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Shwachman-Diamond syndrome

Shwachman-Diamond syndrome
Literature review current through: Sep 2023.
This topic last updated: Aug 12, 2022.

INTRODUCTION — Shwachman-Diamond syndrome (SDS; also known as Shwachman-Bodian-Diamond syndrome, Shwachman-Diamond-Oski syndrome, or Shwachman syndrome) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by exocrine pancreatic dysfunction, cytopenias, and abnormalities of bone.

This topic review discusses the pathophysiology, clinical manifestations, diagnosis, and clinical management of SDS.

Other IBMFS and evaluation of a patient with bone marrow failure or cytopenias are discussed in separate topics:

(See "Congenital neutropenia".)

(See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

(See "Treatment of acquired aplastic anemia in children and adolescents".)

(See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

(See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Shwachman-Diamond syndrome'.)

(See "Dyskeratosis congenita and other telomere biology disorders".)

(See "Hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in children and adolescents", section on 'Introduction'.)

(See "Clinical manifestations and diagnosis of Fanconi anemia".)

(See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

(See "Severe combined immunodeficiency (SCID): Specific defects".)

PATHOGENESIS — Most patients with SDS have pathogenic variants (ie, damaging mutations) in the SBDS gene or other genes that affect ribosome biogenesis and mitosis [1-3].

Biallelic pathogenic variants of SBDS are present in at least 80 to 90 percent of affected individuals [4]. More than 65 percent of mutations are in exon 2 of SBDS and create a truncated protein, but missense and nonsense point mutations and intragenic deletions or duplications have also been reported [3,5-8]. Many variants involve a gene conversion event that recombines SBDS with an adjacent, nonfunctional pseudogene [2]. Genes that encode other proteins active in ribosome assembly or protein translation have also been associated with clinically diagnosed SDS or SDS-like syndromes, including biallelic pathogenic variants in DNAJC21 and EFL1, or a heterozygous pathogenic variant of SRP54 [4,9-16].

SBDS encodes a highly conserved 250 amino acid protein involved in ribosome biogenesis and mitosis that is expressed in all human tissues [2,3,9,17-19]. SBDS appears to cooperate with the GTPase elongation factor-like-1 (EFL1) to catalyze removal of eukaryotic initiation factor 6 from the 60S ribosome subunit, facilitating assembly into the actively translating 80S subunit [3,9,20,21]. SBDS also stabilizes the mitotic spindle, and its loss in hematopoietic progenitors may contribute to the high rate of chromosomal abnormalities in hematopoietic cells [3,19]. SBDS is likely an essential gene product, based on observations that no individuals carrying homozygous null alleles of SBDS have been reported and that homozygous deletion (knockout) of Sbds in mice is lethal early in embryogenesis [3,22].

EPIDEMIOLOGY — The prevalence of SDS is not well-defined, but population-based estimates suggested an incidence of biallelic SBDS mutations of 1 in 1:153,000 to 168,000 live births [23]. In a North American study, the incidence was estimated to be 1 in 77,000 live births, which is approximately 1/20th as frequent as cystic fibrosis in that geographic setting [19,24]. No specific racial or ethnic predilection has been identified, and SDS has been reported in individuals of European, Native American, Chinese, Japanese, Indian (south Asian), and African ancestry [4]. A male:female ratio of 1.7:1 was reported.

Although rare, SDS is one of the more common inherited bone marrow failure syndromes (IBMFS). SDS accounted for 14 percent of cases in a cohort of 259 patients with IBMFS, which was slightly less common than Diamond-Blackfan anemia and Fanconi anemia (17 and 15 percent, respectively) [25].

CLINICAL MANIFESTATIONS

Presenting findings — SDS is a congenital multisystem disorder typically characterized by the triad of exocrine pancreatic dysfunction, cytopenias (particularly neutropenia), and bone abnormalities. However, the advent of molecular detection has revealed a broad and variable phenotypic spectrum that includes single features of the triad and more subtle or clinically inapparent findings.

Classically, SDS presents in infancy or early childhood with failure to thrive, steatorrhea, recurrent infections, and/or growth retardation; nearly all affected children have intermittent or persistent neutropenia at presentation. Neonates generally do not exhibit manifestations of SDS, but early presentations that have been reported include life-threatening infections, bone marrow failure, aplastic anemia, asphyxiating thoracic dystrophy due to rib cage restriction, and severe spondylo-metaphyseal chondrodysplasia [26,27]. In a case series that included 129 patients in 116 families who were diagnosed clinically (before the widespread availability of genetic testing), the median age at diagnosis was one year (range from 0.1 to 13 years) [28]. Prominent clinical findings included steatorrhea (86 percent), short stature (56 percent), skeletal abnormalities (49 percent), and nearly universal hematologic findings.

Genetic testing can identify individuals with more subtle or variable findings [29,30]. A series of 121 patients who were diagnosed using mutational analysis reported the median age at diagnosis was 1.3 years (range 0 to 35.6 years) [31]. A report from the North American Shwachman-Diamond Registry, which included 37 patients with a diagnosis confirmed by SBDS gene analysis, reported a slightly older median age at presentation (3.5 years) [30]. Nearly half presented without the classical combination of neutropenia and steatorrhea; many had isolated diarrhea, isolated neutropenia, or isolated thrombocytopenia, and two individuals were asymptomatic. In a subsequent update that included 83 patients, the median age at diagnosis was yet older (11.1 years) and clinical findings were more heterogeneous [32]. Cytopenias, particularly intermittent neutropenia, were seen in almost all patients. These and other studies have also reported tooth enamel defects, cleft palate, and neurocognitive dysfunction [28,33-36].

Cytopenias/infections — Neutropenia is the most common cytopenia in SDS, and some patients have macrocytic anemia and/or thrombocytopenia. There is an increased risk for infection because of both quantitative and qualitative neutrophil defects.

Neutropenia (absolute neutrophil count [ANC] <1500 cells/microL) is the most common hematologic finding in SDS and it generally begins at an early age [37-40]. Intermittent or persistent neutropenia is recognized first in almost all affected children and is often detected before the diagnosis of SDS is made [28]. Neutropenia is usually progressive through childhood, but it can be mild or severe, variable, or transient. Neutrophils from patients with SDS also demonstrate impaired mobility, migration, and chemotaxis, but oxidative activity and phagocytosis appear to be unaffected [26,41-47].

