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Sly Syndrome

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Synonyms of Sly Syndrome

Disorder Subdivisions

General Discussion

Mucopolysaccharidoses, which are also known as mucopolysaccharide storage (MPS) diseases, are a group of rare genetic disorders caused by the deficiency of one of ten specific lysosomal enzymes. The lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates (mucopolysaccharides) into simpler molecules. The accumulation of these large, undegraded mucopolysaccharides in the cells of the body causes a number of physical symptoms and abnormalities.

Sly syndrome (MPS-VII) is an MPS storage disease caused by a deficiency of the enzyme beta-glucuronidase that leads to an accumulation of dermatan sulfate (DS), heparan sulfate (HS) and chondroitin sulfate (CS) in many tissues and organs of the body including the central nervous system.

The clinical features of Sly syndrome vary from patient to patient, but all have short stature due to growth retardation, changes in bones visible on X-rays and some degree of mental retardation. Survival into adulthood is common with milder cases and osteoarthritis is a common complication.

The symptoms of Sly Syndrome are similar to those of Hurler Syndrome (MPS I) and the other Mucopolysaccharidoses. Symptoms may include mental retardation, short stature with an unusually short trunk, and/or abnormalities of the intestines, corneas of the eyes, and/or the skeletal system. Sly Syndrome is inherited as an autosomal recessive genetic trait.

Symptoms

In some cases, the symptoms of Sly syndrome may be obvious during early infancy. Other cases of this disorder may be diagnosed during late infancy or childhood. The most common feature of Sly syndrome is moderate and nonprogressive mental retardation that is usually evident around the age of 3 years. Developmental delays in speech and language may occur. Children with this disorder may develop an unusual "coarse" facial appearance. Between the ages of 7 months and 8 years, cloudiness (opacity) may occur in the corneas of the eyes. A severe form of Sly syndrome may affect newborns (neonates) and is characterized by multiple bone malformations at birth and the accumulation of excessive fluid in many parts of the body (hydrops fetalis) and neonatal jaundice.

Children with Sly syndrome may have an unusually short trunk and growth retardation, resulting in short stature (short trunk dwarfism). The head may be excessively large (macrocephalic) and the neck may be short. A variety of multiple bone deformities (dysostosis multiplex), which are frequently observed in people with mucopolysaccharidoses, are also common in children with Sly syndrome. These bone deformities may include a prominent breast bone (pectus carinatum), flared ribs, frequent hip dislocations, "frozen" joints (contractures), club foot, and/or an inward curve of the knees and outward bowing of the ankles (genu valgum). In some rare cases, spinal malformations may be present including mild curvature of the spine from side to side (scoliosis) and/or front to back (kyphosis).

Occasionally, other symptoms of Sly syndrome may include a swollen abdomen due to abnormal enlargement of the liver and/or spleen (hepatosplenomegaly) and protrusion of the intestines through an abnormal opening in the muscular wall of the abdomen (inguinal hernia). In some cases, the intestines may also protrude through the abdominal wall in the area of the navel (umbilical hernia). Some affected children may experience profound hearing loss, recurrent upper respiratory and middle ear infections, thickening of the soft tissues of the throat and/or vocal cords, an abnormally enlarged tongue (macroglossia), and/or heart problems (i.e., heart murmur or aortic regurgitation). Excessive hairiness (hirsutism) may be present.

Survival to age 19-20 years has been reported in mild cases. Life expectancy is reduced as a result of frequent upper respiratory tract infections, neurodegenerative complications and abnormalities of the gastrointestinal tract.

Six cases of a mild form of Sly syndrome, beginning during the 2nd decade of life, have been described in the medical literature. In these cases, the symptoms of the disorder appear to be less severe than classical Sly syndrome and may include minor bony changes and very mild facial coarseness. Growth rate and mental abilities are usually normal. Abnormal enlargement of the liver and spleen has not been noticed in this form of Sly syndrome.

Causes

Sly syndrome is inherited as an autosomal recessive genetic trait. Symptoms develop due to a deficiency of the enzyme beta-glucuronidase. The gene responsible for this disorder is located on the long arm of chromosome 7 (7q21.11) and has been termed the GUSB gene. A variety of different changes (mutations) in this particular gene (allelic variations) may account for the wide range of symptoms and physical findings as well as the variability in the age of onset.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Affected Populations

Sly syndrome is extremely rare, affecting only about one in one million births. Fewer than 100 cases have been reported in the United States. Males and females are affected in equal numbers.

Related Disorders

Symptoms of the following disorders can be similar to those of Sly syndrome. Comparisons may be useful for a differential diagnosis:

The mucopolysaccharidoses are a group of inherited disorders of lysosomal storage characterized by deposits of certain complex carbohydrates (mucopolysaccharides) in many tissues and organs of the body (i.e., eyes, skeleton, arteries, joints, ears, skin, and/or teeth). In general, these disorders are progressive and usually disabling. The symptoms vary greatly depending on the specific enzyme deficiencies. Symptoms of the mucopolysaccharidoses generally include unusual facial features, multisystem involvement with organ enlargement, and/or multiple bone deformities (dysostosis multiplex). (For more information on these disorders, choose "mucopolysaccharidoses" as your search term in the Rare Disease Database.)

Hurler syndrome ([MPS I) is a rare inherited metabolic disorder that appears in 3 forms of varying severity. Newborns with Hurler syndrome (MPS 1-H) usually appear normal, although hernias may be present. Onset of symptoms occurs between the ages of 6 months and 2 years and may include coarse facial features, a prominent forehead, an unusually large tongue, misaligned teeth, and/or clouding of the corneas of the eyes. Repeated upper respiratory infections, noisy breathing, and a persistent nasal discharge may also be present. Other symptoms may include growth delays, mental retardation, joint stiffness, deafness, and/or heart disease. (For more information on this disorder, choose "Hurler" as your search term in the Rare Disease Database.)

