eMedicine Specialties > Pediatrics: General Medicine > Hematology

Shwachman-Diamond Syndrome

Author: Antoinette C Spoto-Cannons, MD, FAAP, Assistant Professor, Department of General Pediatrics, Director, Undergraduate Children's Health Care Education, University of South Florida College of Medicine
Coauthor(s): Jessica Marie Keshishian, BS, University of South Florida College of Medicine; Mudra Kumar, MD, MBBS, MRCP, Associate Professor, Department of Pediatrics, University of South Florida College of Medicine
Contributor Information and Disclosures

Updated: Aug 12, 2008

Introduction

Background

Shwachman-Diamond syndrome (SDS) is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and skeletal abnormalities. In 1964, Shwachman, Diamond, Oski, and Knaw first reported the syndrome in a group of 5 children participating in a cystic fibrosis (CF) clinic at HarvardMedicalSchool.1 Shwachman-Diamond syndrome is the second most common cause of inherited pancreatic insufficiency after cystic fibrosis and the third most common inherited bone marrow failure syndrome after Fanconi anemia and Blackfan-Diamond anemia.2  In most cases, Shwachman-Diamond syndrome is associated with mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene located on chromosome 7.3

Pathophysiology

All patients with Shwachman-Diamond syndrome have some degree of pancreatic insufficiency beginning in infancy. This insufficiency is defined as the loss of exocrine function, resulting in the inability to digest and, therefore, an inability to normally assimilate nutrition. Symptoms of malnutrition typically develop when more than 98% of pancreatic reserve is lost. In individuals with this condition, pancreatic acinar cells do not develop in utero and are replaced by fatty tissue. In contrast to cystic fibrosis, the pancreatic ductal architecture is spared; thus, an intact anion secretion and fluid flow occurs.4 For reasons yet to be identified, pancreatic lipase secretion increases with age, often improving pancreatic function to normal levels of fat absorption. Approximately 50% of patients with Shwachman-Diamond syndrome become pancreatically sufficient throughout childhood and no longer require enzyme replacement therapy.5

Shwachman-Diamond syndrome is considered one of the inherited bone marrow failure syndromes. Another key feature of Shwachman-Diamond syndrome involves ineffective hematopoiesis. The relationship of the genetic defect to the pathophysiology of bone marrow failure is currently unknown.2  A generalized marrow dysfunction with an abnormal bone marrow stroma (in terms of its ability to support and maintain hematopoiesis) is thought to be present in addition to a stem cell defect.6 Neutropenia is the most common hematologic abnormality seen in patients with Shwachman-Diamond syndrome. Data from a large international cohort study consisting of 88 patients with Shwachman-Diamond syndrome revealed neutropenia in 98% of patients, followed by anemia (42%), thrombocytopenia (34%), and pancytopenia (19%).7

More specifically, neutrophils may have defects in mobility, migration, and chemotaxis.8  These abnormalities might be due to abnormal distribution of concanavalin-A receptors on the neutrophils or a cytoskeletal/microtubular abnormality.9 Also, Shwachman-Diamond syndrome has been associated with mutations in the SBDS gene, located on chromosome 7. The SBDS gene may not be required for neutrophil maturation but may act to maintain survival of granulocyte precursor cells.10 The SBDS gene product, the SBDS protein, may play a role in chemotaxis.11

Fetal hemoglobin levels are elevated in 80% of patients. The elevation of heterogeneously distributed fetal hemoglobin reflects "stress" hematopoiesis, ineffective erythropoiesis related to apoptosis, or both.12 New data has demonstrated prosurvival properties of the SBDS gene and indicates that accelerated apoptosis occurs through the Fas pathway when SBDS is inhibited.13  The loss of SBDS is now thought to be sufficient to induce abnormalities in hematopoiesis.14

Failure to thrive has been attributed to nutritional deficits (malabsorption), recurrent infections, and skeletal abnormalities as well as decreased or absent growth hormone levels in individuals with Shwachman-Diamond syndrome.