Patients with SDS are at increased risk for infection because of both neutropenia and abnormal neutrophil function. Infections associated with SDS can be life-threatening, especially in young children [48,49]. In a review of published cases that included 153 patients, the most common infections included pneumonia, recurrent otitis media, skin infections, and abscesses [48]. Despite impaired neutrophil chemotaxis, patients with SDS are able to form empyemas and abscesses, which distinguishes SDS from more severe disorders of neutrophil chemotaxis [43,50]. Low numbers of B and T lymphocytes and impaired immunoglobulin production may also contribute to an increased risk of infection [44].

The prevalence of cytopenias varies according to whether a patient is diagnosed with SDS based on clinical criteria or by genetic testing. In a cohort of patients who were diagnosed clinically (ie, before the widespread availability of genetic testing), neutropenia was present in 98 percent, anemia in 42 percent, and thrombocytopenia in 34 percent [28]. By way of comparison, among patients whose diagnosis was confirmed by genetic testing, 81 percent had neutropenia, 42 percent had anemia, and 27 percent had thrombocytopenia [30,32]. The reticulocyte count is typically inappropriately low and red blood cells are usually macrocytic, but may be normocytic. Thrombocytopenia is generally mild; severe thrombocytopenia and bleeding are rare in the absence of malignant progression.

Severe pancytopenia with aplastic anemia occurs in a subset of individuals. The French Severe Chronic Neutropenia Registry reported that 21 percent of 102 individuals with SDS had persistent severe cytopenias, 9 of which were not related to malignant transformation [51]. The Italian SDS Registry reported a cumulative 10 percent incidence of bone marrow failure/severe cytopenia after 20 years of observation [31]. The incidence of bone marrow failure has been estimated to be 40 percent by age 40 years [52-54].

Bone marrow findings — Bone marrow findings in SDS are non-diagnostic. While hypocellularity is common, increased cellularity has also been reported. Mild and/or fluctuating dysplastic changes are common, but frank myelodysplastic changes suggest malignant transformation.

Myelodysplasia and acute myeloid leukemia — Individuals with SDS are at increased lifelong risk for developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but the rate of malignant transformation is not well-defined. The prognosis for patients with SDS who develop AML is poor.

Risk of transformation – The estimated frequency of malignant transformation in SDS varies widely between studies, due to small sample sizes, variable periods of observation, patient age, and the difficulty of distinguishing early MDS from the non-progressive clonal hematopoiesis (CH) commonly observed in SDS [29].

The Severe Chronic Neutropenia International Registry (SCNIR) reported an 8 percent overall incidence of MDS/AML in 37 individuals with SDS over a 10-year period, corresponding to a rate of progression of 1 percent per year [55,56]. The cumulative risk of transformation was estimated to be 19 percent at 20 years and 36 percent at 30 years in the French Severe Chronic Neutropenia Registry; the risk was higher than that associated with severe congenital neutropenia [57]. The Italian Registry reported a 10 percent incidence of MDS/AML after 20 years of observation [31]. The National Cancer Institute Inherited Bone Marrow Failure Syndrome cohort reported a 65 percent risk by age 50 (but with wide confidence intervals) [54]. Other studies reported rates of MDS/AML from 0 to 87 percent [28,30,35,53,58,59].

A retrospective study of 36 patients from the North American Registry reported that patients who developed AML had a one year median overall survival (OS) and 11 percent three-year OS; corresponding data for patients who developed MDS were eight year median OS and 51 percent three-year OS [60].

Cytogenetic abnormalities – Cytogenetic abnormalities were reported in 65 percent of individuals in the Italian SDS registry [31]. The most common findings are monosomy 7, isochromosome 7, deletion of 7q, and deletion of 20q [3,31,61-64]. Specific abnormalities are associated with different rates of malignant transformation. Monosomy 7 is associated with rapid malignant transformation; in contrast, del(20q) and iso(7) are only rarely associated with transformation to MDS/AML [3,31,61-64]. Except for monosomy 7, these changes may persist, fluctuate or resolve over time, without progression to MDS/AML [65-67].  

Genetic events – Patients with SDS frequently develop multiple hematopoietic clones with characteristic acquired mutations; the clones are infrequent in the first years of life, but they are present in >90 percent of patients by the second decade of life [68]. Development of MDS and/or AML is linked to clones that have biallelic mutations of TP53.

Serial analysis of samples from 110 children and young adults with SDS identified multiple, independently-arising clones (rather than a single clone with complex subclonal evolution) [68]. Most clones carried a mutation in one of only four genes (EIF6, TP53, PRPF8, and CSNK1A1), but they rarely involved genes that are commonly associated with age-related CH (eg, DNMT3A, TET2, ASXL1). Clones with monoallelic mutations of TP53 were observed to persist at a low variant allele frequency in patients for years, but the presence, number, persistence, or allele abundance of somatic TP53 mutations were not predictive of imminent leukemia risk. However, clones that developed biallelic TP53 mutation have increased leukemic potential due to inactivation of p53-associated tumor suppressor checkpoints; the TP53 locus may be disrupted by deletion, copy number/loss-of-heterozygosity, or point mutations. Clones associated with EIF6 mutations were not associated with leukemic transformation, but the acquired EIF6 mutations functionally compensated for the germline SDS abnormality by rescuing the ribosomal defect, improving translation, and reducing p53 activation.

Pancreatic dysfunction — Pancreatic exocrine dysfunction is common in SDS and often presents in the first year of life with steatorrhea and failure to thrive; for unclear reasons, these manifestations may resolve over time; some patients have constipation. Laboratory and imaging studies may reveal subtle, subclinical effects. Diabetes mellitus and pancreatic endocrine dysfunction are not associated with SDS.

Manifestations of pancreatic dysfunction can vary from asymptomatic to severe dysfunction, including steatorrhea (diarrhea with pale, greasy, voluminous, foul-smelling stools), malabsorption of nutrients, and failure to thrive. In a cohort of patients who were diagnosed clinically, 86 percent had steatorrhea [28]. Among patients whose diagnosis was confirmed by genetic testing, 58 percent had diarrhea, but many of the individuals without diarrhea had abnormalities on laboratory testing or pancreatic imaging [30]. For many patients, pancreatic function improves sufficiently over time that it enables discontinuation of enzyme replacement. In a series of 25 individuals with SDS and pancreatic insufficiency, 45 percent showed age-related improvements leading to pancreatic sufficiency, especially after age 4 [34].

The mechanism of pancreatic dysfunction is unclear, although it appears that the defect involves pancreatic acinar aplasia; histopathology reveals few acinar cells and extensive fatty infiltration but normal ductal architecture and islets of Langerhans (picture 1) [34]. A similar acinar defect has been reported in the parotid glands of patients with SDS [69]. Gastrointestinal mucosal biopsies revealed duodenal inflammation in more than half of patients with SDS, suggesting that there may be an enteropathic component to their malabsorption; this may also account for the failure of some to respond adequately to nutritional supplementation and pancreatic enzyme replacement [70].

