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.

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 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, 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.

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. 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 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 such affected individuals reported to date have resulted from a de novo SRP54 pathogenic variant.

If the pathogenic variant(s) in a family are known, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Shwachman-Diamond syndrome (SDS) should be suspected in individuals with some or all of the following clinical findings.

Exocrine pancreatic dysfunction, documented with any one of the following:

• Low serum concentrations of the digestive enzymes pancreatic isoamylase and cationic trypsinogen, adjusted to age (See Note.)
• Low levels of fecal elastase
• Supportive features including:
  • 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)

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 and involving 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 or macrocytosis (with hemoglobin concentration below normal range for age)
• Pancytopenia. Trilineage cytopenia with persistent neutropenia, thrombocytopenia, and anemia
• Abnormal findings on bone marrow examination:
  • 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 (which can include deletion of 20q11, monosomy 7, isochromosome 7, or other chromosomal changes seen in bone marrow failure syndromes).
  • Leukemia. In particular acute myleogenous leukemia

Other primary features [Myers et al 2014]:

• Short stature
• Skeletal abnormalities, most commonly chondrodysplasia or congenital thoracic dystrophy
• Congenital anomalies including cardiac defects, ear malformations / hearing loss, or skin rashes
• Hepatomegaly with or without elevation of serum aminotransferase levels
• Family history consistent with autosomal recessive inheritance

Establishing the Diagnosis

The diagnosis of SDS is established in a proband with the classic clinical findings of exocrine pancreatic dysfunction and bone marrow failure and/or 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) Although the diagnosis of 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. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (3) 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 (concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SDS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of SDS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

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].

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 failure to thrive and poor growth secondary to exocrine pancreatic dysfunction.

It should be noted, however, that the presentation of SDS varies greatly, with nearly half of individuals in the North American SDS Registry presenting without classic neutropenia and steatorrhea [Myers et al 2014].

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 as 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 more than 50%, 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].

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]. 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 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 nonmalignant, and 3 progressing from nonmalignant to malignant) [Donadieu et al 2012].

The risk for myelodysplasia (MDS) or progression to leukemia – typically acute myelogeneous 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 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], pancreatic adenocarcinoma, 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]. Novel cytogenetic abnormalities in the presence or absence of classic del(20)(q11) and i(7)(q10) have been reported in a cohort of 91 Italian individuals with SDS, including unbalanced structural anomalies of chromosome 7, complex rearrangements of the del(20)(q), and unbalanced translocation with partial trisomy 3q and partial monosomy 6q [Valli et al 2017].

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.

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 subclinical.

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. 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].

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]. Elevated bile acids were reported in one Finnish study in seven of 12 individuals with SDS, 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, 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 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 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 including congenital hypopituitarism [Jivani et al 2016], diabetes, and growth hormone deficiency [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 for any of the genes associated with SDS.

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 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.

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].

• 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
• Measurement of iron, folate, and B₁₂
• Bone marrow examination with biopsy and cytogenetic studies at initial assessment
• Immunoglobulins and lymphocyte subpopulations
• 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, 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].

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.

Hematologic abnormalities. 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, treatment with prophylactic antibiotics and granulocyte-colony stimulation factor (G-CSF) can be considered with caution (see Agents/Circumstances to Avoid).

Hematopoietic stem cell transplantation (HSCT) should be considered for treatment of severe pancytopenia, bone marrow transformation to myelodysplastic syndrome, or acute myelogeneous leukemia (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 may be beneficial for those with skeletal dysplasia.

Evaluate for treatment for low bone density if indicated by bone densitometry.

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.

Other. 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 (see Agents/Circumstances to Avoid).

Surveillance

The following are 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
• 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
• Assessment of nutritional status every six months and measurement of serum concentration of vitamins to evaluate effectiveness of or need for pancreatic enzyme therapy
• 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.
• Developmental assessment every six months from birth to age six years and growth every six months
• 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 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. 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.

