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 by identification of biallelic pathogenic variants in DNAJC21, EFL1, or SBDS, or a heterozygous pathogenic variant in SRP54.

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 *
• 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 identification of biallelic pathogenic variants in DNAJC21, EFL1, or SBDS, or a heterozygous pathogenic variant in SRP54 by molecular genetic testing (see Table 1).

Note: 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.

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 classical 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 gender-matched children with cystic fibrosis and sib controls. On a number of measures, those with SDS displayed a far wider range of abilities than controls, from severely impaired to superior. Approximately 20% of children with SDS demonstrated intellectual disability in at least one area, with perceptual reasoning being most affected. They were also far more likely than the general population to have the diagnosis of pervasive developmental disorder (6% 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.