LIPOMATOSIS OF PANCREAS, CONGENITAL
SHWACHMAN-BODIAN SYNDROME
PANCREATIC INSUFFICIENCY AND BONE MARROW DYSFUNCTION
SDS
Congenital lipomatosis of pancreas
Shwachman-Diamond syndrome is characterized primarily by exocrine pancreatic insufficiency, hematologic abnormalities, including increased risk of malignant transformation, and skeletal abnormalities.
For a review of Shwachman-Diamond syndrome, see Dror and Freedman (2002).
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 ... 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. 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. 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.
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 ... 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.
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 ... 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. Boocock et al. (2003) identified 18 positional candidate genes in 7q11, the region to which the Shwachman-Diamond syndrome maps. They discovered mutations associated with a theretofore uncharacterized gene, which they designated SBDS (607444).
The clinical diagnosis of Shwachman-Diamond syndrome (SDS) relies on evidence of exocrine pancreatic dysfunction and bone marrow failure with single- or multi-lineage cytopenia [Rothbaum et al 2002]....
DiagnosisClinical DiagnosisThe clinical diagnosis of Shwachman-Diamond syndrome (SDS) relies on evidence of exocrine pancreatic dysfunction and bone marrow failure with single- or multi-lineage cytopenia [Rothbaum et al 2002].Exocrine pancreatic dysfunction can be documented with any one of the following:An abnormal fecal fat balance study of a 72-hour stool collection (with exclusion of intestinal mucosal disease or cholestatic liver disease) plus abnormal exocrine pancreas on imagingLow serum concentrations of the digestive enzymes pancreatic isoamylase and cationic trypsinogenDeficiency in pancreatic enzyme secretion following quantitative pancreatic stimulation testing with intravenous cholecystokinin and secretinNote: Exocrine pancreatic dysfunction may be difficult to detect because the production of individual pancreatic enzymes varies during childhood and because severe perturbations of enzyme levels are required to meet diagnostic criteria [Schibli et al 2006]:Serum pancreatic isoamylase concentration is not reliable in children younger than age three years [Ip et al 2002].Serum cationic trypsinogen concentration increases to pancreatic-sufficient levels during early childhood in approximately 50% of children with SDS [Durie & Rommens 2004].Pancreatic histopathology reveals few acinar cells and extensive fatty infiltration. Pancreatic imaging studies with ultrasonography or CT reveal small size for age. In a series of persons with mutation-positive SDS, MRI revealed fatty infiltration with retained ductal and islet components [Toiviainen-Salo et al 2008].Hematologic abnormalities caused by bone marrow dysfunction involve one or more of the following:Persistent or intermittent depression of at least one myeloid lineage:Neutropenia (established with an absolute neutrophil count <1,500 neutrophils /mm3 for ≥3 measurements taken over a period of ≥3 months)Thrombocytopenia (persistent, with platelet count <150,000 platelets/mm3)Anemia (with hemoglobin concentration below the normal range for age)Pancytopenia (trilineage cytopenia with persistent neutropenia, thrombocytopenia, and anemia)Bone marrow examination may reveal the following:Varying degrees of hypocellularity and fatty infiltration of the marrow compartments, indicating marrow failure and disordered hematopoiesisMaturation arrest or delay in single- or multiple-myeloid lineagesAplastic anemia and myelodysplasia with or without abnormal cytogenetic findings. When cytogenetic anomalies are present, they can be monosomy 7, isochromosome 7, or other chromosomal changes seen in bone marrow failure syndromes.Studies in which patient and non-patient marrow cells are co-cultured indicate problems with both the stem cell and stromal microenvironment compartments [Dror & Freedman 1999]. These findings, together with the wide range of abnormalities seen in the bone marrow, are consistent with SDS being a bone marrow failure syndrome.Other. Variation in severity and clinical manifestations complicate the ability to establish a definitive diagnosis of SDS. Other primary features used in support of the diagnosis:Short statureSkeletal abnormalitiesHepatomegaly with or without elevation of serum aminotransferase levelsMolecular Genetic TestingGene. SBDS is the only gene presently known to be associated with SDS [Boocock et al 2003].Evidence for locus heterogeneity. A limited number (<10%) of persons with clear clinical indications of SDS do not appear to have mutations in SBDS, suggesting that mutations in another gene(s) may be causative.TestingTargeted mutation analysis. In more than 90% of individuals with SDS, at least one of the mutant SBDS alleles has resulted from a phenomenon known as gene conversion (see Molecular Genetics). The three most common gene conversion mutations account for more than 76% of disease alleles (Note: In >62% of affected individuals, the following mutations account for both disease-causing alleles):c.183_184delinsCTc.258+2T>Cc.