Pancreatic imaging (eg, ultrasound, computed tomography [CT], or magnetic resonance imaging [MRI]) may show a small, shrunken pancreas, lipomatosis, or fatty replacement (image 1) [30,71]. In some patients, abnormal pancreatic imaging only emerges over time [30]. Laboratory studies may identify subclinical manifestations of pancreatic dysfunction. In one series, 82 percent of patients had low levels of fecal elastase, serum trypsinogen, or pancreatic isoamylase [30]. In a cohort of 90 individuals with SDS, compared with 134 unaffected controls, low serum trypsinogen levels in individuals <3 years of age or low serum pancreatic isoamylase levels in those >3 years of age were sensitive measures of pancreatic dysfunction [72].

Management of pancreatic dysfunction with enzyme replacement and/or supplementation with fat-soluble vitamins is discussed below. (See 'GI/nutrition' below.)

Skeletal abnormalities — Various skeletal abnormalities have been reported in SDS, including short stature, osteopenia, metaphyseal dysplasia, thoracic/rib and pelvic dystrophies, short arms and legs, and duplicated distal thumb [28,30,73]. Abnormal bone turnover, involving decreased activity of both osteoclasts and osteoblasts, is present [74].

Skeletal findings are generally symmetrical, may be widespread or localized, and are more marked in the lower limbs. Rib shortening and distal rib flaring or cupping, if present, are detectable from infancy. Metaphyseal changes develop in hips and knees starting at four to six months, and variable broadening of the metaphyses with mixed lytic and sclerotic findings may lead to deformity requiring orthopedic intervention. Nutritional defects (eg, due to pancreatic dysfunction) may contribute to short stature, but cortical thinning and osteopenia occur even with pancreatic enzyme replacement [28,36,75,76].

Other findings — Examples of other clinical manifestations that have been described in individuals with SDS include:

Growth – Children with adequate nutrition and pancreatic enzyme replacement might be expected to have normal growth velocity and appropriate weight for height. Nevertheless, approximately half of children with SDS were reported to be below the third percentile for height and weight [76].

Liver dysfunction – Hepatomegaly and liver dysfunction can be observed in children but tend to resolve with age. Abnormalities may include elevated serum transaminases, hepatomegaly, steatosis, inflammation, and elevated bile acids. In a study of patients who were diagnosed clinically, 60 percent showed elevated transaminases and 15 percent had hepatomegaly [28]. Liver biopsies showed histologic abnormalities in 12 of 13 cases (92 percent), including microvesicular and macrovesicular steatosis; portal and periportal inflammation; and portal, periportal, and bridging fibrosis. In a series of 37 patients diagnosed by genetic testing, 41 percent had elevated transaminases [30].

Similar to pancreatic dysfunction, hepatic dysfunction may improve during childhood. In a series of 12 individuals with SDS who had liver abnormalities, values generally normalized by five years of age, and no additional abnormalities developed during extended observation into adulthood [77]. However, liver complications have been reported in older individuals following allogeneic hematopoietic cell transplantation [78].

Cardiac findings – Cardiac anomalies and heart failure have been reported in SDS. In the North American Registry, 7 of 37 patients had congenital cardiac anomalies, including ventricular septal defect, patent foramen ovale, and patent ductus arteriosus [30]. In a series of 14 patients who underwent echocardiography, all had normal ejection fraction, but one-third had evidence of circumferential strain, suggesting systolic dysfunction [79].

Neurocognitive and behavioral problems – Some patients with SDS have learning and behavioral difficulties. One report used standardized neuropsychological tests to compare cognitive, behavioral, and adaptive functioning of 32 children with SDS with that of their unaffected siblings and a comparison group of children with cystic fibrosis [80]. Compared with controls, approximately 20 percent of children with SDS exhibited intellectual disability in at least one domain (eg, intellectual reasoning, higher order language skills, perceptual reasoning, visual-motor processing, attention) and they were more likely to have pervasive developmental disorder or attention deficits. Other studies have also reported cognitive and/or behavioral impairment in children with SDS [28,36,71,81-83].

Congenital anomalies – A variety of other congenital anomalies have been reported in individuals with SDS, including abnormalities of the urinary tract, cleft palate, intestinal malrotation, imperforate anus, eye and ear anomalies, Arnold-Chiari malformation, and cerebellar tonsillar ectopia [28,30,84].

Dental dysplasia – Tooth enamel defects (eg, hypomaturation, hypocalcification, hypoplasia), dental caries, and tooth surface loss are commonly seen in patients with SDS [37,43,85]. Gingivitis also occurs related to persistent neutropenia.

Endocrine abnormalities Endocrine abnormalities are not common in SDS, and no consistent abnormalities have been identified. Type I diabetes mellitus was reported to occur in 3 percent of patients in the Italian national registry for SDS, which is higher than expected for the reference population [86]. In another series of 25 patients with genetically confirmed SDS, two had low stimulated growth hormone levels, two had elevated thyrotropin (TSH) levels, and five had abnormal oral glucose tolerance tests [87]. A case of congenital hypopituitarism in a patient with SDS was reported [88].

Nonhematopoietic malignancies Nonhematopoietic malignancies are not a major clinical feature of SDS. There are case reports of breast cancer in a 30 year old, dermatofibrosarcoma in a 17 year old, diffuse large B cell lymphoma of the brain in an 18 year old, pancreatic duodenal carcinoma in a 24 year old, pancreatic adenocarcinoma in a 38 year old, and a case of Hodgkin lymphoma [89-93].

EVALUATION

History and physical examination — Evaluation for SDS includes a thorough history of infections, bleeding, growth history and percentiles, and gastrointestinal symptoms, especially steatorrhea. Family history of inherited bone marrow failure syndromes, fetal or early childhood sibling deaths, and possible consanguinity should be assessed.

Physical examination should evaluate the individual for short stature, skeletal abnormalities, cardiac defects, hepatomegaly, and rashes.

Laboratory testing — Screening laboratory studies should include:

Hematology – Complete blood count (CBC) with differential and platelet count, reticulocyte count, and review of the blood smear.

Bone marrow examination – Bone marrow aspirate and biopsy may be performed during the evaluation for a cause of cytopenias. Bone marrow examination should include microscopy and karyotype and/or fluorescence in situ hybridization (FISH) to exclude other bone marrow disorders and to assess karyotypic abnormalities associated with SDS, as described below. (See 'Differential diagnosis' below and 'Bone marrow examinations' below.)

