Disorders of the Exocrine Pancreas

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Chapter 341 Disorders of the Exocrine Pancreas

Steven L. Werlin

Disorders Associated with Pancreatic Insufficiency

Other than cystic fibrosis, conditions that cause pancreatic insufficiency are rare in children. They include Shwachman-Diamond syndrome, isolated enzyme deficiencies, enterokinase deficiency (Chapter 330), chronic pancreatitis, and protein-calorie malnutrition (Chapters 43 and 330).

Cystic Fibrosis (Chapter 395)

Cystic fibrosis is the most common lethal genetic disease and the most common cause of malabsorption among white American or European children. By the end of the 1st yr of life, 85-90% of children with cystic fibrosis (CF) have pancreatic insufficiency, which, if untreated, can lead to malnutrition. Treatment of the associated pancreatic insufficiency leads to improvement in absorption, better growth, and normalized stools. Pancreatic function can be monitored in children with CF with serial measurements of fecal elastase. Certain mutations in the cystic fibrosis gene have been associated with idiopathic chronic pancreatitis. CF is part of the newborn screen in every state in the United States.

Shwachman-Diamond Syndrome (Chapter 125)

Shwachman-Diamond syndrome (SDS) is an autosomal recessive syndrome (1/20,000 births) due in 90-95% of patients to a mutation of the Shwachman-Bodian-Diamond (SBDS) gene on chromosome 7 causing ribosomal dysfunction. Signs and symptoms of SDS include pancreatic insufficiency; neutropenia, which may be cyclic; neutrophil chemotaxis defects; metaphyseal dysostosis; failure to thrive; and short stature. Some patients with SDS have liver or kidney involvement, dental disease, or learning difficulty. SDS is one of the most common causes of congenital neutropenia.

Patients typically present in infancy with poor growth and greasy, foul-smelling stools that are characteristic of malabsorption. These children can be readily differentiated from those with cystic fibrosis by their normal sweat chloride levels, lack of the cystic fibrosis gene, characteristic metaphyseal lesions, and fatty pancreas characterized by a hypodense appearance on CT and MRI scans.

Despite adequate pancreatic replacement therapy and correction of malabsorption, poor growth commonly continues. Pancreatic insufficiency is often transient, and steatorrhea might spontaneously improve with age. Recurrent pyogenic infections (otitis media, pneumonia, osteomyelitis, dermatitis, sepsis) are common and are a common cause of death. Thrombocytopenia is found in 70% of patients and anemia in 50%. Development of a myelodysplastic syndrome can occur, and transformation to acute myeloid leukemia has been reported in ~3% and 24% of patients, respectively. Pathologically, the pancreatic acini are replaced by fat with little fibrosis. Islet cells and ducts are normal.

Pearson Syndrome

Pearson syndrome is caused by a mitochondrial DNA mutation affecting oxidative phosphorylation that manifests in infants with severe macrocytic anemia and variable thrombocytopenia. The bone marrow demonstrates vacuoles in erythroid and myeloid precursors as well as ringed sideroblasts. In addition to its role in severe bone marrow failure, pancreatic insufficiency contributes to growth failure. Mitochondrial DNA mutations are transmitted through maternal inheritance to both sexes or are sporadic.

Isolated Enzyme Deficiencies

Isolated deficiencies of trypsinogen, enterokinase, lipase, and colipase have been reported. Although enterokinase is a brush border enzyme, deficiency causes pancreatic insufficiency because pancreatic proteases remain inactive. Deficiencies of trypsinogen or enterokinase manifest with failure to thrive, hypoproteinemia, and edema. Isolated amylase deficiency is typically developmental and resolves by age 2-3 yr.

Syndromes Associated with Pancreatic Insufficiency

Pancreatic agenesis, the Johanson-Blizzard syndrome (pancreatic insufficiency, deafness, low birthweight, microcephaly, midline ectodermal scalp defects, psychomotor retardation, hypothyroidism, dwarfism, absent permanent teeth, and aplasia of the alae nasae), congenital pancreatic hypoplasia, and congenital rubella are rare causes of pancreatic insufficiency. Some children with both syndromic (Alagille) and nonsyndromic paucity of intrahepatic bile ducts also have pancreatic insufficiency associated with their liver disease. Pancreatic insufficiency has also been reported in duodenal atresia and stenosis and may also be seen in an infant with familial or nonfamilial hyperinsulinemic hypoglycemia, who requires 95-100% pancreatectomy to control hypoglycemia.

Bibliography

Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet. 2003;33:97-101.

Ip WF, Dupuis A, Ellis L, et al. Serum pancreatic enzymes define the pancreatic phenotype in patients with Shwachman-Diamond syndrome. J Pediatr. 2002;141:256-265.

Jacobs LJ, Jongbloed RJ, Wijburg FA, et al. Pearson syndrome and the role of deletion dimmers and duplications in the mtDNA. J Inherit Metab Dis. 2004:47-55.

Toiviainen-Salo S, Raade M, Durie PR, et al. Magnetic resonance imaging findings of the pancreas in patients with Shwachman-Diamond syndrome and mutations in the SBDS gene. J Pediatr. 2008;152:434-436.

Zenker M, Mayerle J, Lerch M, et al. Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome). Nat Genet. 2005;37:1345-1350.

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