Shwachman-Diamond Syndrome 

  • Author: Antoinette C Spoto-Cannons, MD, FAAP; Chief Editor: Max J Coppes, MD, PhD, MBA   more...
 
Updated: Apr 3, 2012
 

Background

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, leukemia predisposition, 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 Harvard Medical School. 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. In most cases, Shwachman-Diamond syndrome is associated with mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene located on chromosome 7.

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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. Thus, patients typically present in early infancy with malabsorption, steatorrhea, failure to thrive, and deficiencies of fat-soluble vitamins A, D, E, and K.[1, 2]

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.[3] Low serum pancreatic trypsinogen and low isoamylase levels are helpful markers for pancreatic insufficiency, depending on the age of the patient. Trypsinogen levels are low in patients younger than 3 years, but this finding becomes less useful as a disease marker in older patients because levels increase to normal range with age. Serum isoamylase levels are low in patients with Shwachman-Diamond syndrome of all ages but use of this test is limited in children younger than 3 years because all children may normally have low circulating isoamylase levels.[3]

Fecal elastase levels and pancreatic enzyme secretion in response to stimulation testing may also be reduced. 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.[4] Pancreatic endocrine functions generally remain intact, although cases of insulin-dependent diabetes mellitus have been reported. Rarely, these patients may present with hypoglycemia, which may be due to severe chronic malabsorption.[4]

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. 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. 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%).

More specifically, neutrophils may have defects in mobility, migration, and chemotaxis. These abnormalities might be due to abnormal distribution of concanavalin-A receptors on the neutrophils or a cytoskeletal/microtubular abnormality. 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. The SBDS gene product, the SBDS protein, may play a role in chemotaxis.[5] Recent studies have shown that the neutrophils in Shwachman-Diamond syndrome have aberrant chemoattractant-induced F-actin properties, which may contribute to the neutrophil chemotaxis defects. The SDS neutrophils have a delayed F-actin cytoskeleton polarization and polymerization, which impairs the directed migration of neutrophils.[6]

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. New data has demonstrated prosurvival properties of the SBDS gene and indicates that accelerated apoptosis occurs through the Fas pathway when SBDS is inhibited. The loss of SBDS is now thought to be sufficient to induce abnormalities in hematopoiesis.

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. 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.

Mild cognitive impairments and variable degrees of development abnormalities may also be seen in patients with Shwachman-Diamond syndrome.[7, 8, 9, 10] These patients have lower performance in most cognitive domains than age-matched controls.[9] Although they do not have gross brain abnormalities, they are frequently found to have significantly reduced brain volumes.[11]

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Epidemiology

Frequency

United States

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

International

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

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.[12]

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).[13] Isochromosome 7q may be a specific marker of myeloid malignant transformation in association with Schwachman-Diamond syndrome.[14]

Whether increased angiogenesis in Schwachman-Diamond syndrome marrow promotes progression of hematologic malignancies is unclear,[15] but increased expression of vascular endothelial growth factor-A and other cytokines may play a role.[16] At the genetic level, spindle instability that contributes to bone marrow failure and leukemia development has also been implicated.[17] Spindle instability may also be attributed, at least in part, to the high frequency of acquired chromosomal anomalies found in patients with Schwachman-Diamond syndrome, which may form the basis of malignant transformation in tissues with high mitotic activity.[18]

Additionally, increased apoptosis of nontransformed cells through Fas stimulation leads to a growth advantage in mutated cells. Deficiency in the SBDS gene results in abnormal accumulation of Fas at the plasma membrane, where it sensitizes the cells to stimulation by the Fas ligand, leading to accelerated apoptosis. This finding suggests that the SBDS gene may play an important role in regulating the Fas-mediated apoptosis pathway and may be responsible for the reduced cellularity in the bone marrow and exocrine pancreas of patients with Shwachman-Diamond syndrome.[19, 20]

Death usually occurs from overwhelming sepsis or malignancy.

Alter et al report that the projected median survival age is older than 35 years for all patients with Schwachman-Diamond syndrome.[21] 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.[21]

Sex

The male-to-female ratio is 1.7:1.[22]

Age

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

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Contributor Information and Disclosures
Author

Antoinette C Spoto-Cannons, MD, FAAP  Pediatric Hospitalist, Florida Pediatric Associates, LLC

Antoinette C Spoto-Cannons, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics and Florida Pediatric Society

Disclosure: Nothing to disclose.

Coauthor(s)

Jessica Marie Keshishian, MD  Resident Physician, Department of Pediatrics, University of South Florida

Jessica Marie Keshishian, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Student Association/Foundation, and Christian Medical & Dental Society

Disclosure: Nothing to disclose.

Sarah Syed  University of South Florida College of Medicine

Sarah Syed is a member of the following medical societies: American Medical Student Association/Foundation

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.

Specialty Editor Board

Sharada A Sarnaik, MBBS  Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Attending Hematologist/Oncologist, Children's Hospital of Michigan

Sharada A Sarnaik, MBBS 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.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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 School of Medicine; 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.

Helen SI Chan, MBBS, FRCP(C), FAAP  Associate Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto Faculty of Medicine, Canada

Helen SI 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  Senior Vice President, Center for Cancer and Blood Disorders, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University School of Medicine; Clinical Professor of Pediatrics, George Washington University School of Medicine and Health Sciences

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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Autosomal recessive inheritance.
 
 
 
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