Pancreatic testing – Documentation of exocrine pancreatic dysfunction can include any of the following [4,94]:

Low serum concentrations of pancreatic isoamylase (age ≥3 and adjusted for age) [95]

Low levels of fecal elastase

Supportive features, include:

-Abnormal fecal fat balance study of a 72 hour stool collection

-Reduced levels of fat-soluble vitamins (ie, vitamins A, D, E, K)

-Pancreatic lipomatosis on imaging

Genetic testing — Genetic testing is important for making the diagnosis of SDS, confirming a clinical diagnosis of SDS, excluding other disorders in the differential diagnosis, and testing of clinically unaffected family members. Pathogenic variants associated with SDS and the role of genetic testing in establishing the diagnosis are discussed above and below. (See 'Pathogenesis' above and 'Diagnosis' below and 'Differential diagnosis' below.)

Molecular testing may include gene-targeted testing by single-gene testing or a multigene panel. In some settings, comprehensive genomic testing (eg, exome sequencing, exome array, genome sequencing) may be preferred for patients with atypical clinical features.

If available, we consider a multigene panel the most efficient and cost-effective way to identify the genetic basis of SDS and exclude other conditions. The multigene panel should include SBDS, DNAJC21, EFL1, SRP54, and genes associated with other conditions in the differential diagnosis. The genes included in the panel, laboratory methods, diagnostic sensitivity, and interpretation of what constitutes a pathogenic mutation versus a variation of uncertain significance will vary by laboratory [96]. In general, clinicians should discuss the results of a multigene panel with a geneticist familiar with bone marrow failure syndromes, in order to provide more expert interpretation of the laboratory report.

If serial single-gene testing is pursued, it should begin with SBDS, which is associated with SDS in at least 80 to 90 percent of cases. SBDS pathogenic variants are considered confirmatory of the diagnosis of SDS if analysis reveals homozygous or compound heterozygous mutations. Targeted sequencing of SBDS detects at least one pathogenic variant in approximately 90 percent of affected individuals and both pathogenic variants in 62 percent of affected individuals with heterozygous variants [2]. Single-gene testing can detect small intergenic deletions/insertions and missense, nonsense, and splice site variants but generally does detect exon or whole gene deletions or duplications. If only one or no pathogenic variant is identified, we suggest serial or concurrent testing of DNAJC21, EFL1, and SRP54 (the other identified causes of SDS) and analysis to detect intergenic deletions or duplications.

The most common SBDS pathogenic variants involve exon 2, including 258+2 T>C and 183-184 TA>CT [30]. If c.[183_184delinsCT; 258+2T>C] (a complex allele resulting from gene conversion with the adjacent SBDSP pseudogene) is reported, it is important to test the parents to distinguish the cis configuration (ie, on the same allele) from the trans configuration (ie, on the other allele).

Laboratories that can provide these services are available on the Genetic Testing Registry (ncbi.nlm.nih.gov/gtr/).

Once a genetic variant is identified, targeted testing of family members should occur, as described below. (See 'Testing and counseling for family members' below.)

DIAGNOSIS — SDS should be suspected in an individual with exocrine pancreatic dysfunction, hematologic abnormalities, or other syndromic manifestations (eg, short stature, skeletal abnormalities, congenital organ abnormalities) or a family history of these conditions. Patients may be encountered while evaluating unexplained neutropenia, other cytopenias, or hematologic malignancy; poor linear growth or failure to thrive, steatorrhea, pancreas or liver dysfunction; or skeletal dysplasia. (See 'Clinical manifestations' above.)

A diagnosis of SDS is confirmed in a proband by identification of biallelic pathogenic variants in SBDS, DNAJC21, or EFL1, or a heterozygous pathogenic variant in SRP54, with or without specific clinical findings. The classic presentation is an infant with growth failure, feeding difficulties, steatorrhea, neutropenia, and/or recurrent infections, but clinical manifestations of SDS are variable and up to half of individuals with genetically-confirmed SDS do not have the classic combination of manifestations.

Rare patients may be diagnosed with SDS on the basis of clinical presentation alone (ie, without genetic confirmation); these individuals may have an as-yet-unidentified genetic basis for the syndrome.

The choice of a method for genetic testing for SDS is described above. (See 'Genetic testing' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of SDS includes other causes of hematologic disorders, exocrine pancreatic dysfunction, or impaired linear growth.

Hematologic conditions — Neutropenia can be caused by numerous conditions, including medications and infections, but these generally cause transient effects and are not associated with syndromic features. Approach to the evaluation of a child with neutropenia or bone marrow failure is presented separately. (See "Overview of neutropenia in children and adolescents".)

Constitutional causes of neutropenia or bone marrow failure that may be associated with syndromic findings include:

Fanconi anemia (FA) – FA is the most common inherited bone marrow failure syndrome (IBMFS). It is caused by defective maintenance of genome stability, due to disordered DNA repair. Transmission may be autosomal recessive or X-linked. Like SDS, FA is characterized by bone marrow failure, short stature, and/or congenital cardiac and bone anomalies. FA has a higher predisposition to hematologic malignancies, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Unlike SDS, FA typically presents during later childhood and is not associated with exocrine pancreatic insufficiency. Patients with FA frequently have congenital anomalies (eg, thumb and radial ray, renal), characteristic skin changes (eg, hypopigmentation, café au lait spots), and carcinomas (eg, head and neck, esophageal, hepatic, vulvar) that are not seen in SDS. Laboratory testing in FA reveals increased sensitivity to chromosomal breakage from DNA crosslinking agents that is not observed in SDS. (See "Clinical manifestations and diagnosis of Fanconi anemia".)

Dyskeratosis congenita (DC) – DC is an IBMFS caused by defective telomere maintenance. The classic presenting triad of DC includes skin pigmentation, nail dystrophy, and oral leukoplakia, but not all may be present. DC can be caused numerous genetic defects and its inheritance may be autosomal or X-linked. Patients with DC usually are diagnosed in adolescence or adulthood, but symptomatic pediatric cases do occur. Bone marrow problems in DC usually present later in life. Like SDS, patients with DC have bone marrow failure that can result in myeloid malignancy. Unlike SDS, individuals with DC may have characteristic skin and nail changes and a predisposition to other malignancies, but no primary pancreatic exocrine dysfunction. (See "Dyskeratosis congenita and other telomere biology disorders".)

