What
is
Shwachman Diamond Syndrome ? ? ?

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The Disorder

The Disorder at a Glance

First described in 1964, Shwachman-Diamond Syndrome is a rare disease which mainly involves the pancreas, bone marrow and skeleton, but other organs may also be affected. Next to Cystic Fibrosis, it is the most common cause of pancreatic insufficiency in children. For that reason, it is sometimes confused with Cystic Fibrosis; but in children with Shwachman-Diamond Syndrome the sweat test is normal. People with Shwachman-Diamond Syndrome usually have a decreased ability to digest food because the cells of the pancreas, in which digestive enzymes are produced, do not work properly. Additionally, there is usually a decreased number of at least one kind of blood cells. In some patients, there is a decrease in all kinds of blood cells. Most frequently, this decrease occurs in the number of neutrophils, the blood cell that is necessary to fight bacteria infections.

Cause

Shwachman-Diamond syndrome is genetic, most likely an autosomal recessive condition. The genetic defect is unknown at present. The inheritance is supported by the presence of more than one effect patient in a family. Males and females are effected with equal frequency. However, the factors which lead to multisystem diseases are unknown.

GENERAL FEATURES

Infants often become ill with symptoms by the age of four or six months old. Early problems include failure to thrive, feeding problems and recurrent infections. Growth soon slows and remains below normal; only a few children show growth beyond the third percentile. Infections are present early in at least 85% of children. These occasionally lead to death. Diagnosis is generally made in the first few years of life, although occasionally diagnosis is delayed.

SPECIFIC FEATURES

Digestive

Diarrhea is almost always present in infancy. Stools contain an excessive amount of fat and are foul smelling and greasy in appearance. Improvement in stools are seen after enzymes replacement therapy is begun. Although weight gain is noted, growth does not seem to improve. Some older patients are able to discontinue enzyme replacement with no clinical consequences.

Bone Marrow

As a result of dysfunction of the bone marrow, patients may have a decrease in any or all types of blood cells. There may be decreased numbers of neutrophils (the white blood cell that helps fight infection), platelets( the blood cell that helps clot the blood), or red blood cells. Blood cell counts should be monitored regularly. Shwachman-Diamond Syndrome patients have apropensity to myelodysplasia or leukemic transformation, for this reason bone marrow aspirates and biopsies are recommended.

Neutropenia

Neutropenia is present when the counts are lower than 1500 per microliter. Neutrophils are a type of white blood cell important in fighting bacteria infections. Neutropenia is seen, at sometime during the course of the disease, in virtually all patients. Many patients are prone to repeated bacterial infection.  Some of these infections may be life threatening. Close attention should be paid to infection, with appropriate treatment instituted as quickly as possible.

Thrombocytopenia

The blood also contains cells called platelets. It is their function to clot the blood when bleeding occurs. Normally, platelet counts are above 150,000 per microliter. In about 35% of patients with Shwachman-Diamond syndrome this count is below that number; this is called thrombocytopenia. Easy bruisability is one indication of thrombocytopenia, but severe bleeding is unusual. Precautions may be required before dental work or surgery, and platelet transfusions or medications may be necessary to diminish the risk of abnormal bleeding.

 

Anemia

Anemia occurs when the hemoglobin level is under 10gm/dl, and has been observed in up to 40% of patients with Shwachman-Diamond Syndrome. Anemia is usually mild and does not respond well to treatment with iron, folic acid and vitamin B-12.

 

Skeleton

Bone lesions have been reported in 10 to 15% of patients. The bone abnormalities are called metaphyseal chondrodysplasia. X-ray changes are most commonly seen in the hip, femur, tibia (leg bone) and ribs. These changes can be severe enough to require surgical correction.

 

Liver

Abnormalities in the structure of the liver and in function are not uncommon. Hepatomegaly (enlarged liver) occurs in about 2/3 of patients under the age of five years of age, but is less frequent in older children. Serum liver enzymes are elevated in 50 to 75% of cases, again most often in young children and tending to fall with age. Chronic liver disease has been reported.

 

Other Involvements

Less frequently reported conditions include cardiac lesions, developmental and intellectual delays, behavior and eating problems, lung disease, renal tubular malfunction, abnormal pulmonary function tests, testicular fibrosis, dental problems, diabetes mellitus and pubertal delays.

Prognosis

Mortalities have been reported. Full growth may not be obtained despite aggressive therapy, particularly if hip disease is severe. The other features of the disease may persist into adulthood.

