Shwachman-Diamond Syndrome

I. Epidemiology

• SDS is an autosomal recessive disorder characterized by:
  • Exocrine pancreatic insufficiency (EPI)
  • Bone marrow dysfunction
  • Skeletal abnormalities
• Clinical presentation is variable and age-dependent.
• Prevalence estimates:
  • ~1 in 50,000 to 1 in 77,000 live births
• 2nd most common inherited cause of pancreatic insufficiency after cystic fibrosis.
• 3rd most common inherited bone marrow failure syndrome.
• Reported in diverse populations: European, Indian, Indigenous North American, Chinese, Japanese, and African ancestry.

II. Pancreatic Function

• Pancreatic acinar cells fail to develop in utero and are replaced by fatty tissue.
• Unlike cystic fibrosis, ductal architecture is preserved, allowing intact anion secretion and fluid flow.
• Biomarkers:
  • ↓ Serum trypsinogen in children <3 years; may normalize with age
  • ↓ Serum isoamylase across all ages; limited diagnostic utility in infants
  • ↓ Fecal elastase in most patients
• Pancreatic function may improve with age; ~50% of patients become pancreatic sufficient in later childhood.

III. Pathogenesis

• ~90% have biallelic mutations in the SBDS gene on chromosome 7q11.
• SBDS protein functions:
  • Ribosome biogenesis
  • RNA processing
  • Mitotic spindle stabilization
  • Neutrophil chemotaxis
• Pancreatic abnormalities:
  • Acinar cell aplasia
  • Fatty replacement of pancreatic tissue
• Hematologic abnormalities:
  • Neutrophil defects in mobility, migration, and chemotaxis
  • Aberrant F-actin polymerization and delayed cytoskeletal polarization
  • SBDS may support granulocyte precursor survival
• Bone marrow abnormalities:
  • Abnormal myeloid clones with chromosome 7 mutations (e.g., monosomy 7)
  • Dysmyelogenesis
  • Risk of leukemia and aplastic anemia with age
• Skeletal abnormalities:
  • No genotype-phenotype correlation
  • Delayed secondary ossification
  • Irregular metaphyses and growth plates
  • Generalized osteopenia

Shwachman-Diamond Syndrome: Extended Review

IV. Clinical Manifestations

• Gastrointestinal: Diarrhea, steatorrhea, failure to thrive
• Hematology:
  • Cyclic or persistent neutropenia (>90%)
  • 1/3 develop myelodysplastic syndrome (MDS)
  • 10–25% develop acute myeloid leukemia (AML)
  • Impaired neutrophil chemotaxis
  • Anemia, thrombocytopenia
  • Pancytopenia (~10–25%) — worst prognosis
• Skeletal Abnormalities:
  • Progressive metaphyseal dysostosis (~45%) — hips and knees most affected
  • Thoracic cage abnormalities (~33%)
  • Short stature (<5th percentile); normal growth velocity
  • Increased risk of slipped capital femoral epiphysis
• Other:
  • Dental caries, enamel defects, delayed dentition
  • Liver: hepatomegaly, elevated transaminases (resolve by age 5)
  • Histology: steatosis, inflammation, fibrosis, glycogenosis
  • Developmental delays in language and perceptual reasoning
  • Behavioral/social difficulties more common than in CF or healthy controls
  • ~50% of children are <3rd percentile for height and weight
  • Median survival: ~35 years; major causes of death include infection and leukemia

V. Laboratory Testing

• Neutropenia and cytopenias in >90%
• Anemia (42–66%), thrombocytopenia (24–60%)
• 90% have biallelic SBDS mutations; 10% diagnosed clinically
• ↓ Lipase, amylase, trypsin secretion after secretin/CCK stimulation
• ↓ Serum trypsinogen and isoamylase in children <3 years
• Trypsinogen and fat absorption may normalize with age
• Isoamylase deficiency and starch malabsorption persist into adulthood
• Imaging:
  • CT/US: fatty pancreas, normal size
  • X-rays: metaphyseal dysostosis, clinodactyly, syndactyly, valgus deformities, enamel defects

VI. Diagnostic Criteria

• Cytopenia in any hematopoietic lineage
• Neutropenia (ANC <1,500/μL) on ≥2 occasions over 2 months
• Anemia, thrombocytopenia on ≥2 occasions over 2 months
• Pancreatic dysfunction:
  • ↓ Fecal elastase
  • ↓ Serum trypsinogen (<3 years)
  • ↓ Serum isoamylase (≥3 years)
  • ↑ Serum lipase

VII. Management

• Pancreatic enzyme replacement therapy (PERT)
• Fat-soluble vitamin supplementation
• Transfusions as needed
• Prompt evaluation of fever/neutropenia; cultures and prophylactic antibiotics
• G-CSF for ANC <500 and recurrent infections (80% response; no AML risk increase)
• Bone marrow transplant: only curative option for marrow failure

VIII. Surveillance

• CBC with differential and platelets every 3–6 months
• Growth and development assessment every 6 months (birth–6 years)
• Nutritional status and vitamin levels every 6 months
• Bone marrow exams every 1–3 years or as needed
• Radiographs of hips/knees during growth spurts
• Bone densitometry before/during/after puberty
• Neuropsychological screening at ages 6–8, 11–13, and 15–17

IX. Differential Diagnosis of Congenital Pancreatic Insufficiency

• Cystic Fibrosis (CF): ↑ Sweat Cl–, ↑ IR trypsinogen in infants
• Johanson-Blizzard Syndrome: nasal hypoplasia, oligodontia, EPI
• Pearson Syndrome: mitochondrial disorder, vacuolated marrow, sideroblastic anemia, lactic acidosis
• Jeune Syndrome: autosomal recessive, EPI, thoracic dystrophy

Comparison of Pancreatic Function in CF vs SDS