Alternative titles; symbols
SNOMEDCT: 89454001; ICD10CM: D61.02; ORPHA: 811; DO: 0060479;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q11.21 | Shwachman-Diamond syndrome 1 | 260400 | Autosomal recessive | 3 | SBDS | 607444 |
A number sign (#) is used with this entry because Shwachman-Diamond syndrome-1 (SDS1), also known as the Shwachman-Bodian-Diamond syndrome, is caused by compound heterozygous or homozygous mutations in the SBDS gene (607444) on chromosome 7q11.
Heterozygous mutations in the SBDS gene have been associated with predisposition to aplastic anemia (609135).
Shwachman-Diamond syndrome is a multisystem autosomal recessive disorder characterized by exocrine pancreatic dysfunction, bony metaphyseal dysostosis, and varying degrees of marrow dysfunction with cytopenias. Myelodysplastic syndrome and acute myeloid leukemia occur in up to one third of patients (summary by Dror and Freedman, 1999).
For a review of Shwachman-Diamond syndrome, see Dror and Freedman (2002).
Genetic Heterogeneity of Shwachman-Diamond Syndrome
Shwachman-Diamond syndrome-2 (SDS2; 617941) is caused by mutation in the EFL1 gene (617538) on chromosome 15q25.
Shwachman et al. (1964) described a syndrome of pancreatic insufficiency (suggesting cystic fibrosis of the pancreas but with normal sweat electrolytes and no respiratory difficulties) and pancytopenia. One sibship contained 2 affected brothers and an affected female. From the early paper of Bartholomew et al. (1959) it appears that so-called primary atrophy of the pancreas may be, in some instances, the same disorder and that manifestations may develop first after the fifth decade of life. The same syndrome was described by Nezelof and Watchi (1961) and later by other authors such as Pringle et al. (1968). Goldstein (1968) and others before him called this condition congenital lipomatosis of the pancreas. He described one affected fraternal twin girl. Affected sibs were referred to by Burke et al. (1967). Pringle et al. (1968) observed associated skeletal changes of the metaphyseal dysostosis type. These are of interest because of the digestive abnormalities (not yet well characterized) and hematologic changes in cartilage-hair hypoplasia (250250), a form of metaphyseal chondrodysplasia. The exocrine pancreas is replaced by fat, whereas the islets of Langerhans are normal.
Although dwarfing is usually moderate and becomes apparent only after 1 or 2 years of life, Danks et al. (1976) described 2 pairs of brothers who showed neonatal respiratory distress, resembling that of Jeune syndrome (208500), due to abnormally short ribs. The true nature of the osseous disorder became clear in the second or third year of life. Susceptibility to infection was marked in 1 family and led to death of 1 of the brothers.
Wulfeck et al. (1991), who referred to this disorder as Shwachman-Diamond syndrome, evaluated 2 affected sisters, aged 8 and 13 years, in whom the most prominent neurologic abnormality was global apraxia, which affected their motor skills. Generalized weakness and hypotonia were also observed.
Mack et al. (1996) reviewed findings in 25 patients. Mean birth weight 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. Neutropenia was the most common hematologic abnormality (88%), but leukopenia, thrombocytopenia, and anemia were also frequently encountered. Eleven patients with hypoplasia of all 3 bone marrow cellular lines had the worst prognosis; 5 patients died, 2 of sepsis and 3 of acute myelogeneous leukemia (AML; 601626).
Ginzberg et al. (1999) collected data from 116 families with Shwachman syndrome. In 88 patients (33 female, 55 male; median age, 5.2 years), their predetermined diagnostic criteria were fulfilled; 63 patients represented isolated cases, and 25 affected sibs 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. Similarities in phenotype between isolated cases and affected sib sets supported the hypothesis that Shwachman syndrome is a single disease entity.
