaired absorption of fat, an abnormal pancreatic response to secretin, TM and by the correction of malabsorption and growth failure by exogenous pancreatic enzymes. The persistence of pancreatic malfunction for years beyond the period of early malnutrition indicates that the lesion was n o t secondary to protein-calorie malnutrition. The absence of an antibody response as reflected in persistently negative serologic titers to rubella virus is somewhat unusual but other patients are reported who have not developed an increase in serum antibody titer
The Journal of Pediatrics August 1975
after infection or immunization. Unfortunately, hemagglutination-inhibition titers were not available in our laboratories until 1967. We have recently seen one infant with rubella and negative serum hemagglutination inhibition titers who infected a young nurse who was caring for him. One may postulate impaired immunologic responsiveness or an unavailability of free antibody because of binding within the system to account for the lack of response. The partial recovery of enzyme function which occurred in our patient has also been described in a number of patients with Shwachman syndrome, which consists of pancreatic insufficiency, bone marrow dysfunction, elevation of fetal hemoglobin concentration, and inconstant galactosuria. 1~ Glucose metabolism is usually normal during childhood but a few patients do develop diabetes during adolesence. Although many features of this syndrome were not present in our patient, and neutropenia was never observed, his disease does have many similarities to it: symptoms were present in early infancy, growth retardation was severe, clinical diabetes was not obvious, and oral glucose tolerance tests were normal. Pancreatic lesions in children who died of the Shwachman syndrome consisted of atrophy of exocrine tissue and replacement of the parenchyma by fat. Since similar changes were observed in children and experimental aninlals who died of generalized Coxsackie virus infection, the authors considered viral infection as one of the possible causes of the syndrome. It is of interest that two patients with Shwachman syndrome who are followed at the Yale New Haven Clinic were born in the fail of 1964, the year of a severe rubella epidemic. It seems probabl e that intrauterine infection by the rubella virus may be another cause of pancreatic insufficiency in infancy. Agressive treatment in this patient was followed by fhe gradual development of adequate pancreatic enzyme levels, although water and bicarbonate secretion remained impaired. REFERENCES
1. Ursing B: Acute pancreatitis in Coxsackie B infections, Br Med J 3:524, 1973. 2. Achord JL: Acute pancreatitis with infectious hepatitis, JAMA 205:837, 1968. 3. Daceau-Voutetaskis C, Constantinidis M, Moschos A, et al: Diabetes mellitus following mumps, Am J Dis Child 127:890, 1973. 4. Gamble CRy. Taylor KW, and Cumming H: Coxsackie viruses and diabetes, Br Med J 4:260, 1973. 5. Forrest JM, Menser M, and Burgess JA: High frequency of diabetes mellitus in young adults with congenital rubella, Lancet 2:332, 1971. 6. Johnson GM, Tudor RB, and Bismarck ND: Diabetes mellitus and congenital rubella infection, Am J Dis Child 120:453, 1970.
Volume 87 Number 2
B r i e f clinical a n d laboratory observations
7. Monif GRC, Avery GB, Korones SB, et al: Post-mortem isolation of rubella virus from three children with rubella syndrome defects, Lancet 1:723, 1965. 8. Bunnell CB, and MonifGRC: Interstitial paucreatitis in the congenital rubella syndrome, J PEDIATR 80:465, 1972. 9. Pappenheimer AM, Kunz LJ, and Richardson S: Passage of Coxsackie virus (Connecticut-5 strain) in adult mice with production of pancreatic disease, J Exp Med 94:45, 1951. 10. Plotkin SA, and Vaheri A: Human fibroblasts infected with rubella virus produce a growth inhibitor, Science 154:659, 1967.
