Shwachman-Diamond syndrome

What every physician needs to know:

Shwachman-Diamond syndrome (SDS) is an autosomal recessively inherited bone marrow failure syndrome. Classically, the disease presents with bone marrow failure and exocrine pancreatic dysfunction. Additional organ systems are also frequently affected. Non-classical presentations are common and thus, clinicians should remain alert to the possibliity of SDS in the appropriate clinical settings (discussed below).

Shwachman-Diamond syndrome is associated with an elevated risk of developing myelodysplastic syndromes (MDS) or leukemia, typically acute myeloid leukemia. Patients with SDS experience increased transplant regimen-related toxicities and require modified conditioning regimens. The majority of patients with SDS harbor biallelic mutations in the SBDS (Shwachman-Bodian-Diamond-Syndrome) gene. Early diagnosis and medical monitoring by a hematologist and multidisciplinary team are essential.

While many patients present in infancy and childhood, some patients first come to medical attention as adults. Patients with SDS typically present with cytopenias secondary to marrow failure, poor growth, and symptoms of fat malabsorption. Neutropenia is the most common cytopenia and is often accompanied by recurrent infections.

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A recent cohort study reported that the classic presentation of neutropenia associated with diarrhea was seen in only ~50% of genetically confirmed SDS patients, and thus the absence of neutropenia or diarrhea at presentation does not exclude a diagnosis of SDS.

Patients may also present with thrombocytopenia or anemia, or red cell macrocytosis, sometimes within the context of a family history of marrow failure, MDS, or AML. Cytopenias may be persistent or intermittent. Additionally, the hematologic abnormalities (i.e., cytopenias, marrow hypocellularity, and marrow dysplasia) may evolve over time even if absent at presentation. Alternative causes of low blood counts, such as infections, medications or drugs, malignancy, infiltrative marrow disease, peripheral destructive processes, and nutritional abnormalities should be ruled out as clinically indicated. Patients may present with aplastic anemia, MDS, or acute myeloid leukemia (AML) as their first manifestation of SDS.

Exocrine pancreatic dysfunction is an important flag to the underlying diagnosis of SDS in a patient presenting with marrow failure. Since only 2% of the exocrine pancreas is needed for clinical function, many patients with SDS may lack overt symptoms. SDS patients may experience improvement in exocrine pancreatic function over time, rendering diagnosis obscure. Laboratory testing can detect pancreatic dysfunction in clinically asymptomatic patients (see below). The finding of a fatty atretic pancreas on imaging studies offers another important diagnostic clue. Intestinal pathology must be excluded as the cause of gastrointestinal symptoms.

The presence of congenital anomalies or other suggestive physical findings (see below) in a patient with marrow failure warrants further workup for potential inherited syndromes such as SDS. A family history of cytopenias, congenital anomalies, cancer predisposition, or excessive sensitivity to chemotherapy or radiation also suggests the possibility of an underlying inherited marrow failure syndrome.

Genetic testing for biallelic mutations in the SBDS gene is a useful diagnostic test, but a negative result does not rule out the diagnosis of SDS. Biallelic mutations in the SBDS gene are found in over 90% of patients fulfilling clinical criteria (marrow failure and exocrine pancreatic dysfunction) for SDS. A subset of patients are diagnosed based on clinical criteria but lack genetic mutations. It is likely that additional SDS genes have yet to be identified. SBDS mutations may be missed in cases with large gene conversion mutations that are not flanked by the exon-directed primers. Some alleles may contain more than one mutation so testing of parents to confirm the presence of mutations on separate alleles may be useful.

Treatment of severe marrow failure in SDS patients differs from the treatment of severe idiopathic acquired aplastic anemia. SDS patients typically respond poorly to anti-thymocyte globulin (ATG) and cyclosporin.

The only curative treatment for severe marrow failure is a hematopoietic stem cell transplant using a reduced intensity conditioning regimen to avoid excessive toxicity. Referral to transplant centers experienced in the treatment of these patients is recommended. Marrow hypocellularity in isolation is not sufficient indication for transplant if the blood counts are adequate. Marrow cellularity is not uniform and biopsies are subject to sampling bias. Some SDS patients continue with stable blood counts despite hypocellular bone marrow biopsy samples. Marrow morphology may appear mildly dysplastic at baseline and may be mistaken for MDS. Consultation with a hematopathologist experienced in the evaluation of SDS is recommended. Supportive measures for neutropenia include granulocyte colony-stimulating factor (G-CSF) therapy.

