Shwachman-Diamond Syndrome: Practice Essentials, Pathophysiology, Epidemiology (original) (raw)

Practice Essentials

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and skeletal abnormalities. [1, 2, 3] Diagnosis of the condition requires the presence of exocrine pancreatic insufficiency and bone marrow dysfunction; skeletal abnormalities and gene mutations are not a requirement to confirm the diagnosis. The goals of Shwachman-Diamond syndrome (SDS) treatment include (1) pancreatic enzyme supplementation, (2) prevention or treatment of serious and/or invasive infections with early attention to febrile illnesses, (3) correction of hematologic abnormalities when possible, and (4) prevention of orthopedic deformities. [4]

SDS 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 Diamond-Blackfan anemia. In 90% of cases, SDS is associated with mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, located on chromosome 7.

In 1964, Shwachman, Diamond, Oski, and Knaw first reported the syndrome in a group of five children participating in a cystic fibrosis (CF) clinic at Harvard Medical School.

Signs and symptoms

Patients with SDS typically present with diarrhea, short stature, weight loss, and dry skin (eczema). 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. [5, 6, 7, 8]

In addition to short stature, skeletal abnormalities in an individual with SDS may include the following:

Clinodactyly
Syndactyly
Supernumerary metatarsals
Coxa vara deformity
Genu and cubitus valgus
Tooth enamel defects (dental dysplasia) [9]

Along with eczema, dermatologic manifestations in patients with SDS include ichthyosis and petechiae.

As with other bone marrow failure syndromes, a predilection for developing severe cytopenias, myelodysplastic syndrome (MDS), and leukemia is observed with SDS.

Workup

A complete blood count (CBC) is used to assess neutropenia, anemia, and thrombocytopenia. Other laboratory studies in SDS include the following:

Neutrophil function studies
Fetal hemoglobin
Iron, folate, and vitamin B12 levels
Secretin-cholecystokinin quantitative stimulation test
Sweat test
Glucose tolerance test
Urinalysis
Serum bicarbonate, PCO2, hydrogen ion concentration (H+), and urinary pH
Liver function tests
Immunoglobulin levels
Growth hormone levels
Vitamin A, D, E and K levels
Serum calcium and phosphorous

Management

A significant proportion of patients with SDS require pancreatic enzymes, a low-fat diet, multivitamins, and fat-soluble vitamins; however, the needs of these patients may decrease with age.

When patients with SDS experience an acute febrile illness, obtain bacterial cultures because of the increased risk of sepsis from the neutrophil migrational defect with or without neutropenia observed in these patients. Empiric treatment with parenteral, broad-spectrum antibiotics may be indicated. Additionally, prophylactic antibiotics may be necessary to help prevent infection.

Anemia and thrombocytopenia may require repeated transfusions if the patient is symptomatic. Additionally, erythropoietin may be beneficial in the treatment of anemia.

Lymphoproliferative and myeloproliferative malignancies and aplastic marrow observed in patients with Shwachman-Diamond syndrome are usually unresponsive to standard chemotherapy and require allogenic hematopoietic stem cell transplantation. [10, 11]

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. [12, 13]

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. [14] 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. [14]

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. [15] 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. [15]

Shwachman-Diamond syndrome is considered one of the inherited bone marrow failure syndromes. [16, 17] Another key feature of Shwachman-Diamond syndrome involves ineffective hematopoiesis. Studies to understand the pathophysiology of bone marrow failure are currently underway. 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. [18] 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. [19] 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. [20]

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, Shwachman-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. [21, 22, 23, 24, 25] These patients have lower performance in most cognitive domains than age-matched controls. [23] Although they do not have gross brain abnormalities, they are frequently found to have significantly reduced brain volumes. [26]

Epidemiology

Frequency

United States

After cystic fibrosis, Shwachman-Diamond syndrome is the second most common cause of pancreatic insufficiency in childhood. Approximately 3% of childhood pancreatic dysfunction is attributed to Shwachman-Diamond syndrome. The incidence of Shwachman-Diamond syndrome has been estimated at 1 case in 77,000 population using comparison cystic fibrosis data. [27]

International

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

Mortality/Morbidity

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

A study by Pichler et al found that a large percentage of children with Shwachman-Diamond syndrome had vitamin A and selenium deficiencies despite receiving pancreatic enzyme replacement therapy. Twenty of 21 children in the study received enzyme replacement therapy; in addition, 11 (52%) were taking multivitamin supplements and 2 (10%) were on zinc and selenium supplementation. The report found vitamin A and selenium deficiencies in 16 (76%) and 10 (48%) children, respectively. Other deficiencies included vitamin E (4 patients, 19%), zinc (7 patients, 33%), and copper (5 patients, 24%). [28]

Recurrent bacterial infections (eg, upper respiratory tract infections, otitis media, sinusitis, pneumonia, aphthous stomatitis, skin infections, paronychia, osteomyelitis, bacteremia) are common in individuals with Shwachman-Diamond syndrome because of neutropenia/neutrophil migration defects. [6]

As with other bone marrow failure syndromes, a predilection for developing severe cytopenias, myelodysplastic syndrome (MDS), and leukemia is also observed with Shwachman-Diamond syndrome. The frequency of leukemia in patients with Shwachman-Diamond syndrome, particularly acute myeloid leukemia (AML), is as much as 36% by age 30 years [29] and increases to 71% by age 50 years. [30] Most of the malignant transformations involve chromosome 7, such as monosomy 7. Isochromosome 7q may be a specific marker of myeloid malignant transformation in association with Shwachman-Diamond syndrome. [31] Ninety-two percent of such transformations occur in males. Other cancers reported in patients with Shwachman-Diamond syndrome include pancreatic adenocarcinoma, [32] CNS B-cell lymphoma, [33] and breast cancer. [34]

Whether increased angiogenesis in Shwachman-Diamond syndrome marrow promotes progression of hematologic malignancies is unclear, [35] but increased expression of vascular endothelial growth factor-A and other cytokines may play a role. [36] At the genetic level, spindle instability that contributes to bone marrow failure and leukemia development has also been implicated. [37] Spindle instability may also be attributed, at least in part, to the high frequency of acquired chromosomal anomalies found in patients with Shwachman-Diamond syndrome, which may form the basis of malignant transformation in tissues with high mitotic activity. [38]

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. [39, 40]

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 Shwachman-Diamond syndrome. [41]

A study by the National Cancer Institute indicated that in patients with one of four types of bone marrow failure syndromes—Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, or Shwachman-Diamond syndrome—the greatest median age for overall survival is associated with Diamond-Blackfan anemia (67 years), with the median survival ages in dyskeratosis congenita, Shwachman-Diamond syndrome, and Fanconi anemia being 51 years, 41 years, and 39 years, respectively. [42]

For patients with Shwachman-Diamond syndrome 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

Shwachman-Diamond syndrome is reported among all racial and ethnic groups. [41]

Sex

The male-to-female ratio is 1.7:1. [8]

Age

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

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Author

Antoinette C Spoto-Cannons, MD, FAAP Associate Professor of Pediatrics, Department of Pediatrics, Primary Care Clerkship Co-Director, University of South Florida, Morsani College of Medicine

Antoinette C Spoto-Cannons, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, Association of American Medical Colleges, Council on Medical Student Education in Pediatrics, Florida Chapter of The American Academy of Pediatrics, Florida Pediatric Society, Gold Humanism Honor Society, Physicians for Social Responsibility