An uncommon inherited disorder that is estimated to occur once in every 100,000 births, manifesting exocrine pancreatic insufficiency with secondary steatorrhea, blood cell deficiencies, and skeletal abnormalities. It was first described in 1964.247,249
Shwachman-Diamond syndrome results from mutations in the SBDS gene on chromosome 7q11, which induces accelerated cellular apoptosis via the FAS pathway.249 The resulting hyperproliferation may account for the abnormal telomere shortening that has been documented in the leukocytes in this condition.250 The pathogenetic mechanism that (1) prevents development of pancreatic acinar cells, (2) results in abnormal bone morphogenesis, and (3) causes marrow impairment of blood cell production is not understood. SBDS knockdown in experimental animals affects expression of genes involved in brain, bone, and marrow development, and may be the result of the gene’s role in RNA processing.251,252 The mutations also result in abnormalities in neutrophil motility and chemotaxis, but pus formation in vivo seems adequate.
Pancreatic insufficiency, steatorrhea, and neutropenia are present in most patients at the time of diagnosis.247,248 Pallor may reflect anemia and easy bruising; epistaxis or bleeding from other sites reflect thrombocytopenia. Neutropenia occurs in approximately 95 percent, anemia in approximately 50 percent, and thrombocytopenia in approximately 35 percent of patients.249 Thus, a substantial plurality of patients has bicytopenia or tricytopenia with an hypoplastic marrow. Fetal hemoglobin levels are elevated in approximately 75 percent of the patients, perhaps secondary to erythroid hypoplasia. Cytogenetic abnormalities involving chromosomes 7 and 20 have been described in marrow cells. Nutritional inadequacies related to intestinal malabsorption result in a failure to thrive. Short stature is characteristic. Skeletal abnormalities are present in most patients, notably osteopenia, but also syndactyly, supernumerary metatarsals, coax vera deformity, and dental enamel defects and caries. Delayed puberty is common. The neutropenia and chemotactic abnormality may result in recurrent infections, including sinusitis, otitis, pneumonia, osteomyelitis, and others. Pancreatic cell lipase production improves with age, and as many as half the patients may have improvement in lipid absorption in the small bowel with time.
Management & treatment
Supportive care, particularly with supplemental pancreatic enzymes, to provide proper nutrition, and appropriate and prompt treatment of bacterial infections with antibiotics is important. Many agents, including G-CSF, glucocorticoids, pancreatic extract, vitamins, have been tried to improve the neutropenia with erratic results. Some agents have potential risks, such as G-CSF fostering clonal evolution and glucocorticoids fostering immunodeficiency. Severe hematopoietic dysfunction and cytopenias can be corrected with allogeneic hematopoietic stem cell transplantation.253
Course and Prognosis
Death from overwhelming sepsis is common. These patients, especially males, have a significant risk of progression to a myelodysplastic syndrome or acute myelogenous leukemia.248,254,255 Survival is a function of the severity of the cytopenias. If the cytopenias are mild, survival is not uncommon into the fourth or fifth decade of life. If symptomatic pancytopenia, especially neutropenia, is present, median survival is about 20 to 30 years.248,255
Other Inherited Aplastic Anemias
Several other rare syndromes are associated with aplastic pancytopenia, and these are described in Table 34–8. Congenital amegakaryocytic thrombocytopenia results from mutations in the thrombopoietin receptor gene, MPL.259,260 Reticular dysgenesis results from a pluripotential stem cell defect as both lymphoid and myeloid progenitors are affected.268,269 The Seckel syndrome results from mutations in the ATR gene, and marrow cells exhibit heightened sister chromatid exchange.270–273 The ataxia-telangiectasia mutated and rad3-related (ATR) kinase orchestrates cellular responses to DNA damage and replication stress. The genetic basis of marrow failure in these four syndromes that involve aplastic pancytopenia is not yet known, but may be related to defects in the ATR-dependent DNA damage-repair pathway.259 Most of these syndromes can be treated by marrow transplantation, but this step, if successful, does not correct somatic abnormalities, only the hematopoietic defect. The restoration of robust hematopoiesis by transplantation may decrease their propensity to undergo clonal evolution to a clonal myeloid or, in some cases, lymphoid disorder.