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 heterozygotes (i.e., carriers of one SDS-related pathogenic variant).
• Occasionally, only one parent is a carrier as 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 rate of de novo pathogenic variants for the other genes is not known.
• Heterozygotes (carriers) are asymptomatic. See Carrier Detection.

Sibs of a proband

• When both parents are known to be carriers, each sib of an affected individual has, at conception, 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.
• When the proband has one inherited and one de novo 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 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, the 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 [J Rommens, unpublished; North American SDS Registry; Author, unpublished].
• Sequence analysis of DNA obtained from bone marrow samples from 77 persons with acute myelogeneous 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.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the SRP54 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.

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 theoretic possibility of parental germline 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 theoretic possibility of reduced penetrance in a parent or parental germline 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 and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, 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 being carriers.

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 testing. While most centers would consider use of prenatal 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 the DNAJC21, EFL1, SBDS, or SRP54. The majority of cases are associated with SBDS, which encodes SBDS, a protein that plays a central role in ribosome biogenesis. Interestingly, the genes more recently found to be associated with SDS – DNAJC21, EFL1, and SRP54 – all play a role in ribosome biogenesis and function.

Acknowledgments

The authors would like to thank individuals with Shwachman-Diamond syndrome and their families and care givers, 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

• 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

Literature Cited

• Aalbers AM, Calado RT, Young NS, Zwaan CM, Kajigaya S, Baruchel A, Geleijns K, de Haas V, Kaspers GJ, Reinhardt D, Trka J, Kuijpers TW, Pieters R, van der Velden VH, van den Heuvel-Eibrink MM. Absence of SBDS mutations in sporadic paediatric acute myeloid leukaemia. Br J Haematol. 2013;160:559–61. [PMC free article: PMC3594451] [PubMed: 23189942]
• Aggett PJ, Harries JT, Harvey BA, Soothill JF. An inherited defect of neutrophil mobility in Shwachman syndrome. J Pediatr. 1979;94:391–4. [PubMed: 423020]
• Alter BP, Giri N, Savage SA, Peters JA, Loud JT, Leathwood L, Carr AG, Greene MH, Rosenberg PS. Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br J Haematol. 2010;150:179–88. [PMC free article: PMC3125983] [PubMed: 20507306]
• Alter BP, Kumar M, Lockhart LL, Sprinz PG, Rowe TF. Pregnancy in bone marrow failure syndromes: Diamond-Blackfan anaemia and Shwachman-Diamond syndrome. Br J Haematol. 1999;107:49–54. [PubMed: 10520024]
