Definition/General
Introduction:
Shwachman-Diamond syndrome (SDS) is the second most common inherited bone marrow failure syndrome after Fanconi anemia
It is characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and skeletal abnormalities
The disorder shows autosomal recessive inheritance with variable clinical expression.
Origin:
Results from mutations in SBDS gene (90% cases) located on chromosome 7q11
The SBDS protein is involved in ribosome biogenesis and cellular stress response
Other genes (DNAJC21, EFL1, SRP54) account for remaining cases
The defect leads to ribosomal dysfunction affecting multiple organ systems.
Classification:
Classified based on genetic mutations: SBDS-associated SDS (90% cases)
DNAJC21-associated SDS
EFL1-associated SDS
SRP54-associated SDS
Classical SDS with pancreatic and hematologic features
Atypical SDS with incomplete phenotype
Severe vs mild clinical presentations.
Epidemiology:
Incidence of approximately 1 in 77,000 births
Higher prevalence in certain populations
Equal gender distribution
Pancreatic insufficiency present from birth
Bone marrow failure develops variably
Malignancy risk significantly increased (MDS/AML).
Clinical Features
Presentation:
Exocrine pancreatic insufficiency (steatorrhea, malabsorption)
Neutropenia (recurrent infections)
Growth retardation and failure to thrive
Skeletal abnormalities (metaphyseal dysostosis)
Hepatomegaly (fatty infiltration)
Short stature and delayed development.
Symptoms:
Steatorrhea and malabsorption from infancy
Recurrent bacterial infections (due to neutropenia)
Growth retardation
Bone pain and deformities
Feeding difficulties
Delayed tooth eruption
Cognitive impairment (some cases).
Risk Factors:
Consanguineous parents
Family history of bone marrow failure
Carrier parents
Ethnic predisposition in some populations
Sibling with SDS
No environmental risk factors identified.
Screening:
Complete blood count (neutropenia, anemia)
Pancreatic function tests (fecal elastase)
Bone marrow examination
Genetic testing for SBDS mutations
Skeletal imaging
Family screening and genetic counseling.
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Gross Description
Appearance:
Bone marrow aspirate shows variable cellularity
Maturation arrest in granulocytic lineage
Lipid vacuoles in cells may be present
Normal to increased erythropoiesis
Variable megakaryopoiesis.
Characteristics:
Hypocellular to normocellular bone marrow
Fatty infiltration in some areas
Prominent myeloid maturation defects
Normal bone architecture
No fibrosis in early stages.
Size Location:
Affects all hematopoietic sites
Variable involvement across different bones
Progressive changes over time
No focal lesions
Spleen may be enlarged.
Multifocality:
Diffuse but variable bone marrow involvement
Progression over time
Age-related changes
Risk of transformation to MDS/AML
Geographic variation within marrow.
Microscopic Description
Histological Features:
Variable cellularity (20-80% for age)
Granulocytic maturation arrest at promyelocyte/myelocyte stage
Lipid vacuoles in granulocytic precursors
Normal to increased erythropoiesis
Variable megakaryopoiesis (may be decreased).
Cellular Characteristics:
Maturation arrest in neutrophilic series
Cytoplasmic vacuolation in myeloid cells
Nuclear-cytoplasmic asynchrony
Dysplastic changes may develop over time
Normal erythroid morphology initially.
Architectural Patterns:
Preserved bone marrow architecture
Uneven distribution of hematopoietic cells
Increased fat content in some areas
Normal sinusoidal pattern
No fibrosis initially.
Grading Criteria:
Severity graded by neutrophil count: Mild (1000-1500/μL)
Moderate (500-1000/μL)
Severe (<500/μL)
Bone marrow cellularity variable
Risk of transformation increases with age.
Immunohistochemistry
Positive Markers:
MPO highlights myeloid cells with maturation arrest
CD34 shows stem cell population
CD15 marks mature neutrophils
Glycophorin A highlights erythroid cells
CD61 identifies megakaryocytes.
Negative Markers:
Lymphoid markers typically negative in excess
Blast markers negative initially
Plasma cell markers not increased
Viral markers negative
Fibroblastic markers negative.
Diagnostic Utility:
Demonstrates myeloid maturation arrest
Quantifies blast percentage
Assesses lineage distribution
Monitors progression to MDS
Helps exclude other disorders
Tracks disease evolution.
Molecular Subtypes:
SBDS-associated SDS (90% cases)
DNAJC21-associated SDS
EFL1-associated SDS
SRP54-associated SDS
Ribosomal dysfunction common pathway
Variable severity by genotype.
Molecular/Genetic
Genetic Mutations:
SBDS gene mutations (90% cases)
DNAJC21 mutations (rare)
EFL1 mutations (rare)
SRP54 mutations (rare)
Biallelic mutations required
Most common mutations: c.258+2T>C and c.183_184deliTT.
Molecular Markers:
Ribosomal dysfunction (hallmark)
Impaired protein synthesis
Cellular stress response activation
p53 pathway activation
Telomere shortening (secondary)
Chromosomal instability (late feature).
Prognostic Significance:
SBDS mutations variable prognosis
Severe mutations worse outcome
Age at diagnosis affects prognosis
Transformation risk 15-30% lifetime
Early transformation worse prognosis
Pancreatic function may improve with age.
Therapeutic Targets:
Granulocyte colony-stimulating factor (G-CSF)
Pancreatic enzyme replacement
Bone marrow transplantation for severe cases
Gene therapy (experimental)
Symptomatic treatment
Malignancy surveillance.
Differential Diagnosis
Similar Entities:
Cyclic neutropenia (periodic pattern)
Chronic idiopathic neutropenia
Kostmann syndrome (severe congenital neutropenia)
Cartilage-hair hypoplasia
Cystic fibrosis (pancreatic insufficiency)
Pearson syndrome.
Distinguishing Features:
SDS: Pancreatic insufficiency
SDS: Skeletal abnormalities
SDS: SBDS mutations
Cyclic neutropenia: Periodic pattern
Cyclic neutropenia: ELANE mutations
CF: CFTR mutations
CF: Pulmonary involvement
Kostmann: Severe neutropenia
Kostmann: ELANE/HAX1 mutations.
Diagnostic Challenges:
Distinguishing from other neutropenia syndromes
Recognizing pancreatic insufficiency
Identifying skeletal abnormalities
Genetic testing complexity
Variable clinical expression
Transformation detection.
Rare Variants:
SDS without pancreatic insufficiency
Isolated neutropenia variant
Late-onset SDS
Atypical skeletal features
SDS with normal SBDS gene
Pancreatic sufficiency with age.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy from [site], adequate for evaluation
Diagnosis
Shwachman-Diamond Syndrome
Classification
Classification: Inherited bone marrow failure syndrome with pancreatic insufficiency
Bone Marrow Cellularity
Cellularity: [X]% for age, with granulocytic maturation abnormalities
Lineage Assessment
Granulopoiesis: maturation arrest at [stage]. Erythropoiesis: [normal/abnormal]. Megakaryopoiesis: [normal/reduced]
Morphological Features
Shows granulocytic maturation arrest with cytoplasmic vacuolation
Special Studies
Genetic testing: recommend SBDS gene analysis
Pancreatic function: [correlation required]
Immunohistochemistry: confirms myeloid maturation defects
Clinical Correlation
Findings consistent with Shwachman-Diamond syndrome. Recommend genetic counseling
Final Diagnosis
Bone marrow showing changes consistent with Shwachman-Diamond syndrome