Diamond-Blackfan anemia (DBA) – DBA generally presents with progressive macrocytic anemia with reticulocytopenia, often with congenital physical features. Bone marrow cellularity is normal, but erythroid precursors are markedly reduced or absent. There is no primary pancreatic exocrine dysfunction associated with DBA. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)

Congenital amegakaryocytic thrombocytopenia (CAMT) – CAMT is an IBMFS associated with isolated thrombocytopenia that can progress to pancytopenia. It is caused by a pathogenic variant in MPL, the gene that encodes the thrombopoietin receptor, which is required for production of megakaryocytes and platelets. Like SDS, CAMT can be associated with bone marrow failure. Unlike SDS, CAMT is not associated with exocrine pancreatic dysfunction, other congenital organ disorders, or other anomalies. Genetic testing in CAMT reveals a pathogenic variant affecting of MPL.

Severe congenital neutropenia (SCN) – SCN is associated with severe neutropenia, but the few neutrophils in peripheral blood generally have normal morphology. Bone marrow examination usually reveals atypical nuclei, cytoplasmic vacuolization, and maturation arrest at the promyelocyte/myelocyte stage. Pathogenic variants in several genes cause SCN, most commonly affecting ELANE (encoding neutrophil elastase). The eponym Kostmann syndrome refers specifically to SCN due to mutations in HAX1. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

Pancreas/GI conditions — SDS is the second most common cause of inherited exocrine pancreatic dysfunction after cystic fibrosis, but other constitutional conditions should be considered in the differential diagnosis of the child with pancreatic dysfunction.

Cystic fibrosis (CF) – CF is an inherited condition associated with exocrine pancreatic dysfunction, chronic respiratory infections, and meconium ileus due to a pathologic variant that affects exocrine glands in the pancreas, bronchi, and gastrointestinal (GI) tract. Like SDS, CF may present in infancy with malabsorption. Unlike SDS, patients with CF may have other manifestations related to glandular dysfunction, including lung disease, biliary cirrhosis, and infertility, and they have an abnormal sweat chloride test; patients with CF do not have bone marrow failure. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)

Pearson syndrome – Pearson syndrome is a congenital multisystem disorder associated with bone marrow failure, exocrine pancreatic insufficiency, lactic acidosis, and failure to thrive. Pearson syndrome is caused by abnormalities in mitochondrial DNA. Many patients with Pearson syndrome die in infancy. Like SDS, patients with Pearson syndrome present in infancy or early childhood with cytopenias and/or exocrine pancreatic insufficiency. Unlike SDS, individuals with Pearson syndrome have normal bone marrow cellularity, ring sideroblasts, and vacuolization of bone marrow progenitors; pancreatic fibrosis rather than lipomatosis; and absence of bone lesions. Genetic testing reveals mitochondrial gene defects (eg, contiguous gene deletions and/or duplications) rather than gene variants associated with SDS. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Pearson syndrome' and "Causes and pathophysiology of the sideroblastic anemias", section on 'Pearson syndrome (large deletion of mitochondrial DNA)'.)

SPINK1-related SPINK1-related severe infantile isolated exocrine pancreatic insufficiency is a constitutional disorder associated with recurrent pancreatitis. The SPINK1 gene encodes a pancreatic secretory trypsin inhibitor expressed in pancreatic acinar cells that serves as an inhibitor of trypsin. Unlike SDS, this condition is not associated with neutropenia or other cytopenias. (See "Pancreatitis associated with genetic risk factors", section on 'SPINK1 gene'.)

Johanson-Blizzard syndrome (JBS) – JBS is an autosomal recessive constitutional disorder associated with exocrine pancreatic dysfunction, impaired growth, intellectual disability, sensorineural hearing loss, and variable dysmorphic features. Like SDS, JBS can present in infancy with pancreatic insufficiency and abnormal growth but is more likely to be associated with hypothyroidism, scalp defects, dental abnormalities, urogenital malformations, and imperforate anus; there are no hematologic abnormalities. Genetic testing reveals mutation of the UBR1 gene. JBS and other congenital causes of steatorrhea in infants and children are presented separately. (See "Overview of the causes of chronic diarrhea in children in resource-abundant settings", section on 'Congenital conditions associated with bowel obstruction'.)

Impaired/delayed growth — Growth impairment may be manifest as short stature, impaired growth, and developmental delay.

Short stature – The approach to evaluation of a child with short stature and/or impaired growth is discussed separately. (See "Diagnostic approach to children and adolescents with short stature".)

Severe malnutrition – Growth impairment due to severe malnutrition is generally consistent with inadequate caloric/protein intake, no underlying syndromic features are present, and there is no evidence of exocrine pancreatic dysfunction. (See "Poor weight gain in children younger than two years in resource-abundant settings: Etiology and evaluation".)

Skeletal dysplasias – There are many constitutional causes of skeletal dysplasia that affect bone length, density, and other features of growth; some are associated with other syndromic features. The approach to evaluation and descriptions of specific disorders are provided separately. (See "Skeletal dysplasias: Approach to evaluation" and "Skeletal dysplasias: Specific disorders".)

BASELINE AND ONGOING MONITORING — We suggest management of the individual with SDS by a multidisciplinary team, including a hematologist, gastroenterologist, and other subspecialists, as clinically indicated. There are no randomized or well-controlled therapeutic trials in SDS, and management suggestions are generally based on clinical experience, extrapolation from other disorders, and SDS Registry data [31,60,97].

Following the diagnosis of SDS, a baseline evaluation should establish the extent of disease and the needs of the individual. Lifelong monitoring is required, but the nature of clinical findings and the resultant monitoring may evolve over time.

We encourage enrollment of all affected individuals in a clinical SDS registry. As an example, the North American Shwachman-Diamond Syndrome Registry can be found at http://sdsregistry.org/. Other nations also have registries for SDS or various bone marrow failure syndromes.

Growth and development — Children should be monitored for growth and development, including height and weight relative to age every six months. (See "Normal growth patterns in infants and prepubertal children".)

We seek to identify treatable factors that may contribute to growth delay, such as deficiencies of calories, vitamins, and micronutrients [98]. Laboratory aspects of monitoring nutritional status and pancreatic function are described below. (See 'Laboratory studies' below.)

Laboratory studies — Routine laboratory testing should include:

Hematology:

Complete blood count (CBC) – CBC with differential and platelet count is performed every three to six months, or more frequently if clinically indicated (eg, for worsening cytopenias or recurrent infections).

Prothrombin time (which may be abnormal due to vitamin K deficiency).

For patients with recurrent infections, we suggest quantitative immunoglobulins for evaluation of hypogammaglobulinemia.

HLA typing should be performed once the diagnosis is made to better understand therapeutic options. Siblings could have targeted genetic testing and HLA typing done at the same blood draw for convenience.

Serum chemistries:

Liver function tests, including aminotransferases.