[183_184delinsCT; 258+2T>C], in which both mutations occur on a single alleleSequence analysis. The common gene conversion mutations can be detected by direct sequencing of exon 2 [Boocock et al 2003], accounting for 76% of the SDS-causing alleles in more than 200 families [Author, unpublished]. Most of the other rare mutations, including splicing mutations, short insertions or deletions, and missense mutations, can be identified by direct sequencing of the five exons of SBDS.Unusual mutations that involve exon deletions [Costa et al 2007], extended conversions of exon 2 and flanking introns, or gene rearrangements involving exon 2 have been observed but may not be detected readily with routine sequencing [Author, unpublished]. In these cases, testing with methods that detect the number of copies of SBDS exons is necessary (e.g., quantitative PCR methods); however, their interpretations must consider the occurrence of the pseudogene. The extent of variation in the pseudogene is not known.Table 1. Summary of Molecular Genetic Testing Used in Shwachman-Diamond SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySBDSTargeted mutation analysisCommon mutations c.183_184delinsCT, c.258+2T>C, and c.[183_184delinsCT; 258+2T>C] 276% 3ClinicalSequence analysisSequence variants, including the common mutations listed above>90% 41. The ability of the test method used to detect a mutation that is present in the indicated gene2. Targeted mutations, and therefore detection frequencies, may vary among laboratories.3. Targeted mutation analysis for these three common mutations can detect at least one mutation in 90% of affected individuals.4. If exocrine pancreatic dysfunction and characteristic hematologic abnormalities have been documented, the proportion of affected individuals with mutations in SBDS is high.Interpretation of test results. To interpret the common gene conversion mutations identified by targeted mutation analysis, parents should be tested to determine whether the mutation(s) observed in their child are:Monoallelic (e.g., c.[183_184delinsCT; 258+2T>C] on one chromosome and a normal allele on the other chromosome) OR Biallelic (e.g., c.183_184delinsCT on one chromosome and c.258+2T>C on the other chromosome)For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyConfirmation of the diagnosis in a proband. If both exocrine pancreatic dysfunction and characteristic hematologic abnormalities are present, it is appropriate to proceed with molecular genetic testing of SBDS:Targeted mutation analysis for the three common mutations in exon 2 can detect at least one mutation in 90% of affected individuals.If no mutation or only one mutation is identified using targeted mutation analysis, sequence analysis of the whole coding region can be performed.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with variations in SBDS.Note: (1) Although a recent publication suggested that carriers with one normal and one disease-causing SBDS allele may be at higher-than-average risk for aplastic anemia [Calado et al 2007], methodic problems with this study may include the following:Background risk of being a SBDS carrier (1/139) did not appear to be considered.Criteria for performing sequence analysis on individuals with aplastic anemia were not clearly delineated.(2) Aplastic anemia has not been observed in SBDS heterozygotes (i.e., carriers) of more than 200 families with SDS [Authors, personal observation].(3) Sequence analysis of DNA obtained from bone marrow samples from 77 persons with acute myelogeneous leukemia (AML) did not reveal any SBDS mutations [Majeed et al 2005].
The clinical spectrum of Shwachman-Diamond syndrome (SDS) is broad and varies among affected individuals, even sibs [Ginzberg et al 1999]. Despite this variability, both gastrointestinal and hematologic findings are observed in all affected individuals [Cipolli et al 1999, Ginzberg et al 1999]....
