Shwachman syndrome, also known as Shwachman-Diamond syndrome (SDS), is a rare inherited disorder that usually affects the bone marrow, pancreas, and skeletal system.
The main function of bone marrow is to produce blood cells for the body. These include red blood cells (which bring oxygen to tissues), white blood cells (which help fight infection), and platelets (which help in blood clotting). In patients with SDS, there is a dysfunction in the bone marrow, which may lead to bone marrow failure.
The pancreas is the organ responsible for making digestive enzymes that help to break down food into nutrients that can be absorbed. In patients with SDS, the pancreas loses the ability to make these enzymes.
More than 50% of patients with SDS are of short stature that is unrelated to nutritional problems. Bone abnormalities, also called metaphyseal chondrodysplasia, are seen mainly in the femur and tibia (leg bones) and the ribs.
An infant with SDS will first present with diarrhea and foul-smelling, oily stools. This is due to the inability to absorb fat. By 4-6 months of age, feeding and growth problems become apparent. Once enzyme replacement is given, fat is able to be absorbed and diarrhea becomes less problematic. Other digestive problems include the inability to absorb fat-soluble vitamins, which include vitamins A, D, E, and K. Any patient with SDS may have recurrent infections because of a decrease in white blood cells, particularly the neutrophils (also known as neutropenia). These white blood cells are an important part of the immune system, which helps the body fight off disease and infection. Patients may also experience low levels of red blood cells (called anemia), low levels of platelets (called thrombocytopenia), and bone abnormalities (including short stature).
Researchers are not sure how common Shwachman-Diamond syndrome is; medical researchers estimate that it affects one in every 50,000 births. The disease affects slightly more males than females.
There is limited information on the survival rates of patients with SDS, but on average, patients live to be about 35 years old. The leading causes of death in patients with SDS are infection, leukemia, and bone marrow failure.
There is no cure or specific treatment for Shwachman syndrome. Instead, treatment focuses on reducing symptoms and treating complications.
General: About 90% of patients with Shwachman-Diamond syndrome (SDS) have a mutation in the SBDS gene (named after Shwachman-Bodian-Diamond). The gene provides instructions on how to make a protein that is found in cells throughout the body. The actual function of this protein is not known. It is hypothesized that the SBDS gene is involved with RNA metabolism or ribosome assembly.
The major role of this gene in the signs and symptoms of SDS is also unknown. However, this gene is found in high numbers in the pancreas, bone marrow, and white blood cells (called leukocytes). It is suspected that normal functioning of this gene is necessary for the development of these tissues.
Inheritance: Each gene has two variations, called alleles. One allele is inherited from each parent. Because SDS is an autosomal recessive condition, a person must inherit the mutated gene from both parents. If a person has one faulty gene, he or she is a carrier but does not have symptoms of the disease.
If both parents are carriers of the disease, there is a 25% chance that the child will have the disease. There is a 50% chance that the patient will have one mutated gene and one normal gene and become a carrier of the disease. There is also a 25% chance that the child will inherit two normal genes from the parents.
Other: Some patients have SDS that is not associated with the SBDS gene. In these cases, the cause is unknown.
SIGNS AND SYMPTOMS
Blood abnormalities: Premature blood cells, called "stem cells," are made in the bone marrow where they can differentiate (or mature) into functional red blood cells, white blood cells, and platelets. White blood cells help to fight infections, while red blood cells carry oxygen to tissues. The main function of platelets is to help clot the blood and stop bleeding. Patients with Shwachman syndrome (SDS) have poorly functioning bone marrow resulting in at least one blood abnormality.
The most common abnormality is neutropenia, or low neutrophil count, which occurs in more than 80% of people with SDS. Neutrophils are white blood cells that help fight infections. Neutropenia may occur from time to time (intermittent) or continuously (low counts present all the time). About 67% of SDS neutropenia occurrences are intermittent. This may lead to an increase in number of infections.
Other SDS blood abnormalities with lower incidences include anemia, thrombocytopenia, and pancytopenia. Anemia is a low red blood cell count and occurs in about 40% of SDS patients. It may cause pale skin and decreased energy. Thrombocytopenia is a low platelet count, and it occurs in about 30% of patients. This causes bleeding, bruising, and small red/purple dots on the skin (called petechiae). Pancytopenia occurs when all cell counts are low and this occurs in about 19% of SDS patients.
Pancreatic problems: The pancreas has two major functions: production of digestive enzymes and production of insulin (which regulates blood sugar). People with SDS usually have normal insulin but have defects in the production of digestive enzymes.
