Shwachman-Diamond Syndrome

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 myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is an early finding. Short stature and recurrent infections are common.

Diagnosis/testing.

The diagnosis of SDS is established in a proband with the classic clinical findings of exocrine pancreatic dysfunction and bone marrow dysfunction and/or biallelic pathogenic variants in DNAJC21, EFL1, or SBDS or a heterozygous pathogenic variant in SRP54 identified by molecular genetic testing.

Management.

Treatment of manifestations: Care by a multidisciplinary team is highly 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 thrombocytopenia. If recurrent infections are severe and absolute neutrophil counts are persistently ≤500/mm³, treatment with granulocyte-colony stimulation factor (G-CSF) can be considered and may be especially helpful when interventions such as complex dental procedures or orthopedic surgery are being considered. Hematopoietic stem cell transplantation (HSCT) should be considered for treatment of severe bone marrow failure, MDS, or AML. Early pulmonary and orthopedic referral is essential for treatment of thoracic dystrophy; orthopedic management of other skeletal manifestations including skeletal dysplasia, asymmetric growth, and joint deformities. Multidisciplinary team management of liver disease; neuropsychological testing, developmental services, and educational support; referral to endocrinology for pubertal delay and other endocrine manifestations; dental care for oral manifestations.

Surveillance: Assessment of nutritional status and measurement of serum concentration of fat-soluble vitamins every six months. Complete blood count with white blood cell differential and platelet count at least every three to six months; bone marrow examination every one to three years or more frequently if bone marrow changes are observed. Monitor for orthopedic complications with radiographs of the hips and knees during the most rapid growth stages. Bone densitometry before puberty, during puberty, and thereafter based on individual findings. Development assessment every six months from birth to age six years; neuropsychological screening in children ages six to eight years, eleven to 13 years, and 15 to 17 years. Clinical examination for skin and dental manifestations and assessment for recurrent urinary tract infections at each visit. Dental visits to monitor tooth development, assess oral health, and screen for mouth ulcers and gingivitis every 12 months or more frequently as needed. Assess growth and for clinical signs and symptoms of additional endocrine manifestations every six months.

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.

Evaluation of relatives at risk: It is appropriate to evaluate the older and younger sibs of a proband in order to identify those who will benefit from treatment and preventive measures as soon as possible. It is essential to evaluate any potential related donor for SDS to avoid using an asymptomatic relative with SDS as an HSCT donor.

Pregnancy management: High-risk pregnancy care including consultation with a hematologist.

Genetic counseling.

SDS is inherited in an autosomal recessive (most commonly) or an autosomal dominant manner.

Autosomal recessive SDS: SDS caused by pathogenic variants in DNAJC21, EFL1, or SBDS is inherited in an autosomal recessive manner. Most parents of children with autosomal recessive SDS are heterozygotes (carriers of one pathogenic variant); however, de novo pathogenic variants have been reported. If both parents are known to be heterozygous for an autosomal recessive SDS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a clinically asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for relatives at risk is possible if both pathogenic variants in a family are known.

Autosomal dominant SDS: SDS caused by pathogenic variants in SRP54 is inherited in an autosomal dominant manner. Most individuals diagnosed with SRP54-related SDS have the disorder as the result of a de novo pathogenic variant.

Once the SDS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

SDS should be suspected in individuals with any combination of the following clinical findings [Nelson & Myers 2018].

Exocrine pancreatic dysfunction

• Low serum concentrations of the pancreatic enzymes trypsinogen and/or isoamylase for age. Note: Measurement of trypsinogen concentration should be used in children age <3 years, and measurement of isoamylase concentration should be used in children age >3 years [Ip et al 2002].
• Low levels of fecal elastase
• Evidence of pancreatic lipomatosis on imaging. Note: Pancreatic imaging can be normal early in the disease [Myers et al 2014].
• Abnormal fecal fat balance study of a 72-hour stool collection (with exclusion of intestinal mucosal disease or cholestatic liver disease)