Infantile achalasia I n h e r i t e d as an a u t o s o m a l recessive disorder C. Ross Westley, M.D.,* John J. Herbst, M.D., Stanford Goldman, M.D., and Wilmer C. Wiser, Ph.D., Phoenix, Ariz., a n d Salt L a k e City, Utah
A C H A L A S I A in c h i l d h o o d is rare; c h i l d r e n u n d e r 14 years of age constitute only 4-5% o f r e c o r d e d cases? A s y n d r o m e o f familial a u t o s o m a l recessive deafness associated with short stature, vitiligo, muscle wasting, a n d achalasia has b e e n describedY In addition, only four reports o f achalasia in siblings were f o u n d in the world literature? -6 W e present six cases o f achalasia with symptoms starting in infancy in three sibships o f a n A p a c h e I n d i a n kindred. CASE REPORTS The following case summaries are from three related Apache Indian sibships (Fig. 1). Case 1 0/-8). Since birth this Apache boy (S. N.) had frequent vomiting, coughing, and recurrent pulmonary infections which caused death in early infancy. His symptoms were similar to those of younger affected siblings; he probably had unrecognized congenital achalasia. Case 2 0/-11). This 16-year-old boy (D. N.) is the oldest of the three living siblings with congenital achalasia. The onset of recurrent emesis and aspiration pneumonia occurred in the first weeks of life. At 9 months of age an esophagram revealed From the United States Public Health Service, Phoenix, and Department o f Pediatrics University o f Utah College of Medicine. *Reprint address: Public Health Service lndian Medical Center, 4212 North Sixteenth St., Phoenix, Ariz. 85016.
243
11. Horstman D, Banatvala JE, Riordan J, Payne M, Whittemore R, Opton E, and duVeFloray C: Maternal rubella and the rubella syndrome, Am J Dis Child 110:428, 1965. 12. Hadorn B, Zoppi G, Shmerling DH, et al: Quantitative assessment of exocrine pancreatic function in infants and children J P~DIATR 73:39, 1968. 13. Shwachman H, Diamond LK, Oski F, et al: The syndrome of pancreatic insufficiency and bone marrow dysfunction, J PEDIATR65:645, 1964.
classical findings of achalasia (Fig. 2, A). Over the next 15 years a Wendel esophagoplasty (longitudinal incision of all layers of the esophagus with transverse closure) followed by intermittent bougienage, a Heller procedure (longitudinal incision of the esophageal musculature at the cardioesophageal junction), and finally a colonic interposition was performed because of severe reflux esophagitis and stricture formation. At present he is doing well. Case 3 0/-12). This 14-year-old boy (G. N.) had failure to thrive and persistent emesis at 3 months of age. At that time only distal narrowing of the esophagus was noted on barium swallow. Intermittent bougienage was instituted without relief of symptoms. At 15 months of age repeat examination by barium swallow showed dilatation of the proximal esophagus as well as persistent narrowing of the cardioesophageal junction (Fig. 2, B). A Wendel esophagoplasty was performed. At present there are no pulmonary symptoms, but he does have occasional postprandial nausea and regurgitation. Case 4 0/-13). This 5-year-old boy (L. N.) has had feeding difficulties since birth associated with recurrent pneumonia and frequent emesis of uncurdled milk. At 18 months, a cineesophagogram showed normal deglutition and normal esophageal size, but abnormal esophageal peristalsis. Symptoms persisted until age 3 when classical findings of achalasia were noted on barium swallow. A Heller procedure was performed, and a biopsy of the distal esophagus revealed normal ganglion cells. At present the height and weight are normal, and a barium swallow showed adequate esophageal emptying with occasional gastroesophageal reflux. Case 5 0/-2). This 14-year-old boy (R. T.) is both a maternal and a paternal second cousin to the above described patients (Cases 1 to 4). He has had frequent emesis and recurrent aspiration pneumonia since he was 3 months of age. Classical roentgenographic findings of achalasia were noted at 21A years of age, and a Wendel esophagoplasty was performed. He is presently free of symptoms. Case 6 0/-14). This 3-year-old female (L. G.) had occasional emesis from birth, which increased in severity by one month of age. She had aspiration pneumonia at 6 month s of age; at this time a barium swallow showed the classical signs of achalasia. A Heller myotomy was performed; subsequently she has been symptom-free.