• Ball HL, Zhang B, Riches JJ, Gandhi R, Li J, Rommens JM, Myers JS. Shwachman-Bodian Diamond syndrome is a multi-functional protein implicated in cellular stress responses. Hum Mol Genet. 2009;18:3684–95. [PMC free article: PMC2742402] [PubMed: 19602484]
• Bellanné-Chantelot C, Schmaltz-Panneau B, Marty C, Fenneteau O, Callebaut I, Clauin S, Docet A, Damaj GL, Leblanc T, Pellier I, Stoven C, Souquere S, Antony-Debré I, Beaupain B, Aladjidi N, Barlogis V, Bauduer F, Bensaid P, Boespflug-Tanguy O, Berger C, Bertrand Y, Carausu L, Fieschi C, Galambrun C, Schmidt A, Journel H, Mazingue F, Nelken B, Quah TC, Oksenhendler E, Ouachée M, Pasquet M, Saada V, Suarez F, Pierron G, Vainchenker W, Plo I, Donadieu J. Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome. Blood. 2018;132:1318–31. [PMC free article: PMC6536700] [PubMed: 29914977]
• Bhatla D, Davies SM, Shenoy S, Harris RE, Crockett M, Shoultz L, Smolarek T, Bleesing J, Hansen M, Jodele S, Jordan M, Filipovich AH, Mehta PA. Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome. Bone Marrow Transplant. 2008;42:159–65. [PubMed: 18500373]
• Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet. 2003;33:97–101. [PubMed: 12496757]
• Booij J, Reneman L, Alders M, Kuijpers TW. Increase in central striatal dopamine transporters in patients with Shwachman–Diamond syndrome: Additional evidence of a brain phenotype. Am J Med Genet A. 2013;161A:102–7. [PubMed: 23239620]
• Calado RT, Graf SA, Wilkerson KL, Kajigaya S, Ancliff PJ, Dror Y, Chanock SJ, Lansdorp PM, Young NS. Mutations in the SBDS gene in acquired aplastic anemia. Blood. 2007;110:1141–6. [PMC free article: PMC1939897] [PubMed: 17478638]
• Carapito R, Konantz M, Paillard C, Miao Z, Pichot A, Leduc MS, Yang Y, Bergstrom KL, Mahoney DH, Shardy DL, Alsaleh G, Naegely L, Kolmer A, Paul N, Hanauer A, Rolli V, Muller JS, Alghisi E, Sauteur L, Macquin C, Morlon A, Sancho CS, Amati-Bonneau P, Procaccio V, Mosca-Boidron A-L, Marle N, Osmani N, Lefebvre O, Goetz JG, Unal S, Akarsu NA, Radosavljevic M, Chenard M-P, Rialland F, Grain A, Bene M-C, Eveillard M, Vincent M, Guy J, Faivre L, Thauvin-Robinet C, Thevenon J, Myers K, Fleming MD, Shimamura A, Bottollier-Lemallaz E, Westhof E, Lengerke C, Isidor B, Bahram S. Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features. J Clin Invest. 2017;127:4090–103. [PMC free article: PMC5663364] [PubMed: 28972538]
• Carvalho CM, Zuccherato LW, Williams CL, Neill NJ, Murdock DR, Bainbridge M, Jhangiani SN, Muzny DM, Gibbs RA, Ip W, Guillerman RP, Lupski JR, Bertuch AA. Structural variation and missense mutation in SBDS associated with Shwachman-Diamond syndrome. BMC Med Genet. 2014;15:64. [PMC free article: PMC4057820] [PubMed: 24898207]
• Cesaro S, Oneto R, Messina C, Gibson BE, Buzyn A, Steward C, Gluckman E, Bredius R, Boogaerts M, Vermylen C, Veys P, Marsh J, Badell I, Michel G, Güngör T, Niethammer D, Bordigoni P, Oswald C, Favre C, Passweg J, Dini G, et al. Haematopoietic stem cell transplantation for Shwachman-Diamond disease; a study from the European Group for blood and marrow transplantation. Br J Haematol. 2005;131:231–6. [PubMed: 16197455]
• Cipolli M. Shwachman-Diamond syndrome: clinical phenotypes. Pancreatology. 2001;1:543–8. [PubMed: 12120235]
• Cipolli M, D'Orazio C, Delmarco A, Marchesini C, Miano A, Mastella G. Shwachman's syndrome: pathomorphosis and long-term outcome. J Pediatr Gastroenterol Nutr. 1999;29:265–72. [PubMed: 10467990]