Natural HistoryThe clinical spectrum of Shwachman-Diamond syndrome (SDS) is broad and varies among affected individuals, even sibs [Ginzberg et al 1999]. Despite this variability, both gastrointestinal and hematologic findings are observed in all affected individuals [Cipolli et al 1999, Ginzberg et al 1999].Neonates generally do not show manifestations of SDS; however, early presentations have included acute life-threatening infections and asphyxiating thoracic dystrophy caused by rib cage restriction. Rare neonatal presentations have also included severe bone marrow failure and aplastic anemia [Kuijpers et al 2005] or severe spondylometaphyseal dysplasia [Nishimura et al 2007].More commonly, SDS presents in infancy with failure to thrive and poor growth secondary to exocrine pancreatic dysfunction, and recurrent infections secondary to neutropenia and impaired neutrophil chemotaxis, which are likely the most critical contributors to frequent recurrent infections, especially in young children [Dror & Freedman 2002, Stepanovic et al 2004, Kuijpers et al 2005]. Persistent or intermittent neutropenia is recognized first in almost all affected children, often before the diagnosis is made; in one series of 88 children, neutropenia was a presenting finding in 98% [Ginzberg et al 1999]. Acute and deep-tissue infections can be life threatening, particularly in young children [Cipolli 2001, Grinspan & Pikora 2005].The risk for leukemia, typically AML, may be 15%-25% or higher in individuals with SDS than in the general population [Dror & Freedman 2002]. Although information is limited to a few studies, a retrospective survey over 25 years revealed that seven of 21 individuals with SDS developed myelodysplastic syndrome; five of the seven developed AML [Smith et al 1996]. In a more recent study, eight of 71 persons with SDS developed MDS and/or leukemia over a ten-year period [Donadieu et al 2005].The risks for transformation with dysplastic cytologic abnormalities and AML are considered to be lifelong; AML is generally associated with poor outcome [Donadieu et al 2005]. The risk for malignancies other than AML does not appear to be increased, but information to date is limited.Characteristic skeletal changes appear to be present in all mutation-positive individuals [Mäkitie et al 2004]; however, skeletal manifestations vary among individuals and over time. In some individuals the skeletal findings may be sub-clinical.Cross-sectional and longitudinal data from the study of Mäkitie et al [2004] revealed the following:Delayed appearance of secondary ossification centers, causing bone age to appear to be delayedVariable widening and irregularity of the metaphyses in early childhood (i.e., metaphyseal chondrodysplasia), followed by progressive thickening and irregularity of the growth platesGeneralized osteopeniaOf note, the epiphyseal maturation defects tended to normalize with age and the metaphyseal changes tended to progress (worsen) with age [Mäkitie et al 2004].Additional skeletal findings can include rib abnormalities and joint abnormalities, the latter of which can result from asymmetric growth and can be sufficiently severe to warrant surgical intervention.Children with adequate nutrition and pancreatic enzyme supplementation have normal growth velocity and appropriate weight for height; however, approximately 50% of children with SDS are below the third percentile for height and weight [Durie & Rommens 2004].Hepatomegaly and liver dysfunction with elevated serum aminotransferase concentration can be observed in young children, but tend to resolve by age five years. Mild histologic changes may also be evident in biopsies, and although they do not appear to be progressive, it has been noted that liver complications have occurred in older individuals following bone marrow transplantation [Ritchie et al 2002].Other possible findings:Ichthyosis and eczematous lesionsOral disease including delayed dental development, increased dental caries in both primary and permanent teeth, and recurrent oral ulcerations [Ho et al 2007]Cognitive and/or behavioral problems [Cipolli et al 1999, Ginzberg et al 1999]; however, few studies have described their full extent and range [Kent et al 1990; E Kerr, personal communication].Immune dysfunction [Dror et al 2001]Kidney or urinary tract anomalies
No genotype-phenotype correlations have been observed with SBDS mutations [Mäkitie et al 2004; Kawakami et al 2005; Kuijpers et al 2005; Author, unpublished]; this is consistent with the earlier observed phenotypic variability among affected sibs [Ginzberg et al 1999]....
