Campomelic dysplasia

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Campomelic dysplasia

Definition

Campomelic dysplasia is a rare, often lethal, genetic condition characterized by multiple abnormalities including short limbs, bowed legs, distinctive facial features, and a narrow chest. It is also often associated with abnormal development of the sex (reproductive) organs in males.

Description

Campomelic dysplasia is also known as campomelic syndrome, campomelic dwarfism, CMD1, and CMPD1. This condition affects the bones and cartilage of the body, causing significantly short arms and legs, bowing of the legs, small chest size, and other skeletal (bony) and non-skeletal problems. Some genetic males with campomelic dysplasia have female sex organs. Death often results in the newborn period due to breathing problems related to the small chest size. Campomelic dysplasia is caused by an alteration (mutation) in a gene called SOX9. It usually occurs randomly in a family.

Genetic profile

Campomelic dysplasia is caused by an alteration in the SOX9 gene, which plays a role in bone formation and testes development. Genes are units of hereditary material found on chromosomes , which are passed from a parent to a child through the egg and sperm. The information contained in genes is responsible for the development of all the cells and tissues of the body.

The SOX9 gene is located on chromosome 17 (one of the 22 non-sex chromosomes) and it plays a role in both bone formation and testes development. The testes are responsible for producing male hormones. Every developing baby in the womb (fetus), whether genetically male (XY) or female (XX), starts life with the capacity to develop either male or female sex organs. After a few weeks, in an XY fetus, the genitals develop into male genitals if male hormones are present. In the absence of male hormones, a female body type with female genitals results.

In individuals with campomelic dysplasia, the SOX9 gene is altered such that it does not work properly. This causes the testes to form improperly and the male hormones are not produced; thus, individuals who are genetically male (XY) can develop as normal females. This is known as sex-reversal and occurs in about 66% of genetic males with campomelic dysplasia. Since SOX9 is also important for proper bone formation, the bones of the body are also affected causing short stature, bowed legs, and other problems.

There are usually two normal copies of the SOX9 gene: one copy of the gene is inherited from the mother and one copy is inherited from the father. Campomelic dysplasia is inherited as a dominant condition. In dominant conditions, a person only needs one altered gene copy to develop the condition. The alteration in the SOX9 gene that causes campomelic dysplasia is usually random. This means that some unknown event has caused the SOX9 gene (which functions normally in the parent) to become altered in either the sperm of the father or the egg of the mother. When this altered sperm or egg is fertilized, the child that results has campomelic dysplasia. The chance for parents of a child with campomelic dysplasia to have a second child with the same condition is slightly higher than it would be for another couple who has not had a child with this condition. A person who has campomelic dysplasia can pass on their altered SOX9 gene to his or her future children; however, there have not been any reports of individuals with campomelic dysplasia having children.

Demographics

Campomelic dysplasia is a rare condition that affects males and females of all ethnic groups. It is estimated that approximately one in 10,000 newborns are affected with this condition.

Signs and symptoms

Campomelic dysplasia can affect the body in several ways. Campomelic means "curved limb" and refers to the fact that individuals with campomelic dysplasia typically have curved or bowed legs. Usually there is a dimple in the leg just below the knee. The condition causes significantly short stature, which is evident from birth.

Other features include very small shoulder blades; a very small chest; a curved and twisted spine (kyphoscoliosis); feet that are often turned inwards (clubfeet); dislocated hips; short fingers and toes; and often there are 11 pairs of ribs instead of the usual 12. In some individuals, the pelvic bones and the bones of the spine can also be affected.

A large head size and distinctive facial features such as a high forehead; a flat, small face; small chin; low set ears; and widely spaced eyes are also common. Some individuals have an incomplete closure of the roof of the mouth (cleft palate). Breathing problems are common and are often the cause of death in newborns. The breathing problems usually result from the small chest size, small lungs, and narrow airway passages. Those who survive into early infancy frequently have feeding problems and difficulty breathing.

Individuals with campomelic dysplasia may also have heart defects and hearing loss. Some females with the condition have a Y chromosome. Females with campomelic dysplasia who have a Y chromosome are genetically male; however, their sex organs are female and thus they should be treated as normal females. The intellect of individuals with campomelic dysplasia is usually normal although there have been reports of some individuals who are mentally delayed.

Diagnosis

The diagnosis of campomelic dysplasia is based on the presence of certain clinical features. Some of the bony abnormalities are more obvious on x ray. The features that suggest a diagnosis of campomelic dysplasia include significantly short stature present from birth, small shoulder blades, 11 pairs of ribs instead of 12, small chest size, bowed legs, and a dimple on the leg below the knee.

The diagnosis of campomelic dysplasia can be confirmed through genetic testing which requires a blood sample from the affected individual. The genetic test involves identifying the specific alteration in the SOX9 gene. Parents of an affected child may seek testing for campomelic dysplasia in future pregnancies. This can be performed on the developing baby before birth through amniocentesis or chorionic villus sampling if an alteration in the SOX9 gene is identified in the previously affected individual. Prenatal testing should only be considered after the gene alteration has been confirmed in the affected individual and the couple has been counseled regarding the risks of recurrence.

Treatment and management

Campomelic dysplasia is associated with a significant risk for death in the newborn period due to the small chest and small lungs. There is no effective treatment to expand the size of the chest. Those who survive into early infancy have feeding problems and often have difficulty breathing. An occupational therapist may be able to assist with the feeding issues. Breathing problems may necessitate that the child be placed on oxygen.

Some individuals with campomelic dysplasia have significant twisting and bending of their spine (kyphoscoliosis) which can interfere with breathing. A bone specialist (orthopedist) should be consulted for advice on potential treatments such as bracing or surgery. An orthopedist should also be consulted regarding the other bony problems such as clubfoot and bowed legs. Individuals with campomelic dysplasia should also have their hearing assessed and their heart examined because of the increased risk for hearing loss and heart defects, respectively.

In females with campomelic dysplasia who have a Y chromosome, the gonads (the organs that will later become either testes or ovaries during fetal development) do not develop properly into ovaries. It is generally recommended that the gonads be surgically removed because there is an increased chance for tumors to occur in the gonads when they do not develop properly.

Very few individuals with campomelic dysplasia live beyond the newborn period but most who do are of normal intelligence. During the school years, it may be necessary to make some changes (such as providing the individual with a step-stool in the bathroom) to foster independence. For some, meeting other individuals of short stature may be beneficial. Groups such as the Little People of America (LPA) serve as a source of information and offer opportunities to meet other people facing similar challenges. Individuals with campomelic dysplasia and their families may benefit from genetic counseling , which can provide them with further information on the condition itself and recurrence risks for future pregnancies.

Prognosis

Campomelic dysplasia is associated with a significant risk for death in the newborn period. Most newborns die during the first few hours after birth from breathing problems due to the small chest size and small, underdeveloped lungs. A few individuals with campomelic dysplasia have lived to be adults.

Resources

ORGANIZATIONS

Greenberg Center for Skeletal Dysplasias. 600 North Wolfe St., Blalock 1012C, Baltimore, MD 21287-4922. (410) 614-0977. <http://www.med.jhu.edu/Greenberg.Center/Greenbrg.htm>.

Johns Hopkins University—McKusick Nathans Institute of Genetic Medicine 600 North Wolfe St., Blalock 1008, Baltimore, MD 21287-4922. (410) 955-3071.

Little People of America, Inc. National Headquarters, PO Box 745, Lubbock, TX 79408. (806) 737-8186 or (888) LPA-2001. [email protected]. <http://www.lpaonline.org>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.