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Shwachman-Diamond Syndrome

Synonyms: Pancreatic Insufficiency and Bone Marrow Dysfunction, Shwachman-Bodian-Diamond Syndrome, Shwachman Syndrome
, MD
Assistant Professor of Pediatrics, Division of Blood and Marrow Transplantation and Immune Deficiency
The Cancer and Blood Diseases Institute
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio

Initial Posting: ; Last Update: September 11, 2014.


Clinical characteristics.

Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; hematologic abnormalities with single- or multilineage cytopenias and susceptibility to myelodysplasia syndrome (MDS) and acute myelogeneous leukemia (AML); and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is a common presenting finding, often before the diagnosis of SDS is made. Short stature and recurrent infections are common.


The diagnosis of SDS relies on clinical findings, including pancreatic dysfunction and characteristic hematologic problems. The diagnosis is confirmed by detection of biallelic pathogenic variants in SBDS.


Treatment of manifestations: Care by a multidisciplinary team is recommended. Exocrine pancreatic insufficiency is treated with oral pancreatic enzymes and fat-soluble vitamin supplementation. Blood and/or platelet transfusions may be considered for anemia and/or thrombocytopenia associated with bi- or trilineage cytopenia. If recurrent infections are severe and absolute neutrophil counts are persistently 500/mm3 or less, treatment with granulocyte-colony stimulation factor (G-CSF) can be considered. Hematopoietic stem cell transplantation (HSCT) should be considered for treatment of severe pancytopenia, MDS, or AML.

Prevention of secondary complications: Aggressive dental hygiene should be pursued to promote oral health. Consider prophylactic antibiotics and G-CSF to reduce risk of infection during complex dental procedures or orthopedic surgery.

Surveillance: Complete blood counts at least every three to six months; assessment of development, growth, and nutritional status every six months. Following baseline examination, repeat bone marrow examination every one to three years or more frequently if bone marrow changes are observed. Monitor for orthopedic complications with x-rays of hips and knees during the most rapid growth stages. Perform bone densitometry before puberty, during puberty, and thereafter based on individual findings. Perform neuropsychological screening in children age 6-8 years, 11-13 years, and 15-17 years.

Agents/circumstances to avoid: Prolonged use of cytokine and hematopoietic growth factors (e.g., G-CSF) should be considered with caution. Some drugs used in standard HSCT preparative regimens (e.g., cyclophosphamide and busulfan) may not be suitable because of possible cardiac toxicity; milder ablation regimens have shown promising results in small studies.

Genetic counseling.

SDS is inherited in an autosomal recessive manner. Most parents of children with SDS are carriers; however, de novo SBDS pathogenic variants have been reported. When both parents are known to be carriers, the sibs of a proband have a 25% chance of being affected, a 50% chance of being an unaffected carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for relatives at risk and prenatal testing for pregnancies at increased risk are possible if both SBDS pathogenic variants in a family are known.


Although the diagnosis of Shwachman-Diamond syndrome (SDS) has classically relied on evidence of exocrine pancreatic dysfunction and bone marrow failure with single- or multilineage cytopenia [Rothbaum et al 2002, Dror et al 2011, Myers et al 2013a], a publication based on the North American SDS registry reported that almost half of the 37 individuals with genetically confirmed SDS did not have this classic combination of manifestations [Myers et al 2014], indicating that the phenotypic spectrum of SDS is broader than previously thought, leading to underdiagnosis when the diagnosis is based on clinical findings alone. Myers et al [2014] found that the features supporting the diagnosis of SDS in individuals with neutropenia included bone marrow abnormalities (hypocellularity, dysplasias, and clonality for deletion 20q11), as well as the presence of congenital anomalies and a family history consistent with autosomal recessive inheritance of SDS.

The majority of individuals with SDS harbor biallelic pathogenic variants in SBDS; approximately 10% of individuals with clinically diagnosed SDS do not. A clinical diagnosis of SDS in these individuals may still be made on the basis of the classic findings of (documented) exocrine pancreatic dysfunction and hematologic manifestations.