Cipolli et al. (1999) provided long-term follow-up of 13 patients with Shwachman syndrome diagnosed in infancy. At diagnosis, growth retardation and pancreatic insufficiency were present in all. Hematologic features, repeated respiratory infections during the first years of life, and skeletal abnormalities were frequently observed. Other associated features included hepatic involvement and occasional renal dysfunction. One patient died in infancy of respiratory infection. Six were under observation at other centers. Of the 6 patients followed up by the authors (mean age of 10 years at the time of study), a significant growth improvement was observed. In 5, the pancreatic stimulation test showed values of lipase within reference range outputs, whereas fat balance or fecal fat losses were normal in all but 1. Of 7 subjects assessed by psychologic evaluation, IQ test results were markedly abnormal in one and bordered on abnormality in the others. This study underlined the possibility of improvement or normalization of exocrine pancreatic function, as well as decreasing the frequency of infections, with age.
Toiviainen-Salo et al. (2008) investigated brain structures by MRI in 9 patients (7 males, age range 7-37 years) with SDS and mutations in the SBDS gene and in 18 age- and gender-matched controls. Eight of the 9 SBDS mutation-verified patients reported learning difficulties. Patients with SDS had smaller occipitofrontal head circumferences than the controls, and decreased global brain volume; both gray matter and white matter volumes were reduced. Patients with SDS had no macroscopic brain malformations, but they had significantly smaller age- and head size-adjusted areas of posterior fossa, vermis, corpus callosum, and pons, and significantly larger cerebrum-vermis ratio than the healthy controls.
Hematologic Abnormalities and Leukemic Transformation
Patients with Shwachman-Diamond syndrome are predisposed to hematologic malignancies similar to those that occur with Fanconi anemia (227650) (Woods et al., 1981).
Smith et al. (1996) reported hematologic abnormalities in 21 children diagnosed with Shwachman-Diamond syndrome at their institution over 25 years. Anemia was found in 14 patients, thrombocytopenia in 5, and pancytopenia in 2. Bone marrow cellularity was decreased in 5 and increased in 3 of 13 patients studied. Cytogenetic examination of the bone marrow showed clonal abnormalities in 4 of 12 children at the time of diagnosis, and 1 boy developed a clonal abnormality later in the course of his illness. Chromosome 7 was involved in rearrangements in 4 children. Myelodysplastic syndrome developed in 7 patients (including all 5 with clonal bone marrow abnormalities); 5 of these persons developed acute myeloid leukemia and died. Smith et al. (1996) showed that the actual risk of leukemic transformation in the patients with Shwachman-Diamond syndrome is much higher than 5% (as it was previously considered), and that clonal cytogenetic abnormalities in the bone marrow predispose to such transformation.
Dokal et al. (1997) described 3 men (2 of whom were brothers) with Shwachman-Diamond syndrome who presented with acute myeloid leukemia in adulthood. The brothers were 37 and 43 at time of presentation. The third patient was 25 years old. Dokal et al. (1997) pointed out that of the cases of acute myeloid leukemia in Shwachman-Diamond syndrome, approximately one-quarter (5 in 18) have M6 morphology. They suggested that the only therapy likely to be successful is allogeneic bone marrow transplantation, which was reportedly successful in several cases.
In 8 SDS patients who did not have evidence of MDS or AML, Leung et al. (2006) found increased bone marrow microvessel density compared to controls. Vessels from SDS patients were more tortuous and showed collapsed or constricted lumens, whereas control specimens showed more open and organized vascular architecture. Stromal expression of VEGF (192240), stromal VEGF secretion, and secretion and serum and marrow levels of VEGF did not differ between the 2 groups. As increased marrow angiogenesis and morphologic abnormalities are characteristically observed in patients MDS and AML, even in the absence of SDS, Leung et al. (2006) postulated that the marrow changes observed in this study may be associated with the increased risk for MDS or AML in SDS patients.
Genieser et al. (1982) demonstrated the usefulness of computed tomography (CT scan) in the diagnosis.