Hematopoietic stem cell transplant is the treatment of choice for MDS and AML in SDS patients. Of note, the diagnosis of MDS in SDS should be made with caution as SDS patients can have some baseline marrow dysplasia and may develop clonal cytogenetic abnormalities whose clinical significance is unclear (see bone marrow discussion below). Chemotherapy for MDS or AML should be administered with caution since SDS patients may experience prolonged or intractable cytopenias. If the proband is known to have SBDS mutations, all potential sibling donors must be screened for SBDS mutations.

Since transplant outcomes are best when initiated prior to the development of leukemia or complications from severe aplastic anemia (infections, iron overload secondary to chronic red cell transfusions), regular monitoring of the blood counts and bone marrow evaluations are recommended. The recommendation from a recent clinical consensus meeting is to check blood counts every 3 to 6 months. Unexplained progressively falling or rising blood counts warrant bone marrow evaluation.

There are no data to guide recommendations regarding the frequency of bone marrow evaluations. For patients with stable blood counts and unremarkable marrow findings, a bone marrow evaluation every 1 to 3 years is reasonable. For patients with high risk clones, clonal cytogenetic abnormalities of unclear clinical significance, progressive or severe marrow dysplasia, or unexplained falling/rising blood counts, more frequent marrow evaluations are warranted. Patients with high risk clones should be referred for consultation to a transplant center experienced in the care of SDS.

Are you sure your patient has Shwachman-Diamond syndrome? What should you expect to find?

Bone marrow failure

The most common hematologic finding is neutropenia defined as an absolute neutrophil count less than 1,500 X 10 9/L. Neutropenias may be persistent or intermittent. Patients with neutropenia may present with recurrent or serious infections, aphthous ulcers, or poor dental health secondary to caries or periodontal disease. Thrombocytopenia (platelet count less than 150,000X10 9/L) or anemia (defined as low hemoglobin for age and gender) may also develop. Red cells may be macrocytic with elevated fetal hemoglobin.

A subset of patients develop severe aplastic anemia. Alterations in neutrophil chemotaxis properties have been variably described; however, patients retain the ability to develop purulent abscesses and empyemas in response to infections.

Bone marrow findings are variable. The marrow biopsy is typically hypocellular, though normal or increased cellularity has also been described. A recent update from the North American Shwachman-Diamond Syndrome Registry reported that the bone marrow biopsies of all 32 genetically-confirmed SDS patients studied were hypocellular for age. Mild dysplastic features may be present. Severe dysplasia warrants consideration of MDS.

Clonal chromosome abnormalities may arise and their significance should be interpreted within the context of marrow morphology and peripheral blood counts as some clones may remain stable or disappear over time. The most frequently found are an isochromosome for long arms of chromosome 7, i(7)(q10) and an interstitial deletion of long arms of chromosome 20, del(20)(q11). The clinical course of patients bearing these abnormalities as isolated anomalies is often indolent. High risk cytogenetic clones bear close monitoring and consideration of hematopoietic stem cell transplant.

Patients with SDS are at increased risk for myelodysplastic syndrome (MDS) or acute myeloid leukemia. A striking male predominance has been noted amongst SDS patients with leukemia. The reason for this gender bias is unclear.

Exocrine pancreatic dysfunction

Patients may present with poor growth, failure to thrive, steatorrhea, and fatty food intolerance. Fat-soluble vitamin deficiencies (vitamin A,D,E, or K) may develop. Pancreatic dysfunction typically presents in early infancy. Symptoms may improve or disappear with age in around 50% of patients.


Hepatomegaly and elevated liver transaminases may be found in a subset of infants and young children, typically less than 5 years of age. These clinical findings are self-limited and spontaneously improve over time without treatment. It is possible that underlying subclinical liver abnormalities might contribute to increased susceptibility to transplant-related complications.