• Costa E, Duque F, Oliveira J, Garcia P, Gonçalves I, Diogo L, Santos R. Identification of a novel AluSx-mediated deletion of exon 3 in the SBDS gene in a patient with Shwachman-Diamond syndrome. Blood Cells Mol Dis. 2007;39:96–101. [PubMed: 17376717]
• Crescenzi B, La Starza R, Sambani C, Parcharidou A, Pierini V, Nofrini V, Brandimarte L, Matteucci C, Aversa F, Martelli MF, Mecucci C. Totipotent stem cells bearing del(20q) maintain multipotential differentiation in Shwachman Diamond syndrome. Br J Haematol. 2009;144:116–9. [PubMed: 19016724]
• Cunningham J, Sales M, Pearce A, Howard J, Stallings R, Telford N, Wilkie R, Huntly B, Thomas A, O'Marcaigh A, Will A, Pratt N. Does isochromosome 7q mandate bone marrow transplant in children with Shwachman-Diamond syndrome? Br J Haematol. 2002;119:1062–9. [PubMed: 12472589]
• Dale DC, Bolyard AA, Schwinzer BG, Pracht G, Bonilla MA, Boxer L, Freedman MH, Donadieu J, Kannourakis G, Alter BP, Cham BP, Winkelstein J, Kinsey SE, Zeidler C, Welte K. The Severe Chronic Neutropenia International Registry: 10-year follow-up report. Support Cancer Ther. 2006;3:220–31. [PubMed: 18632498]
• Dhanraj S, Matveev A, Li H, Lauhasurayotin S, Jardine L, Cada M, Zlateska B, Tailor CS, Zhou J, Mendoza-Londono R, Vincent A, Durie PR, Scherer SW, Rommens JM, Heon E, Dror Y. Biallelic mutations in DNAJC21 cause Shwachman-Diamond syndrome. Blood. 2017;129:1557–62. [PubMed: 28062395]
• Donadieu J, Fenneteau O, Beaupain B, Beaufils S, Bellanger F, Mahlaoui N, Lambilliotte A, Aladjidi N, Bertrand Y, Mialou V, Perot C, Michel G, Fouyssac F, Paillard C, Gandemer V, Boutard P, Schmitz J, Morali A, Leblanc T, Bellanné-Chantelot C, et al. Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome. Haematologica. 2012;97:1312–9. [PMC free article: PMC3436231] [PubMed: 22491737]
• Donadieu J, Michel G, Merlin E, Bordigoni P, Monteux B, Beaupain B, Leverger G, Laporte JP, Hermine O, Buzyn A, Bertrand Y, Casanova JL, Leblanc T, Gluckman E, Fischer A, Stephan JL. Hematopoietic stem cell transplantation for Shwachman-Diamond syndrome: experience of the French neutropenia registry. Bone Marrow Transplant. 2005;36:787–92. [PMC free article: PMC7091863] [PubMed: 16151425]
• Dror Y, Donadieu J, Koglmeier J, Dodge J, Toiviainen-Salo S, Makitie O, Kerr E, Zeidler C, Shimamura A, Shah N, Cipolli M, Kuijpers T, Durie P, Rommens J, Siderius L, Liu JM. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N Y Acad Sci. 2011;1242:40–55. [PubMed: 22191555]
• Dror Y, Freedman MH. Shwachman-Diamond syndrome: an inherited preleukemic bone marrow failure disorder with aberrant hematopoetic progenitors and faulty microenvironment. Blood. 1999;94:3048–54. [PubMed: 10556188]
• Dror Y, Freedman MH. Shwachman-diamond syndrome. Br J Haematol. 2002;118:701–13. [PubMed: 12181037]
• Dror Y, Ginzberg H, Dalal I, Cherepanov V, Downey G, Durie P, Roifman CM, Freedman MH. Immune function in patients with Shwachman-Diamond syndrome. Br J Haematol. 2001;114:712–7. [PubMed: 11553003]
• Durie PR, Rommens JM. Shwachman-Diamond syndrome. In: Walker WA, Goulet O, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR, eds. Pediatric Gastrointestinal Disease. 4 ed. Lewiston, NY: BC Decker Inc; 2004:1624-33.