Hematologic features of bone marrow dysfunction

• Neutropenia (absolute neutrophil count <1,500 neutrophils/mm³) on at least two occasions
• Anemia or macrocytosis not explained by other causes (e.g., iron or B₁₂ deficiency)
• Thrombocytopenia (platelet count <150,000 platelets/mm³) on at least two occasions
• Bone marrow examination: hypocellularity for age, myelodysplasia, leukemia, characteristic cytogenic abnormalities (e.g., deletion of 20q11, monosomy 7, isochromosome 7)

Other primary features [Myers et al 2014]

• Short stature (postnatal, proportionate)
• Skeletal abnormalities: delayed epiphyseal ossification, metaphyseal dysplasia, congenital thoracic dystrophy
• Congenital cardiac anomalies
• Ear malformations / hearing loss
• Eczematous-like skin rash or ichthyosis
• Hepatomegaly with or without elevation of serum aminotransferase concentrations

Establishing the Diagnosis

Clinical diagnosis. The clinical diagnosis of SDS is established in a proband with exocrine pancreatic dysfunction (low serum trypsinogen in child age <3 years, low isoamylase concentration in an individual age >3 years, and/or low fecal elastase) and hematologic features of bone marrow dysfunction (cytopenia, macrocytic red cells, and/or characteristic bone marrow findings) (see Suggestive Findings).

Molecular diagnosis. The molecular diagnosis of SDS is established in a proband with any suggestive findings and biallelic pathogenic (or likely pathogenic) variants in DNAJC21, EFL1, or SBDS or a heterozygous pathogenic (or likely pathogenic) variant in SRP54 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 2

When the diagnosis of SDS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: Because the complex SBDS c.[183_184delinsCT;258+2T>C] allele occurs through a gene conversion event, parental testing is needed to determine if the two variants are present in cis or trans.

Table 1.

Molecular Genetic Testing Used in Shwachman-Diamond Syndrome

Clinical Description

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 myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); and bone abnormalities. To date, more than 500 individuals have been identified with biallelic pathogenic variants in DNAJC21, EFL1, or SBDS or a heterozygous pathogenic variant in SRP54. The following description of the phenotypic features associated with this condition is based on these reports [Han et al 2023].

Table 2.

Shwachman-Diamond Syndrome: Frequency of Select Features

Presentation. 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 poor weight gain and poor growth secondary to exocrine pancreatic dysfunction. However, the presentation of SDS varies greatly, with nearly half of individuals in the North American SDS Registry presenting without neutropenia or steatorrhea [Myers et al 2014].

Exocrine pancreatic dysfunction results from severe depletion of pancreatic acinar cells. The manifestations of pancreatic dysfunction are most evident in the first year of life, often in the first six months. Severity can vary widely from asymptomatic to severe dysfunction with significant malabsorption of nutrients, steatorrhea, poor weight gain, and growth delay. For unclear reasons, the clinical manifestations of pancreatic dysfunction resolve with age; up to 50% of individuals are able to discontinue pancreatic enzyme supplementation and have normal fat absorption by age four years, even when pancreatic enzyme secretion is less than normal [Mack et al 1996].

Pancreatic histopathology reveals few acinar cells and extensive fatty infiltration. Pancreatic imaging studies by ultrasound or CT examination may reveal small pancreas size for age. In individuals with SBDS-related SDS, MRI revealed fatty infiltration with retained ductal and islet components [Toiviainen-Salo et al 2008b].

Additional gastrointestinal manifestations. A general acinar defect has also been identified, with increased parotid acinar dysfunction in persons with SDS compared to controls [Stormon et al 2010]. Duodenal inflammation was identified on gastrointestinal mucosal biopsies in more than 50% of symptomatic individuals with SDS [Shah et al 2010], suggesting a possible enteropathic component to their disease. This enteropathy may contribute to vitamin deficiencies observed in some individuals with SDS despite nutritional supplementation and enzymatic replacement [Pichler et al 2015].

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]. Despite impaired neutrophil chemotaxis, individuals with SDS maintain the ability to form empyema and abscess, in contrast to other disorders of neutrophil chemotaxis [Aggett et al 1979, Rothbaum et al 1982]. 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%-100%) affected children, often before the diagnosis of SDS is identified [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 41/102 (40%) individuals with SDS demonstrated significant hematologic manifestations, including those with intermittent severe cytopenias and 21 with persistent severe cytopenias (nine classified as malignant, nine as nonmalignant, and three progressing from nonmalignant to malignant) [Donadieu et al 2012].