A variety of skeletal abnormalities have been described in SDS patients. Metaphyseal dysostosis, particularly of the femoral head and knees may be found. Metaphyseal abnormalities may vary over time. Delayed appearance of secondary ossification centers have been reported. Thoracic abnormalities, such as short flared ribs or asphyxiating thoracic dystrophy (Jeune syndrome) are also seen. Low turnover osteopenia is common despite early institution of vitamin D supplementation.

Immune system

Abnormalities in B and T cell numbers and function have been noted in some SDS patients. Immunoglobulin levels may be low. Poor antibody response to both protein and polysaccharide vaccines have been described. Lymphocyte abnormalities have also been described in mouse models of SDS.


Structural central nervous system abnormalities have been found in a subset of patients. A range of neurocognitive abnormalities have been described.


Eczematous rash may develop in some infants and young children. This generally improves with age.


Cardiomyopathies and congenital heart disease are reported in SDS patients and increased susceptibility to cardiomyopathies during hematopoietic stem cell transplant is observed.


Reports of endocrine abnormalities in SDS patients include insulin-dependent diabetes, growth hormone deficiency, and hypogonadotrophic hypogonadism.

Additional findings

Syndactyly, supernumerary digits, dental dysplasia, delayed eruption of permanent teeth, and kidney abnormalities have been reported.

There are a few case reports describing solid tumors arising in SDS patients, these include breast carcinoma, adenocarcinoma of the pancreas, pancreatoduodenal carcinoma, and primary CNS lymphoma. Whether SDS is associated with an increased risk of solid tumors warrants further investigation.

Beware of other conditions that can mimic Shwachman-Diamond syndrome:

Cystic fibrosis may present with exocrine pancreatic dysfunction and infections. Sweat chloride testing should be performed.

Pearson syndrome is characterized by exocrine pancreatic dysfunction and cytopenias. Patients exhibit metabolic abnormalities such as lactic acidosis. Bone marrow findings include vacuolated precursors and ring sideroblasts. The pancreas is fibrotic rather than lipomatous. Genetic testing for mitochondrial genomic deletions is available.

Other marrow failure syndromes:

  • Severe congenital neutropenia

– The cytopenias are classically limited to the neutrophil lineage. Genetic testing is available.

  • Dyskeratosis congenita

– This is associated with very short telomere lengths in multiple leukocyte subsets. Telomere length testing and genetic testing are available.

  • Fanconi anemia

– This is associated with increased chromosomal breakage with mitomycin C (MMC) or diepoxybutane (DEB).

  • Diamond-Blackfan anemia

– This typically presents with red cell aplasia. Red cell adenosine deaminase levels may be elevated. Genetic testing is available

  • Cartilage hair hypoplasia (cytopenias, metaphyseal dysostosis, skeletal abnormalities, fine sparse hypopigmented hair, gastrointestinal abnormalities)

– Associated with mutations in RNase MRP.

Other rare causes of exocrine pancreatic dysfunction such as Johanson-Blizzard syndrome may be considered.

Which individuals are most at risk for developing Shwachman-Diamond syndrome:

SDS is found across different races and affects both genders equally.

A family history of SDS increases suspicion for this disorder since it is transmitted in an autosomal recessive fashion. All siblings of an affected proband should be tested for SDS even in the absence of clinical findings.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Patients should be evaluated for marrow failure and exocrine pancreatic dysfunction.

  • Complete blood count

– A complete blood count with differential to look for cytopenias and macrocytosis. The blood smear should be examined for dysplasia.

  • Bone marrow examination

– A bone marrow examination with aspirate and biopsy is useful to assess for marrow failure, dysplasia, clonal cytogenetic abnormalities, or leukemic transformation. The aspirate should be sent for morphology, iron stain for ring sideroblasts, cytogenetics including FISH (fluorescence in-situ hybridization) studies for MDS, and flow cytometry. A biopsy is recommended to assess marrow cellularity.

  • Hemoglobin F may be elevated

  • Serum trypsinogen and pancreatic isoamylase

– Serum trypsinogen and pancreatic isoamylase are low, though values are age-dependent. Trypsinogen is more reliable in younger patients while pancreatic isoamylase is more helpful patients 3 years of age or older.

  • Fecal fat

Elevated fecal fat measured in a 72 hour stool collection (in the absence of intestinal pathology) plus a fatty atretic pancreas on imaging studies.