Suggestive Findings

Exocrine pancreatic dysfunction can be documented with any one of the following:

  • Low serum concentrations of the digestive enzymes pancreatic isoamylase and cationic trypsinogen, adjusted to age *
  • Low levels of fecal elastase
  • Supportive features include:
    • An abnormal fecal fat balance study of a 72-hour stool collection (with exclusion of intestinal mucosal disease or cholestatic liver disease)
    • Evidence of pancreatic lipomatosis on imaging
    • Reduced levels of fat soluble vitamins (A, D, E, K)
    • Deficiency in pancreatic enzyme secretion following quantitative pancreatic stimulation testing with intravenous cholecystokinin and secretin (typically performed in a research setting)

* Note: 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]. Additionally:

  • 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].

Hematologic abnormalities caused by bone marrow dysfunction involve one or more of the following:

  • Hypoproductive cytopenias. Persistent or intermittent depression of at least one lineage (for ≥2 measurements taken over a period of ≥3 months):
    • Neutropenia (absolute neutrophil count <1,500 neutrophils /mm3)
    • Thrombocytopenia (platelet count <150,000 platelets/mm3)
    • Anemia (with hemoglobin concentration below normal range for age)
  • Pancytopenia. Tri-lineage 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 for age, indicating marrow failure and disordered hematopoiesis
  • Aplastic anemia and/or myelodysplasia with or without abnormal cytogenetic findings. When cytogenetic anomalies are present, they can be deletion of 20q11, monosomy 7, isochromosome 7, or other chromosome changes seen in bone marrow failure syndromes.
  • Leukemia

Studies in which patient and non-patient marrow cells are co-cultured indicate problems with both the stem cell compartments and stromal microenvironment [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 primary features used in support of the diagnosis [Myers et al 2014]:

  • Short stature
  • Skeletal abnormalities, most commonly chondrodysplasia or congenital thoracic dystrophy
  • Hepatomegaly with or without elevation of serum aminotransferase levels
  • Congenital anomalies
  • Family history consistent with autosomal recessive inheritance

Establishing the Diagnosis

The diagnosis of SDS is confirmed by detection of biallelic pathogenic variants in SBDS (Table 1) in the majority of individuals with SDS. A limited number (<10%) of persons with clear clinical indications of SDS do not appear to have pathogenic variants in SBDS, suggesting that pathogenic variants in another gene(s) may also be causative.

One approach is testing of SBDS by either of the following:

  • Targeted analysis for the three common SBDS pathogenic variants in exon 2 (c.183_184delinsCT, c.258+2T>C, and the combination of c.[183_184delinsCT; 258+2T>C] on one allele) detects at least one pathogenic variant in 90% of affected individuals and both pathogenic variants in approximately 62% of affected individuals [Boocock et al 2003]. Targeted analysis can be followed as needed by sequence analysis and then deletion/duplication if only one or no SBDS pathogenic variant is found.
  • Sequence analysis of SBDS, followed by deletion/duplication analysis if only one or no pathogenic variant is found.
    Note: Sequence analysis will identify the three common pathogenic variants as well as small intragenic deletions/insertions and missense, nonsense, and splice site variants.

Another approach is use of a multigene panel that includes SBDS and other genes of interest (see Differential Diagnosis). The genes included and the methods used in multigene panels vary by laboratory and over time.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Interpretation of test results. In single-gene testing and use of a multigene panel, the correct interpretation of the three common variants (which can result from gene conversion – see Molecular Genetics, Pathogenic variants) requires testing of the parents to determine if the variants in the child are:

  • In cis configuration (i.e., c.[183_184delinsCT; 258+2T>C] on the same allele); OR
  • In trans configuration (i.e., c.183_184delinsCT on one allele and c.258+2T>C on the other allele)

Table 1.

Molecular Genetic Testing Used in Shwachman-Diamond Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
SBDSTargeted analysis for pathogenic variants 276% 3
Sequence analysis 4>90%
Deletion/duplication analysis 5<2% 6

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.


Pathogenic variants included in a panel may vary by laboratory.


J Rommens, personal communication


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Unusual variants 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. The rare c.297_300delAAGA pathogenic variant is also likely the consequence of gene conversion with SBDSP but involves only the exon 3 region [Carvalho et al 2014; J Rommens, personal communication]. Interpretations may be difficult as the extent of variation in the pseudogene is not known.

Clinical Characteristics

Clinical Description

The clinical spectrum of Shwachman-Diamond syndrome (SDS) is broad and varies among affected individuals, including sibs [Ginzberg et al 1999]. Earlier studies suggested that gastrointestinal and hematologic findings were observed in all affected individuals [Cipolli et al 1999, Ginzberg et al 1999]; with wider use of molecular genetic testing, however, this belief has been challenged (see Diagnosis) [Myers et al 2014].