The risk for MDS or progression to leukemia, typically AML, is significant in individuals with SDS; however, data remain limited, with specific reports varying by definition of MDS and cohort age. In one 25-year survey, seven of 21 individuals with SDS developed MDS; five of these seven developed AML [Smith et al 1996]. The Severe Congenital Neutropenia International Registry 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 [Hashmi et al 2011]. In 55 individuals with SDS in the French Severe Chronic Neutropenia Registry, rates of transformation to MDS/AML were 18.8% and 36.1% at 20 years and 30 years, respectively [Donadieu et al 2012].

Of note, the above findings contrast with other reports from the Israeli Inherited Bone Marrow Failure Registry (3 individuals) [Tamary et al 2010] and an NIH inherited bone marrow failure syndromes cohort (17 individuals) [Alter et al 2010] 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].

Individuals with SDS may develop characteristic cytogenetic clonal changes such as deletion of 20q11 and isochromosome 7 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, Khan et al 2021]. Novel cytogenetic abnormalities in the presence or absence of deletion of 20q11 and isochromosome 7 have been reported in a cohort of 91 Italian individuals with SDS, including unbalanced structural anomalies of chromosome 7, complex rearrangements of the deletion of 20q, and unbalanced translocation with partial trisomy 3q and partial monosomy 6q [Valli et al 2017].

Survival remains poor for individuals that develop MDS/AML [Myers et al 2020a]; some individuals are diagnosed with MDS/AML on their first bone marrow biopsy, highlighting the need for prompt and regular surveillance upon diagnosis.

Recent evidence has suggested acquired pathogenic variants in hematopoietic cells in individuals with SDS can either alleviate ribosomal defects or increase leukemogenic potential via disruption of cellular checkpoints; somatic biallelic loss-of-function TP53 pathogenic variants in individuals with SDS are associated with myeloid malignancies [Kennedy et al 2021, Reilly & Shimamura 2023].

To date, other reported malignancies in individuals with SDS have been rare, including isolated reports of bilateral breast cancer [Singh et al 2012], dermatofibrosarcoma [Sack et al 2011], pancreatic adenocarcinoma, central nervous system lymphoma [Sharma et al 2014], and ovaran and esophageal carcinoma [Bou Mitri et al 2021].

Growth. Children with SDS who are provided with adequate nutrition and pancreatic enzyme supplementation have normal growth velocity and appropriate weight for height; however, approximately 50% of all children with SDS are below the third percentile for height and weight [Durie & Rommens 2004]. SDS-specific growth charts have been developed and are helpful to track growth velocity in individuals with SDS [Pegoraro et al 2024]. Growth hormone can be used to treat growth hormone deficiency with resultant improvement in growth velocity and height [Bogusz-Wójcik et al 2021].

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 subclinical.

Cross-sectional and longitudinal data from Mäkitie et al [2004] revealed:

• Delayed appearance of secondary ossification centers, causing bone age to appear to be delayed;
• Variable widening and irregularity of the metaphyses in early childhood, 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 10/11 individuals with molecularly confirmed SDS, including reduced bone mineral density. Vertebral compression fractures were reported in three individuals, and vitamin D and K deficiencies, both detrimental to bone health, were each identified in six individuals. It is important to ensure accurate measurement of bone mineral density, as adults with SDS have short stature and may have an incorrectly reported low bone mineral density due to low height z score [Shankar et al 2017].

Liver manifestations. Hepatomegaly and liver dysfunction with elevated serum aminotransferase concentrations can be observed in young children but tend to resolve by age five years [Toiviainen-Salo et al 2007]. Elevated bile acids were reported in seven of 12 individuals in one Finnish study, three of whom had persistent or intermittent elevation over time, raising concern for ongoing cholestasis [Toiviainen-Salo et al 2009]. Mild histologic changes may also be evident in liver biopsies, and although they do not appear to be progressive, liver complications have occurred in older individuals following bone marrow transplantation [Ritchie et al 2002]. Mitochondrial abnormalities have been described, which may mimic histologic characteristics seen in inborn errors of metabolism [Kaufman et al 2024], and early-onset cirrhosis has also been reported [Reddy et al 2023].