  • Low fecal elastase levels

  • Pancreatic stimulation testing is generally deferred

– Pancreatic stimulation testing is generally deferred, in favor of less invasive testing above. Abnormal pancreatic enzyme secretion, following stimulation testing with cholecystokinin and secretin, is reported in SDS.

Genetic testing

More than 90% of patients with SDS harbor biallelic mutations in the SBDS gene located on chromosome 7. These common mutations are consistent with a gene conversion event from the adjacent highly conserved pseudogene. These mutations are c.[183_184TA>CT], a null mutation that results in a premature stop codon, and c.[258 + 2T>C], a mutation that causes a splicing error with only small amounts of full length protein produced. Homozygosity for the c.[183_184TA>CT] mutation has never been found. Testing of the parents may be helpful to confirm that both alleles are affected and for family counseling. All siblings of an affected proband should be tested regardless of whether clinical symptoms are present.

Additional testing that is helpful for medical management
  • Prothrombin time to test for vitamin K-dependent coagulopathy

  • Vitamin A, D, E, and K levels

  • Routine skeletal survey has been proposed by some physicians

– Other physicians recommend skeletal survey if clinically indicated, or in cases where the diagnosis of SDS is unclear. The radiation exposure in patients with a cancer predisposition syndrome must be weighed against the clinical benefit of the studies.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of Shwachman-Diamond syndrome?

Pancreatic imaging studies showing an atretic fatty pancreas can be helpful in making the diagnosis of SDS. Ultrasound is convenient but the pancreas may be obscured by gastric air. Magnetic resonance imaging (MRI) scans also avoid exposure to ionizing radiation in patients with a cancer-prone syndrome. Pancreatic abnormalities can be detected on computed tomography (CT) scans.

If you decide the patient has Shwachman-Diamond syndrome, what therapies should you initiate immediately?

The clinical phenotype is highly variable and can include a broad spectrum of abnormalities that guide management.

For patients presenting with MDS or leukemia, referral to a bone marrow transplant center with expertise in the treatment of SDS patients is recommended. Patients with SDS experience increased transplant regimen-related toxicities and require modified conditioning regimens.

For patients with severe or symptomatic cytopenias, supportive measures may include red cell transfusions for anemia or platelet transfusions for thrombocytopenia. Leukoreduced products may minimize the risk of allosensitization. Since SDS patients may have immunologic abnormalities, irradiated products should be considered. To minimize the risk of allosensitization in a disorder that potentially requires a bone marrow transplant, family member directed blood donors are avoided.

Patients with recurrent or serious infections in the setting of severe neutropenia (for example, absolute neutrophil counts less than 500) may benefit from treatment with G-CSF. The dose of G-CSF should be titrated to the minimum dose required to maintain the neutrophil counts in an appropriate range. Data to guide the use of prophylactic G-CSF in asymptomatic patients without a history of infections are sparse. The potential role of G-CSF in promoting malignant transformation remains an area of active research. Where feasible, a bone marrow evaluation is recommended prior to the initiation of G-CSF. G-CSF should not be withheld if it is clinically indicated to treat a serious infection.

Pancreatic enzyme supplements and fat soluble vitamin supplements (A, D, E and K) should be given as clinically indicated after evaluation by a gastroenterologist.

More definitive therapies?

The only curative therapy for the hematologic complications of SDS is a hematopoietic stem cell transplant. The indications for transplant include severe or symptomatic cytopenias, severe aplastic anemia, MDS, and leukemia. Marrow cellularity should be interpreted in the context of the peripheral blood counts since biopsies are subject to sampling variations. Clonal cytogenetic abnormalities of unclear clinical significance should be considered together with marrow morphology and peripheral blood counts.

Since increased transplant-related complications have been described in SDS patients, reduced intensity regimens are currently recommended. Early human leukocyte antigen (HLA) typing of the patient and any siblings is useful for transplant planning. If the proband carries SBDS mutations, all potential sibling donors should be tested for SBDS mutations regardless of symptoms. If the proband lacks known mutations, then extensive evaluation of any potential sibling donor should be performed prior to final donor selection.

What other therapies are helpful for reducing complications?