Genotype-Phenotype CorrelationsNo genotype-phenotype correlations have been observed with SBDS mutations [Mäkitie et al 2004; Kawakami et al 2005; Kuijpers et al 2005; Author, unpublished]; this is consistent with the earlier observed phenotypic variability among affected sibs [Ginzberg et al 1999].
Features of Shwachman-Diamond syndrome (SDS) in early childhood, such as poor growth and transient neutropenia, may have multiple causes in young children....
Differential DiagnosisFeatures of Shwachman-Diamond syndrome (SDS) in early childhood, such as poor growth and transient neutropenia, may have multiple causes in young children.Pancreatic DysfunctionCystic fibrosis, which often presents with both upper-respiratory infections and exocrine pancreatic dysfunction, can be distinguished from SDS by sweat chloride testing and absence of primary bone marrow failure.Other conditions with exocrine pancreatic dysfunction:Johanson-Blizzard syndrome, which can be distinguished from SDS by the characteristic anomalies, severe developmental delays, and absence of hematologic abnormalitiesPearson bone marrow-pancreas syndrome, a rare mitochondrial disorder with both exocrine pancreatic dysfunction and bone marrow dysfunction, which can be distinguished from SDS by bone marrow examination and molecular genetic testingExocrine pancreatic insufficiency can also result from severe malnutrition.Other bone marrow failure syndromes that overlap in some respects with SDS include the following:Diamond-Blackfan anemiaFanconi anemiaDyskeratosis congenitaThese conditions and aplastic anemia can often be excluded by clinical investigations and bone marrow examination. Primary exocrine pancreatic dysfunction is not known to occur is these related syndromes.NeutropeniaTransient neutropenia can result from medications or infections.Clinical findings, repeated assessments of hematologic findings, and molecular genetic testing reliably distinguish SDS from Kostmann congenital neutropenia and ELANE-related neutropenia.Skeletal DysplasiaCartilage-hair hypoplasia (CHH) syndrome has gastrointestinal, skeletal, hematologic, and immunologic features. However, the skeletal anomalies of CHH can be distinguished from those of SDS, and the gastrointestinal features of CHH are secondary to complications of infections rather than to exocrine pancreatic insufficiency.
To establish the extent of disease following the initial diagnosis of Shwachman-Diamond syndrome (SDS), the following evaluations to assess the status of the pancreas, liver, bone marrow, and skeleton are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease following the initial diagnosis of Shwachman-Diamond syndrome (SDS), the following evaluations to assess the status of the pancreas, liver, bone marrow, and skeleton are recommended:Assessment of growth: height, weight in relation to ageAssessment of developmental milestones (including pubertal development)Assessment of nutritional status to determine if supplementation with pancreatic enzymes is necessary and/or effective:Measurement of fat-soluble vitamins (vitamin A, 25-OH-vitamin D, and vitamin E) or their related metabolitesMeasurement of prothrombin time (to detect vitamin K deficiency)Assessment of serum concentration of the digestive enzyme cationic trypsinogen and, if sufficiency is observed, followed by confirmation with 72-hour fecal fat balance study (with discontinuation of enzyme supplementation for at least a 24-hour period)Assessment of serum aminotransferase levelsComplete blood count with white cell differential and platelet count at six-month intervals (or more often as clinically indicated)Bone marrow examination with biopsy and cytogenetic studies at initial assessment Note: Current practice typically involves these studies; discussions to develop uniform recommendations are ongoing.Skeletal survey with radiographs of at least the hips and lower limbsTreatment of ManifestationsA multidisciplinary team that includes specialists from the following fields is recommended: hematology, gastroenterology, medical genetics, orthopedics, endocrinology, immunology, dentistry, child development, psychology, and social work as needed [Dror & Freedman 2002, Rothbaum et al 2002, Durie & Rommens 2004].Exocrine pancreatic insufficiency can be treated with the same oral pancreatic enzymes commonly used in treatment of cystic fibrosis; dose should be based