Peter R. Durie

Mutations in SBDS are associated with Shwachman–Diamond syndrome

Shwachman–Diamond syndrome (SDS; OMIM 260400) is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, hematological dysfunction and skeletal abnormalities. Here, we report identification of disease-associated mutations in an uncharacterized gene, SBDS, in the interval of 1.9 cM at 7q11 previously shown to be associated with the disease. We report that SBDS has a 1.6-kb transcript and encodes a predicted protein of 250 amino acids. A pseudogene copy (SBDSP) with 97% nucleotide sequence identity resides in a locally duplicated genomic segment of 305 kb. We found recurring mutations resulting from gene conversion in 89% of unrelated individuals with SDS (141 of 158), with 60% (95 of 158) carrying two converted alleles. Converted segments consistently included at least one of two pseudogene-like sequence changes that result in protein truncation. SDBS is a member of a highly conserved protein family of unknown function with putative orthologs in diverse species including archaea and eukaryotes. Archaeal orthologs are located within highly conserved operons that include homologs of RNA-processing genes, suggesting that SDS may be caused by a deficiency in an aspect of RNA metabolism that is essential for development of the exocrine pancreas, hematopoiesis and chrondrogenesis.

Shwachman syndrome: Phenotypic manifestations of sibling sets and isolated cases in a large patient cohort are similar

OBJECTIVESnWith the use of clinical data from a large international cohort, we evaluated and compared affected siblings and isolated cases.nnnSTUDY DESIGNnData from 116 families were collected, and patients conforming to our predetermined diagnostic criteria were analyzed. Phenotypic manifestations of affected siblings and singletons were compared with the use of t tests, Wilcoxon scores, and chi2 analysis.nnnRESULTSnEighty-eight patients (33 female, 55 male; median age 5.20 years) fulfilled our predetermined diagnostic criteria for Shwachman syndrome; 63 patients were isolated cases, and 25 affected siblings were from 12 multiplex families. Steatorrhea was present in 86% (57 of 66), and 91% (78 of 86) displayed a low serum trypsinogen concentration. Patients older than 4 years more often had pancreatic sufficiency. Neutropenia occurred in 98%, anemia in 42%, and thrombocytopenia in 34%. Myelodysplasia or cytogenetic abnormalities were reported in 7 patients. Short stature with normal nutritional status was a prominent feature.nnnCONCLUSIONSnClinical features among patients with Shwachman syndrome varied between patients and with age. Similarities in phenotype between isolated cases and affected sibling sets support the hypothesis that Shwachman syndrome is a single disease entity.

Shwachman syndrome: Exocrine pancreatic dysfunction and variable phenotypic expression

BACKGROUND & AIMSnShwachman syndrome is an inherited condition with multisystemic abnormalities, including exocrine pancreatic dysfunction. The aim of this study was to evaluate the occurrence and progression of features in a large cohort of patients.nnnMETHODSnClinical records of 25 patients with Shwachman syndrome were reviewed.nnnRESULTSnMean birth weight (2.92 +/- 0.51 kg) was at the 25th percentile. However, by 6 months of age, mean heights and weights were less than the 5th percentile. After 6 months of age, growth velocity was normal. Severe fat maldigestion due to pancreatic insufficiency was present in early life (fecal fat, 26% +/- 17% of fat intake; age, < 2 years). Serial assessment of exocrine pancreatic function showed persistent deficits of enzyme secretion, but 45% of patients showed moderate age-related improvements leading to pancreatic sufficiency. Neutropenia was the most common hematologic abnormality (88%), but leukopenia, thrombocytopenia, and anemia were also frequently encountered. Patients with hypoplasia of all three bone marrow cellular lines (n = 11) had the worst prognosis; 5 patients died, 2 of sepsis and 3 of acute myelogenous leukemia. Other findings included hepatomegaly and/or abnormal liver function test results and skeletal abnormalities.nnnCONCLUSIONSnA wide and varied spectrum of phenotypic abnormalities among patients with Shwachman syndrome is described. Pancreatic acinar dysfunction is an invariable abnormality. Patients with severe bone marrow involvement may have a guarded prognosis.

Shwachman-Diamond Syndrome with Exocrine Pancreatic Dysfunction and Bone Marrow Failure Maps to the Centromeric Region of Chromosome 7

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency and hematologic and skeletal abnormalities. A genomewide scan of families with SDS was terminated at approximately 50% completion, with the identification of chromosome 7 markers that showed linkage with the disease. Finer mapping revealed significant linkage across a broad interval that included the centromere. The maximum two-point LOD score was 8.7, with D7S473, at a recombination fraction of 0. The maximum multipoint LOD score was 10, in the interval between D7S499 and D7S482 (5.4 cM on the female map and 0 cM on the male map), a region delimited by recombinant events detected in affected children. Evidence from all 15 of the multiplex families analyzed provided support for the linkage, consistent with a single locus for SDS. However, the presence of several different mutations is suggested by the heterogeneity of disease-associated haplotypes in the candidate region.