Brief clinical and laboratory observations
Pancreatic insufficiency and the congenital rubella syndrome Mark Donowitz, M.D., and J o y c e D. Gryboski, M.D.,*
New Haven, Conn.
A L T H O U G H ACUTE PANCREATIC DISEASE has b e e n associated with such viral infections as infectious m o n o nucleosis, infectious hepatitis, Coxsackie B infection, a n d mumps, 1'~ it is u n c e r t a i n w h e t h e r viral infections c a n cause chronic pancreatic disease in m a n . I n d i r e c t evidence suggesting such a n association is p r o v i d e d b y the occurrence of diabetes mellitus within days to weeks after m u m p s a n d within several years after Coxsackie B or rubella infections. 3-6 A l t h o u g h the r u b e l l a virus has b e e n isolated from pancreatic tissue o f infants with the congenital rubella syndrome, interstitial pancreatitis has b e e n described in only one i n f a n t a n d n o n e has h a d clinically d o c u m e n t e d acute or chronic pancreatitis. 7, 8 It is therefore the purpose o f this report to describe a n i n f a n t with congenital rubella w h o h a d b o t h clinical a n d l a b o r a t o r y d o c u m e n t a t i o n o f chronic p a n c r e a t i c insufficiency.
CASE REPORT Patient P. S., a white male, was born November 18, 1964 after a 40-week gestation. His mother was exposed to rubella late in the first trimester of the pregnancy and was treated with gamma globulin. Several weeks later one of her children developed rubella and she herself experienced myalgia but had no exanthem. The infant's birth weight was 2,895 gm (tenth percentile); length, 48.2 cm (tenth percentile), head circumference, 32.8 cm (less than third percentile), and Apgar score, 8. Rubella virus was isolated from a throat culture taken at delivery, but complement fixation and indirect neutralization tests in green monkey kidney wire negative. He had a partial cleft palate and developed hyperbilirubinemia to 23 mg/dl on the third day of life. The jaundice subsided gradually and he seemed well until 3 weeks of age when he developed greasy, foul-smelling stools, vomiting, and pain after feedings. Viral studies during the first three weeks of life on two occasions were positive for rubella virus in throat cultures though serum titers were negative. By 12 weeks he was extremely malnourished and was admitted to the hospital.
From the Department of Pediatrics, Yale University School of Medicine. Supported by a grant from the National Institutes of Health, RR0012510. *Reprint address: Department of Pediatrics, Yale University School of Medicine, 333 Cedar St., New Haven, Conn. 06510.
24 1
He appeared markedly emaciated with loss of subcutaneous tissue and wasting of musculature. The abdomen was scaphoid, bowel sounds were hyperactive, the liver was palpable 2 cm below the right costal margin, and all measurements were below the third percentile for age. Labol"atory data included a normal hematocrit value and hemoglobin concentration and a white blood cell count of 8,100/ mm 8 with 31% polymorphonuclear cells, 49% lymphocytes, and 17% monocytes. The stools contained no ova, parasites, bacterial pathogens, or trypsin on three occasions. Measurements of concentrations of serum electrolytes, proteins, immunoglobulins, fasting blood sugar, and measurements of renal, hepatic, and thyroid function were normal. The serum carotene concentration was 78 /~g/dl and an oral xylose absorption test showed 3.5% excretion of the sugar. Stool PH determinations ranged from 5.5 to 6.5, but mono- and disaccharide tolerance tests were normal. Concentrations of sweat electrolytes (CI-) measured 18 and 21 mEq/1. A 72-hour stool collection contained 1.9 gm fat/24 hours (83% absorption of ingested fat). Radiologic examinations of the gastrointestinal and urinary tracts were normal. A jejunal biopsy showed normal morphology and the duodenal fluid contained no lipase or trypsin and less than 20 units of amylase. He remained irritable and failed to gain wright while taking 120 cal/kg of Enfamil and later