on results of routine assessment of pancreatic function and nutritional status. Steatorrhea often resolves in early childhood, but pancreatic enzyme levels can remain low; routine monitoring (see Surveillance) is recommended.Supplementation with fat-soluble vitamins (A, D, E, and K) is recommended.Blood and/or platelet transfusions may be considered for anemia and bi- or trilineage cytopenia.If recurrent infections are severe and absolute neutrophil counts are persistently 500/mm3 or less, treatment with prophylactic antibiotics and granulocyte-colony stimulation factor (G-CSF) can be considered.Hematopoietic stem cell transplantation (HSCT) can be considered for treatment of severe pancytopenia, bone marrow transformation to myelodysplastic syndrome, or AML. Cells from both bone marrow and cord blood have been used. Although earlier reports indicate that survival is fair, cautious myeloablation and newer regimens show promise for improving outcomes [Cesaro et al 2005; Vibhakar et al 2005; Sauer et al 2007; R Harris, personal communication].Note: Bone marrow abnormalities, per se, are not treated unless severe aplasia, myelodysplastic fluxes, or leukemic transformation are present.Children with poor growth and delayed puberty benefit from ongoing consultation with an endocrinologist, who may also consult with orthopedists regarding possible surgical management of asymmetric growth and joint deformities.Although cognitive, learning, and behavioral features of SDS have been less well investigated than other aspects, remedial interventions are considered beneficial [E Kerr, personal communication].For pregnancies in women with SDS, high-risk pregnancy care including consultation with a hematologist is recommended.Prevention of Secondary ComplicationsFrequent dental visits to monitor tooth development and oral health are recommended to reduce the incidence of mouth ulcers and gingivitis. Home care should include aggressive dental hygiene with topical fluoride treatments to help prevent dental decay [M Glogauer, personal communication].Prophylactic antibiotics and G-CSF may be especially helpful when interventions such as complex dental procedures or orthopedic surgery are being considered.SurveillanceThe following is recommended given the intermittent nature of some features of SDS and the evolution of the phenotype over time [Rothbaum et al 2002]:Developmental and growth assessment every six monthsAssessment of nutritional status every six months and measurement of serum concentration of vitamins to evaluate effectiveness of or need for pancreatic enzyme therapyComplete blood counts with white blood cell differential and platelet counts at least every six months, or more frequently if infections are recurrent and debilitatingCurrent practice is to repeat bone marrow examinations every one to three years following the baseline examination. These should be more frequent if changes in bone marrow function or cellularity are observed. Note: Discussions to develop uniform recommendations are ongoing.Monitoring for orthopedic complications resulting from growth during childhood with bone density measurements and x-rays of hips and knees during the most rapid growth stagesAgents/Circumstances to AvoidProlonged use of cytokine and hematopoietic growth factors such as G-CSF is cautioned against in view of the potential for contribution to leukemic transformation [Rosenberg et al 2006].Some drugs, such as cyclophosphamide or cyclophosphamide and busulfan, typically used in standard preconditioning or preparative regimens for bone marrow transplantation may not be suitable because of possible cardiac toxicity [Mitsui et al 2004, Cesaro et al 2005, Vibhakar et al 2005, Sauer et al 2007].Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Shwachman-Diamond Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSBDS7q11.21Ribosome maturation protein SBDSResource of Asian Primary Immunodeficiency Diseases (RAPID) SBDS homepage - Mendelian genesSBDSData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Shwachman-Diamond Syndrome (View All in OMIM) View in own window 260400SHWACHMAN-DIAMOND SYNDROME; SDS 607444SBDS GENE; SBDSNormal allelic variants. The SBDS locus involves a total of five exons and spans less than 9 kb. Notable aspects of the gene are its pericentromeric location on chromosome 7q and occurrence within a 305-kb segment that appears