Celiac disease in a patient with a congenital deficiency of intestinal enteropeptidase.

We report on a 40-yr-old man with both primary enteropeptidase deficiency and celiac disease. He suffered from severe intestinal malabsorption and growth failure as a child. Enteropeptidase deficiency was found and pancreatic enzyme replacement therapy resulted in a growth spurt. Enteropeptidase levels in his intestinal mucosa and intraluminal fluid remained very low throughout childhood and early adult life. Celiac disease was confirmed by characteristic abnormalities in tests of intestinal function and in mucosal biopsies, which recovered when he instituted a gluten-free diet. He remains clinically intolerant to gluten as an adult. Enteropeptidase levels have remained abnormally low whether or not his intestinal mucosa has been normal in response to gluten restriction. Enteropeptidase levels have previously been shown to be normal in untreated celiac patients. The relationship between the two disorders remains unclear.

Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis.

The clinical presentation and outcome of 32 children with primary sclerosing cholangitis (PSC) are reviewed, the largest North American series. The majority of patients were diagnosed in their second decade (median age: 13 years). Four children presented before the age of 2 years, but none in the neonatal period. Seventeen patients had inflammatory bowel disease (IBD), all with colitis, 14 ulcerative colitis, and 3 Crohn's disease. Eight patients presented with chronic liver disease before clinical onset of IBD. Only 8 of 32 patients were jaundiced at presentation. Fifteen of 32 had a normal serum alkaline phosphatase (ALP) level at presentation. Nine children presented with features similar to those of autoimmune hepatitis. Cholangiography was performed in all cases and classified by a scoring system specifically developed for pediatric patients. Intrahepatic disease predominated; in only three cases a common bile duct stricture was identified requiring stenting. Findings on the initial liver biopsy were classified according to Ludwig's criteria for staging PSC: there were 15 biopsies in stages 1 to 2 and 17 biopsies stages 3 to 4. HLA class I and II antigens were determined in 27 patients. An increased incidence of HLA B8 and DR2(15) but not DRw52a (DRB3*0101) was found. Anti-neutrophil cytoplasmic antibody (ANCA) was positive in 10 of 24 patients tested. Survival analysis indicated that a later age at presentation, splenomegaly, and prolonged prothrombin time (PT) at presentation were significant contributors to the prediction of poor outcome (i.e., death or listing for transplantation). Liver transplantation was successfully performed in seven children. Physicians must maintain a high index of suspicion of PSC in any child or young adult presenting with chronic liver disease, especially in the presence of IBD, even with a normal serum alkaline phosphatase level.

Allelic association and linkage studies in Wilson disease.

We have studied 21 families with Wilson disease (WND), using restriction fragment length polymorphisms (RFLPs) in the 13q14.3 region, to measure linkage of these markers to the disease locus. In addition to previously described markers, we include linkage data for a newly isolated marker (D13S86) and an established marker (D13S56), which were previously not placed on the genetic map in the region of the WND locus. Our data, including those from two recombinant families, support the location of WND between the markers D13S31 and D13S59. We have examined the distribution of marker alleles at the loci studied and have found that D13S31 and D13S228, and associated microsatellite marker, show a non-random distribution on chromosomes carrying the WND mutation. The significant linkage disequilibrium indicates that these two markers must be close to the WND locus.

Atypical features of the hepatic form of carnitine palmitoyltransferase deficiency in a Hutterite family.

We describe hepatic carnitine palmitoyltransferase (CPT I) deficiency in three children (a brother and sister and their second cousin) from an extended inbred Hutterite kindred. The patients were first seen between 8 and 18 months of age with recurrent episodes of hypoketotic hypoglycemia accompanied by a decreased level of consciousness and hepatomegaly. One patient had two Reye syndrome-like episodes. Abnormal organic acids were rarely detected in urine. Serum total and free carnitine levels were elevated in all three patients. Fibroblast acyl-coenzyme A dehydrogenase activities were normal in all, but palmitic acid oxidation, performed in fibroblasts from one patient, was less than 10% of control values. Activity of CPT I in cultured skin fibroblasts from the three patients was 10% to 15% of control levels; CPT II activity was normal. Activity of CPT I and CPT II in muscle from one patient was normal. Atypical features in two of these patients were greatly elevated levels of liver enzymes and creatine kinase during acute episodes. The patients have recently been successfully treated with medium-chain triglycerides and avoidance of fasting. Early identification and treatment of this disorder may avert potentially fatal episodes of hypoglycemia.

Floating-Harbor syndrome and celiac disease.

We report on a 17-year-old young woman with a speech impediment, developmental delay, short stature, and facial anomalies consistent with the Floating-Harbor syndrome (FHS). In addition, she has clinical and histological evidence of celiac disease, which was observed in 1 of the 6 previously reported cases of FHS, suggesting a possible association between the 2 conditions or pleiotropism of a presumed autosomal recessive disorder.

Pediatric Crohn's disease.

This paper reviews our 10 year clinical experience (1974 to 1983) with 33 patients with Crohn's disease; eight were diagnosed during the first five years and 25 during the second five years of the review. There were only 10 patients with ulcerative colitis during this period. The median age of diagnosis was 13 years, range 6 to 16 years. The main presenting clinical features were abdominal pain (29 patients), weight loss (26 patients), and diarrhea (23 patients). The method of diagnosis included radiological investigations and fiberoptic endoscopy with biopsy. The colon was involved in 20 patients. The therapy included Salazopyrine, steroids, parenteral nutrition (11 patients) including home parenteral nutrition (seven patients) and surgery (13 patients). Significant weight gain was observed in patients after intestinal resection. There were no deaths. We conclude that the incidence of pediatric Crohn's disease appears to be increasing, is more common than ulcerative colitis, and requires surgical treatment in a high proportion of patients. In our experience these patients respond well to aggressive nutritional therapy including home parenteral nutrition and carefully selected surgical treatment.