Fat-soluble vitamins (eg, vitamin A, 25-OH vitamin D, vitamin E) and micronutrients (eg, selenium, zinc, copper) should be measured at least annually.

Folate and vitamin B12; iron and iron binding capacity should be performed if the patient is very anemic and/or red blood cells are microcytic.

Pancreatic function: Initial evaluation of pancreatic exocrine function should be performed in all patients, as some may have subclinical deficits. Evaluation of pancreatic function is similar to the approach for cystic fibrosis, as described separately. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

Laboratory testing should evaluate exocrine pancreatic dysfunction [30,34]:

For children ≥3 years, we suggest pancreatic isoamylase and fecal elastase.

For children <3 years of age, we suggest fecal elastase, because serum pancreatic isoamylase is not a reliable test in children <3 years and serum cationic trypsinogen concentration increases to the normal range in early childhood in approximately half of children [72]. Testing for serum trypsinogen is acceptable, but not widely available.

If pancreatic dysfunction and/or steatorrhea are present, the individual should be further characterized with a timed quantitative fecal fat measurement. Measurement of fat-soluble vitamins and micronutrients are described above, and imaging is described below. (See 'Imaging' below.)  

Ongoing monitoring of pancreatic exocrine function is needed to monitor the efficacy of enzyme replacement, assess resolution of pancreatic dysfunction, or detect declining function. Frequency of testing depends on prior deficits, use of pancreatic supplements, and symptoms. Since many patients will have improvement of pancreatic function in later childhood, we suggest a trial off of supplements during a school vacation in older children (eg, ≥10 years). (See 'Pancreatic dysfunction' above.)

Bone marrow examinations — A baseline bone marrow biopsy and aspirate should be performed soon after SDS is diagnosed. The evaluation should include karyotype and fluorescence in situ hybridization (FISH) for specific chromosomal abnormalities associated with SDS (eg, iso(7) and del[20q]). Assessment of acquired mutations (eg, EIF6 or TP53) is not routinely performed outside of a clinical study at present.

The frequency of repeat bone marrow examinations should be individualized and may be influenced by the degree and trajectory of cytopenias; size and nature of clonality; degree of dysplasia or percentage blasts; and treatment with granulocyte colony-stimulating factor (G-CSF). Some experts perform surveillance bone marrow examinations every year for children receiving G-CSF and every one to two years for others. Other experts suggest performing a bone marrow examination only if there is a change in peripheral blood counts. However, in the North American Registry series, 6 of 15 (40 percent) of SDS patients developed MDS in the setting of stable blood counts; this study suggested that serial surveillance bone marrow examinations to evaluate transformation to AML or MDS may be associated with improved outcomes [60].

Imaging — Abdominal ultrasound should be performed to establish a baseline image and determine if there is pancreatic atrophy or lipomatosis. Further imaging and/or follow-up studies should be guided by the clinical and imaging findings.

Radiographs of the hips and knees should be performed at baseline and during rapid growth phases. Bone densitometry should be performed before puberty, during puberty, and as clinically indicated, based on individual findings. (See "Society guideline links: Pediatric bone health".)

CLINICAL CONDITIONS

Neutropenia and infections — There is no consensus regarding optimal management of neutropenia in SDS, and no controlled trials have compared various approaches. Management of neutropenia should be individualized, based on the severity of neutropenia, evidence of dysplasia and/or chromosomal abnormalities, presence of recurrent and/or severe infections or gingivitis, frequency of febrile events, and patient/family values and preferences. For all patients, it is important to maintain age-appropriate schedules of immunizations, including seasonal influenza. (See "Standard immunizations for children and adolescents: Overview" and "Standard immunizations for nonpregnant adults".)

Our approach follows:

For patients with absolute neutrophil count (ANC) persistently ≤500/microL, recurrent or severe infections, and/or progressive gingivitis with risk of tooth loss, our approach is informed by the degree of hematopoietic dysplasia and/or chromosomal abnormalities:

For patients with monosomy 7 or substantial or progressive dysplasia, we suggest prompt allogeneic hematopoietic cell transplantation (HCT) rather than treatment with granulocyte colony-stimulating factor (G-CSF) or observation alone, based on the high probability of transformation to acute myeloid leukemia (AML) associated with these findings. (See 'Myelodysplasia and acute myeloid leukemia' above.)

Cautions regarding donor selection and conditioning regimens are presented below. (See 'Hematopoietic cell transplantation (HCT)' below.)

For patients with lesser degrees of dysplasia and/or chromosomal findings other than monosomy 7, we consider observation alone or treatment with G-CSF to be acceptable options; we generally do not offer allogeneic HCT as initial treatment in this setting. A decision to treat with G-CSF versus observation alone must be individualized and is influenced by the severity of infections, degree of gingivitis/dental loss, and frequency of febrile events. We consider that the reduction of severe infections/gingivitis with G-CSF outweighs an uncertain risk that G-CSF may accelerate progression to AML in this setting [57]. For patients who continue to have recurrent or severe infections despite treatment with G-CSF, allogeneic HCT may be warranted.

For patients with less severe neutropenia (eg, ANC >500 /microL) and without recurrent and/or severe infections or progressive gingivitis, we generally advise supportive care. We do not offer allogeneic HCT unless the risk of AML is high (eg, monosomy 7 or substantial or progressive dysplasia) and we do not routinely treat with G-CSF because of an uncertain risk that G-CSF may accelerate progression to AML [57].

This approach requires educating the patient and family about the importance of a prompt response to fever or other infectious symptoms. For temperature >101.5° F (>37.5° C) or other findings suggestive of infection, the patient should present to an emergency department immediately for evaluation, including a complete blood count (CBC) and differential and blood cultures. Patients with ANC <500/microL require hospitalization with broad spectrum antibiotics until resolution of the fever; G-CSF may be added during the hospital stay. For patients with ANC ≥500/microL, immediate hospitalization may not be required, but management should be individualized. Evaluation and management of febrile neutropenia is discussed separately. (See "Management of children with non-chemotherapy-induced neutropenia and fever" and "Overview of neutropenia in children and adolescents", section on 'Patients with bone marrow hypoplasia and/or severe infections'.)

For patients without persistent neutropenia who have recurrent sinopulmonary, gastrointestinal, or cutaneous infections, we investigate for other immune defects, such as IgG deficiency (total or subclass) or a subtle T cell defect. Intravenous immune globulin (IVIG) supplementation may be beneficial in reducing the incidence of febrile illnesses in this setting. (See "Primary humoral immunodeficiencies: An overview" and "Immune globulin therapy in inborn errors of immunity".)