• Erdos M, Alapi K, Balogh I, Oroszlan G, Rakoczi E, Sumegi J, Marodi L. Severe Shwachman-Diamond syndrome phenotype caused by compound heterozygous missense mutations in the SBDS gene. Exp Hematol. 2006;34:1517–21. [PubMed: 17046571]
• Finch AJ, Hilcenko C, Basse N, Drynan LF, Goyenechea B, Menne TF, González Fernández A, Simpson P, D'Santos CS, Arends MJ, Donadieu J, Bellanné-Chantelot C, Costanzo M, Boone C, McKenzie AN, Freund SM, Warren AJ. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 2011;25:917–29. [PMC free article: PMC3084026] [PubMed: 21536732]
• Ganapathi KA, Austin KM, Lee CS, Dias A, Malsch MM, Reed R, Shimamura A. The human Shwachman-Diamond syndrome protein, SBDS, associates with ribosomal RNA. Blood. 2007;110:1458–65. [PMC free article: PMC1975835] [PubMed: 17475909]
• Ginzberg H, Shin J, Ellis L, Morrison J, Ip W, Dror Y, Freedman M, Heitlinger LA, Belt MA, Corey M, Rommens JM, Durie PR. Shwachman syndrome: phenotypic manifestations of sibling sets and isolated cases in a large patient cohort are similar. J Pediatr. 1999;135:81–8. [PubMed: 10393609]
• Giri N, Reed HD, Stratton P, Savage SA, Alter BP. Pregnancy outcomes in mothers of offspring with inherited bone marrow failure syndromes. Pediatr Blood Cancer. 2018;65(1) [PMC free article: PMC7408308] [PubMed: 28801981]
• Goobie S, Popovic M, Morrison J, Ellis L, Ginzberg H, Boocock GR, Ehtesham N, Betard C, Brewer CG, Roslin NM, Hudson TJ, Morgan K, Fujiwara TM, Durie PR, Rommens JM. Shwachman-Diamond syndrome with exocrine pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7. Am J Hum Genet. 2001;68:1048–54. [PMC free article: PMC1275624] [PubMed: 11254457]
• Grinspan ZM, Pikora CA. Infections in patients with Shwachman-Diamond syndrome. Pediatr Infect Dis J. 2005;24:179–81. [PubMed: 15702050]
• Hashmi SK, Allen C, Klaassen R, Fernandez CV, Yanofsky R, Shereck E, Champagne J, Silva M, Lipton JH, Brossard J, Samson Y, Abish S, Steele M, Ali K, Dower N, Athale U, Jardine L, Hand JP, Beyene J, Dror Y. Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation. Clin Genet. 2011;79:448–58. [PubMed: 20569259]
• Henson AL, Moore JB, Alard P, Wattenberg MM, Liu JM, Ellis SR. Mitochondrial function is impaired in yeast and human cellular models of Shwachman Diamond syndrome. Biochem Biophys Res Commun. 2013;437:29–34. [PubMed: 23792098]
• Ho W, Cheretakis C, Durie P, Kulkarni G, Glogauer M. Prevalence of oral diseases in Shwachman-Diamond syndrome. Spec Care Dentist. 2007;27:52–8. [PubMed: 17539220]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Ip WF, Dupuis A, Ellis L, Beharry S, Morrison J, Stormon MO, Corey M, Rommens JM, Durie PR. Serum pancreatic enzymes define the pancreatic phenotype in patients with Shwachman-Diamond syndrome. J Pediatr. 2002;141:259–65. [PubMed: 12183724]
• Jivani N, Torrado-Jule C, Vaiselbuh S, Romanos-Sirakis E. A unique case of Shwachman-Diamond syndrome presenting with congenital hypothyroidism. J Pediatr Endocrinol Metab. 2016;29:1325–1327. [PubMed: 27754968]
• Kent A, Murphy GH, Milla P. Psychological characteristics of children with Shwachman syndrome. Arch Dis Child. 1990;65:1349–52. [PMC free article: PMC1793082] [PubMed: 1702966]
• Kerr EN, Ellis L, Dupuis A, Rommens JM, Durie PR. The behavioral phenotype of school-age children with Shwachman Diamond syndrome indicates neurocognitive dysfunction with loss of Shwachman-Bodian-Diamond syndrome gene function. J Pediatr. 2010;156:433–8. [PubMed: 19906387]
