Pathology
The mutant gene SBDS maps to chromosome 7q11 and is responsible for the multisystem, pleiotropic phenotype in 90% of cases. Pancreatic insufficiency is due to failure of pancreatic acinar development. Fatty replacement of pancreatic tissue is prominent. Bone marrow failure is characterized by a generalized marrow cell and microenvironmental dysfunction that does not support and maintain normal hematopoiesis.
Clinical Manifestations.
Although most patients have symptoms of fat malabsorption from birth caused by pancreatic insufficiency, the absence of steatorrhea does not exclude a diagnosis of SDS. Approximately 50% of patients appear to exhibit a modest improvement in pancreatic enzyme secretion with advancing age.
Short stature is a consistent feature of the syndrome; most patients show normal growth velocity, yet remain consistently below the 3rd percentile for height and weight. The occasional adult achieves the 25th percentile for height.
The clinical picture can be dominated by complications of hematologic cytopenia. Pancytopenia is diagnosed at a mean age of 7.5 yr (range, 0–35 yr). Bacterial and fungal infections secondary to neutropenia and neutrophil dysfunction and immune deficiency can occur. Although skeletal abnormalities are variable, classic findings are delayed bone maturation, metaphyseal dysplasia, short or flared ribs, thoracic dystrophy, and bifid thumb. Most patients have dental abnormalities and poor oral health. Many have neurocognitive problems and poor social skills.
Laboratory Findings.
Neutropenia is present in virtually all patients on at least 1 occasion. It can be chronic, cyclic, or intermittent. It has been identified in some neonates during an episode of sepsis. Anemia, thrombocytopenia, and pancytopenia are seen in 66%, 60%, and up to 44% of cases, respectively. Pancytopenia can be severe as a result of full-blown aplastic anemia.
Bone marrow biopsy specimens and aspirates usually show varying degrees of marrow hypoplasia and fat infiltration.
The fatty pancreatic replacement can be visualized by CT scan or ultrasonography. Fat malabsorption is confirmed by a 72 hr fecal fat balance study. Pancreatic function studies show markedly impaired enzyme secretion, but ductal function is preserved. Serum trypsinogen and isoamylase levels are reduced.
Treatment.
Fat malabsorption responds to oral pancreatic enzyme replacement and supplemental fat-soluble vitamins, following guidelines similar to those for cystic fibrosis . A long-term plan should be initiated to monitor changes in peripheral blood counts that require corrective action and to look for early evidence of malignant myeloid transformation. The latter requires serial bone marrow aspirates for smears and cytogenetics and marrow biopsy. One recommendation is to do marrow testing annually.
Daily subcutaneous G-CSF for profound neutropenia is effective in inducing a sustained increase in neutrophils. Some patients require transfusional support to manage severe anemia or thrombocytopenia. Experience with erythropoietin is limited. Small numbers of patients have been treated with corticosteroids, with hematologic improvement in approximately 50%. Some patients have received androgens plus steroids and have had improved blood counts. The only curative option for severe marrow failure in SDS is allogeneic HSCT, although experience has been limited. About 50% of transplanted SDS patients have died of complications related to the preparative therapy. The risk of cardiotoxicity has been noted.
Prognosis.Approximately 50% of patients spontaneously convert from pancreatic insufficiency to sufficiency due to improvement in pancreatic enzyme secretion. Enzyme replacement therapy is then no longer needed. Although all patients have some degree of hematologic cytopenia, the changes in most patients are mild to moderate and do not require therapeutic intervention. Severe neutropenia responds well to G-CSF, but there is concern that the predisposition to MDS and acute leukemia can be heightened by its powerful growth stimulus on marrow cells. HSCT for severe marrow failure produces a 50% survival rate. Malignant marrow transformation is ominous.
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