About Shwachman-Diamond Syndrome

Background: Shwachman-Diamond syndrome (SDS) is a rare congenital disorder characterized by pancreatic insufficiency, bone marrow dysfunction, and short stature. In 1964, Shwachman, Diamond, Oski, and Knaw first reported the syndrome in a group of 5 children participating in a cystic fibrosis (CF) clinic at Harvard Medical School. SDS is the second most common cause of inherited pancreatic insufficiency.

Pathophysiology: All patients with SDS have varying degrees of pancreatic insufficiency, which is defined as the loss of exocrine function resulting in the inability to digest and therefore assimilate nutrition normally. Symptoms of malnutrition typically develop when greater than 98% of pancreatic reserve is lost. In individuals with this condition, pancreatic acinar cells do not develop in utero and are replaced by fatty tissue. In contrast to CF, the pancreatic ductal architecture is spared; thus, an intact anion secretion and fluid flow occurs. For reasons as yet unknown, the pancreatic lipase secretion increases slightly with age in patients with SDS, resulting in increased pancreatic function with slowing and decrease in fat excretion.

The definitive pathogenic defect responsible for the associated hematologic abnormalities in persons with SDS is unknown. Almost one half of patients with SDS have pancytopenia; however, some may have variable degrees of anemia, thrombocytopenia, or neutropenia. The absolute neutrophil count (ANC) may be intermittently or persistently low in more than 95% of patients. The neutropenia may be mild, moderate, or severe. Irrespective of the total number of neutrophils, patients with SDS have defective neutrophil chemotaxis. Defective neutrophil chemotaxis is linked to a defect in chromosome 7. Some patients with SDS have been shown to have a defect in chromosome 7. An unusual surface distribution of concanavalin A on neutrophils may reflect a cellular cytoskeletal defect. Hematologic abnormalities may be due to a stem cell abnormality because patients with SDS have demonstrated decreased colony-forming unit's granulocyte-macrophage (CFU-GM) and colony-forming unit's erythrocyte (CFU-E) growth potential on culture.

Failure to thrive has been attributed to nutritional deficits (malabsorption), recurrent infections, and skeletal abnormalities as well as decreased or absent growth hormone levels in individuals with SDS.

The exact pathophysiology of skeletal anomalies is unknown; however, skeletal anomalies are reported to occur in more than 75% of patients with SDS.