The exact pathophysiology of skeletal anomalies is unknown; however, skeletal anomalies are reported to occur in more than 75% of patients with Shwachman-Diamond syndrome.15 In addition to skeletal dysplasia, Schwachman-Diamond syndrome is associated with a more generalized bone disease characterized by low bone mass, low bone turnover, and vertebral fragility fractures. Osteoporosis may result from a primary defect in bone metabolism and could be related to the bone marrow dysfunction and neutropenia.16

Frequency

United States

After cystic fibrosis, Schwachman-Diamond syndrome is the second most common cause of pancreatic insufficiency in childhood.2 Approximately 3% of childhood pancreatic dysfunction is attributed to Schwachman-Diamond syndrome.4 The incidence of Schwachman-Diamond syndrome has been estimated at 1 case in 75,000 population using comparison cystic fibrosis data.17

International

More than 200 cases of Schwachman-Diamond syndrome have been reported in the literature.18

Mortality/Morbidity

Prognosis for individuals with the disorder is uncertain. Because Schwachman-Diamond syndrome was described relatively recently, limited data are available regarding follow-up in these patients.

  • Recurrent bacterial infections (eg, upper respiratory tract infections, otitis media, sinusitis, pneumonia, aphthous stomatitis, skin infections, paronychia, osteomyelitis, bacteremia) are common in individuals with Schwachman-Diamond syndrome because of neutropenia/neutrophil migration defects.5
  • Like other bone marrow failure syndromes, a predilection for developing severe cytopenias, myelodysplastic syndrome (MDS), and leukemia is also observed with Schwachman-Diamond syndrome. The frequency of leukemia in patients with Schwachman-Diamond syndrome is 5-10%; most cases are acute myeloid leukemia (AML).2 Isochromosome 7q may be a specific marker of myeloid malignant transformation in association with Schwachman-Diamond syndrome.12 Whether increased angiogenesis in Schwachman-Diamond syndrome marrow promotes progression of hematologic malignancies is unclear.19 At the genetic level, spindle instability contributing to bone marrow failure and leukemia development has also been implicated.20
  • Death usually occurs from overwhelming sepsis or malignancy.
  • Alter et al (1998) report that the projected median survival age is older than 35 years for all patients with Schwachman-Diamond syndrome.18 For patients whose course is complicated by aplastic anemia, the median survival age is 24 years, whereas patients whose course is complicated by leukemia have a median survival age of 10 years.

Race

Schwachman-Diamond syndrome is reported among all racial and ethnic groups.18

Sex

The male-to-female ratio is 1.7:1.7

Age

Schwachman-Diamond syndrome is usually diagnosed during the newborn period or infancy when patients present with malabsorption and recurrent infections.

Clinical

History

  • Patients with Shwachman-Diamond syndrome (SDS) typically present with diarrhea, short stature, weight loss, and dry skin (eczema).
    • They may have fatty stools that usually improve with age.21
    • Imperforate anus and Hirschsprung disease have been associated with Shwachman-Diamond syndrome. These associations may delay diagnosis of Shwachman-Diamond syndrome because the presenting symptom is constipation and not diarrhea.
  • Recurrent bacterial infections of the upper respiratory tract, otitis media, sinusitis, pneumonia, osteomyelitis, bacteremia, skin infections, aphthous stomatitis, fungal dermatitis, and paronychia are common because of a neutropenia/neutrophil migration defect.15,5,22,7
  • Hearing loss may occur secondary to recurrent otitis media.
  • A history of pallor, easy bruising, epistaxis, melena, hematemesis, or hematuria may be present in individuals with Shwachman-Diamond syndrome.
  • Unlike patients with cystic fibrosis, patients with Shwachman-Diamond syndrome have a paucity of pulmonary symptoms,23 although some patients may present with recurrent upper and lower respiratory tract infections.
  • Delayed dental development, gingival bleeding upon brushing, and pain with eating (associated with recurrent oral ulcerations) may occur.24
  • Saliva production is decreased; however, no significant clinical symptoms are associated with this phenomenon.
  • Patients with Shwachman-Diamond syndrome typically experience delayed puberty.4
  • Mild-to-moderate psychomotor and/or developmental delay may be observed in as many as 15% of affected individuals.