Ip et al. (2002) used a classification and regression tree analysis (CART) to define a pancreatic phenotype based on serum trypsinogen and isoamylase measurements in 90 patients confirmed to have SDS compared to 134 controls. They then studied the usefulness of the CART-defined pancreatic phenotype in determining the diagnosis of SDS in 35 patients with 'probable' and 39 patients with 'improbable' SDS. All confirmed patients older than 3 years were classified correctly using the CART analysis. The CART-defined pancreatic phenotype was found in 82% of 'probable' and 7% of 'improbable' SDS patients older than 3 years. Ip et al. (2002) concluded that the pancreatic phenotype was diagnostically useful.
Rothbaum et al. (1982) postulated that abnormal polymorphonuclear chemotaxis reflects defective cytoskeletal integrity in the Shwachman syndrome. In support of this idea, they demonstrated abnormal distribution of concanavalin-A receptors on polymorphonuclear leukocytes.
Dror and Freedman (1999) showed that the bone marrow of patients with SDS is characterized by a decreased frequency of CD34+ (142230) cells and that marrow CD34+ cells have a reduced ability to form hematopoietic colonies in vitro. For these reasons, and because apoptosis is central in the pathogenesis of bone marrow dysfunction in myelodysplastic syndrome, Dror and Freedman (2001) studied the role of apoptosis in the pathogenesis of marrow failure in 11 children with SDS. Compared to normal controls, the patients' marrow mononuclear cells plated in clonogenic cultures showed a significantly higher tendency to undergo apoptosis. The defect was found in patients with and without myelodysplastic syndrome. They concluded that SDS hematopoietic progenitors are intrinsically flawed and have faulty proliferative properties and increased apoptosis. Bone marrow failure is linked to an increased propensity for apoptosis, which in turn is linked to increased expression of the Fas antigen (134637) and to hyperactivation of the Fas signaling pathway.
Although immunologic abnormalities are not traditionally perceived as part of SDS, patients with the disorder are prone to recurrent infections even in the face of protective neutrophil counts. Dror et al. (2001) studied immune function in 11 patients. Seven suffered from recurrent bacterial infections and 6 from recurrent viral infections. All patients had neutropenia; total lymphocyte counts, however, were normal in all but 1 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 of 9 patients studied had at least one T-cell abnormality. Five of 6 patients studied had decreased percentages of circulating natural killer cells. Moreover, neutrophil chemotaxis was significantly low in all of the patients studied.
Bone marrow failure is believed to be the underlying condition that drives the expansion of the paroxysmal nocturnal hemoglobinuria (PNH; 300818) clone. Circulating PNH blood cells have been identified in patients with acquired aplastic anemia and with hypoplastic myelodysplasia. To determine whether PNH blood cells are also present in patients with inherited aplastic anemia, Keller et al. (2002) screened a large group of patients with Shwachman-Diamond syndrome. None of the patients analyzed had detectable circulating PNH blood cells, indicating that bone marrow failure in Shwachman-Diamond syndrome does not select for PNH progenitor cells.
Thornley et al. (2002) found that telomere length in leukocytes derived from SDS patients was significantly shortened compared to controls. The mean telomere length was 1.4-kb shorter than controls and did not differ according to disease severity. Thornley et al. (2002) suggested that bone marrow stem cell hyperproliferation is a feature of SDS from the outset.
Austin et al. (2008) found that primary bone marrow stromal cells and lymphoblasts from SDS patients exhibited an increased incidence of abnormal mitoses. Depletion of the SBDS gene using siRNA in normal skin fibroblasts resulted in increased mitotic abnormalities and aneuploidy that accumulated over time. Treatment of primary cells from SDS patients with nocodazole, a microtubule destabilizing agent, led to increased mitotic arrest and apoptosis compared to treated wildtype cells. In addition, SDS patient cells were resistant to taxol, a microtubule stabilizing agent. These findings suggested that spindle instability in SDS contributes to bone marrow failure and leukemogenesis. In wildtype human cells, Austin et al. (2008) found that SBDS colocalized with mitotic spindles and bound to purified microtubules, preventing genomic instability.
