An 11-Month-Old Boy With Chronic Diarrhea, Failure to Thrive, and Hepatomegaly

Steven Liu, MD; Jonathan E. Markowitz, MD, MSCE; Petar Mamula, MDSeries Editors: David A. Piccoli, MD; Petar Mamula, MD


September 12, 2007


Shwachman-Diamond syndrome is a rare autosomal recessive disorder characterized by exocrine pancreatic dysfunction, bone marrow failure, and skeletal abnormalities. It has also been known as "Shwachman syndrome," "Shwachman-Bodian syndrome," and "congenital lipomatosis of the pancreas." This disorder was described by Shwachman, Diamond, Oski, and Knaw in 1964 in 5 children showing evidence of exocrine pancreatic insufficiency and leukopenia, and was described a few months afterwards by Bodian and colleagues. Associated skeletal abnormalities of the metaphyseal dysostosis type were observed a few years later, and became the third fundamental feature of the syndrome.

Shwachman-Diamond syndrome is the most common inherited cause of exocrine pancreatic insufficiency after cystic fibrosis. It is also likely the third most common inherited bone marrow failure syndrome after Fanconi's anemia and Diamond-Blackfan anemia. However, Shwachman-Diamond syndrome has a low prevalence, estimated at 1 in 50,000. It has a slight male predominance (ratio 1.7:1) and is reported among all racial and ethnic groups.

All patients with Shwachman-Diamond syndrome have varying degrees of pancreatic insufficiency, which is related to poor acinar cell development in utero. The acinar cells are replaced with fat, although the ductular architecture remains intact, in contrast to cystic fibrosis. Patients often present with steatorrhea and failure to thrive, requiring pancreatic enzyme supplementation. However, the exocrine pancreatic function has been reported to improve with age, resulting in decreased fat malabsorption. Approximately 50% of affected patients will show enough improvement with increasing age such that pancreatic enzyme supplementation becomes unnecessary. Although fat malabsorption certainly contributes to failure to thrive in these patients, other factors that may contribute to poor growth include recurrent infections, skeletal abnormalities, and decreased growth hormone levels.

Neutropenia is the most common manifestation of bone marrow failure in patients with Shwachman-Diamond syndrome, and is found in 88% to 100% of patients. The neutropenia is intermittent in two thirds of patients and is chronic in the remaining one third. Because most Shwachman-Diamond syndrome patients suffer from neutropenia, they are susceptible to recurrent bacterial infections, particularly of the upper respiratory tract, oropharynx, and skin. Not only do Shwachman-Diamond syndrome patients have decreased neutrophil counts, but they also seem to have defective neutrophil chemotaxis, further predisposing these patients to infection. Patients can also have variable degrees of anemia or thrombocytopenia, and almost 50% of patients with Shwachman-Diamond syndrome have pancytopenia. Myelodysplastic syndromes and acute leukemias develop in up to one third of patients.

More than 75% of patients with Shwachman-Diamond syndrome have skeletal abnormalities. These commonly include metaphyseal dysostosis, which usually involves the femoral head. Abnormally shortened ribs with flared anterior ends, costochondral thickening, and a narrow rib cage have also been described. Other skeletal anomalies reported include delayed secondary ossification, generalized osteopenia, clinodactyly, syndactyly, supernumerary digits, pes cavus, kyphosis, and scoliosis. The patient featured in this case did not have a skeletal survey performed to look for metaphyseal dysostosis, although on physical exam he was noted to have a narrow thorax.

Hepatic involvement in children with Shwachman-Diamond syndrome is common. Hepatomegaly and increased aminotransferase levels are commonly seen, with liver biopsies demonstrating microvesicular and macrovesicular steatosis and mild portal fibrosis. Liver biopsy findings in our patient were not consistent with steatosis and were nonspecific. Progressive liver dysfunction is uncommon, and most patients have normalization of liver enzymes as they become older.

Other organ systems involved in Shwachman-Diamond syndrome include the endocrine system, with abnormalities such as insulin-dependent diabetes and growth hormone deficiencies. Dermatologic abnormalities may include eczema, ichthyosis, and petechiae. Delayed dentition of permanent teeth, dental dysplasia, and increased risk for dental caries may occur. Mild-to-moderate psychomotor or developmental delay can be seen in up to 15% of patients with Shwachman-Diamond syndrome.

The diagnostic work-up for a patient suspected of having Shwachman-Diamond syndrome should include complete blood cell counts that may suggest bone marrow dysfunction. A 72-hour fecal fat measurement with concurrent measurement of fat intake to calculate fat clearance can show an increase in fecal fat losses, and a decreased fecal pancreatic elastase level can suggest exocrine pancreatic insufficiency. Serum trypsinogen and isoamylase testing have also proven to be useful in identifying pancreatic insufficiency in Shwachman-Diamond syndrome. A sweat chloride test should be performed, which is normal in Shwachman-Diamond syndrome. Ultrasound examination of the pancreas may demonstrate increased echogenicity, and a computed tomography scan can show lipomatosis of the pancreas. A skeletal survey may uncover skeletal abnormalities, such as thoracic dysostosis, delayed bone age, tubulation of the long bones, and valgus deformities of the elbows and knees. A bone marrow aspiration and biopsy can be performed, and although there are no pathognomonic bone marrow features in Shwachman-Diamond syndrome, the examination may exclude alternative diagnoses, as well as screen for leukemia or myelodysplastic syndromes. Neutrophil chemotaxis assays can be considered for detection of defective chemotaxis. Finally, testing is available for mutations in the SBDS gene, located on chromosome 7q11. Approximately 90% of patients meeting clinical criteria for Shwachman-Diamond syndrome have mutations in the SBDS gene.

Because Shwachman-Diamond syndrome affects multiple organ systems, patients should be referred to the appropriate medical subspecialties for management, including gastroenterology, hematology, endocrinology, and genetics. Nutritional therapy for Shwachman-Diamond syndrome typically involves pancreatic enzyme supplementation. Dietary administration of fat-soluble vitamins, medium-chain triglycerides, and other high-calorie supplements may also be needed. Because most patients with Shwachman-Diamond syndrome are neutropenic, clinicians should have a low threshold for the evaluation and treatment of potential infections. Granulocyte colony-stimulating factor administration can be considered in Shwachman-Diamond syndrome patients with repeated or serious life-threatening infections. Bone marrow transplant is the only curative therapy for severe hematologic manifestations of Shwachman-Diamond syndrome. For those with short stature, growth hormone can be used for Shwachman-Diamond syndrome patients who have growth hormone deficiency.

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