The mucolipidoses are a family of similar disorders, producing symptoms very much like those of the mucopolysaccharidoses.

Sialidosis (mucolipidosis I) is a very rare inherited metabolic disorder characterized by a deficiency of the enzyme alpha-neuraminidase and belongs to a group of diseases known as lysosomal storage disorders. Type I and Type II Sialidosis have been identified. The symptoms of sialidosis type I, which typically begin during the 2nd decade of life, may include sudden involuntary muscle contractions (myoclonus), the appearance of red spots (cherry-red macules) in the eyes, and/or other neurological findings. Sialidosis type II may begin during infancy or later. It is characterized by the same visual abnormalities as sialidosis type I as well as other findings such as mildly coarse facial features, skeletal changes, and/or mild mental retardation. Sialidosis is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Sialidosis" as your search term in the Rare Disease Database.)

I-Cell Disease (mucolipidosis II) is a rare inherited metabolic disorder characterized by multiple enzyme deficiencies. The symptoms of this disorder usually begin around the age of 6 months and may include coarse facial features (i.e., depressed nasal bridge), a long and narrow head, excessive hair growth, and/or a low forehead. Skeletal changes may also occur including curvature of the spine, misalignment of the spinal vertebrae, widening of the ribs, "frozen" or immovable joints, and/or pointing of the long bones of the hands. Mental retardation and growth delays are also common. Frequent respiratory infections occur as well as clouding of the corneas of the eyes. (For more information on this disorder, choose "I-Cell" as your search term in the Rare Disease Database.)

Mucolipidosis III (ML III) is a rare inherited metabolic disorder characterized by the accumulation of certain complex carbohydrates (mucopolysaccharides) and fatty substances (mucolipids) in various tissues of the body. The symptoms of this disorder are less severe than those of I-Cell Disease (ML II) and may include progressive joint stiffness, curvature of the spine (scoliosis), and/or skeletal deformities of the hands (e.g., claw- hands). Growth delays accompanied by deterioration of the hip joints typically develop in children with mucolipidosis III. Other symptoms may include clouding of the corneas of the eyes, mild to moderate coarseness of facial features, mild mental retardation, easy fatigability, and/or heart disease (i.e., congestive heart failure). (For more information on this disorder, choose "Mucolipidosis III" as your search term in the Rare Disease Database.)

Galactosialidosis is a rare inherited metabolic disorder characterized by deficiencies of the enzymes neuraminidase and beta-galactosidase. Symptoms may include severe swelling of many soft tissues of the body and abdominal swelling due to the development of fluid-filled sacs (ascites). Cherry red spots in the eyes, skeletal abnormalities, abnormal enlargement of many organs of the body (visceromegaly), and/or mental retardation may also occur. Growth delays, joint stiffness, and/or coarse facial features are also characteristic of this disorder. Galactosialidosis is inherited as an autosomal recessive genetic trait. The symptoms of this disorder may be very difficult to distinguish from those of sialidosis.

Standard Therapies

Diagnosis
Urinary levels of the mucopolysaccharides dermatan sulfate, heparan sulfate and chondroitin sulfate are increased in affected individuals. The diagnosis of Sly syndrome may be confirmed by a thorough clinical evaluation that includes a detailed patient history and specialized tests that measure the level of beta-glucuronidase activity in skin fibroblasts or blood leukocytes. Prenatal diagnosis is also possible through amniocentesis or chorionic villus sampling for beta-glucuronidase activity.

Treatment
The treatment of Sly syndrome is symptomatic and supportive. Bone deformities and hernias may require surgical correction. Ocular and cardiovascular abnormalities may also be treated surgically. Patients with MSP storage disorders may be sensitive to anesthesia because of malformations in the airway or cervical spine; therefore, precautions should be taken prior to surgery. Genetic counseling will be helpful for people with Sly syndrome and their families.

Investigational Therapies

Enzyme replacement therapy and bone marrow transplantation are being investigated for the treatment of this disorder. Scientific study of these therapies in animal models raises the hope that they may someday be made available to people with genetic disorders such as Sly syndrome or other Mucopolysaccharidoses. Neither therapy has been attempted yet in humans.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Sly Syndrome Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

TEXTBOOKS
Clarke JTR. MPS-VII. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:481.

Beighton P, McKusick VA. Heritable Disorders of Connective Tissue, 5th ed. St. Louis: CV Mosby, 1993.

JOURNAL ARTICLES
Nash D and Varma S. Mucopolysaccharidosis Type VII. From: eMedicine article, Last Update: 8/14/02.

FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 253220; Last Update: 5/8/03.

Kjellen L, Lindahl V. The proteoglycans structures and functions. Ann Rev Biochem 1991:60:443-475.

Peterson L, et al. Mucopolysaccharidosis type VII. A morphoplogic, cytochemical, and ultrastructural study of the blood and bone marrow. Am J Clin Pathol 1992;78(4):544-48.

Tomatsu S, et al. Mucopolysaccharidosis type VII: Characterization of mutations and molecular heterogeneity. Am J Hum Genet 1991;48(1):89-96.

Kagie MJ, et al. Beta-glucuronidase deficiency as a cause of fetal hydrops. Am J Med Genet 1992;42(5):693-5.

De Kramer RD, et al. Mucopolysaccharidosis type VII (beta-glucuronidase deficiency): A chronic variant with an oligosymptomatic severe skeletal dysplasia. Am J Med Genet 1992;44(2):145-52.

Report last updated: 2008/05/12 00:00:00 GMT+0