Treatment

If the pancreas is not working properly, enzyme replacement should be begun immediately. Guidelines for enzyme use are similar to those for Cystic Fibrosis. Enzyme replacement should decrease diarrhea and foul, greasy stools. This may not, however, improve growth. Multivitamins and supplemental fat-soluble vitamins (vitamins A,D,E,and K) should be given daily. The diet should provide protein and energy adequate for nutritional needs and may require supplementation with high calorie foods or prepared supplements. Infections should be treated vigorously with appropriate antibiotics. Bleeding problems and anemia may require blood and platelet transfusions or other intervention (such as DDAVP). Hip disease should be monitored closely and may require surgical intervention. Developmental delays may be helped by physical and speech therapy.

Sick Kids researchers identify gene for Shwachman-Diamond syndrome

TORONTO - Researchers at The Hospital for Sick Children (HSC) and the University of Toronto (U of T) have identified the gene that is altered in Shwachman-Diamond syndrome. The researchers studied 250 Shwachman-Diamond syndrome families from around the world and identified two major disease-causing mutations in a gene on chromosome 7. This research is reported in the January issue of the scientific journal Nature Genetics. Shwachman-Diamond syndrome (SDS) is a relatively rare genetic disorder that occurs in approximately one in 50,000 births. SDS affects many organs in the body. Primary features of SDS include a defect in the pancreas that leads to difficulties in digesting food, hematologic (blood) problems with inadequate production of some types of white blood cells, skeletal abnormalities, and short stature. The hematologic problems make people with SDS prone to severe, sometimes fatal infections, and some die from blood complications such as leukemia or bone marrow failure. "The identification of the gene is important because it will allow for accurate diagnosis and screening of Shwachman-Diamond syndrome. It will also help us to determine what goes wrong at the molecular level, and this will open the door to the development of new therapies," said Dr. Johanna Rommens, the study's principal investigator, an HSC senior scientist and associate professor of Molecular and Medical Genetics at U of T. "This discovery will aid in the clinical management of Shwachman-Diamond syndrome," said Dr. Peter Durie, co-principal investigator of the study, an HSC gastroenterologist and senior scientist, and a professor of Paediatrics at U of T. "It is also very important to the families affected by this disease. We have received patient samples from around the world, and the Shwachman-Diamond parent groups from many countries supported this research financially." Shwachman-Diamond syndrome is an autosomal recessive disease, meaning that a child needs to inherit two mutated genes (one from each parent) in order to have the disease. The SDS gene resides in a region of the human genome that was very difficult to map because it contains a lot of highly repetitious DNA sequence. It was found that in the normal state, every chromosome 7 has two copies of the SDS gene - a functional gene and a non-functional gene relic, called a 'pseudogene'. "We have determined that the type of genetic mutation that causes Shwachman-Diamond syndrome is gene conversion, in that a piece of the non-functional pseudogene has been introduced into the good copy of the gene, thus disrupting its function. These types of mutations have been seen in more than 90 per cent of SDS patients," said Graeme Boocock, the study's lead author and a University of Toronto graduate student. Boocock is a recipient of a Canadian Institutes of Health Research doctoral research award. Other members of the research team are Jodi Morrison, Maja Popovic, Nicole Richards, and Lynda Ellis, all from The Hospital for Sick Children. This research was supported by the Canadian Institutes of Health Research, Shwachman-Diamond Syndrome Canada, Shwachman-Diamond Syndrome International, Shwachman-Diamond Support of Great Britain, The Harrison Wright Appeal, Shwachman-Diamond Syndrome Support of Australia, Paediatric Consultants Inc., Canadian Genetic Diseases Network of Centres of Excellence, and The Hospital for Sick Children Foundation. The Hospital for Sick Children, affiliated with the University of Toronto, is Canada's most research-intensive hospital and the largest centre dedicated to improving children's health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health. For more information, please visit www.sickkids.ca. Further information for families affected by Shwachman-Diamond syndrome is available on the HSC Web site at www.sickkids.ca/mediaroom/custom/SDSgeneQA.asp. For more information, please contact: Laura Greer, Public Affairs (away December 24-January 6) The Hospital for Sick Children (416) 813-5046 laura.greer@sickkids.ca Lisa Lipkin, Public Affairs The Hospital for Sick Children (416) 813-6380 lisa.lipkin@sickkids.ca