Cognitive/psychological. Individuals with SDS have been reported to have cognitive and/or behavioral impairment as well as structural brain changes, including decreased brain volume and smaller posterior fossa [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, Perobelli et al 2015]. Kerr et al [2010] compared the neuropsychological function of 32 children with SDS with age- and sex-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% vs 0.6%). Attention deficits were also more common in children with SDS and in their unaffected sibs than in children with cystic fibrosis.

Other reported 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, including congenital hypopituitarism [Jivani et al 2016], diabetes, and growth hormone deficiency [Myers et al 2013b]
• Congenital anomalies, including cardiac (septal defects, patent ductus arteriosus), gastrointestinal, urinary tract / kidney, eye, or ear anomalies [Myers et al 2014]
• Vision abnormalities, including rod-cone dystrophy [Zhang et al 2024]
• Inflammatory conditions, including juvenille idiopathic arthritis, chronic recurrent multifocal osteomyeltitis, scleroderma, and other inflammtory eye conditions [Furutani et al 2020]

Phenotype Correlations by Gene

No phenotype correlations by gene have been identified.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed for any of the genes associated with SDS [Thompson et al 2022].

Nomenclature

Previously used terms for SDS:

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

Prevalence

It has been estimated that SDS occurs in one in 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, Indigenous American, Chinese, Japanese, and African ancestry.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SDS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Shwachman-Diamond Syndrome: Recommended Evaluations Following Initial Diagnosis

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications by a multidisciplinary team is highly recommended. This can include specialists in hematology, gastroenterology, clinical 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] (see Table 5).

Table 5.

Shwachman-Diamond Syndrome: Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations – given the intermittent nature of some features of SDS and the evolution of the phenotype over time – the evaluations in Table 6 are recommended [Rothbaum et al 2002, Dror et al 2011, Myers et al 2013a, Furutani et al 2022].

Table 6.

Shwachman-Diamond Syndrome: Recommended Surveillance

Agents/Circumstances to Avoid

Prolonged use of cytokine and hematopoietic growth factors such as granulocyte-colony stimulation factor 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 hematopoietic stem cell transplantation (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

For early diagnosis and treatment. 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. Early evaluation can also avert use of an asymptomatic affected sib as an HSCT donor. Evaluations can include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Testing for exocrine pancreatic dysfunction and evidence of bone marrow failure with single- or multilineage cytopenia if the pathogenic variants in the family are not known.

For hematopoietic stem cell donation. It is essential to evaluate any potential related donor for SDS to avoid using an asymptomatic relative with SDS as an HSCT donor.

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]. Women with SDS are at increased risk for recurrent miscarriages, but the rates of elective abortion, live birth, and spontaneous miscarriage are comparable to the general population [Giri et al 2018].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Shwachman-Diamond syndrome (SDS) caused by pathogenic variants in EFL1, DNAJC21, or SBDS is inherited in an autosomal recessive manner. SDS caused by pathogenic variants in SRP54 is inherited in an autosomal dominant manner.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are usually heterozygous for an SDS-related pathogenic variant. Occasionally, only one parent is a carrier and the affected child has one inherited and one de novo pathogenic variant. Approximately 10% of SBDS pathogenic variants are de novo [Steele et al 2014]. The frequency of de novo pathogenic variants in EFL1 and DNAJC21 is not known.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an SDS-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Steele et al 2014]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic. See Carrier detection.

Sibs of a proband

• If both parents are known to be heterozygous for an SDS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• The clinical spectrum of SDS is broad and varies among affected sibs [Ginzberg et al 1999, Myers et al 2014].
• When the proband has one inherited and one de novo pathogenic variant (i.e., only one parent is a carrier of an SDS-related pathogenic variant), each sib of an affected individual has at conception a 50% chance of being an asymptomatic carrier and a 50% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are clinically asymptomatic. See Carrier detection.

