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 myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is an early finding. 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 highly 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 thrombocytopenia. If recurrent infections are severe and absolute neutrophil counts are persistently ≤500/mm³, treatment with granulocyte-colony stimulation factor (G-CSF) can be considered and may be especially helpful when interventions such as complex dental procedures or orthopedic surgery are being considered. Hematopoietic stem cell transplantation (HSCT) should be considered for treatment of severe bone marrow failure, MDS, or AML. Early pulmonary and orthopedic referral is essential for treatment of thoracic dystrophy; orthopedic management of other skeletal manifestations including skeletal dysplasia, asymmetric growth, and joint deformities. Multidisciplinary team management of liver disease; neuropsychological testing, developmental services, and educational support; referral to endocrinology for pubertal delay and other endocrine manifestations; dental care for oral manifestations.

Surveillance: Assessment of nutritional status and measurement of serum concentration of fat-soluble vitamins every six months. Complete blood count with white blood cell differential and platelet count at least every three to six months; bone marrow examination every one to three years or more frequently if bone marrow changes are observed. Monitor for orthopedic complications with radiographs of the hips and knees during the most rapid growth stages. Bone densitometry before puberty, during puberty, and thereafter based on individual findings. Development assessment every six months from birth to age six years; neuropsychological screening in children ages six to eight years, eleven to 13 years, and 15 to 17 years. Clinical examination for skin and dental manifestations and assessment for recurrent urinary tract infections at each visit. Dental visits to monitor tooth development, assess oral health, and screen for mouth ulcers and gingivitis every 12 months or more frequently as needed. Assess growth and for clinical signs and symptoms of additional endocrine manifestations every six months.

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.

Evaluation of relatives at risk: It is appropriate to evaluate the older and younger sibs of a proband in order to identify those who will benefit from treatment and preventive measures as soon as possible. It is essential to evaluate any potential related donor for SDS to avoid using an asymptomatic relative with SDS as an HSCT donor.

Pregnancy management: High-risk pregnancy care including consultation with a hematologist.

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

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. If both parents are known to be heterozygous for an autosomal recessive SDS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a clinically asymptomatic 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.

Autosomal dominant SDS: SDS caused by pathogenic variants in SRP54 is inherited in an autosomal dominant manner. Most individuals diagnosed with SRP54-related SDS have the disorder as the result of a de novo pathogenic variant.

Once the SDS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.