Fever with neutropenia requires prompt medical evaluation, blood cultures, and treatment with broad spectrum antibiotics.

Regular dental exams and careful attention to dental hygiene are essential to preserve dental health in patients with chronic neutropenia.

Adequate calcium intake and regular weight bearing exercise to minimize bone loss is recommended. Screening for treatable causes of osteopenia, such as thyroid hormone and parathryoid hormone deficiencies, may be considered.

Early neurocognitive evaluations allow early institution of interventions to maximize learning and development. Serial assessments may be indicated at different ages.

Patients with hypogammaglobulinemia are treated with intravenous immunoglobulin (IVIG) infusions in consultation with an immunologist.

What should you tell the patient and the family about prognosis?

The clinical spectrum of SDS is broad. Genotype: phenotype correlations have not emerged despite extensive study to date. The percentages of patients who will develop severe marrow failure or malignant transformation over the course of their lifetime are unknown.

What if scenarios.

Some patients may be asymptomatic with only mild cytopenias and no gastrointestinal symptoms. These patients remain at risk for marrow failure or malignant transformation so regular blood counts and bone marrow evaluations are recommended. Prompt evaluation of febrile illnesses is also recommended, since the neutrophil counts may fall during infections.

Marrow hypocellularity in isolation is not sufficient indication for transplant if the blood counts are adequate. Marrow cellularity is not uniform and biopsies are subject to sampling bias. Many SDS patients continue with stable blood counts despite seemingly empty bone marrows by biopsy.

Marrow morphology may appear mildly dysplastic at baseline and may be mistaken for MDS. Consultation with a hematopathologist experienced in the evaluation of SDS, is recommended.

The presence of cytogenetic clones of unclear clinical significance must be evaluated within the context of marrow morphology and peripheral blood counts. Some clones may remain stable or disappear over time. Cytogenetic clones that, in the absence of other abnormalities, typically follow a benign or indolent clinical course in SDS patients include deletion 20q and isochromosome 7q. When a cytogenetic clone first appears, more frequent bone marrow evaluations to assess for potential progression may be warranted.

Chemotherapy should be administered with caution since SDS patients may experience prolonged or intractable cytopenias. Preparation for potential stem cell backup should be instituted.

All siblings of a proband with SBDS mutations should be tested regardless of clinical symptoms. This is particularly important during evaluation of potential sibling transplant donors.

Some families are interested in preimplantation genetic diagnosis to screen for SBDS mutations as well as HLA type. The SBDS mutations of the affected proband must be known. Appropriate counseling should be provided.


The SBDS gene is located on chromosome 7. There is an adjacent pseudogene that shares 97% homology to the SBDS gene. The majority of SBDS gene mutations are consistent with gene conversion with the adjacent pseudogene.

The SBDS gene encodes a highly evolutionarily conserved protein with a broad tissue expression pattern. Evidence to date indicates that SBDS is a multifunctional protein. The yeast orthologue Sdo1 plays a role in the formation of the active mature ribosome through a pathway involving Tif6. Tif6 functions in 60S ribosome maturation and the joining of the 40S to the 60S subunit to form the mature 80S subunit. The human SBDS protein shuttles into the nucleolus and associates with the 60S ribosome.

Other inherited marrow failure syndromes such as Diamond-Blackfan anemia and dyskeratosis congenita also affect ribosome homeostasis but through different mechanisms. SBDS associates with the mitotic spindle and stabilizes microtubules. Loss of SBDS is associated with genomic instability. SBDS also associates with F-actin and SBDS loss results in alterations in actin polymerization.

Defects in both the hematopoietic cells and marrow stromal cells from SDS patients have been described. Hematopoietic cell-intrinsic defects were also demonstrated in a mouse transplant model. The role of SBDS in marrow stroma was elegantly demonstrated by a mouse model wherein SBDS was specifically deleted in osteoprogenitor cells but remained intact in the hematopoietic cells. These mice with SBDS-deficient osteoprogenitor cells developed hematological abnormalities that were not corrected by transplantation of exogenous wildtype bone marrow.

What other clinical manifestations may help me to diagnose Shwachman-Diamond syndrome?

Important or unusual questions/symptoms to ask on history

Since the pancreatic symptoms may improve with age, specific history about diarrhea, or foul-smelling/greasy stools or fatty food intolerance during infancy and early childhood should be sought.

