This is a rare autosomal recessive disease characterized by exocrine pancreatic insufficiency, skeletal abnormalities (e.g., metaphyseal dysostosis), growth retardation, recurrent infections, and hematological abnormalities (neutropenia, hypoplastic anemia, thrombocytopenia, or pancytopenia) (Dror and Freedman 1999) (see Table 1 for diagnostic criteria). The risk of leukemia in Shwachman–Diamond syndrome was calculated to increase 27-fold (Woods et al. 1981). A range of leukemic types have been described in this condition including ALL, AML, chronic myeloid leukemia (CML), and erythroleukemia. Although the risk of leukemic transformation had been considered to be 5–10 %, Smith et al. (1996) suggested that this was an underestimate. The Shwachman–Diamond syndrome gene maps to 7q11 and encodes a protein of 250 amino acids (Boocock et al. 2003). Most mutations appeared to result from gene conversion events with a pseudogene.
Table 1 Diagnostic criteria for Shwachman–Diamond syndrome
|Fulfilling at least two of the following criteria (1–4)|
|1. At least two of the following:|
|(a) Chronic cytopenia(s) detected on at least two occasions over at least 3 months|
|(b) Reduced marrow progenitors (granulocyte–monocyte colony-forming units, erythroid burst forming units, and granulocyte, erythroid, monocyte, megakaryocyte colony-forming units)|
|(c) Persistent elevation of hemoglobin F (on at least two occasions over at least 3 months apart)|
|(d) Persistent red blood cell macrocytosis (on at least two occasions over at least 3 months apart) (not caused by hemolysis or a nutritional deficiency)|
|2. At least one of the following:|
|(a) Evidence of pancreatic lipomatosis (e.g., by ultrasound, computed tomography, magnetic resonance imaging, or pathological examination of the pancreas e.g. by autopsy)|
|(b) Reduced levels of at least two pancreatic enzymes adjusted to age (fecal elastase, serum trypsinogen, serum isoamylase, or duodenal enzymes following stimulation test)|
|3. Positive genetic testing (SBDS and others once they become available)|
|4. First-degree family history of Shwachman–Diamond syndrome|
Adapted from Hashmi et al. (2011)
There is no apparent prognostic significance to genotype analysis.
Patients with Shwachman–Diamond syndrome with very early symptoms or cytopenia at diagnosis are considered at a high risk of severe hematological complications (Donadieu et al. 2012). When comparing Shwachman– Diamond syndrome with other inherited bone marrow failure syndromes such as Diamond–Blackfan, Fanconi anemia, Kostmann syndrome, and dyskeratosis congenita, one of the main differences between Shwachman–Diamond syndrome and the other types of inherited bone marrow failures was that the combination of isolated neutropenia and high HbF or MCV was more likely to present at time of diagnosis in Shwachman–Diamond syndrome, whereas severe neutropenia and thrombocytopenia are less common at presentation (Hashmi et al. 2011).