Dyschondrosteosis

Definition

Dyschondrosteosis (DCO) is a genetic form of dwarfism characterized by short forearms, short lower legs, normal-sized torso, normal-sized head, and a wrist and arm bone abnormality called Madelung deformity.

Description

Dyschondrosteosis (DCO) was first described by Leri and Weill in 1929. Leri and Weill described patients with dwarfism characterized by short lower legs, normal-sized torso, and a specific wrist and arm bone abnormality called Madelung's deformity. Other names for DCO include Leri-Weill dyschondrosteosis (LWD), Leri-Weill syndrome (LWS), Leri-Weill disease, Mesomelic dwarfism-Madelung deformity, Lamy-Bienefeld syndrome, Langer's syndrome, Langer's mesomelic dwarfism, and Langer's mesomelic dysplasia .

Genetic profile

Dyschondrosteosis (DCO) is a pseudoautosomal dominant condition caused by a change or mutation in one of two genes called SHOX and SHOY. The SHOX gene is located on the short arm of the X chromosome in the pseudoautosomal region (Xpter-p22.32). SHOY is located on the Y chromosome in the pseudoautosomal region (Ypter-p11.2). Chromosomes are the structures found in all cells that contain genes. In each cell, there are 46 chromosomes, which come in 23 pairs. One member of each pair comes from the mother, and the other from the father. The first 22 pairs are called autosomes, and are the same in males and females. The last pair of chromosomes is the sex chromosomes, X and Y. Females have two X chromosomes and males have one X chromosome and one Y chromosome. On the sex chromosomes, there are regions that contain the same genes. These regions are called the pseudoautosomal region because the genes in those regions behave as if they were on an autosomal chromosome and are the same in males and females. In 2004, it was found that 70% of families affected by DCO have a mutation in the SHOX gene. The remaining families have a mutation in the SHOY gene, or possibly another gene related to the SHOX and SHOY genes that leads to problems in bone development.

When DCO is caused by a mutated SHOX or SHOY gene, it is inherited through the family in an pseudoautosomal dominant pattern. In a pseudoautosomal dominant condition, only one nonworking copy of the gene for a particular condition is necessary for a person to experience symptoms of the condition. If a parent has a pseudoautosomal dominant condition, there is a 50% chance for each child to have the same or similar condition. DCO can also appear in an individual for the first time, and not be found in the affected individual's parents. An individual who is the first member of the family to be affected by DCO passes DCO to their children in a pseudoautosomal dominant pattern of inheritance . Accordingly, the individual who has de novo (new) DCO has the same 50% chance to have affected children.

Individuals inheriting the same nonworking gene in the same family can have very different symptoms. For example, some family members affected by DCO may be affected by proportional dwarfism with no visible arm bone deformity, while other family member may have very short (mesomelic) arms and legs and severe Made-lung deformity. The difference in physical findings within the same family is known as variable penetrance, or intrafamilial variability.

Studies in 1998 and 1999 suggested that another form of severe dwarfism, called Langer mesomelic dysplasia, is the result of inheriting two copies of the mutated gene that causes DCO. Langer mesomelic dysplasia is characterized by severe short stature with under-developed or missing arm bones.

Demographics

Dyschondrosteosis (DCO) is a rare genetic condition. The ethnic origins of individuals affected by DCO are varied, and DCO is not more common in any specific ethnicity. There are more females than males affected by DCO, and females affected by DCO appear to be more severely affected than males.

Signs and symptoms

Most individuals affected by Dyschrondrosteosis have short stature, short lower legs and forearms (mesomelia), normal head size, normal torso size, and a specific form of arm bone abnormality called Made-lung deformity. Madelung deformity occurs when one of the bones of the forearms (the radius) is short and bends toward the shortened and partially dislocated and bent ulna (subluxation), which causes the wrist to be shifted toward the thumb. Affected individuals may also exhibit abnormalities of the large bone of the upper arm (humerus), abnormal bony growths projecting outward from the surface of the shin bones (exostoses of the tibia), unusually short, broad bones in the fingers and toes, and abnormalities of the hipbones. One study in 2000 found that some males have overdeveloped muscles (or muscular hypertrophy). There is also some evidence that conductive hearing loss may be found as a symptom in some individuals. Depending on the individual, DCO can result in severe to very mild symptoms (variable expression). Females affected by DCO tend to have more severe symptoms, including a more frequent occurrence of Madelung deformity.

