SUMMARY
1. Shwachman-diamond syndrome (SDS) is an autosomal recessive disorder that affects 1 in 50,000 live births. It is characterized by the following clinical features:
-Exocrine pancreatic insufficiency
-Bone marrow failure with neutropenia
-Variable humoral and cell-mediated immunodeficiency
-Short stature
-Metaphyseal chondrodysplasia
-Neurodevelopmental delay
-Increased risk for myelodysplastic syndrome and leukemia
2. Patients present in infancy with failure to thrive and foul smelling stools due to pancreatic insufficiency. One-half of patients have improvement in pancreatic function by the age 4 years allowing for normal digestion without pancreatic enzyme replacement.
3. Neutropenia is present in almost all patients and results in recurrent infections such as otitis media, pneumonia, and sepsis. Patients with milder forms of disease can present later in childhood. Two-thirds of patients have intermittent neutropenia while one-third have persistent neutropenia. Anemia and thrombocytopenia develop in up to 40% of patients over time.
4. In addition to neutropenia, low T, B and NK cell numbers have been reported in patients. Low IgG levels with decreased specific antibody responses and decreased in vitro T cell proliferative responses have also been described.
5. Skeletal abnormalities include short stature, irregular metaphyses, pathologic fractures, and osteopenia.
6. Myelodysplastic syndrome and AML develops in approximately 10% of patients.
7. This disease is caused by mutations in the SBDS gene. The exact function of this gene product has not been elucidated.
8. The diagnosis should be suspected in patients with the characteristic clinical findings of pancreatic insufficiency, bone marrow failure/neutropenia and metaphyseal chondrodysplasia.
9. The management of the clinical manifestations are as follows:
-Pancreatic insufficiency Pancreatic enzyme and fat soluble vitamin (ADEK) supplementation.
-Neutropenia G-CSF therapy is effective in increasing absolute neutrophil counts. Patients with neutropenia and fever should be evaluated promptly and placed on empiric broad spectrum antibiotics while blood culture results are pending.
-Bone Marrow Failure The only curative treatment for this complication is HSCT. Patients appear to be at greater risk for toxicity from chemotherapeutic conditioning regimens. Recently, full engraftment and minimal toxicity has been reported with the use of reduced intensity conditioning. HSCT therapy is also a consideration for the treatment of myelodysplastic syndrome or AML.
OVERVIEW
Shwachman-diamond syndrome (SDS) is an autosomal recessive disorder that affects 1 in 50,000 live births. It is characterized by the following clinical features:
-Excocrine pancreatic insufficiency
-Bone marrow failure with neutropenia
-Variable humoral and cell-mediated immunodeficiency
-Short stature
-Metaphyseal chondrodysplasia
-Neurodevelopmental delay
-Increased risk for myelodysplastic syndrome and leukemia
Patients present in infancy with failure to thrive and foul smelling stools due to pancreatic insufficiency. One-half of patients have improvement in pancreatic function by the age 4 years allowing for normal digestion without pancreatic enzyme replacement.
Neutropenia is present in almost all patients and results in recurrent infections such as otitis media, pneumonia, and sepsis. Patients with milder forms of disease can present later in childhood. Two-thirds of patients have intermittent neutropenia while one-third have persistent neutropenia. Anemia and thrombocytopenia develop in up to 40% of patients over time.
In addition to neutropenia, low T, B and NK cell numbers have been reported in patients. Low IgG levels with decreased specific antibody responses and decreased in vitro T cell proliferative responses have also been described. Skeletal abnormalities include short stature, irregular metaphyses, pathologic fractures, and osteopenia. Myelodysplastic syndrome and AML develops in approximately 10% of patients.
This disease is caused by mutations in the SBDS gene. The exact function of this gene product has not been elucidated.
EVALUATION
The diagnosis of SDS should be suspected in patients with characteristic clinical findings including pancreatic insufficiency, bone marrow failure/neutropenia and metaphyseal chondrodysplasia.
Step 1: Immune Evaluation
-CBC with Differential
-Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)
-T-cell proliferation to Mitogens (PHA)
-IgG, IgA, IgM levels
-Specific Antibody levels (if older than 6 months)
-The CBC with differential typically reveals neutropenia. Anemia and thrombocytopenia may also be present due to bone marrow failure.
-Decreased T, B and NK cell numbers have been reported in patients.
-Decreased T-cell proliferation to mitogens may be present.
-Hypogammaglobulinemia has been described in some patients with SDS.
-Vaccine responses to protein (Tetanus, Diphtheria) and polysaccharide (pneumococcal) antigens should be evaluated. Low specific antibody responses have been reported in SDS.
Step 2: Evaluation for Pacreatic Insufficiency
-Serum trypsinogen and pancreatic isoamylase
-Fecal elastase
-Elevated 72 hour fecal fat collection
-Vitamin A, D, E, and K levels
-Low serum trypsinogen (in patients younger than 3 years) or low pancreatic isoamylase (in patients older than 3 years) levels may be present.
-Low fecal elastase levels may be present in pancreatic insufficiency
-Elevated 72 hour fecal fat collection is suggestive of pancreatic insufficiency
-Fat malabsorption can lead to low serum levels of fat soluble vitamins (A, D, E, and K)
Step 3: Additional Useful Studies
-Bone Marrow Biopsy
-Skeletal Survey
-Sweat Chloride Test
-A bone marrow biopsy may be normal in some patients but it is useful to obtain this study (with cytogenetic analysis) to evaluate for myelodysplastic syndromes and monosomy 7 as well as marrow aplasia.
-Skeletal surveys are useful to detect bone abnormalities such as metaphyseal dysplasia, irregular growth plates and progressive deformities.
-A sweat chloride test is useful to exclude cystic fibrosis, which can also present with exocrine pancreatic insufficiency and recurrent pulmonary infections.
Step 4 Gene Sequencing
-SBDS Gene Sequencing
-Sequencing of this gene is currently available commercially through Gene Dx.
MANAGEMENT
The management of the clinical manifestations is as follows:
-Pancreatic insufficiency - This can be treated with pancreatic enzyme and fat soluble vitamin (ADEK) supplementation.
-Neutropenia - G-CSF therapy is effective in increasing absolute neutrophil counts. Patients with neutropenia and fever should be evaluated promptly and placed on empiric broad spectrum antibiotics while blood culture results are pending.
-Bone Marrow Failure - The only curative treatment for this complication is HSCT. Patients appear to be at greater risk for toxicity from chemotherapeutic conditioning regimens. Recently, full engraftment and minimal toxicity has been reported with the use of reduced intensity conditioning. HSCT therapy is also a consideration for the treatment of myelodysplastic syndrome or AML.
RESOURCES
Diagnostic Resources
1. GENE DX - SBDS gene sequencing
Literature Resources
1. Burroughs 2009
Shwachman Diamond (review)
2. Dror 2001
Immune Function in Shwachman-Diamond Syndrome
3 Bhatla 2008
Reduced Intensity Conditioning is safe and effective for SDS HSCT
4 Mehta 2010
BMT for bone marrow failure syndromes