The acinar cells are the pancreatic cells responsible for producing digestive enzymes. In normal patients there is an excess of these cells, and only 2% are needed to make sufficient amounts of digestive enzymes. A person with SDS has an inadequate number of acinar cells, which leads to pancreatic insufficiency. A decrease in digestive enzymes causes loose, foul smelling, and fatty stools (steatorrhea) and a decrease in the ability to absorb nutrients. About half of people with SDS show improvement in enzyme production later in life, although the pancreas remains defective. This can be treated with replacement enzymes taken with every meal.
Skeletal abnormalities: About 50-75% of children with SDS have some kind of skeletal abnormality. One feature of SDS is small stature due to a defect in the metaphysis (the part of the bone that grows), also called metaphyseal dysostosis or metaphyseal chondrodysplasia. It usually affects the hips and knees and is visible on an X-ray.
Some children may be born with a narrow rib cage or shortened ribs with flared ends. These may lead to breathing problems in newborns but it is uncommon. Costochondral thickening (cartilage changes near the ribcage) can also be seen on an X-ray but do not tend to cause any problems.
Less common skeletal abnormalities include bent fingers, dislocated femur, curvature of the spine, cleft palate, webbed fingers, an extra thumb, and osteopenia (thinning of bone).
Less common symptoms:
Dental problems: Children with SDS may have poorly developed teeth and enamel defects, known as dental dysplasia. They are also at an increased risk of gum infections and tooth decay due to neutropenia. All individuals with neutropenia should see their dentists at least every six months.
Liver disorders: About 60% of patients with SDS have increased ALT and AST (liver enzymes). Fifteen percent of patients have enlarged livers (hepatomegaly), which may cause steatosis (fatty liver). These symptoms are more common in younger patients and may decrease with age.
Kidney disorders: Occasionally, patients with SDS develop kidney stones. It is believed that SDS patients have increased absorption of oxalate (a salt found in some foods), which may increase the risk of kidney stones. Renal tubular acidosis (incorrect pH in the urine) has rarely been reported.
Skin problems: Children with SDS may have skin problems early in childhood either on the scalp or elsewhere. These problems can be minor rashes or ichthyosis, which causes dry, rough, or scaly skin. Severe eczema has also been seen.
Psychological disorders: Most children with SDS are of normal intelligence, although some may have developmental delays that may lead to learning disabilities. Some studies have shown that learning disorders, attention deficit disorders, and social problems are more common in children with SDS.
Heart problems: There have been a few cases of an enlarged heart in patients with SDS. However, the common cause of the enlarged heart is often chronic lung disease.
General: In order to diagnose Shwachman-Diamond syndrome (SDS), a physical exam, complete history, and several tests are necessary. Assessment of exocrine pancreatic function and blood abnormalities are essential in the diagnosis of SDS. It is also important to rule out cystic fibrosis (CF), another disease that affects the pancreas and digestive enzymes.
Blood tests: Blood is taken to evaluate the white blood cells, red blood cells, and platelets. Patients with SDS may have low levels of white blood cells, particularly neutrophils, low levels of red blood cells, and/or low levels of platelets.
Biopsy: A biopsy of the bone marrow can also be done. During a biopsy, a solid portion of the bone marrow is examined under a microscope. Doctors can also take a bone marrow aspirate, in which a needle is used to remove the liquid portion of the marrow. The doctor then looks for abnormalities in the blood cells, bone marrow failure, or leukemia. The patient can choose to be sedated with intravenous medications or to have local anesthesia, in which the patient is awake and the area to be biopsied is numbed. Pain is usually felt after the sedation or anesthesia wears off and may last a few days to a couple of weeks. These procedures rarely have any complications, and if they arise, they are usually mild. Risks may include excessive bleeding, infection, long-lasting pain, and allergic reaction (to sedatives or anesthesia).
Pancreatic tests: A pancreatic stimulation test is used to examine the function of the pancreas and digestive enzymes. This test measures the ability of the pancreas to respond to secretin, a hormone that ensures that the pancreatic digestive enzymes are working. Stool may also be collected to look for excess fat (called steatorrhea). The pancreas may be visualized with ultrasonography or computed tomography (CT) scans. In patients with SDS, the pancreas is typically smaller than normal and contains an excess of fatty tissue.
Genetic testing: Genetic testing is currently only available at private genetic testing facilities and can be very expensive.