Offspring of a proband

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

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

Carrier detection

• Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
• Note that carriers are clinically asymptomatic.
  • Although it has been suggested that carriers (heterozygotes) with one pathogenic SBDS allele may be at higher-than-average risk for aplastic anemia [Calado et al 2007], aplastic anemia has not been observed among SBDS heterozygotes (i.e., carriers) in more than 200 families with SDS [North American SDS Registry; A Nelson & K Myers, unpublished data; J Rommens, unpublished data].
  • Sequence analysis of DNA obtained from bone marrow samples from 77 persons with acute myelogenous leukemia (AML) did not reveal any SBDS pathogenic variants [Majeed et al 2005]. Subsequently, in a larger cohort of 160 children with AML, heterozygous SBDS pathogenic variants were present at similar frequencies to those of healthy blood donor controls, and no homozygous or compound heterozygous pathogenic variants were identified [Aalbers et al 2013].

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• To date, most individuals diagnosed with SRP54-related SDS have the disorder as the result of a de novo pathogenic variant.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent is known to have the SRP54 pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the SRP54 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the SRP54 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SRP54-related SDS because of the possibility of reduced penetrance in a parent or parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with SRP54-related SDS has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

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

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 having SDS-related pathogenic variant(s).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the SDS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Schwachman-Diamond syndrome (SDS) is caused by pathogenic variants in DNAJC21, EFL1, SBDS, or SRP54. These genes encode proteins that play a role in ribosome biogenesis and function.

Ribosome maturation protein SBDS (SBDS), encoded by SBDS, is believed to play a role in RNA metabolism and ribosome biogenesis. SBDS associates with the large 60S ribosomal subunit, as well as multiple ribosomal proteins [Ganapathi et al 2007, Ball et al 2009]. Studies examining the interaction of SBDS with the elongation factor-like GTPase 1 (EFL1; encoded by EFL1) [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.

SBDS has also been implicated in mitochondrial function. Reduced expression of SBDS decreases mitochondrial membrane potential and increases the production of reactive oxygen species, which may contribute to SDS pathophysiology [Henson et al 2013].

Some residual activity of SBDS may be required for development. 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].

Deletion of the yeast DNAJC21 homolog Jjj1 leads to reduced levels of mature ribosomes and dysfunctional 60S ribosome subunit biogenesis.

EFL1 is a partner for SBDS and is involved in the formation of mature ribosomes. EFL1 interacts with the 60S ribosomal subunit to prevent premature association of the ribosomal subunits in the nucleus. EFL1 pathogenic variants do not disrupt protein folding but rather prevent release of the protein from the 60S subunit, resulting in abnormal ribosomes with altered translating capabilities.

Signal recognition particle subunit SRP54 (SRP54), encoded by SRP54, is involved in protein translation. It is part of a single RNA molecule made up of six polypeptides (SRP9, SRP14, SRP19, SRP54, SRP68, and SRP72). SRP54 plays a central role in the ribonucleoprotein complex signal pathway, facilitating signal sequencing at the endoplasmic reticulum surface. SRP54 pathogenic variants lead to both quantitative and qualitative disruption of secreted and membrane-bound protein synthesis, along with changes in cellular protein content.

Mechanism of disease causation. Loss of function

Gene-specific laboratory technical considerations

• SBDS. Analysis of SBDS is complicated by the presence of the highly homologous pseudogene SBDSP. More than 90% of individuals with SDS have ≥1 pathogenic variant in exon 2 that apparently arose by gene conversion, a process by which a small segment of SBDS is replaced by a segment copied from 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.

Table 8.

Pathogenic Variants Referenced in This GeneReview by Gene

Acknowledgments

The authors would like to thank individuals with Shwachman-Diamond syndrome and their families and caregivers, as well as 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)
Adam Nelson, MBBS (2018-present)
Johanna M Rommens, PhD; University of Toronto (2008-2014)

Revision History

• 19 September 2024 (sw) Comprehensive update posted live
• 18 October 2018 (ha) Comprehensive update posted live
• 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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