duplicated and inverted, 5.8 megabases (Mb) distally [Boocock et al 2003]. Some of the normal allelic variants reflect the sequence of the pseudogene (SBDSP), indicating that they may have arisen by gene conversion events between the gene and the pseudogene.Pathologic allelic variants. The abnormalities identified in individuals with SDS lead to prematurely truncated proteins, splicing aberrations, and missense alterations.At least one allele in >90% of individuals with Shwachman-Diamond syndrome (SDS) has a mutation that apparently arose by gene conversion. The gene conversion event occurred between functional SBDS and a nonfunctional pseudogene copy (SBDSP), which has 97% sequence identity to SBDS. The high sequence identity between these two genes facilitates gene conversion, a phenomenon whereby a small segment of SBDS is replaced by a segment copied from the SBDSP pseudogene. Therefore, this segment of SBDS has sequence variants typical of the pseudogene; the variants that inactivate normal SBDS gene expression and/or translation of normal protein are pathogenic.The three most common converted pathologic alleles:c.183_184delinsCTc.258+2T>Cc.[183_184delinsCT; 258+2T>C]. Note: This allele has a longer converted segment with both variants occurring on one allele.These three alleles account for more than 76% of disease-causing alleles.Other alleles with more extensive converted regions involving exon 2, neighboring introns, and exon 1 have also been found [Authors, unpublished]. The rare c.297_300delAAGA mutation is also likely the consequence of gene conversion with SBDSP but involves only the exon 3 region.More than 38 novel sequence variants identified in the five exons of SBDS are consistent with loss-of-function alterations [Boocock et al 2003; Nakashima et al 2004; Woloszynek et al 2004; Nicolis et al 2005; Maserati et al 2006; Taneichi et al 2006; Author, unpublished]. Seven have been found in multiple, apparently unrelated, families (see Table 2).Except for one reported case to date, affected individuals with rare mutations occur as compound heterozygotes with one of the three common gene conversion mutations. In the one exception, an individual with a clinical diagnosis of SDS had two rare missense alleles in exons 3 and 4, respectively [Erdos et al 2006].Table 2. Selected SBDS Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference SequencesNormalc.141C>T 2p.(=) 3NM_016038.2 NP_057122.2c.201A>G 2p.(=)c.635T>C 4p.Ile212Thrc.651C>Tp.(=)Pathologicc.119delGp.Ser41Alafs*18c.183_184delinsCT 2(c.183TA>CT) p.Lys62Xc.[183_184delinsCT; 258+2T>C] 2p.Lys62Xc.258+1G>C--c.258+2T>C 2p.Cys84Tyrfs*4 c.297_300delAAGA 2p.Glu9Aspfs*20c.377G>Cp.Arg126Thrc.505C>Tp.Arg169Cysc.624+1G>C--c.652C>Tp.Arg218XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. Likely the consequence of gene conversion with SBDSP3. The designation p.(=) means that the protein has not been analyzed, but no change is expected.4. Initially reported to be a possible pathogenic alleleNormal gene product. SBDS encodes a highly conserved protein of 250 amino acids that appears to occur in all animals, plants, and archea [Boocock et al 2003]. The structural analysis of an archeal ortholog indicates that the SBDS protein contains three domains [Savchenko et al 2005, Shammas et al 2005].The modeling of several of the identified missense mutations onto the three-domain structure of the solved archael SBDS protein ortholog supports the likelihood that they are pathogenic [Savchenko et al 2005, Shammas et al 2005]. The SBDS protein is thought to play a role in RNA metabolism and ribosome biogenesis, and more recent genetic studies of the yeast homolog support a role in 60S ribosomal subunit biogenesis and translational activation [Menne et al 2007].Abnormal gene product. The mutations identified in individuals with SDS led to prematurely truncated proteins, splicing aberrations, and missense alterations. These mutations are predicted to result in absence or loss of function of the SBDS protein. Despite the relatively common occurrence of the null allele c.183_184delinsCT (p.Lys62X), no homozygotes have been reported. This is consistent with the observations of a mouse model in which complete loss of both Sbds alleles was not compatible with life [Zhang et al 2006]. It is therefore anticipated that some residual activity of the SBDS protein is required for development to occur.