• Kuijpers TW, Alders M, Tool AT, Mellink C, Roos D, Hennekam RC. Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype-phenotype relationship. Blood. 2005;106:356–61. [PubMed: 15769891]
• Mack DR, Forstner GG, Wilschanski M, Freedman MH, Durie PR. Shwachman syndrome: exocrine pancreatic dysfunction and variable phenotypic expression. Gastroenterology. 1996;111:1593–602. [PubMed: 8942739]
• Majeed F, Jadko S, Freedman MH, Dror Y. Mutation analysis of SBDS in pediatric acute myeloblastic leukemia. Pediatr Blood Cancer. 2005;45:920–4. [PubMed: 16007594]
• Mäkitie O, Ellis L, Durie PR, Morrison JA, Sochett EB, Rommens JM, Cole WG. Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS. Clin Genet. 2004;65:101–12. [PubMed: 14984468]
• Maserati E, Minelli A, Pressato B, Valli R, Crescenzi B, Stefanelli M, Menna G, Sainati L, Poli F, Panarello C, Zecca M, Curto FL, Mecucci C, Danesino C, Pasquali F. Shwachman syndrome as mutator phenotype responsible for myeloid dysplasia/neoplasia through karyotype instability and chromosomes 7 and 20 anomalies. Genes Chromosomes Cancer. 2006;45:375–82. [PubMed: 16382447]
• Maserati E, Pressato B, Valli R, Minelli A, Sainati L, Patitucci F, Marletta C, Mastronuzzi A, Poli F, Lo Curto F, Locatelli F, Danesino C, Pasquali F. The route to development of myelodysplastic syndrome/acute myeloid leukaemia in Shwachman-Diamond syndrome: the role of ageing, karyotype instability, and acquired chromosome anomalies. Br J Haematol. 2009;145:190–7. [PubMed: 19222471]
• Menne TF, Goyenechea B, Sanchez-Puig N, Wong CC, Tonkin LM, Ancliff PJ, Brost RL, Costanzo M, Boone C, Warren AJ. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nat Genet. 2007;39:486–95. [PubMed: 17353896]
• Mitsui T, Kawakami T, Sendo D, Katsuura M, Shimizu Y, Hayasaka K. Successful unrelated donor bone marrow transplantation for Shwachman-Diamond syndrome with leukemia. Int J Hematol. 2004;79:189–92. [PubMed: 15005350]
• Myers KC, Bolyard AA, Otto B, Wong TE, Jones AT, Harris RE, Davies SM, Dale DC, Shimamura A. Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry. J Pediatr. 2014;164:866–70. [PMC free article: PMC4077327] [PubMed: 24388329]
• Myers KC, Davies SM, Shimamura A. Clinical and molecular pathophysiology of Shwachman-Diamond syndrome: an update. Hematol Oncol Clin North Am. 2013a;27:117–28. [PMC free article: PMC5693339] [PubMed: 23351992]
• Myers KC, Rose SR, Rutter MM, Mehta PA, Khoury JC, Cole T, Harris RE. Endocrine evaluation of children with and without Shwachman-Bodian-Diamond syndrome gene mutations and Shwachman-Diamond syndrome. J Pediatr. 2013b;162:1235–40. [PMC free article: PMC5693331] [PubMed: 23305959]
• Nicolis E, Bonizzato A, Assael BM, Cipolli M. Identification of novel mutations in patients with Shwachman-Diamond syndrome. Hum Mutat. 2005;25:410. [PubMed: 15776428]
• Nishimura G, Nakashima E, Hirose Y, Cole T, Cox P, Cohn DH, Rimoin DL, Lachman RS, Miyamoto Y, Kerr B, Unger S, Ohashi H, Superti-Furga A, Ikegawa S. The Shwachman-Bodian-Diamond syndrome gene mutations cause a neonatal form of spondylometaphysial dysplasia (SMD) resembling SMD Sedaghatian type. J Med Genet. 2007;44:e73. [PMC free article: PMC2598034] [PubMed: 17400792]
