Shwachman-Diamond syndrome (SDS)

Introduction and Genetics

Shwachman-Diamond syndrome (SDS) is a rare, inherited multisystem bone marrow failure syndrome characterized primarily by exocrine pancreatic insufficiency, bone marrow dysfunction (predominantly neutropenia), and skeletal abnormalities.
It is classified as a ribosomopathy, with the underlying genetic defect occurring in ribosome biogenesis and assembly.
The disorder is most commonly inherited in an autosomal recessive pattern.
Approximately 80-90% of cases are caused by biallelic mutations in the SBDS gene located on chromosome 7q11.
Other implicated genes include DNAJC21 and EFL1, which also exhibit autosomal recessive inheritance.
Monoallelic pathogenic variants in SRP54 (autosomal dominant) can also cause a partial or classical SDS phenotype, though it more commonly presents as severe congenital neutropenia.

The SBDS gene plays a critical role in the late stages of pre-60S ribosome subunit maturation, where it binds to the EFL1 GTPase and facilitates the release of eIF6 to enable 80S monosome formation.
Exocrine pancreatic insufficiency results from the failure of exocrine pancreatic acinar development, leading to prominent fatty replacement of pancreatic tissue.
Bone marrow failure is driven by dysfunctional hematopoietic stem cells (HSCs), accelerated apoptosis of bone marrow progenitors, and a defective bone marrow microenvironment that fails to support normal hematopoiesis.

Neutropenia is the most common hematologic finding, observed in approximately 90% of patients. It can be chronic, persistent, or intermittent, and varies from mild to severe.
Neutrophils may exhibit functional defects in mobility, migration, and chemotaxis due to altered cytoskeletal or microtubular function.
Anemia is seen in 46% of patients, thrombocytopenia in 42%, and frank pancytopenia occurs in approximately 21% of cases.

Symptoms of fat malabsorption and steatorrhea are frequently present from birth due to exocrine pancreatic insufficiency.
Approximately 50% of patients experience spontaneous clinical improvement in pancreatic enzyme secretion as they grow older.
Hepatomegaly and elevated liver transaminases are observed in about 61% of patients.

Short stature is a consistent feature, with 66% of patients exhibiting normal growth velocity but remaining below the 3rd percentile for height and weight.
Skeletal anomalies are present in 70% of cases, classically including metaphyseal dysplasia (53%), osteopenia, delayed appearance of secondary ossification centers, short or flared ribs, and thoracic dystrophy.

Patients frequently suffer from poor oral health and dental abnormalities.
Neurocognitive problems and poor social skills are commonly noted.
Immunologic defects may be present, including low IgG/IgG subclasses, decreased B-cell and circulating T-cell counts, and impaired in vitro lymphocyte proliferation.

SDS patients have a markedly elevated risk for developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
Clonal marrow cytogenetic abnormalities, MDS, or leukemia develop in approximately 25% of patients by age 18, and about one-third of patients develop leukemia by age 30.
Isochromosome 7q [i(7q)] is a particularly common cytogenetic abnormality, alongside monosomy 7, translocations involving 7q, and deletions of 20q.

Clinical diagnosis historically relies on evidence of at least two of the following three features: bone marrow dysfunction, exocrine pancreatic insufficiency, and metaphyseal dysplasia.
Because 20% of patients lack clear exocrine pancreatic defects at diagnosis and up to 60% lack metaphyseal dysplasia initially, all patients with unexplained hypoplastic marrow, pancreatic insufficiency, or metaphyseal dysplasia should undergo genetic testing.
Confirmatory genetic testing for SBDS, DNAJC21, and EFL1 establishes a definitive diagnosis in almost all cases.

Pancreatic evaluation reveals reduced age-adjusted serum trypsinogen, low pancreatic isoamylase, and reduced fecal elastase.
A 72-hour stool collection confirms fat malabsorption, and serum levels of fat-soluble vitamins (A, D, and E) and prothrombin time are frequently abnormal due to impaired absorption.
Ultrasound or CT scans of the pancreas characteristically demonstrate fatty replacement (pancreatic lipomatosis).
Bone marrow aspirate and biopsy typically show varying degrees of hypoplasia and fat infiltration, though the marrow may appear normocellular or hypercellular in early childhood or during leukemic transformation.

Exocrine pancreatic insufficiency is managed with oral pancreatic enzyme replacement therapy and supplementation of fat-soluble vitamins, following guidelines similar to those for cystic fibrosis.
Daily subcutaneous Granulocyte Colony-Stimulating Factor (G-CSF) is highly effective for managing severe, profound neutropenia to induce a sustained increment in neutrophils and prevent recurrent infections.
G-CSF use must be carefully monitored due to concerns that its growth-promoting effects may accelerate the expansion of undetected MDS or AML clones.
Judicious red blood cell and platelet transfusions are utilized for the management of severe symptomatic anemia and thrombocytopenia.

A rigorous long-term plan is essential, typically including complete blood counts every 3 months.
Bone marrow aspirations and biopsies (with cytogenetics) must be performed every 1 to 3 years to monitor for early evidence of malignant myeloid transformation.

Allogeneic HSCT remains the only curative option for the hematologic complications of SDS, including severe bone marrow failure, advanced MDS, and leukemia.
Traditional myeloablative HSCT carries a high treatment-related mortality (35–50%) in this population.
Reduced-intensity conditioning regimens, particularly those incorporating fludarabine, appear to be safer and have demonstrated effectiveness in SDS patients.