Low blood cell counts: Patients with SDS are at a higher risk of developing myelodysplastic syndrome (MDS) and aplastic anemia, conditions in which blood cell counts are low.
Leukemia: In patients with SDS, there are also increased reports of acute myeloid leukemia (AML), a cancer that affects the blood cells. It has been reported that about 5% of children with SDS will develop AML; this risk increases to about 25% by the time the patient reaches adulthood.
Infections: Because patients with SDS have low levels of neutrophils, they cannot fight off infections as well as healthy individuals. This can lead to various illnesses, including pneumonia, recurrent ear infections, and skin infections. Sometimes these infections can be serious or life-threatening.
Malnutrition: Because the pancreas is often affected in SDS, it may not be able to make digestive enzymes that are important for breaking down food into nutrients that can be absorbed. This malabsorption may lead to malnutrition and vitamin deficiencies, especially of the fat-soluble vitamins A, D, E, and K.
General: There is no cure for Shwachman syndrome (SDS). Rather, treatment is focused on reducing symptoms. Specific treatment depends on the patient's current health, age, and tolerance for the necessary medications or procedures.
Pancreatic enzyme replacement: Pancrelipase is a medication available as a powder (for infants), tablet, or capsule. It is used to replace pancreatic enzymes that are deficient in patients with SDS and is taken with meals (including snacks) to aid in digestion. Pancrelipase can thus relieve steatorrhea, diarrhea, and malabsorption of vitamins. Dosing depends on the extent of symptoms (steatorrhea) and the tolerance of side effects. The main side effects include nausea, abdominal pain, constipation, and diarrhea. Also seen are allergic reactions, irritation of the mouth and anus, and high levels of uric acid, which usually occurs only at high doses. High uric acid levels will only cause a gout attack in those SDS patients who are predisposed. A fat-soluble vitamin supplement (ADEKs©) may be given to increase levels of nutrients along with pancreatic enzymes.
Antibiotics: Antibiotics may be used to treat infections commonly associated with SDS. Intravenous broad spectrum antibiotics, which kill many different types of bacteria, are sometimes given for serious infections. If the bacteria causing the infection can be identified, oral antibiotics may be used. Side effects can vary depending on the antibiotic used; the most common side effects of oral antibiotics are gastrointestinal problems, such as diarrhea or abdominal pain.
Granulocyte colony stimulating factor (G-CSF): Filgrastim (Neupogen©), pegylated filgrastim (Neulasta©), and lenograstim (Granocyte©) are growth factors that help the bone marrow increase the number of white blood cells produced. These medications are usually reserved for severe infections, and therapy is highly individualized. It is injected subcutaneously (under the skin) daily. Side effects may include nausea, vomiting, bone pain, and flu-like symptoms.
Orthopedic surgery: Depending on the skeletal problems of the patient, surgery can be used to correct the defects.
Blood product replacement: Blood and/or platelet transfusions may be necessary if red blood cells are severely low or if the patient is at risk for severe bleeding. This treatment, however, is not common. Side effects may include fever, headache, allergic reaction, and infection.
Bone marrow transplant: Since leukemia may develop and there is a poor prognosis in patients with SDS, bone marrow transplants may be suggested, specifically among those who have severe myelodysplastic syndrome (MDS), the condition in which all blood cells are low. Research in this area is limited, but SDS patients seem to have a similar overall outcome to non-SDS patients with MDS or acute myeloid leukemia (AML). However, SDS patients appear to have more bone marrow transplant-related problems (like graft-versus-host disease) and more toxicity from medications used before the procedure.
Unclear or conflicting scientific evidence:
ADEKs©: ADEKs© is a multivitamin with minerals, mainly consisting of vitamins A, D, E, and K. Vitamin C, B-complex vitamins, folic acid, and zinc are also found in this supplement. ADEKs© may be given to increase these necessary nutrients along with pancreatic enzymes. This preparation uses high doses of fat-soluble vitamins (A, D, E, and K) in a water-miscible form. It is available as a tablet, liquid, drops, and chewable tablet that must be chewed or crushed before swallowing. Patients should speak with their doctors before taking any supplements, especially before taking ADEKs©. Recommended doses should not be exceeded due to the risk of toxicity. Pregnant women and patients taking anticoagulant therapy should use ADEKs© with caution.
There is currently no known way to prevent Shwachman syndrome (SDS). If a person has a family history of the disease, it is possible to get genetic testing to determine if he or she is a carrier. However, not everyone with SDS has a mutation of the SBDS gene.
This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
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