of Nutramigen. At 16 weeks he was given pancreatic enzyme supplementation as Cotazym and within two weeks his stools appeared normal and he gained 500 gm. Vomiting decreased and the quantitative determinations of stool fat decreased to 0.5 gm/24 hours and fat absorption increased to 98%. By one year body measurements reached the tenth percentile and by 18 months, the twenty-fifth percentile for his age. He remained well except for episodes of diarrhea whenever pancreatic enzymes were omitted or if he had an intercurrent respiratory infection. At 35 months he was readmitted for evaluation of pancreatic function and for a new complaint, epigastric pain. Radiologic studies remained normal and measurements of urinary and serum enzymes were normal except for one occasion when the sert~m lipase concentration was 1.9 ~/ml. Secretin stimulation of pancreatic enzymes resulted in a normal amylase response (1,100 i~/kg/50 min) but the lipase (4.6/~/kg/50 min), bicarbonate (0.3 mEq/kg/50 min), and volume (1.09 ml/kg/50 min) responses were depressed. By 87 months the pancreatic response to secretin stimulation was essentially unchanged except for an increase in lipase to 40/z/ kg/50 min. Enzyme therapy was gradually decreased over the next year and fat absorption remained normal without necessitating supplementation. At 10 years of age he remains in the twenty-fifth percentiles for height and weight and has an IQ of 90. He complains only occasionally of abdominal pain. Glucose tolerance tests stool fat concentrations, serum and urinary amylase, and serum lipase values remain normal. Studies of T and B cell lymphocyte functions are normal. DISCUSSION A l t h o u g h histologic changes are described for the heart, eye, liver s kidney, a n d bone, pathologic changes in the pancreas are usually n o t i n c l u d e d in surveys o f c o n g e n i t a l
242
Brief clinical and laboratory observations
rubella lesions. Chronic interstitial pancreatitis with extensive lymphocytic infiltration of both interstitial and periglandular tissue has been reported in only one infant who died of pneumonia and heart failure at 3 months of age? The development of diabetes or d!abetic-type glucose tolerance curves in 20% of older patients with congenital rubella certainly indicates that the virus affects islet cell function? Until more data are available, however, we can only speculate about the pathogenesis of the disease in our patient. Experimentally, acute pancreatic necrosis has followed picornavirus infection in the animal model, and pancreatic insufficiency has followed Coxsackie infection in adult mice. 9 It is known that the rubella virus causes both decreased cell formation and increased cell destruction in affected organs. Furthermore, incubation of the virus with fibroblasts in tissue culture leads to an inhibition of mitosis which appears to be mediated through a protein, the "rubella virus-inhibiting protein," which is released into the medium by the virus. 1~ The early impairment of enzyme as well as bicarbonate and volume response in our patient suggests involvement of both acinar and ductular cells. Since intrauterine viral infections are now implicated as etiologic agents in causing biliary atresia, such agents may work similarly to affect the pancreatic ducts and give rise to both cellular dysfunction and repeated bouts of pancreatitis. Such an hypothesis would then explain the development Of recurrent bouts of abdominal pain in the symptom-complex of rubella "pancreatic insufficiency." There is no doubt that this infant had congenital rubella because he was one of a group first reported by Horstman and associates11 in the 1965 rubella symposium. The disease was documented by a positive history of maternal exposure to the virus, recovery of the virus at birth and again during the first few weeks of life, cleft palate, and microcephaly. Neonatal hyperbilirubinemia may well have represented neonatal hepatitis, but laboratory measurements of liver function were not obtained. Failure-tothrive