Neonates generally do not show manifestations of SDS; however, early presentations have included acute life-threatening infections, severe bone marrow failure, aplastic anemia [Kuijpers et al 2005], asphyxiating thoracic dystrophy caused by rib cage restriction, and 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.

Exocrine pancreatic dysfunction resulting from severe depletion of pancreatic acinar cells is a classic feature of SDS, with the majority of dysfunction identified within the first year of life, often in the first six months. Manifestations vary widely from asymptomatic to severe dysfunction with significant malabsorption of nutrients, steatorrhea, and failure to thrive.

For unclear reasons, in many individuals manifestations resolve with age, with as many 50% being able to discontinue pancreatic enzyme supplementation with normal fat absorption by age four years even when enzyme secretion remains deficient [Mack et al 1996].

A general acinar defect has also been identified, with increased parotid acinar dysfunction in persons with SDS compared to controls [Stormon et al 2010]. In a study of histologic changes in gastrointestinal mucosal biopsies of symptomatic individuals with SDS, Shah et al [2010] identified duodenal inflammation in greater than 50%, suggesting a possible enteropathic component to their disease.

Pancreatic histopathology reveals few acinar cells and extensive fatty infiltration. Pancreatic imaging studies with ultrasonography or CT may reveal small size for age. In a series of individuals with SDS in whom SBDS pathogenic variants had been identified, MRI revealed fatty infiltration with retained ductal and islet components [Toiviainen-Salo et al 2008b]. Normal imaging studies do not rule out the diagnosis of SDS as these abnormal findings may emerge over time [Myers et al 2014].

Hematologic abnormalities. Neutropenia and impaired neutrophil chemotaxis are likely the most critical contributors to recurrent infections seen in young children [Dror & Freedman 2002, Stepanovic et al 2004, Kuijpers et al 2005]. Acute and deep-tissue infections can be life threatening, particularly in young children [Cipolli 2001, Grinspan & Pikora 2005]. Persistent or intermittent neutropenia is recognized first in almost all (88 to 100%) affected children often before the diagnosis of SDS is made [Ginzberg et al 1999].

Although anemia and thrombocytopenia are also seen in the majority of individuals with SDS, these findings may be intermittent or clinically asymptomatic. Severe aplastic anemia with pancytopenia occurs in a subset of individuals. The French Severe Chronic Neutropenia Registry found that 41 (40%) of 102 individuals with SDS demonstrated significant hematologic manifestations, including those with intermittent severe cytopenias and 21 with persistent severe cytopenias (9 classified as malignant, 9 as non-malignant, and 3 progressing from nonmalignant to malignant) [Donadieu et al 2012].

The risk for myelodysplasia (MDS) or progression to leukemia – typically acute myeloid leukemia (AML) – is significant in individuals with SDS; however, data remain limited with specific reports varying by definition of MDS and cohort age.

  • One 25-year survey revealed that seven of 21 individuals with SDS developed myelodysplastic syndrome; five of these seven developed AML [Smith et al 1996].
  • In 55 individuals with SDS in the French registry, rates of transformation to MDS/AML were 18.8% and 36.1% at 20 years and 30 years, respectively [Donadieu et al 2012].
  • The Severe Congenital Neutropenia International Registry (SCNIR) reported an overall incidence of 8.1% of MDS/AML in 37 individuals with SDS over a ten-year period, representing a 1% per year rate of progression to MDS or AML [Dale et al 2006, Rosenberg et al 2006].
  • A cumulative transformation rate of 18% was reported in 34 individuals with SDS by the Canadian Inherited Bone Marrow Failure Study (CIBMFS) [Hashmi et al 2011].

Of note, the above findings contrast with other recent reports from the Israeli (3 individuals) [Tamary et al 2010] and NIH (17 individuals) [Alter et al 2010] registries in which no one developed MDS/AML. Conclusions remain difficult given the small sample sizes; however, these differences may be attributable to cohort age [Myers et al 2013a].

The risk for malignant transformation involving dysplasia or AML is considered to be lifelong, with AML generally associated with poor outcome [Donadieu et al 2005]. To date, reported malignancies other than AML have been rare; they include isolated case reports of bilateral breast cancer [Singh et al 2012], dermatofibrosarcoma [Sack et al 2011], and CNS lymphoma [Sharma et al 2014].

