What is the pathophysiology of Shwachman-Diamond syndrome (SDS)?

Updated: Nov 17, 2020
  • Author: Antoinette C Spoto-Cannons, MD, FAAP; Chief Editor: Hassan M Yaish, MD  more...
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Answer

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]


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