and malabsorption were present from the early neonatal period and the diagnosis of pancreatic insufficiency was confirmed by the absence of stool trypsin, impaired absorption of fat, an abnormal pancreatic response to secretin, TM and by the correction of malabsorption and growth failure by exogenous pancreatic enzymes. The persistence of pancreatic malfunction for years beyond the period of early malnutrition indicates that the lesion was n o t secondary to protein-calorie malnutrition. The absence of an antibody response as reflected in persistently negative serologic titers to rubella virus is somewhat unusual but other patients are reported who have not developed an increase in serum antibody titer
The Journal of Pediatrics August 1975
after infection or immunization. Unfortunately, hemagglutination-inhibition titers were not available in our laboratories until 1967. We have recently seen one infant with rubella and negative serum hemagglutination inhibition titers who infected a young nurse who was caring for him. One may postulate impaired immunologic responsiveness or an unavailability of free antibody because of binding within the system to account for the lack of response. The partial recovery of enzyme function which occurred in our patient has also been described in a number of patients with Shwachman syndrome, which consists of pancreatic insufficiency, bone marrow dysfunction, elevation of fetal hemoglobin concentration, and inconstant galactosuria. 1~ Glucose metabolism is usually normal during childhood but a few patients do develop diabetes during adolesence. Although many features of this syndrome were not present in our patient, and neutropenia was never observed, his disease does have many similarities to it: symptoms were present in early infancy, growth retardation was severe, clinical diabetes was not obvious, and oral glucose tolerance tests were normal. Pancreatic lesions in children who died of the Shwachman syndrome consisted of atrophy of exocrine tissue and replacement of the parenchyma by fat. Since similar changes were observed in children and experimental aninlals who died of generalized Coxsackie virus infection, the authors considered viral infection as one of the possible causes of the syndrome. It is of interest that two patients with Shwachman syndrome who are followed at the Yale New Haven Clinic were born in the fail of 1964, the year of a severe rubella epidemic. It seems probabl e that intrauterine infection by the rubella virus may be another cause of pancreatic insufficiency in infancy. Agressive treatment in this patient was followed by fhe gradual development of adequate pancreatic enzyme levels, although water and bicarbonate secretion remained impaired. REFERENCES
1. Ursing B: Acute pancreatitis in Coxsackie B infections, Br Med J 3:524, 1973. 2. Achord JL: Acute pancreatitis with infectious hepatitis, JAMA 205:837, 1968. 3. Daceau-Voutetaskis C, Constantinidis M, Moschos A, et al: Diabetes mellitus following mumps, Am J Dis Child 127:890, 1973. 4. Gamble CRy. Taylor KW, and Cumming H: Coxsackie viruses and diabetes, Br Med J 4:260, 1973. 5. Forrest JM, Menser M, and Burgess JA: High frequency of diabetes mellitus in young adults with congenital rubella, Lancet 2:332, 1971. 6. Johnson GM, Tudor RB, and Bismarck ND: Diabetes mellitus and congenital rubella infection, Am J Dis Child 120:453, 1970.
Volume 87 Number 2
B r i e f clinical a n d laboratory observations
7. Monif GRC, Avery GB, Korones SB, et al: Post-mortem isolation of rubella virus from three children with rubella syndrome defects, Lancet 1:723, 1965. 8. Bunnell CB, and MonifGRC: Interstitial paucreatitis in the congenital rubella syndrome, J PEDIATR 80:465, 1972. 9. Pappenheimer AM, Kunz LJ, and Richardson S: Passage of Coxsackie virus (Connecticut-5 strain) in adult mice with production of pancreatic disease, J Exp Med 94:45, 1951. 10. Plotkin SA, and Vaheri A: Human fibroblasts infected with rubella virus produce a growth inhibitor, Science 154:659, 1967.