It is well recognized that individuals with SDS may develop certain characteristic cytogenetic clonal changes, such as del(20)(q11) and i(7)(q10), in the absence of overt MDS or AML. It has been suggested that these changes may persist and fluctuate over time without high risk of progression to MDS/AML [Cunningham et al 2002, Crescenzi et al 2009, Maserati et al 2009].

Growth. 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].

Characteristic skeletal changes appear to be present in all individuals with a molecularly confirmed diagnosis [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 delayed
  • Variable widening and irregularity of the metaphyses in early childhood (i.e., metaphyseal chondrodysplasia), followed by progressive thickening and irregularity of the growth plates
  • Generalized osteopenia

Of note, the epiphyseal maturation defects tended to normalize with age and the metaphyseal changes tended to progress (worsen) with age [Mäkitie et al 2004].

Further skeletal findings can include rib and joint abnormalities, the latter of which can result from asymmetric growth and can be sufficiently severe to warrant surgical intervention.

Additionally, low-turnover osteoporosis has been reported as a feature of SDS. Toiviainen-Salo et al [2007] reported bone abnormalities in ten of 11 individuals with genetically confirmed SDS including reduced bone mineral density by Z-scores. Vertebral compression fractures were reported in three. Vitamin D and K deficiencies, both detrimental to bone health, were each identified in six individuals.

Hepatomegaly and liver dysfunction with elevated serum aminotransferase concentration can be observed in young children but tend to resolve by age five years [Toiviainen-Salo et al 2007]. Mild histologic changes may also be evident in liver 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].

Cognitive/psychological. Individuals with SDS have also been recognized to have cognitive and/or behavioral impairment as well as structural brain changes [Kent et al 1990, Cipolli et al 1999, Ginzberg et al 1999, Toiviainen-Salo et al 2008a, Perobelli et al 2012, Booij et al 2013]. Kerr et al [2010] compared the neuropsychological function of 32 children with SDS with age- and gender-matched children with cystic fibrosis and sib controls. On a number of measures, those with SDS displayed a far wider range of abilities than controls, from severely impaired to superior.

Approximately 20% of children with SDS demonstrated intellectual disability in at least one area, with perceptual reasoning being most affected. They were also far more likely than the general population to have the diagnosis of pervasive developmental disorder (6% versus 0.6%). Attention deficits were also more common in children with SDS and in their sibs than in children with cystic fibrosis.

Other possible findings

  • Ichthyosis and eczematous lesions
  • Oral disease including delayed dental development, increased dental caries in both primary and permanent teeth, and recurrent oral ulcerations [Ho et al 2007]
  • Endocrine dysfunction [Myers et al 2013b]
  • Immune dysfunction [Dror et al 2001]
  • Congenital anomalies including: cardiac, gastrointestinal, neurologic, urinary tract/kidney, or eye and ear anomalies [Myers et al 2014]

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed with SBDS pathogenic variants [Mäkitie et al 2004, Kawakami et al 2005, Kuijpers et al 2005], a finding consistent with the observed phenotypic variability among affected sibs [Ginzberg et al 1999].


SDS has previously been known as:

  • Shwachman’s syndrome
  • Congenital lipomatosis of the pancreas
  • Shwachman-Bodian syndrome


It has been estimated that SDS occurs in one of 77,000 births based on the observation that it is approximately 1/20th as frequent as cystic fibrosis in North America [Goobie et al 2001].

SDS occurs in diverse populations including those with European, Indian, aboriginal (North America), Chinese, Japanese, and African ancestry.

Differential Diagnosis

Features of Shwachman-Diamond syndrome (SDS), such as poor growth and transient neutropenia, may have multiple causes in young children.

Pancreatic Dysfunction

Cystic 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 abnormalities
  • Pearson 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 testing

Exocrine pancreatic insufficiency can also result from severe malnutrition.

Other bone marrow failure syndromes that overlap in some respects with SDS include the following:

These 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.


Transient 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 (which includes cyclic neutropenia and severe congenital neutropenia).