A family history of cytopenias, congenital anomalies, cancer at an unusually young age, or excessive toxicity from chemotherapy or radiation may be suggestive of an underlying inherited marrow failure syndrome.

A history of osteopenia or failure to thrive in a patient with marrow failure raises suspicion for an underlying inherited marrow failure syndrome.

Important or unusual signs or findings on physical exam

Congenital anomalies together with marrow failure raise suspicion for an inherited marrow failure syndrome. The full clinical spectrum of SDS remains unclear.

Skeletal abnormalities such as thoracic malformations may be present. Many bone abnormalities are only apparent on X-ray. Bone abnormalities may vary over time.

Isochromosome 7q is common in SDS but relatively rare in acquired MDS, and hence may provide a clue to the underlying diagnosis.

What other additional laboratory studies may be ordered?

Large gene conversion mutations may be missed by standard exon-directed sequencing approaches. In cases with a high degree of clinical suspicion, additional genetic testing may be required.

Importantly, the absence of SBDS mutations does not rule out the diagnosis of SDS in patients who fulfill the clinical diagnostic criteria of marrow failure and exocrine pancreatic dysfunction.

It is likely that additional as yet unidentified genes may also cause SDS.

What’s the evidence?

Bhatla, D, Davies, SM, Shenoy, S. “Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome”. . vol. 42. 2008. pp. 159-165. (Series of SDS patients successfully transplanted with a reduced intensity conditioning regimen.)

Boocock, GR, Morrison, JA, Popovic, M. “Mutations in SBDS are associated with Shwachman-Diamond syndrome”. . vol. 33. 2003. pp. 97-101. (Identification of the SBDS gene.)

Myers, KC, Davies, SM, Shimamura, S. “Clinical and molecular pathophysiology of Shwachman-Diamond syndrome: an update”. Hematol Oncol Clin North Am. vol. 27. 2013. pp. 117-128. (Recent comprehensive review on SDS.)

Myers, KC, Bolyard, A, Otto, C. “Variable clinical presentation of Shwachman-Diamond Syndrome: update from the North American Shwachman-Diamond Syndrome Registry”. The Journal of Pediatrics. vol. 164. 2014. pp. 866-870. (Recent report on the clinical presentation of 37 genetically-confirmed patients with SDS.)

Dror, Y, Donadieu, J, Koglmeier, J. “Draft consensus guidelines and treatment of Shwachman-Diamond syndrome”. . vol. 1242. 2011. pp. 40-55. (Consensus guidelines for treatment of SDS.)

Dror, Y, Durie, P, Ginzberg, H. “Clonal evolution in marrows of patients with Shwachman-Diamond syndrome: a prospective 5-year follow-up study”. . vol. 30. 2002. pp. 659-669. (Longitudinal study of hematological abnormalities in 14 SDS patients describing clonal marrow cytogenetic abnormalities may be indolent or disappear over time.)

Dror, Y, Ginzberg, H, Dalal, I. “Immune function in patients with Shwachman-Diamond syndrome”. . vol. 114. 2001. pp. 712-717. (Report of immunologic abnormalities in SDS patients.)

Grinspan, Z.M, Pikora, C.A. “Infections in patients with Shwachman-Diamond syndrome”. . vol. 24. 2005. pp. 179-81. (A review of infectious complications in SDS patients.)

Ip, WF, Dupuis, A, Ellis, L. “Serum pancreatic enzymes define the pancreatic phenotype in patients with Shwachman-Diamond syndrome”. . vol. 141. 2002. pp. 259-265. (Study of serum trypsinogen and pancreatic isoamylase levels as a screen for the pancreatic phenotype in patients with SDS.)

Makitie, O, Ellis, L, Durie, PR. “Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS”. . vol. 65. 2004. pp. 101-112. (Study of skeletal abnormalities in SDS.)

Hauet, Q, Beaupain, B, Micheau, M. “Cardiomyopathies and congenital heart diseases in Shwachman-Diamond Syndrome: a national survey”. Int Journal of Cardiology. vol. 167. 2012. pp. 1048-1050. (Report of the cardiac findings in 102 genetically-confirmed SDS patients.)