Shwachman-Diamond syndrome (SDS) is a rare inherited disorder affecting multiple areas of the body, with symptoms often appearing by four to six months of age. The condition primarily impacts the pancreas, bone marrow, and skeletal system. Due to its varied presentation from person to person, it can be challenging to diagnose and manage. Individuals with SDS require lifelong medical attention to address its various effects.
Genetic Origins of the Disorder
Shwachman-Diamond syndrome is a genetic condition caused by gene mutations. In about 90% of cases, the disorder is traced to alterations in the SBDS gene on chromosome 7. This gene provides instructions for making a protein that helps build ribosomes, the cellular structures that produce other proteins. When the SBDS gene is mutated, this process is disrupted due to an insufficient or impaired protein supply.
The inheritance pattern for SDS is autosomal recessive. This means a child must inherit one mutated copy of the SBDS gene from each parent to develop the condition. The parents, known as carriers, each have one copy of the altered gene and usually show no symptoms. When two carriers have a child, there is a 25% chance with each pregnancy that the child will be affected by SDS.
In about 10% of cases, the specific genetic cause has not been identified, suggesting other genes may be involved. A new mutation, known as a de novo mutation, can also occur during the formation of reproductive cells or in early development. This can lead to the disorder even without a family history.
Physical Manifestations
One of the most common features of SDS is exocrine pancreatic insufficiency. This occurs because the pancreatic cells that produce digestive enzymes are depleted and replaced with fatty tissue. Without enough enzymes to break down food, the body cannot properly absorb fats and other nutrients. This malabsorption leads to poor weight gain, failure to thrive, and steatorrhea—frequent, greasy, and foul-smelling stools.
Bone marrow dysfunction is another primary characteristic. The bone marrow fails to produce enough new blood cells, most frequently resulting in neutropenia. Neutropenia is a low count of neutrophils, a type of white blood cell that fights bacterial infections. This shortage makes individuals with SDS susceptible to recurrent infections, including pneumonia, ear infections, and skin infections.
The bone marrow may also fail to produce other blood cells, leading to anemia or thrombocytopenia. Anemia is a shortage of red blood cells causing fatigue, while thrombocytopenia is a low platelet count that can result in easy bruising and bleeding. The bone marrow itself is often hypocellular, meaning it has fewer cells than normal and shows delayed cell maturation.
Skeletal abnormalities are also common in SDS. Many children have short stature and grow slower than their peers, often linked to metaphyseal dysostosis. This condition affects the growth plates of bones, particularly in the arms and legs. Other skeletal issues can include a deformed rib cage with unusually short ribs, which may cause breathing difficulties.
The Diagnostic Process
Diagnosing Shwachman-Diamond syndrome involves clinical observations and specific tests. Physicians often suspect SDS in infants or children with poor growth, chronic diarrhea, and frequent infections. These signs prompt a thorough investigation to confirm the cause and rule out similar conditions like cystic fibrosis.
The evaluation begins with blood tests to assess bone marrow function. A complete blood count (CBC) measures the levels of different blood cells, with a primary finding for SDS being neutropenia. Tests may also reveal anemia or thrombocytopenia. Blood tests are often repeated over months to see if low counts are persistent or intermittent, a common feature of the disorder.
To assess pancreatic function, doctors measure digestive enzyme levels. The most common test is a non-invasive fecal elastase test, where low levels of the enzyme in a stool sample indicate exocrine pancreatic insufficiency. Other tests may include measuring serum levels of pancreatic enzymes like trypsinogen and isoamylase, which are also low in SDS.
A definitive diagnosis is achieved through genetic testing. A blood sample is analyzed for mutations in the SBDS gene, found in about 90% of patients with clinical features of SDS. A skeletal survey using X-rays is performed to identify abnormalities like metaphyseal dysostosis. A bone marrow aspiration and biopsy may also be conducted to examine marrow cellularity and check for abnormal cell development.
Management and Surveillance Strategies
Management of Shwachman-Diamond syndrome focuses on addressing symptoms and monitoring for long-term complications. As there is no cure, care is supportive and involves a multidisciplinary team of specialists, such as hematologists, gastroenterologists, and orthopedic surgeons. This approach aims to improve quality of life and prevent serious health issues.
Daily management focuses on pancreatic and bone marrow symptoms. To treat exocrine pancreatic insufficiency, individuals take Pancreatic Enzyme Replacement Therapy (PERT), which are enzyme capsules taken with meals to improve nutrient absorption. Nutritional support is also provided through regular monitoring and supplementation of fat-soluble vitamins (A, D, E, and K). For severe neutropenia, treatment with granulocyte colony-stimulating factor (G-CSF) may be used to boost neutrophil production and reduce infection risk.
Long-term surveillance for hematologic complications is a primary part of managing SDS. Individuals have an increased risk of developing severe bone marrow conditions like myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). MDS is a disorder where the bone marrow produces abnormal blood cells and can progress to AML, a cancer of the blood-forming tissue.
Monitoring for these changes requires regular follow-ups, including complete blood counts every three to four months. Bone marrow aspiration and biopsy procedures are recommended annually, or more often if blood counts change, to find early signs of MDS or leukemia. This monitoring allows for early detection and timely intervention. A hematopoietic stem cell transplant (HSCT) is the only curative treatment for severe bone marrow failure or leukemia in SDS.