Shwachman-Diamond syndrome (SDS) is a rare multisystemic syndrome characterized by chronic and usually mild neutropenia, pancreatic exocrine insufficiency associated with steatorrhea and growth failure, skeletal dysplasia with short stature, and an increased risk of bone marrow aplasia or leukemic transformation.
Worldwide prevalence is estimated at about 1/350,000 and birth-prevalence at around 1/200,000 live births.
SDS shows a variable clinical picture, even within families. It generally manifests during infancy or early childhood. The most common anomaly is usually intermittent and moderate neutropenia that is associated with recurrent infections. Mild anemia and thrombocytopenia may also occur. Exocrine pancreatic insufficiency results in failure to thrive, growth retardation, and chronic steatorrhea. Bone involvement is characterized by delayed bone age and maturation with metaphyseal dysplasia resulting in short stature, pectus carinatum, and generalized osteopenia. Other features include cutaneous (e.g. eczema or ichthyosis) and dental anomalies, and psychomotor retardation. Mild or severe intellectual disability (50% of patients) causes learning difficulties. Hematologic manifestations may be complicated by bone marrow aplasia, acute myeloid leukemia or a myelodysplastic syndrome (see these terms). In the neonatal period there are generally no symptoms observed but some cases were reported with pancytopenia, respiratory distress, and severe spondylometaphyseal dysplasia (see this term).
SDS is caused in 95% of cases by mutations in the SBDSgene (7q11.22) encoding a ribosomal protein involved in ribosomal biogenesis and other cellular processes.
Diagnosis is based on clinical, laboratory, and radiologic findings. Blood analysis shows neutropenia (absolute neutrophil count <1500/mL) that can be associated with mild to moderate thrombocytopenia, moderate anemia, and a rise in fetal hemoglobin. Exocrine pancreatic insufficiency can be detected by serum analysis showing low levels of pancreatic isoamylase and/or trypsinogen, stool analysis showing low fecal elastase, and magnetic resonance imaging (MRI) revealing a characteristic pancreatic aspect with fat degeneration (MRI could be normal until the age of 5). Imagery also allows detection, usually after the age of 5, of metaphyseal anomalies and abnormal growth plate development. Bone marrow smears usually reveal varying degrees of hypocellularity with dysgranulopoieisis or dyserythropoieisis. Diagnosis is confirmed by genetic testing.
Differential diagnoses include cystic fibrosis, Pearson syndrome, Fanconi anemia, Johanson-Blizzard syndrome, Blackfan-Diamond anemia, celiac disease, and autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (see these terms).
Prenatal diagnosis is feasible in families in which the disease-causing mutation has already been identified.
Transmission is autosomal recessive. Recurrence risk is of 25%.
Management is multidisciplinary, associating usually a hematologist, a gastroenterologist and other specialists such as a nutritionist, endocrinologist, or orthopedist. Pancreatic insufficiency requires pancreatic enzyme supplementation, adapted to the diet. Antibiotic therapy prophylaxis may be sufficient to avoid infections; otherwise, granulocyte colony-stimulating factor can be proposed. Severe hematological complications require hematopoietic stem cell transplantation. Surgery may be proposed for skeletal anomalies. Patients with learning difficulties require specific educational support.
Prognosis is variable. Life-threatening complications include bone marrow aplasia and leukemic transformation, and occasionally viral infections. About 1/3 of patients present such complications, and some can be treated successfully by bone marrow transplant.
Last update: June 2014