• Perobelli S, Nicolis E, Assael BM, Cipolli M. Further characterization of Shwachman-Diamond syndrome: psychological functioning and quality of life in adult and young patients. Am J Med Genet A. 2012;158A:567–73. [PubMed: 22315206]
• Pichler J, Meyer R, Köglmeier J, Ancliff P, Shah N. Nutritional status in children with Shwachman-Diamond syndrome. Pancreas. 2015;44:590–5. [PubMed: 25742431]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Ritchie DS, Angus PW, Bhathal PS, Grigg AP. Liver failure complicating non-alcoholic steatohepatitis following allogenic bone marrow transplantation for Shwachman-Diamond syndrome. Bone Marrow Transplant. 2002;29:931–3. [PubMed: 12080360]
• Rosenberg PS, Alter BP, Bolyard AA, Bonilla MA, Boxer LA, Cham B, Fier C, Freedman MA, Kannourakis G, Kinsey S, Schwinzer B, Zeidler C, Welte K, Dale D, et al. The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood. 2006;107:4628–35. [PMC free article: PMC1895804] [PubMed: 16497969]
• Rothbaum R, Perrault J, Vlachos A, Cipolli M, Alter BP, Burroughs S, Durie P, Elghetany MT, Grand R, Hubbard V, Rommens J, Rossi T. Shwachman-Diamond syndrome: report from an international conference. J Pediatr. 2002;141:266–70. [PubMed: 12183725]
• Rothbaum RJ, Williams DA, Daugherty CC. Unusual surface distribution of concanavalin A reflects a cytoskeletal defect in neutrophils in Shwachman's syndrome. Lancet. 1982;2:800–1. [PubMed: 6181360]
• Sack JE, Kuchnir L, Demierre M-F. Dermatofibrosarcoma protuberans arising in the context of Shwachman-Diamond syndrome. Pediatr Dermatol. 2011;28:568–9. [PubMed: 21073512]
• Sauer M, Zeidler C, Meissner B, Rehe K, Hanke A, Weltke K, Lohse P, Sykora KW. Substitution of cyclophosphamide and busulfan by fludarabine, treosulfan and melphalan in a preparative regimen for children and adolescents with Shwachman-Diamond syndrome. Bone Marrow Transplant. 2007;39:143–7. [PubMed: 17211437]
• Savchenko A, Krogan N, Cort JR, Evdokimova E, Lew JM, Yee AA, Sanchez-Pulido L, Andrade MA, Bochkarev A, Watson JD, Kennedy MA, Greenblatt J, Hughes T, Arrowsmith CH, Rommens JM, Edwards AM. The Shwachman-Bodian-Diamond syndrome protein family is involved in RNA metabolism. J Biol Chem. 2005;280:19213–20. [PubMed: 15701634]
• Schibli S, Corey M, Gaskin KJ, Ellis L, Durie PR. Towards an ideal quantitative pancreatic function test: analysis of test variables that influence validity. Clin Gastroenterol Hepatol. 2006;4:90–7. [PubMed: 16431310]
• Shah N, Cambrook H, Koglmeier J, Mason C, Ancliff P, Lindley K, Smith VV, Bajaj-Elliott M, Sebire NJ. Enteropathic histopathological features may be associated with Shwachman-Diamond syndrome. J Clin Pathol. 2010;63:592–4. [PubMed: 20501449]
• Shammas C, Menne TF, Hilcenko C, Michell SR, Goyenechea B, Boocock GR, Durie PR, Rommens JM, Warren AJ. Structural and mutational analysis of the SBDS protein family. Insight into the leukemia-associated Shwachman-Diamond Syndrome. J Biol Chem. 2005;280:19221–9. [PubMed: 15701631]
• Shankar RK, Giri N, Lodish MB, Sinaii N, Reynolds JC, Savage SA, Stratakis CA, Alter BP. Bone mineral density in patients with inherited bone marrow failure syndromes. Pediatr Res. 2017;82:458–64. [PMC free article: PMC5570650] [PubMed: 28486441]