Skeletal Dysplasia

Cartilage-hair hypoplasia (CHH) syndrome has gastrointestinal, skeletal, hematologic, and immunologic features. However, the skeletal anomalies of CHH can be distinguished from those of SDS. Furthermore the gastrointestinal features of CHH are secondary to complications of infection rather than to exocrine pancreatic insufficiency.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual following the initial diagnosis of Shwachman-Diamond syndrome (SDS), current consensus practice typically recommends the following evaluations to assess the status of the pancreas, liver, bone marrow, and skeleton [Dror et al 2011]; discussions to update recommendations are ongoing.

  • Assessment of growth: height, weight in relation to age
  • 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 metabolites
    • Measurement of prothrombin time (to detect vitamin K deficiency)
  • Assessment of serum concentration of the digestive enzyme cationic trypsinogen and, if sufficiency is observed, subsequent confirmation with a 72-hour fecal fat balance study (with discontinuation of enzyme supplementation for at least a 24-hour period)
  • Pancreatic imaging by ultrasound
  • Complete blood count with white cell differential and platelet count at three- to six-month intervals (or more often as clinically indicated)
  • Bone marrow examination with biopsy and cytogenetic studies at initial assessment
  • Skeletal survey with radiographs of at least the hips and lower limbs
  • Bone densitometry as clinically indicated
  • Assessment of serum aminotransferase levels
  • Assessment of developmental milestones (including pubertal development) with neuropsychological evaluation
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

A multidisciplinary team including 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, Dror et al 2011, Myers et al 2013a].

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.

Hematologic abnormalities. 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) should be considered for treatment of severe pancytopenia, bone marrow transformation to myelodysplastic syndrome, or AML. Chemotherapy can be utilized as a bridge to HSCT in individuals with SDS and AML; however, sustained complete remission is problematic and prompt continuation to HSCT remains imperative. Although earlier reports indicate that survival is fair, cautious myeloablation and newer reduced intensity regimens have demonstrated improved outcomes in small cohorts [Cesaro et al 2005, Vibhakar et al 2005, Sauer et al 2007, Bhatla et al 2008].

Note: Bone marrow abnormalities are not treated unless severe aplasia, myelodysplastic changes, or leukemic transformation are present.

Skeletal abnormalities. Skeletal manifestations of SDS may range from clinically asymptomatic to severe, and can evolve or progress over time. Severe manifestations such as asphyxiating thoracic dystrophy due to rib cage restriction will require subspecialty care including pediatric pulmonary and orthopedic specialists. Other rib and joint abnormalities may require surgical intervention if severe and consultation with an orthopedic surgeon familiar with SDS for those with skeletal dysplasia may be beneficial.

Growth. 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.


  • Bone densitometry should be considered if clinically indicated, or in early adulthood.
  • Cognitive, learning, and behavioral complications can be features of SDS, and remedial interventions are considered beneficial.

Prevention of Secondary Complications

Frequent 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.

Prophylactic antibiotics and G-CSF may be especially helpful when interventions such as complex dental procedures or orthopedic surgery are being considered.


The following is recommended given the intermittent nature of some features of SDS and the evolution of the phenotype over time [Rothbaum et al 2002, Dror et al 2011, Myers et al 2013a]:

  • Complete blood counts with white blood cell differential and platelet counts at least every three to six months, or more frequently if peripheral blood counts are changing or infections are recurrent and debilitating
  • Developmental assessment every six months from birth to age six years and growth every six months.
  • Assessment of nutritional status every six months and measurement of serum concentration of vitamins to evaluate effectiveness of or need for pancreatic enzyme therapy
  • Repeat bone marrow examinations every one to three years following the baseline examination, and more frequently if changes in bone marrow function or cellularity are observed.
  • Monitoring for orthopedic complications with x-rays of hips and knees during the most rapid growth stages
  • Bone densitometry before puberty, during puberty, and thereafter based on individual findings. Results must be interpreted in the context of stature and pubertal status.
  • Neuropsychological screening in children age 6-8 years, 11-13 years, and 15-17 years

Note: Discussions to update and maintain recommendations are ongoing.

Agents/Circumstances to Avoid

Prolonged use of cytokine and hematopoietic growth factors such as G-CSF is cautioned against in view of their potential contribution to leukemic transformation [Rosenberg et al 2006].

Some drugs (e.g., cyclophosphamide and busulfan) used in standard HSCT preparative regimens 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 Risk

It is appropriate to evaluate as early as possible the older and younger sibs of a proband in order to identify those who will benefit from treatment and preventive measures. This can also potentially prevent asymptomatic affected sibs from being used as bone marrow transplant donors.