Other cytopenias — Anemia is generally mild and may be intermittent and asymptomatic. Severe aplastic anemia occurs in only a small percentage of patients with SDS. Other contributing factors (eg, iron deficiency, vitamin B12 or folate deficiency) should be evaluated and managed, as needed.

The indications for red blood cell (RBC) transfusion are guided by clinical symptoms and the hemoglobin level compared with the patient's baseline. RBC transfusion generally is appropriate for patients with symptomatic anemia (eg, decreased activity level, excessive fatigue, shortness of breath). Leukoreduced blood products should be used in all patients with SDS, beginning at the time of diagnosis, to reduce the risks of febrile reactions and cytomegalovirus (CMV) infection. Some clinicians favor use of irradiated blood products to minimize the risk of transfusion-associated graft-versus-host disease or reduce risk for viral reactivation in patients who may eventually need HCT, but there is little evidence to support this approach. (See "Red blood cell transfusion in infants and children: Administration and complications" and "Red blood cell transfusion in infants and children: Selection of blood products".)

Related donors should not be used for blood products, because of the possible future need for HCT. There is an increased risk for graft rejection in individuals who have received blood products from a related individual who may share antigens with the subsequent related donor.

Platelet transfusion is needed occasionally for management of bleeding or severe bruising or for platelets <10,000/microL, especially if associated with fever or infection or in anticipation of the need for an invasive procedure. Single-donor apheresis platelets are preferred to minimize donor exposure, and all platelets should be leukoreduced prior to transfusion, to reduce the risks of febrile reactions, CMV infection, and ta-GVHD as in red cells. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Preparation for an invasive procedure'.)  

Hematologic malignancies — Progression of SDS to myelodysplastic syndrome (MDS) or AML is an ominous finding that requires intensive treatment, including HCT. Allogeneic HCT is the only curative therapy for SDS-associated bone marrow failure and/or progression to MDS or AML. HCT will not improve pancreatic exocrine function.

Management of hematologic malignancies in SDS with allogeneic HCT is discussed below. (See 'Hematopoietic cell transplantation (HCT)' below.)

GI/nutrition — Exocrine pancreatic insufficiency can be treated with oral pancreatic enzymes and vitamins should be repleted. Careful attention to calorie and nutrient intake may benefit from input from a dietician/nutritionist.

Management includes:

Pancreatic enzyme replacement – Clinically significant pancreatic dysfunction (eg, symptomatic steatorrhea, fat malabsorption) is treated with oral pancreatic enzyme supplementation, with the goal of preventing malabsorption of vitamins, fats, and proteins. Management is as described for treatment of cystic fibrosis. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

Vitamin supplementation – Fat-soluble vitamins (A, D, E, and K) and deficient minerals should be supplemented, as needed. Ongoing monitoring of vitamin levels to ensure adequate supplementation is described above. (See 'Laboratory studies' above.)

Other management

Dental health – Referral to a dentist should occur at an early age (generally by age 3) because a significant number of patients have dental abnormalities (eg, enamel defects, increased risk of dental caries). Routine adherence to use of fluoride toothpaste and avoidance of sugary snacks is also important. If neutropenia and gingivitis are present, some experts offer oral antibacterial rinses with chlorhexidine gluconate; however, chlorhexidine rinses are unpleasant to use routinely, there is only weak evidence of benefit (eg, reduced dental plaque, symptoms of gingivitis, or aerosolization of bacteria), and there are substantial adverse effects (eg, staining of teeth, potential antibacterial resistance, and rare, fatal anaphylactic reactions) [99]. (See "Preventive dental care and counseling for infants and young children".)

Orthopedic – Orthopedic complications should be assessed and followed, especially during rapid phases of growth.

Neuropsychologic – Neuropsychologic dysfunction and depression should be considered at every visit. We generally refer individuals with possible neuropsychologic dysfunction or depression for formal testing and/or therapy.

TREATMENTS

G-CSF — Treatment with granulocyte colony-stimulating factor (G-CSF; filgrastim, and biosimilars) can reduce the risk of recurrent and severe infections and gingivitis.

A bone marrow examination, including cytogenetics and fluorescence in situ hybridization (FISH) for informative chromosomal abnormalities, is required prior to the initiation of chronic G-CSF and should be repeated annually while the patient is on G-CSF to monitor for development of progressive clonal hematopoiesis, myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML). (See 'Bone marrow examinations' above.)

Treatment with G-CSF should begin at 5 mcg/kg subcutaneously daily with the goal of maintaining a nadir absolute neutrophil count (ANC) of 800 to 1000/microL. The schedule should be adjusted to the lowest dose and/or fewest number of days of treatment per week, but ≥3/week is usually needed to maintain an adequate ANC.

The primary adverse reaction to G-CSF in children is mild to moderate musculoskeletal pain; the pain is typically less with more frequent, low doses versus fewer high doses and generally diminishes with repeated injections. Other adverse effects (≥5 percent more frequent than placebo) are splenomegaly, anemia, epistaxis, diarrhea, hypoesthesia, and alopecia; although total infection-related events were similar, patients treated with G-CSF had more upper respiratory tract and urinary tract infections [100]. All of these adverse effects are dose-related and generally mild. Decreased bone density, vasculitis, rash, and arthralgias have also been reported [101].

In the North American SDS Registry, only 14 of 86 patients with SDS were chronically treated with G-CSF [32].

For patients who have severe, persistent, or symptomatic neutropenia despite treatment with G-CSF and prophylactic antibiotics, hematopoietic cell transplantation is a consideration. (See 'Hematopoietic cell transplantation (HCT)' below.)

Hematopoietic cell transplantation (HCT) — HCT has the potential to cure the hematologic manifestations of SDS, but it does not affect pancreatic exocrine dysfunction or other nonhematologic manifestations. Cautions regarding SDS-specific sibling donor selection and reduced-intensity conditioning (RIC) regimens must be considered. We suggest referral to a center that is experienced with transplantation for bone marrow failure syndromes.

Outcomes with allogeneic HCT are better when transplantation is performed prior to the transformation to AML or MDS [60,102-104]. Patients with AML or high-grade MDS should undergo HCT as soon as an acceptable donor is identified. The optimal timing for the patient with less-advanced MDS is uncertain and should balance the risks of HCT against the potential for cure. HCT may also be appropriate for patients with severe persistent or symptomatic neutropenia that is refractory to G-CSF. (See 'Neutropenia and infections' above.)

