Shwachman-Diamond Syndrome

Clinical characteristics: Shwachman-Diamond syndrome (SDS) is characterized by: exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; hematologic abnormalities with single- or multilineage cytopenias and susceptibility to myelodysplasia syndrome (MDS) and acute myelogeneous leukemia (AML); and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is a common presenting finding, often before the diagnosis of SDS is made. Short stature and recurrent infections are common.

Diagnosis/testing: The diagnosis of SDS is established in a proband with the classic clinical findings of exocrine pancreatic dysfunction and bone marrow dysfunction and/or biallelic pathogenic variants in DNAJC21, EFL1, or SBDS or a heterozygous pathogenic variant in SRP54 identified by molecular genetic testing.

Management: Treatment of manifestations: Care by a multidisciplinary team is recommended. Exocrine pancreatic insufficiency is treated with oral pancreatic enzymes and fat-soluble vitamin supplementation. Blood and/or platelet transfusions may be considered for anemia and/or thrombocytopenia associated with bi- or trilineage cytopenia. If recurrent infections are severe and absolute neutrophil counts are persistently ≤500/mm³, treatment with granulocyte-colony stimulation factor (G-CSF) can be considered. Hematopoietic stem cell transplantation (HSCT) should be considered for treatment of severe pancytopenia, MDS, or AML.

Prevention of secondary complications: Aggressive dental hygiene should be pursued to promote oral health. Consider prophylactic antibiotics and G-CSF to reduce risk of infection during complex dental procedures or orthopedic surgery.

Surveillance: Complete blood counts at least every three to six months; assessment of development, growth, and nutritional status every six months. Following baseline examination, repeat bone marrow examination every one to three years or more frequently if bone marrow changes are observed. Monitor for orthopedic complications with x-rays of hips and knees during the most rapid growth stages. Perform bone densitometry before puberty, during puberty, and thereafter based on individual findings. Perform neuropsychological screening in children age 6-8 years, 11-13 years, and 15-17 years.

Agents/circumstances to avoid: Prolonged use of cytokine and hematopoietic growth factors (e.g., G-CSF) should be considered with caution. Some drugs used in standard HSCT preparative regimens (e.g., cyclophosphamide and busulfan) may not be suitable because of possible cardiac toxicity.

Genetic counseling: SDS is inherited in an autosomal recessive (most commonly) or an autosomal dominant manner.

1. Autosomal recessive SDS. SDS caused by pathogenic variants in DNAJC21, EFL1, or SBDS is inherited in an autosomal recessive manner. Most parents of children with autosomal recessive SDS are heterozygotes (carriers of one pathogenic variant); however, de novo pathogenic variants have been reported. When both parents are known to be carriers, the sibs of a proband have a 25% chance of being affected, a 50% chance of being an unaffected carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for relatives at risk is possible if both pathogenic variants in a family are known.

2. Autosomal dominant SDS. SDS caused by pathogenic variants in SRP54 is inherited in an autosomal dominant manner; most such affected individuals reported to date have resulted from a de novo SRP54 pathogenic variant.

If the pathogenic variant(s) in a family are known, prenatal and preimplantation genetic testing are possible.