If the SBDS pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

For pregnancies in women with SDS, high-risk pregnancy care including consultation with a hematologist is recommended [Alter et al 1999].

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Shwachman-Diamond syndrome (SDS) is inherited in an autosomal recessive manner. The mode of inheritance of SDS in individuals without identified SBDS pathogenic variants is unknown.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are usually heterozygotes (i.e., carriers of one SBDS pathogenic variant).
  • Occasionally, only one parent is a carrier as the affected child has one inherited and one de novo SBDS pathogenic variant. Approximately 10% of SBDS pathogenic variants are de novo [Steele et al 2014].
  • Heterozygotes are asymptomatic. See Genetically Related Disorders.

Sibs of a proband

  • When both parents are known to be carriers
    • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
    • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of an SBDS pathogenic variant is 2/3.
  • When the proband has one inherited and one de novo SBDS pathogenic variant. At conception, each sib of an affected individual has a 50% chance of being an asymptomatic carrier and a 50% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic. See Genetically Related Disorders.

Offspring of a proband

  • The offspring of an individual with SDS are obligate heterozygotes (carriers) for a pathogenic variant in SBDS.
  • In the rare event that the reproductive partner of the proband is a carrier, the offspring are at a 50% risk of being affected and a 50% risk of being a carrier.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier of an SBDS pathogenic variant. (If one variant is de novo, this risk only applies to the sibs of the carrier parent.)

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the SBDS pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SBDS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for Shwachman-Diamond syndrome are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Associazione Italiana Sindrome di Shwachman
    Via S. Anna 15/A
    Post Office nr. 10025625
    Montecassiano 62010
  • Shwachman-Diamond Syndrome Canada
    2152 Gatley Road
    Mississauga Ontario L5H 3L9
    Phone: 866-462-8907 (toll-free)
  • Shwachman-Diamond Syndrome Foundation
    127 Western Avenue
    Sherborn MA 01770
    Phone: 888-825-7373 (toll-free)
    Fax: 888-825-7373 (toll-free)
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Phone: 49-761-270-34450
  • National Cancer Institute Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
    Phone: 800-518-8474
  • Shwachman-Diamond Syndrome Registry
    Phone: 617-355-4685; 513-803-7656

Molecular Genetics

Information 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 Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Shwachman-Diamond Syndrome (View All in OMIM)


Gene structure. SBDS has 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]. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Some of the benign variants reflect the sequence of the pseudogene SBDSP, indicating that they may have arisen by gene conversion events between the gene and the pseudogene.

Pathogenic variants. The abnormalities identified in individuals with SDS lead to prematurely truncated proteins, splicing aberrations, and missense alterations.

At least one allele in more than 90% of individuals with Shwachman-Diamond syndrome (SDS) has a pathogenic variant in exon 2 that apparently arose by gene conversion, a process by which a small segment of the functional gene, SBDS, is replaced by a segment copied from the highly homologous nonfunctional pseudogene SBDSP. As a result, this segment of SBDS has sequence variants (typical of the pseudogene) that inactivate normal SBDS gene expression and/or translation of normal protein.

The three most common pathogenic alleles resulting from gene conversion and accounting for more than 76% of disease-causing alleles in more than 200 families are the following [J Rommens, unpublished]:

  • c.183_184delinsCT
  • c.258+2T>C
  • c.[183_184delinsCT; 258+2T>C], in which both pathogenic variants occur on one allele

More than 40 novel sequence variants identified in the five exons of SBDS are consistent with loss-of-function alterations [Boocock et al 2003, Nicolis et al 2005, Maserati et al 2006, Taneichi et al 2006]. Seven have been found in multiple, apparently unrelated, families (see Table 2).

Except for one reported case to date, affected individuals with rare pathogenic variants are compound heterozygotes with one of the three common gene conversion variants. In the one exception, an individual with a clinical diagnosis of SDS had two rare missense alleles in exons 3 and 4 [Erdos et al 2006].

Table 2.

