Background
Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and skeletal abnormalities. [1, 2, 3] However, although 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 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]
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 Diamond-Blackfan anemia. In 90% of cases, Shwachman-Diamond syndrome is associated with mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, located on chromosome 7.
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. [5, 6]
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. [7] 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 of all ages with Shwachman-Diamond syndrome, but use of this test is limited in children younger than 3 years because all children may normally have low circulating isoamylase levels. [7]
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. [8] 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. [8]
Shwachman-Diamond syndrome is considered one of the inherited bone marrow failure syndromes. [9, 10] 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. [11] 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. [12] 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. [13]
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. Data have demonstrated prosurvival properties of the SBDS gene and indicate 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 developmental abnormalities may also be seen in patients with Shwachman-Diamond syndrome. [14, 15, 16, 17, 18] These individuals have lower performance in most cognitive domains than age-matched controls. [16] Although they do not have gross brain abnormalities, they are frequently found to have significantly reduced brain volumes. [19]
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. [20]
Mortality/Morbidity
The prognosis for individuals with Shwachman-Diamond syndrome is uncertain. Because the disorder was described relatively recently (1964), 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. Also found were deficiencies of vitamin E (4 patients, 19%), zinc (7 patients, 33%), and copper (5 patients, 24%). [21]
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. [22]
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 [23] and increases to 71% by age 50 years. [24] 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. [25] Ninety-two percent of such transformations occur in males.
Other cancers reported in patients with Shwachman-Diamond syndrome include pancreatic adenocarcinoma, [26] central nervous system (CNS) B-cell lymphoma, [27] and breast cancer. [28]
A study by Reed et al reported that persons with Shwachman-Diamond syndrome have a 38-fold higher likelihood of developing lymphoid malignancy. [29]
Whether increased angiogenesis in Shwachman-Diamond syndrome marrow promotes progression of hematologic malignancies is unclear, [30] but increased expression of vascular endothelial growth factor A and other cytokines may play a role. [31] At the genetic level, spindle instability that contributes to bone marrow failure and leukemia development has been implicated as well. [32] 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. [33]
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. [34, 35]
Death usually occurs from overwhelming sepsis or malignancy. Alter et al reported that the projected median survival age is older than 35 years for all patients with Shwachman-Diamond syndrome. [36]
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. [37]
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. [36]
Sex
The male-to-female ratio is 1.7:1. [38]
Age
Shwachman-Diamond syndrome is usually diagnosed during the newborn period or infancy, when patients present with malabsorption and recurrent infections.
Prognosis
Long-term prognosis for individuals with Shwachman-Diamond syndrome is uncertain and varies.
Patients with Shwachman-Diamond syndrome are at an increased risk for infection secondary to neutropenia and a neutrophil migration defect. Sepsis and death may occur. [39]
An increased incidence of myelodysplasia and transformation to acute myeloid leukemia is reported. Acute myeloid leukemia is usually unresponsive to conventional chemotherapy and requires allogeneic hematopoietic stem cell transplantation. [40, 41] Even after stem cell transplantation, the prognosis in these patients is poor, mainly due to organ toxicity related to treatment (specifically cardiotoxicity). [25] This has led to a debate regarding whether patients with Shwachman-Diamond syndrome have a predisposed myocardium, through genetic mechanisms that become clinically significant after stress of treatment with cardiotoxic conditioning regimens (such as whole-body radiation and cyclophosphamide). [42]
Patient Education
Educate families on all aspects of this disease and the importance of notifying a physician whenever the patient has a fever or is not acting well.
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Autosomal recessive inheritance.