Systemic histiocytosis: an unusual cause of perianal disease in a child.

A male child first presented with chronic perianal skin disease at 33 months of age and later developed gingival disease and loose teeth associated with alveolar bone erosion. Biopsy of gingival and perianal lesions showed histiocytic proliferation. Following therapy with vinblastine, prednisone, methotrexate, and cyclophosphamide, the lesions healed but disease recurred in the mastoid and was successfully treated with vinblastine alone. Although the perianal area is an unusual site of skin involvement in systemic histiocytosis, this disorder should be considered in any child with chronic unexplained perianal disease, and biopsy of these lesions should be obtained.

Symposium on the treatment of inflammatory bowel disease in children and adolescents. Medical management.

Children and adolescents with inflammatory bowel disease experience problems that their adult counterparts do not share. Although there are some similarities, the goals of therapy are different. The general medical management of these patients consists of stabilization in the acute phase and control of the disease to allow the patient to grow and lead as normal a life as possible in the chronic phase. Nutritional therapy is a very important aspect of this management, but drugs such as steroids and sulfasalazine and, under special circumstances, other medications are useful adjuncts. Supportive psychotherapy is also important.

Relationship between lower esophageal sphincter pressure and serum gastrin concentration in the newborn infant.

We measured lower esophageal sphincter pressure in 22 healthy unsedated term neonates (mean age 8.25 hours) with a double-lumen tube, continuously perfused manometric system. Studies were repeated in 18 infants on day 4. Serum gastrin concentration was measured with 34 studies and in 22 adult controls. Mean (+/- SD) LESP and serum gastrin concentration, respectively, were 41.9 mm Hg (+/- 10.9) and 142.6 pg/ml (+/- 56.0) on day 1 and 39.1 mm Hg (+/- 11.5) and 144.9 pg/ml (+/- 54.5) on day 4. LESP did not correlate with age on day 1 or with serum gastrin concentration on either day 1 or 4. Serum gastrin concentration in the adult controls (98.9 pg/ml +/- 35.4) was significantly higher than that of the neonates. We conclude that LESP is well developed in the healthy term neonate. Although neonatal serum gastrin concentrations are higher than in the adult, they do not correlate with LESP, and endogenous gastrin probably plays no role in the maintenance of basal LESP in the newborn infant.

Lower esophageal sphincter function in children with and without gastroesophageal reflux.

Resting lower esophageal sphincter (LES) pressure was assessed in infants and children 2 weeks to 12 years of age. There were 62 control subjects and 35 patients with reproducible gastroesophageal reflux (GER) determined radiologically. In control subjects without GER: (1) LES pressure was well developed by 2 weeks of age; (2) in children less than 1 year of age, mean LES pressure (43.3 +/- 2.4 mm Hg) was significantly greater than mean LES pressure (30.6 +/- 2.3 mm Hg) children older than 1 year of age; (3) LES sphincter length increased with age; and (4) bethanechol 0.1 mg per kg subcutaneously caused a rise in LES pressure that increased in magnitude as LES resting pressures increased. In patients with GER: (1) only 16 or 35 children had LES pressures below the normal range for their appropriate age group; (2) LES length was shorter than control values in children beyond 6 months of age; (3) GER usually occurred in the absence of hiatus hernia; (4) clinical improvement was common and in patients with low LES pressure was associated with a rise in LES pressures to normal, even in the presenece of hiatus hernia; and (5) bethanechol caused a change and an absolute rise in LES pressure that were not significantly different from those observed in controls. These results indicate that in infants and children low LES pressure is not the sole determinant of GER, and that pharmacological stimulation of the Les could prove to be a useful adjunct to the medical management of GER.

Membranoproliferative glomerulonephritis in childhood cirrhosis associated with alpha1-antitrypsin deficiency.

Three alpha1-antitrypsin (alpha1AT) deficient, protease inhibitor type ZZ children who died from cirrhosis and its complications had membranoproliferative glomerulonephritis at postmortem examination. During life, all three had clinical and laboratory evidence of renal disease which became apparent when hepatic decompensation developed. Immunofluorescence studies and electron microscopy performed in one patient revealed subendothelial deposits of alpha1AT, complement, and immune globulins along the glomerular basement membrane. The pathogenesis of these renal lesions is speculative. Glomerular lesions were not observed in kidney sections of 16 children who died from cirrhosis but who were not alpha1AT-deficient. The present study suggests that renal involvement may be yet another manifestation of disease associated with alpha1AT deficiency.

Liver disease associated with alpha1-antitrypsin deficiency in childhood.

Liver disease in children with alpha1-antitrypsin deficiency and protease inhibitor type ZZ does not necessarily carry a bad prognosis. Fourteen of our 18 patients presented with the neonatal hepatitis syndrome and four had hepatomegaly without jaundice. Although four patients have died of cirrhosis and its complications, and three have severe liver disease, most of the 11 others, of whom four are over 13 years of age, have relatively little clinical, biochemical, or histologic evidence of liver disease. Persistent elevation of SGOT during the third year of life and renal or pulmonary problems were associated with a poor prognosis. Liver biopsy early in the course of the disease was not helpful prognostically but was useful in assessment of the severity of liver disease and demonstration of alpha1AT storage, alpha1AT deficiency was found in 29% of our patients who presented with the neonatal hepatitis syndrome. One of seven apparently healthy Pi type ZZ sibs of our patients had significant liver disease which had not been suspected previously.