Using single-cell RNA sequencing, Joyce et al. (2019) found that TGFB (TGFB1; 190180) signaling was selectively activated through TGFBR1 (190181) in stem and multipotent progenitors of bone marrow (BM) cells from patients with SDS. TGFB pathway activation suppressed hematopoiesis in SDS BM progenitors and contributed to BM failure in patients with SDS. In contrast, attenuation of TGFB signaling by TGFBR1 inhibitors improved SDS hematopoiesis. Furthermore, levels of TGFB ligands were elevated in blood plasma of SDS patients. The results suggested that TGFB signaling underlies hematopoietic dysfunction and BM failure in SDS.
Ginzberg et al. (2000) determined estimates of segregation proportion in a cohort of 84 patients with Shwachman-Diamond syndrome with complete sibship data under the assumption of complete ascertainment, using the Li and Mantel estimator (Li and Mantel, 1968), and of single ascertainment with the Davie modification (Davie, 1979). A third estimate was computed with the expectation-maximization algorithm. All 3 estimates supported an autosomal recessive mode of inheritance, but complete ascertainment was found to be unlikely. No consistent differences were found in levels of serum trypsinogen (to indicate exocrine pancreatic dysfunction) between parents (presumed heterozygotes) and a normal control population. Ginzberg et al. (2000) suggested that although genetic heterogeneity could not be excluded, the results indicated that a recessive model of inheritance for this syndrome should be considered.
Tada et al. (1987) found increased frequencies of spontaneous chromosome aberrations in a patient's PHA-stimulated circulating lymphocytes; however, the lymphocytes did not show increased sensitivity to mitomycin C. In 2 affected sisters, Fraccaro et al. (1988) were unable to confirm the observation of Tada et al. (1987) of increased chromosome aberrations.
Masuno et al. (1995) observed a de novo and apparently balanced reciprocal translocation, t(6;12)(q16.2;q21.2), in an 18-month-old girl with Shwachman syndrome, characterized by exocrine pancreatic insufficiency in bone marrow dysfunction. They suggested that the translocation breakpoints in this patient are candidate regions for a gene responsible for Shwachman syndrome. Both 6q and 12q were excluded by linkage studies reported by Goobie et al. (1999). The genetic analysis was performed on members of 13 Shwachman-Diamond syndrome families with 2 or 3 affected children.
Smith et al. (1995) described a 5-year-old boy with this disorder in whom acute monoblastic leukemia developed following a period of myelodysplasia associated with a clonal cytogenetic abnormality involving chromosome 7.
Children with SDS are predisposed to myelodysplasia and AML, often with chromosome 7 abnormalities. Cunningham et al. (2002) reported on 9 children with SDS, 8 of whom had clonal abnormalities of chromosome 7. They presented evidence suggesting that isochromosome 7q may represent a separate disease entity in SDS children, which is interesting given that the SDS gene maps to the centromeric region of chromosome 7. Their clinical observations suggested that isochromosome 7q is a relatively benign rearrangement and that it is not advisable to offer allogeneic transplants to SDS children with isochromosome 7q alone in the absence of other clinical signs of disease progression.
From an investigation of 14 patients with Shwachman syndrome (SS), using standard and molecular cytogenetic methods and molecular genetic techniques, Maserati et al. (2006) made several observations. They showed that the i(7)(q10) is not, or is not always, an isochromosome but may arise from a more complex mechanism, retaining part of the short arm; that the i(7)(q10) has no preferential parental origin; and that clonal chromosome changes, such as chromosome 7 anomalies and del(20)(q11), may be present in the bone marrow for a long time without progressing to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). The del(20)(q11) involves the minimal region of deletion typical of MDS/AML. The rate of chromosome breaks is not significantly higher than in controls, from which it can be concluded that SS should not be considered a breakage syndrome. A specific kind of karyotype instability is present in SS, with chromosome changes possibly found in single cells or small clones, often affecting chromosome 7 and 20, in the bone marrow. Maserati et al. (2006) considered these findings as confirming their previous hypothesis that the SS mutation itself implies a mutator effect that is responsible for MDS/AML through these specific chromosome anomalies. The conclusion supports the practice of including cytogenetic monitoring in the follow-up of SS patients.