Skeletal phenotype in patients with Shwachman–Diamond syndrome and mutations in SBDS

Pancreatic exocrine and bone marrow dysfunctions are considered to be universal features of Shwachman–Diamond syndrome (SDS) whereas the associated skeletal dysplasia is variable and not consistently observed. The genetic defect in SDS has recently been identified; causative mutations have been shown in the SBDS gene. The aims of this study were to characterize the nature, frequency, and age‐related changes of radiographic skeletal abnormalities in patients with SBDS mutations and to assess genotype–phenotype correlation. Fifteen patients (mean age 9.7 years) with a clinical diagnosis of SDS and documented SBDS gene mutations were included. Review of their skeletal radiographs showed abnormalities in all patients. The skeletal changes were variable, even in patients with identical genotypes. The typical features were (1) delayed appearance of secondary ossification centers, (2) variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates, and (3) generalized osteopenia. There was a tendency towards normalization of the epiphyseal maturation defect and progression of the metaphyseal changes with age. The results suggest that the characteristic skeletal changes are present in all patients with SDS and SBDS mutations, but their severity and localization varies with age. No phenotype–genotype correlation was observed.

Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome

Shwachman‐Diamond syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic exocrine insufficiency and bone marrow failure, often associated with neurodevelopmental and skeletal abnormalities. Mutations in theu2002SBDSu2002gene have been shown to cause SDS. The purpose of this document is to provide draft guidelines for diagnosis, evaluation of organ and system abnormalities, and treatment of hematologic, pancreatic, dietary, dental, skeletal, and neurodevelopmental complications. New recommendations regarding diagnosis and management are presented, reflecting advances in understanding the genetic basis and clinical manifestations of the disease based on the consensus of experienced clinicians from Canada, Europe, and the United States. Whenever possible, evidence‐based conclusions are made, but as with other rare diseases, the data on SDS are often anecdotal. The authors welcome comments from readers.

Immune function in patients with Shwachman–Diamond syndrome

Shwachman–Diamond syndrome (SDS) is an inherited multisystem disorder characterized by exocrine pancreatic dysfunction and varying degrees of cytopenia. In addition, various immunological abnormalities have been noted. To clarify the issue of immunological competence or incompetence in SDS, we prospectively studied immune function in 11 patients with SDS. Seven suffered from recurrent bacterial infections and six from recurrent viral infections. Varying degrees of impairment were readily identified. All patients had neutropenia; total lymphocyte counts, however, were normal in all except one patient. Nine patients had B‐cell defects comprising one or more of the following abnormalities: low IgG or IgG subclasses, low percentage of circulating B lymphocytes, decreased in vitro B‐lymphocyte proliferation and a lack of specific antibody production. Seven out of nine patients studied had at least one T‐cell abnormality comprising a low percentage of total circulating T lymphocytes or CD3+/CD4+ cell subpopulations or decreased in vitro T‐lymphocyte proliferation. Five out of six patients studied had decreased percentages of circulating natural killer cells. Moreover, neutrophil chemotaxis was significantly low in all the patients studied. These data point to a major immunodeficiency component in SDS that places patients at heightened risk of infections, even if neutrophil numbers are protective. This finding broadens the definition of the syndrome substantially: it suggests that the SDS marrow defect occurs at the level of an early haematological–lymphocytic stem cell or that a combined marrow and thymic stromal defect accounts for the aberrant function of haematopoietic and lymphopoietic lineages.

The behavioral phenotype of school-age children with shwachman diamond syndrome indicates neurocognitive dysfunction with loss of Shwachman-Bodian-Diamond syndrome gene function.

OBJECTIVEnTo investigate the cognitive, behavioral and adaptive functioning of children with Shwachman-Diamond syndrome (SDS).nnnSTUDY DESIGNnThirty-two children with SDS (6-17 years) were evaluated by use of standardized neuropsychological tests. Results were compared with normative data, unaffected siblings (n = 13), and age-and sex-matched children with cystic fibrosis (CF; n = 20).nnnRESULTSnAlthough intragroup variability in performance was evident, children with SDS displayed weaker overall intellectual reasoning, higher-order language skills, perceptual reasoning, visual-motor processing speed, visual motor- integration, visual executive problem-solving, attention, and aspects of academic achievement, as well as lower functional level of independence relative to the general population. Significant issues with behavior were also identified, including prior formal diagnoses and social problems. Lower abilities were found relative to sibling and CF control subjects and were not associated with secondary complications of SDS, age, or sex.nnnCONCLUSIONnNeurocognitive deficits in subjects with SDS are largely independent of family environment and having a chronic illness and are likely the consequences of Shwachman-Bodian-Diamond syndrome gene dysfunction. There is a need for a broad-based approach to the assessment of cognitive function and appropriate remediation of individuals with SDS.

The natural history of Shwachman-Diamond syndrome-associated liver disease from childhood to adulthood.

OBJECTIVESnIn order to characterize the natural course of Shwachman-Diamond syndrome (SDS)-associated hepatopathy we evaluated liver biochemistry and imaging findings, and their evolution with age, in patients with SDS and verified SBDS mutations.nnnSTUDY DESIGNnRetrospective and cross-sectional liver imaging, biochemical and histologic data of 12 patients (age range 2.1 to 37 years) with SBDS mutations were analyzed. Hepatic volume and parenchymal structure were determined from magnetic resonance imaging data.nnnRESULTSnHepatomegaly and aminotransaminase elevation was observed in most of the patients with SDS at an early age; values normalized by age 5 years and remained normal over extended follow-up. Mild to moderate serum bile acid elevation was noted in 7 patients (58%). On magnetic resonance imaging, no patients (n = 11) had evidence of hepatic steatosis, cirrhosis, or fibrosis. Three middle-aged patients had hepatic microcysts.nnnCONCLUSIONSnSDS-associated hepatopathy has overall good prognosis. No major hepatic abnormalities developed during extended follow-up to adulthood. Mild cholestasis in follow-up even after normalization of transaminase levels may reflect primary alterations in liver metabolism in SDS.