Infantile achalasia I n h e r i t e d as an a u t o s o m a l recessive disorder C. Ross Westley, M.D.,* John J. Herbst, M.D., Stanford Goldman, M.D., and Wilmer C. Wiser, Ph.D., Phoenix, Ariz., a n d Salt L a k e City, Utah
A C H A L A S I A in c h i l d h o o d is rare; c h i l d r e n u n d e r 14 years of age constitute only 4-5% o f r e c o r d e d cases? A s y n d r o m e o f familial a u t o s o m a l recessive deafness associated with short stature, vitiligo, muscle wasting, a n d achalasia has b e e n describedY In addition, only four reports o f achalasia in siblings were f o u n d in the world literature? -6 W e present six cases o f achalasia with symptoms starting in infancy in three sibships o f a n A p a c h e I n d i a n kindred. CASE REPORTS The following case summaries are from three related Apache Indian sibships (Fig. 1). Case 1 0/-8). Since birth this Apache boy (S. N.) had frequent vomiting, coughing, and recurrent pulmonary infections which caused death in early infancy. His symptoms were similar to those of younger affected siblings; he probably had unrecognized congenital achalasia. Case 2 0/-11). This 16-year-old boy (D. N.) is the oldest of the three living siblings with congenital achalasia. The onset of recurrent emesis and aspiration pneumonia occurred in the first weeks of life. At 9 months of age an esophagram revealed From the United States Public Health Service, Phoenix, and Department o f Pediatrics University o f Utah College of Medicine. *Reprint address: Public Health Service lndian Medical Center, 4212 North Sixteenth St., Phoenix, Ariz. 85016.
243
11. Horstman D, Banatvala JE, Riordan J, Payne M, Whittemore R, Opton E, and duVeFloray C: Maternal rubella and the rubella syndrome, Am J Dis Child 110:428, 1965. 12. Hadorn B, Zoppi G, Shmerling DH, et al: Quantitative assessment of exocrine pancreatic function in infants and children J P~DIATR 73:39, 1968. 13. Shwachman H, Diamond LK, Oski F, et al: The syndrome of pancreatic insufficiency and bone marrow dysfunction, J PEDIATR65:645, 1964.
classical findings of achalasia (Fig. 2, A). Over the next 15 years a Wendel esophagoplasty (longitudinal incision of all layers of the esophagus with transverse closure) followed by intermittent bougienage, a Heller procedure (longitudinal incision of the esophageal musculature at the cardioesophageal junction), and finally a colonic interposition was performed because of severe reflux esophagitis and stricture formation. At present he is doing well. Case 3 0/-12). This 14-year-old boy (G. N.) had failure to thrive and persistent emesis at 3 months of age. At that time only distal narrowing of the esophagus was noted on barium swallow. Intermittent bougienage was instituted without relief of symptoms. At 15 months of age repeat examination by barium swallow showed dilatation of the proximal esophagus as well as persistent narrowing of the cardioesophageal junction (Fig. 2, B). A Wendel esophagoplasty was performed. At present there are no pulmonary symptoms, but he does have occasional postprandial nausea and regurgitation. Case 4 0/-13). This 5-year-old boy (L. N.) has had feeding difficulties since birth associated with recurrent pneumonia and frequent emesis of uncurdled milk. At 18 months, a cineesophagogram showed normal deglutition and normal esophageal size, but abnormal esophageal peristalsis. Symptoms persisted until age 3 when classical findings of achalasia were noted on barium swallow. A Heller procedure was performed, and a biopsy of the distal esophagus revealed normal ganglion cells. At present the height and weight are normal, and a barium swallow showed adequate esophageal emptying with occasional gastroesophageal reflux. Case 5 0/-2). This 14-year-old boy (R. T.) is both a maternal and a paternal second cousin to the above described patients (Cases 1 to 4). He has had frequent emesis and recurrent aspiration pneumonia since he was 3 months of age. Classical roentgenographic findings of achalasia were noted at 21A years of age, and a Wendel esophagoplasty was performed. He is presently free of symptoms. Case 6 0/-14). This 3-year-old female (L. G.) had occasional emesis from birth, which increased in severity by one month of age. She had aspiration pneumonia at 6 month s of age; at this time a barium swallow showed the classical signs of achalasia. A Heller myotomy was performed; subsequently she has been symptom-free.