In a genomewide scan of families with SDS, Goobie et al. (2001) identified chromosome 7 markers that showed linkage with the disorder. Finer mapping revealed significant linkage across a broad interval that included the centromere. The maximum 2-point lod score was 8.7, with D7S473, at a recombination fraction of 0.0. 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 was suggested by the heterogeneity of disease-associated haplotypes in the candidate region.
Popovic et al. (2002) constructed a physical map of the pericentromeric region of chromosome 7 containing the locus for SDS, by using somatic cell hybrid, radiation hybrid, and STS-content mapping of YAC and BAC clones. A total of 34 SDS families of diverse ethnic origin were studied by linkage disequilibrium analysis, which identified 6 extended haplotypes to co-segregate with the disease in unrelated families of common ethnic origin. These observations suggested existence of multiple founder chromosomes (allelic heterogeneity) in SDS. Detection of ancestral and intrafamilial recombination events refined the SDS locus to a 1.9-cM critical interval (predicted size: 3.3 Mb) between markers D7S2429 and D7S502 at chromosome 7q11.
Boocock et al. (2003) identified 18 positional candidate genes in 7q11, the region to which the Shwachman-Diamond syndrome maps. In patients with SDS, they identified mutations in a theretofore uncharacterized gene, which they designated SBDS (see 607444.0001-607444.0004).
By Sanger sequencing in 2 patients with SDS, Yamada et al. (2020) identified compound heterozygous mutations in the SBDS gene: c.258+2T-C (607444.0002) on one allele and c.183-184TA-CT (607444.0001) and c.201A-G on the other allele. However, the c.183-184TA-CT and c.201A-G variants were not identified by whole-exome sequencing in either patient. Yamada et al. (2020) concluded that these variants were missed by whole-exome analysis due to mismapping of reads resulting from the inability to discriminate between SBDS and the SBDSP1 pseudogene. All 3 variants were identified with transcriptome analysis via RNAseq in blood samples from both patients, leading Yamada et al. (2020) to conclude that RNA-seq is an effective assay for the diagnosis of SDS.
Exclusion Studies
Dale et al. (2000) found no mutations in the neutrophil elastase gene (130130) in 3 patients with Shwachman-Diamond syndrome.
By sequence analysis in 5 SDS patients, Popovic et al. (2002) found no disease-causing mutations in the tyrosylprotein sulfotransferase 1 gene (TPST1; 603125). Large-scale gene rearrangements were also excluded by Southern blot analysis, and RT-PCR analysis failed to detect alterations in gene expression, thereby excluding TPST1 as the causative gene for SDS.
Kuijpers et al. (2005) sequenced the SBDS gene in 20 unrelated patients with clinical SDS and identified mutations in 15 (75%), with identical compound heterozygosity in 11 patients (see 607444.0001 and 607444.0002). The authors examined hematologic parameters over 5 years of follow-up and observed persistent neutropenia in 43% in the absence of apoptosis and unrelated to chemotaxis defects or infection rate. Irrespective of the absolute neutrophil count in vivo, abnormal granulocyte-monocyte colony formation was observed in all patients with SDS tested (14 of 14), whereas erythroid and myeloid colony formation was less often affected (9 of 14). Cytogenetic aberrations occurred in 5 of 19 patients in the absence of myelodysplasia. Kuijpers et al. (2005) concluded that in patients with genetically proven SDS, a genotype/phenotype relationship does not exist in clinical and hematologic terms.
Scott Hamilton, 1984 Olympic Gold Medalist figure skater, was ill as a child with Shwachman syndrome.
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