Some individuals affected by DCO can also be affected by other symptoms not usually considered part of the DCO features. These features, such as mental retardation, Hodgkin's lymphoma, kidney disease, and skin disorders, are believed to be caused by errors in genes close to the mutated SHOX or SHOY gene. In 1995, based on a finding of two sisters with dyschondrosteosis who both developed Hodgkin's lymphoma in late adolescence, it was suggested that a gene that increased the risk to develop Hodgkin's lymphoma may be located very near to the SHOX and SHOY genes. Individuals affected by Hodgkin's lymphoma, or other unusual symptoms, and DCO are most likely affected by an Xp22.3 contiguous gene syndrome. The name refers to a syndrome caused by the deletion or incorrect working of several genes found side-by-side on the X chromosome.

Diagnosis

Diagnosis of dyschondrosteosis is usually made from physical examination by a medical geneticist and x rays of the legs and arms. The characteristic Madelung deformity of the arms is generally not yet present in children through physical exam, but the first signs of the Madelung deformity, like forearm bone bowing, can be identified by x rays between children aged 2–5 years. The condition's characteristic bone abnormalities become more pronounced during adolescence. Clinical genetic testing for dyschondrosteosis is now available to examine portions of the SHOX or SHOY genes to look for a mutation that would cause the gene not to work correctly. Although clinical testing is available, testing cannot identify all mutations causing DCO. Physical exam and x rays may diagnosis an individual without an identifiable mutation SHOX or SHOY. In families in which a mutation is identified, prenatal diagnosis through amniocentesis is available.

Treatment and management

Dyschondrosteosis (DCO) is a genetic disorder and does not have a specific therapy that removes, cures, or fixes all signs of the condition. Treatment and management of DCO focuses on treatment of specific symptoms of the disorder. Some progress in increasing height has been made by growth hormone (GH) supplementation in affected children. However, hormone supplementation causes disproportionate growth, leading to longer arms and trunk and shorter legs. The Madelung deformity found in many individuals with DCO can be treated surgically by addressing the deforming bone ligaments, correcting the abnormal position of the lower arm bones, and equalizing the length of the arm's radius and ulna bones. Operative treatment for the Madelung deformity is indicated for pain relief and appearance of the arm and wrist, but may not greatly improve the wrists' range of motion. Individuals with conductive hearing loss may wish to consider surgery or hearing aids to improve hearing.

Prognosis

The symptoms of individuals affected by DCO can be severe or mild, and prognosis depends on the severity of the symptoms. Severe Madelung deformity may cause pain in adolescence that is most often relieved through surgery. Individuals affected by DCO are of short stature and may need adjustments in their living space to optimize their living conditions. Individuals affected by DCO have an excellent prognosis.

Resources

BOOKS

Rieser, Patricia, and Heino F. L. Mayer-Bahlburg. Short and OK: A Guide for Parents of Short Children. Falls Church, VA: Human Growth Foundation, 1997.

PERIODICALS

Binder, G., et al. "SHOX Haploinsufficiency and Leri-Weill Dyschondrosteosis: Prevalence and Growth Failure in Relation to Mutation, Sex, and Degree of Wrist Deformity." J Clin Endocrinol Metab. 89, no. 9 (September 2004): 4403–08.

ORGANIZATIONS

Human Growth Foundation. 997 Glen Cove Road, Glen Head, NY 11545. (516) 671-4041 or (800) 451-6434. E-mail: [email protected]. (April 9, 2005.) <http://www.hgfound.org>.

Little People of America, Inc. P.O. Box 65030Lubbock, TX 79464-5030. (888) 572-2001. E-mail: [email protected]. (April 9, 2005.) <http://www.lpaonline.org>.

MAGIC Foundation for Children's Growth. 6645 West North Avenue, Oak Park, IL 60302. (708) 383-0808 or (800) 362-4423. E-mail: [email protected]. (April 9, 2005.) <http://www.magicfoundation.org>.

WEB SITES

On-line Mendelian Inheritance in Man (OMIM). (April 9, 2005.) <http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=158300>.

Support group for people with dyschondrosteosis (DCS)and/or Madelung wrist deformity (MWD). (April 9, 2005.) <http://www.divdev.fsnet.co.uk/dysch.htm>.

Dawn Jacob Laney