It is critical to evaluate potential sibling donors for pathogenic variants related to SDS, and to exclude affected individuals as donors. The optimal graft source and conditioning regimen for HCT in SDS are unknown, and data on the outcome of HCT in individuals with SDS are limited. Standard intensive conditioning regimens are not well-tolerated in individuals with SDS (as with many inherited bone marrow failure syndromes) and certain agents (eg, cyclophosphamide, busulfan) should be avoided because of possible cardiac toxicity. Poor outcomes are related to end-organ toxicities rather than graft failure [39,105].

Small case series by the European Group for Blood and Marrow Transplantation and the French Severe Chronic Neutropenia Registry described one-year overall survival of approximately 65 percent and five-year event-free survival of 60 percent in children with SDS [106,107]. In one series of seven patients with SDS who underwent HCT with an RIC regimen, all patients had donor-derived hematopoiesis and morbidity was modest (no grade ≥3 graft-versus-host disease); all patients were alive at a median follow-up of approximately 1.5 years [108]. Clinical trials evaluating the role of RIC regimens and other modifications to reduce the toxicity of the procedure in individuals with SDS and other inherited and nonmalignant conditions are ongoing [109].

Additional information regarding the use of HCT in other inherited bone marrow failure syndromes is presented separately. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Shwachman-Diamond syndrome' and "Hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in children and adolescents", section on 'Introduction'.)

Pancreatic enzyme replacement therapy — Pancreatic enzyme replacement therapy is discussed separately. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

PROGNOSIS — The natural history of SDS is poorly characterized due to its rarity. There is no accepted prognostic model for SDS and clinical features and specific genetic findings do not appear to predict clinical outcome.

It is important to recognize that patients with less severe clinical phenotypes may not have been properly diagnosed prior to the advent of genetic testing, resulting in a biased estimate of the median survival based on diagnosis of only the most severe cases [30]. In one report, the median survival of patients with SDS was more than 35 years [37]. Progression to a hematologic malignancy is an ominous finding, as described above. (See 'Myelodysplasia and acute myeloid leukemia' above.)

TESTING AND COUNSELING FOR FAMILY MEMBERS — Genetic testing in family members of affected individuals is important for identification of subclinical disease and for genetic/preconception counseling. Testing and counseling are generally pursued once the proband (index patient) has a confirmed molecular diagnosis, unless the need for diagnosis of siblings is urgent due to clinical symptoms or need for urgent transplantation. In general, all siblings should have testing for the pathogenic variants in the proband because of the variable clinical manifestations. Siblings with homozygous or compound heterozygous pathogenic variants are diagnosed with SDS and should be managed the same as for any other person with SDS. (See 'Baseline and ongoing monitoring' above.)

Family members who are heterozygous for an SBDS mutation are considered carriers of the disease. Such carriers do not require a bone marrow examination or further evaluation. For family members of child-bearing potential, education concerning preconception genetic testing and counseling regarding the risk of an affected child as well as testing of the partner should be offered. (See "Genetic testing" and "The preconception office visit".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone marrow failure syndromes".)

SUMMARY AND RECOMMENDATIONS

Shwachman-Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome characterized by exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; neutropenia and/or multilineage cytopenias that may progress to bone marrow failure, myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML); and abnormalities of bone.

Most patients with SDS have pathogenic variants (ie, mutations) in the Shwachman-Bodian-Diamond syndrome (SBDS) gene or other genes (eg, DNAJC21, EFL1, or SRP54) that affect ribosome biogenesis and mitosis. (See 'Pathogenesis' above.)

SDS classically presents in infancy with a triad of exocrine pancreatic dysfunction (eg, failure to thrive, growth retardation), cytopenias (eg, recurrent infections), and bone abnormalities; nearly all affected children have intermittent or persistent neutropenia at presentation. However, the advent of molecular detection has revealed a broad and variable spectrum of findings that may be clinically subtle or inapparent. (See 'Clinical manifestations' above.)

Clinical evaluation, laboratory testing, and molecular studies to evaluate individuals suspected of SDS are described above. (See 'Evaluation' above.)

SDS should be suspected in an individual with exocrine pancreatic dysfunction, hematologic abnormalities, or other syndromic manifestations (eg, short stature, skeletal abnormalities, congenital organ findings) or in an individual with a family history of these conditions.

The diagnosis of SDS is established in a proband by identification of biallelic pathogenic variants in SBDS, DNAJC21, EFL1, or a heterozygous pathogenic variant in SRP54, with or without characteristic clinical findings. (See 'Diagnosis' above.)

Rare patients may be diagnosed clinically as having a Shwachman-like condition on the basis of syndromic manifestations alone, without genetic confirmation.

The differential diagnosis of SDS includes other causes of hematologic disorders, exocrine pancreatic dysfunction, and impaired or delayed growth. (See 'Differential diagnosis' above.)

Individuals diagnosed with SDS require monitoring of hematologic status, pancreatic function, and growth by clinical evaluation, laboratory studies, and bone marrow examination, as described above. (See 'Baseline and ongoing monitoring' above.)

Management of neutropenia should be individualized, based on the severity of neutropenia, evidence of dysplasia and/or chromosomal abnormalities, presence of recurrent and/or severe infections, and patient/parent values and preferences (see 'Neutropenia and infections' above):

For patients with absolute neutrophil count (ANC) persistently ≤500/microL, our approach is informed by evidence of dysplasia and/or chromosomal abnormalities:

-For patients with monosomy 7 or substantial or progressive dysplasia, we suggest prompt allogeneic hematopoietic cell transplantation (HCT) rather than treatment with granulocyte colony-stimulating factor (G-CSF) (Grade 2C). This suggestion is based on the high probability of progression and the grave prognosis of AML in SDS. (See 'Myelodysplasia and acute myeloid leukemia' above.)

-For patients with lesser degrees of dysplasia and chromosomal findings other than monosomy 7, we suggest treatment with G-CSF rather than immediate HCT (Grade 2C). This suggestion is based on the potential for G-CSF to reduce the risk for life-threatening infections, including gingivitis with tooth loss, and the possible disappearance of chromosomal abnormalities by clonal evolution.

For patients with less severe neutropenia (eg, ANC >500/microL) and without recurrent and/or severe infections or progressive gingivitis, we generally offer supportive care. This approach requires instructing the patient and family about the importance of a prompt response to fever or other infectious symptoms, as discussed above. (See 'Neutropenia and infections' above.)

Management using G-CSF, HCT, and pancreatic replacement therapy is discussed above. (See 'Treatments' above.)

Family members of a proband should undergo genetic testing and affected individuals should receive appropriate management and genetic/preconception counseling. (See 'Testing and counseling for family members' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Akiko Shimamura, MD, PhD, who contributed to earlier versions of this topic review.

The UpToDate editorial staff also acknowledges the extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.

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Topic 5914 Version 39.0

References

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