Sly Syndrome

Sly Syndrome

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Sly Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Beta-Glucuronidase Deficiency
  • MPS Disorder, type VII
  • MPS VII
  • mucopolysaccharidosis type VII
  • GUSB deficiency

Disorder Subdivisions

  • None

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.

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

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.

Resources

CLIMB (Children Living with Inherited Metabolic Diseases)

Climb Building

176 Nantwich Road

Crewe, CW2 6BG

United Kingdom

Tel: 4408452412173

Fax: 4408452412174

Email: enquiries@climb.org.uk

Internet: http://www.CLIMB.org.uk



Vaincre Les Maladies Lysosomales

2 Ter Avenue

Massy, 91300

France

Tel: 0169754030

Fax: 0160111583

Email: accueil@vml-asso.org

Internet: http://www.vml-asso.org



The Arc

1825 K Street NW, Suite 1200

Washington, DC 20006

Tel: (202)534-3700

Fax: (202)534-3731

Tel: (800)433-5255

TDD: (817)277-0553

Email: info@thearc.org

Internet: http://www.thearc.org



National MPS Society, Inc.

PO Box 14686

Durham, NC 27709

Tel: (919)806-0101

Fax: (919)806-2055

Tel: (877)677-1001

Email: info@mpssociety.org

Internet: http://www.mpssociety.org



NIH/National Institute of Diabetes, Digestive & Kidney Diseases

Office of Communications & Public Liaison

Bldg 31, Rm 9A06

31 Center Drive, MSC 2560

Bethesda, MD 20892-2560

Tel: (301)496-3583

Email: NDDIC@info.niddk.nih.gov

Internet: http://www2.niddk.nih.gov/



Society for Mucopolysaccharide Diseases

MPS House

Repton Place

White Lion Road

Amersham

Buckinghamshire, HP7 9LP

United Kingdom

Tel: 08453899901

Fax: 08453899902

Email: mps@mpssociety.co.uk

Internet: http://www.mpssociety.co.uk



Canadian Society for Mucopolysaccharide and Related Diseases, Inc.

PO Box 30034

RPO Parkgate

North Vancouver

British Columbia, V7H 2Y8

Canada

Tel: 6049245130

Fax: 6049245131

Tel: 8006671846

Email: info@mpssociety.ca

Internet: http://www.mpssociety.ca



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Hide & Seek Foundation for Lysosomal Disease Research

6475 East Pacific Coast Highway Suite 466

Long Beach, CA 90803

Tel: (877)621-1122

Fax: (866)215-8850

Email: info@hideandseek.org

Internet: http://www.hideandseek.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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