• Sharma A, Sadimin E, Drachtman R, Glod J. CNS lymphoma in a patient with Shwachman Diamond syndrome. Pediatric Blood & Cancer. 2014;61:564–6. [PubMed: 24307640]
• Singh SA, Vlachos A, Morgenstern NJ, Ouansafi I, Ip W, Rommens JM, Durie P, Shimamura A, Lipton JM. Breast cancer in a case of Shwachman Diamond syndrome. Pediatr Blood Cancer. 2012;59:945–6. [PubMed: 22213587]
• Smith OP, Hann IM, Chessells JM, Reeves BR, Milla P. Haematological abnormalities in Shwachman-Diamond syndrome. Br J Haematol. 1996;94:279–84. [PubMed: 8759887]
• Steele L, Rommens JM, Stockley T, Berivan Baskin B, Ray PN. De novo mutations causing Shwachman-Diamond syndrome and a founder mutation in SBDS in the French Canadian population. J Invest Genom. Available online. 2014. Accessed 11-10-22.
• Stepanovic V, Wessels D, Goldman FD, Geiger J, Soll DR. The chemotaxis defect of Shwachman-Diamond syndrome leukocytes. Cell Motil Cytoskeleton. 2004;57:158–74. [PubMed: 14743349]
• Stepensky P, Chacon-Flores M, Kim KH, Abuzaitoun O, Bautista-Santos A, Simanovsky N, Siliqi D, Altamura D, Mendez-Godoy A, Gijsbers A, Eddin AN, Dor T, Charrow J, Sanchez-Puig N, Elpeleg O. Mutations in ELF1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in a Shwachman-Diamond like syndrome. J Med Genet. 2017;54:558–66. [PubMed: 28331068]
• Stormon MO, Ip WF, Ellis L, Schibli S, Rommens JM, Durie PR. Evidence of a generalized defect of acinar cell function in Shwachman-Diamond syndrome. J Pediatr Gastroenterol Nutr. 2010;51:8–13. [PubMed: 20512054]
• Tamary H, Nishri D, Yacobovich J, Zilber R, Dgany O, Krasnov T, Aviner S, Stepensky P, Ravel-Vilk S, Bitan M, Kaplinsky C, Ben Barak A, Elhasid R, Kapelusnik J, Koren A, Levin C, Attias D, Laor R, Yaniv I, Rosenberg PS, Alter BP. Frequency and natural history of inherited bone marrow failure syndromes: the Israeli Inherited Bone Marrow Failure Registry. Haematologica. 2010;95:1300–7. [PMC free article: PMC2913078] [PubMed: 20435624]
• Taneichi H, Kanegane H, Futatani T, Otsubo K, Nomura K, Sato Y, Hama A, Kojima S, Kohdera U, Nakano T, Hori H, Kawashima H, Inoh Y, Kamizono J, Adachi N, Osugi Y, Mizuno H, Hotta N, Yoneyama H, Nakashima E, Ikegawa S, Miyawaki T. Clinical and genetic analyses of presumed Shwachman-Diamond syndrome in Japan. Int J Hematol. 2006;84:60–2. [PubMed: 16867904]
• Toiviainen-Salo S, Durie PR, Numminen K, Heikkila P, Marttinen E, Savilahti E, Makitie O. The natural history of Shwachman-Diamond syndrome-associated liver disease from childhood to adulthood. J Pediatr. 2009;155:807–811.e2. [PubMed: 19683257]
• Toiviainen-Salo S, Makitie O, Mannerkoski M, Hamalainen J, Valanne L, Autti T. Shwachman-Diamond syndrome is associated with structural brain alterations on MRI. Am J Med Genet A. 2008a;146A:1558–64. [PubMed: 18478597]
• 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]
• Valli R, De Paoli E, Nacci L, Frattini A, Pasquali F, Maserati E. Novel recurrent chromosome anomalies in Shwachman-Diamond syndrome. Pediatr Blood Cancer. 2017;64:e26454. [PubMed: 28130858]
• Venet T, Masson E, Talbotec C, Billiemaz K, Touraine R, Gay C, Destombe S, Cooper DN, Patural H, Chen JM, Férec C. Severe infantile isolated exocrine pancreatic insufficiency caused by the complete functional loss of the SPINK1 gene. Hum Mutat. 2017;38:1660–5. [PubMed: 28945313]
• 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]