Physical

  • Patients with Shwachman-Diamond syndrome may appear emaciated, with abdominal distension accentuated by hypotonia and hepatomegaly.
  • More than 50% of these individuals have short stature with a normal growth velocity.7 Their height and weight are usually below the third percentile but may occasionally reach the 25th percentile.4
  • In addition to short stature, skeletal abnormalities in an individual with Shwachman-Diamond syndrome may include the following:
    • Clinodactyly
    • Syndactyly
    • Supernumerary metatarsals
    • Coxa vara deformity
    • Genu and cubitus valgus
    • Tooth enamel defects (dental dysplasia) including hypomaturation, hypocalcification, and hypoplasia (Dental caries and tooth surface loss are seen in about a third of patients.25 )
  • Dermatologic manifestations in a person with Shwachman-Diamond syndrome include the following:
    • Eczema
    • Ichthyosis
    • Petechiae

Causes

Shwachman-Diamond syndrome is inherited in an autosomal recessive fashion.26 In 90% of patients with Shwachman-Diamond syndrome, mutations have been found in the SBDS gene located on chromosome 7q11. The most frequent mutations are due to gene conversion between the SBDS gene and its pseudogene (SBDSP). The SBDS gene contains 5 exons, which encode a 250-amino-acid protein of unknown function.3 SBDS is a highly conserved protein.27 In a mouse model, it was demonstrated to be essential for early mammalian development.28

Experiments reveal that SBDS knockdown affects expression of critical genes involved in brain development and function, bone morphogenesis, blood cell proliferation and differentiation, and cell adhesion.29 This may be due to its role in ribosome biogenesis or RNA processing, which has been shown in yeast.30 Interestingly, mutations that affect ribosome assembly or function are associated with other inherited bone marrow failure syndromes,31 (Shimamura, 2006) and models of how impairment of ribosomal pathways might affect hematopoiesis and tumorigenesis are currently under investigation.32

More on Shwachman-Diamond Syndrome

Overview: Shwachman-Diamond Syndrome
Differential Diagnoses & Workup: Shwachman-Diamond Syndrome
Treatment & Medication: Shwachman-Diamond Syndrome
Follow-up: Shwachman-Diamond Syndrome
References
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References

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Further Reading

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Keywords

Schwachman-Diamond syndrome, SDS, bone marrow dysfunction, pancreatic insufficiency, short stature, congenital lipomatosis of pancreas, metaphyseal dysplasia, pancreatic hypoplasia, marrow dysfunction, pancreatic hypoplasia, marrow dysfunction, metaphyseal dysplasia, Shwachman-Bodian syndrome, Shwachman-Diamond-Oski-Knaw syndrome, cystic fibrosis, Fanconi anemia, Blackfan-Diamond, skeletal dysplasia, osteoporosis, upper respiratory tract infections, otitis media, sinusitis, pneumonia, aphthous stomatitis, skin infections, paronychia, osteomyelitis, bacteremia, myelodysplastic syndrome, MDS, leukemia, malabsorption, imperforate anus, Hirschsprung disease, constipation, diarrhea, hearing loss, tooth enamel defects, hypomaturation, hypocalcification, hypoplasia

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Contributor Information and Disclosures

Author

Antoinette C Spoto-Cannons, MD, FAAP, Assistant Professor, Department of General Pediatrics, Director, Undergraduate Children's Health Care Education, University of South Florida College of Medicine
Antoinette C Spoto-Cannons, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, Council on Medical Student Education in Pediatrics, and Florida Pediatric Society
Disclosure: Nothing to disclose.

Coauthor(s)

Jessica Marie Keshishian, BS, University of South Florida College of Medicine
Jessica Marie Keshishian, BS is a member of the following medical societies: American Medical Student Association/Foundation and Christian Medical & Dental Society
Disclosure: Nothing to disclose.

Mudra Kumar, MD, MBBS, MRCP, Associate Professor, Department of Pediatrics, University of South Florida College of Medicine
Mudra Kumar, MD, MBBS, MRCP is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Sharada A Sarnaik, MB, BS, Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Attending Hematologist/Oncologist, Children's Hospital of Michigan
Sharada A Sarnaik, MB, BS is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
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