Selected SBDS Variants

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
Benignc.141C>T 2p.(=) 3NM_016038​.2
c.201A>G 2p.(=)
c.635T>C 4p.Ile212Thr
c.183_184delinsCT 2
c.[183_184delinsCT; 258+2T>C] 2p.Lys62Ter
c.258+2T>C 2p.Cys84TyrfsTer4
c.297_300delAAGA 2p.Glu9AspfsTer20

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


Likely the consequence of gene conversion with SBDSP


The designation p.(=) means that the protein has not been analyzed, but no change is expected.


Initially reported to be a possible pathogenic allele

Normal 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 archaeal ortholog indicates that the SBDS protein contains three domains [Savchenko et al 2005, Shammas et al 2005].

The modeling of several of the identified pathogenic missense variants onto the three-domain structure of the solved archaeal SBDS protein ortholog supports the likelihood that they are pathogenic [Savchenko et al 2005, Shammas et al 2005]. Recently, the crystal structure of Methanothermobacter SBDS was revealed to a resolution of 1.75 Å by Ng et al [2009] and nuclear magnetic resonance was utilized to demonstrate the structure of human SBDS [de Oliveira et al 2010].

The SBDS protein is believed to play a role in RNA metabolism and ribosome biogenesis. Studies have demonstrated SBDS protein association with the large 60S ribosomal subunit, as well as association with multiple ribosomal proteins [Ganapathi et al 2007, Ball et al 2009]. Genetic studies of the yeast homolog also support a role in 60S ribosomal subunit biogenesis and translational activation [Menne et al 2007]. Recent studies examining the interaction of SBDS with the GTPase elongation factor-like 1 (ELF1) [Finch et al 2011] endorse a model in which SBDS initiates the joining of the 40S and 60S subunits for active translation through the creation of the active 80S ribosome.

The SBDS protein has also been implicated in the bone marrow stromal microenvironment [Nihrane et al 2009, Raaijmakers et al 2010], actin polymerization [Orelio & Kuijpers 2009, Orelio et al 2009], and microtubule stabilization [Austin et al 2008].

Abnormal gene product. The pathogenic variants identified in individuals with SDS led to prematurely truncated proteins, splicing aberrations, and missense alterations. These pathogenic variants 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.Lys62Ter), 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.


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  • Toiviainen-Salo S, Mäyränpää MK, Durie PR, Richards N, Grynpas M, Ellis L, Ikegawa S, Cole WG, Rommens J, Marttinen E, Savilahti E, Mäkitie O. Shwachman-Diamond syndrome is associated with low-turnover osteoporosis. Bone. 2007;41:965–72. [PubMed: 17920346]
  • Toiviainen-Salo S, Raade M, Durie PR, Ip W, Marttinen E, Savilahti E, Mäkitie O. Magnetic resonance imaging findings of the pancreas in patients with Shwachman-Diamond syndrome and mutations in the SBDS gene. J Pediatr. 2008b;152:434–6. [PubMed: 18280855]
  • Vibhakar R, Radhi M, Rumelhart S, Tatman D, Goldman F. Successful unrelated umbilical cord blood transplantation in children with Shwachman-Diamond syndrome. Bone Marrow Transplant. 2005;36:855–61. [PubMed: 16113664]
  • Zhang S, Shi M, Hui CC, Rommens JM. Loss of the mouse ortholog of the shwachman-diamond syndrome gene (Sbds) results in early embryonic lethality. Mol Cell Biol. 2006;26:6656–63. [PMC free article: PMC1592835] [PubMed: 16914746]

Suggested Reading

  • Dokal I, Vulliamy T. Inherited aplastic anaemias/bone marrow failure syndromes. Blood Rev. 2008;22:141–53. [PubMed: 18164793]
  • Huang JN, Shimamura A. Clinical spectrum and molecular pathophysiology of Shwachman-Diamond syndrome. Curr Opin Hematol. 2011;18:30–5. [PMC free article: PMC3485416] [PubMed: 21124213]

Chapter Notes


The author would like to thank individuals with Shwachman-Diamond syndrome and their families and care givers, as well as Dr Johanna Rommens, Dr Peter Durie, Dr Akiko Shimamura and Dr Stella Davies.

Author History

Peter R Durie, MD, FRCPC; University of Toronto (2008-2014)
Kasiani Myers, MD (2014-present)
Johanna M Rommens, PhD; University of Toronto (2008-2014)

Revision History

  • 11 September 2014 (me) Comprehensive update posted live
  • 17 July 2008 (me) Review posted live
  • 7 January 2008 (jr) Original submission
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