Related Disorders List

Information on the following diseases can be found in the Related Disorders section of this report:

• Achondroplasia
• Hypophosphatasia
• Osteogenesis Imperfecta
• Nonsyndromal congenital bowing of the legs
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Symptoms

Campomelic syndrome is a rare form of skeletal dysplasia characterized by bowing and an angular shape of the long bones of the legs. Eleven sets of ribs instead of the usual twelve may be present. The pelvis and shoulder blade may be underdeveloped. The skull may be large, long and narrow. The face may appear flat with forward tilting nostrils, high forehead, small chin, and cleft palate. Babies may regurgitate formula through the nose, are susceptible to middle ear infections and frequently experience respiratory distress.

Respiratory distress due to an underdeveloped ribcage is the most serious symptom of campomelic syndrome. The lungs may not have sufficient space to grow properly due to the underdeveloped ribcage.

Other symptoms that may occur in some patients with campomelic syndrome are dislocated hips, clubfoot, underdeveloped lungs, abnormal cervical and thoracic vertebrae,and heart and kidney abnormalities.

Some individuals with campomelic syndrome have sex reversal in which they are chromosomally male but have female genitalia and reproductive system.
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Causes

Campomelic syndrome was once thought to be inherited as an autosomal recessive genetic trait but this is no longer thought to be true. Molecular genetic research has shown that a change (mutation) in a single copy of the SOX9 gene on chromosome 17 or disturbance in the regulation of this gene causes campomelic syndrome. The regulation of the SOX9 gene is sometimes disturbed by a rearrangement of genes on chromosome 17 (translocation). It is now believed that campomelic syndrome is inherited as an autosomal dominant trait. Some families have been reported in which multiple children are affected but both parents are unaffected. This may be due to one parent having a mixture of sperm or egg cells with normal and abnormal SOX9 genes (gonadal mosaicism). As a result, one or more of this parent’s children may inherit the gene mutation and exhibit the disorder even though the parent has no apparent symptoms.

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.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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Affected Populations

Campomelic syndrome is a rare disorder that is thought to affect females twice as often as males. These numbers may not be accurate as some patients with this disorder have associated sex reversal and have been mistakenly identified as the opposite sex. Approximately one hundred cases of this disorder have been reported in the medical literature.

Related Disorders

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

Achondroplasia is a rare musculoskeletal disorder belonging to a group of congenital abnormalities known as the chondrodystrophies. The chondrodystrophies are disorders that affect the manner in which cartilage is converted into bone. Acondroplasia is characterized by short-limbed dwarfism along with curvature of the spine and abnormalities of the skull. (For more information on this disorder, choose "Achondroplasia" as your search term in the Rare Disease Database.)

Hypophosphatasia is a rare genetic metabolic bone disorder characterized by skeletal defects due to failure of bone mineral to be deposited in uncalcified bone and cartilage at the end of the long bones. Infants affected with this form of the disorder often have increased pressure inside the skull which may result in bulging eyes. The bones usually become weak and bent and kidney failure may occur. (For more information on this disorder, choose "Hypophosphatasia" as your search term in the Rare Disease Database.)

Osteogenesis imperfecta is a rare hereditary connective tissue disorder. Symptoms of this disorder may include: frequent fractures of the bones, poor or delayed growth, bowed legs, spinal deformities, and a triangular shaped face. Osteogenesis imperfecta is grouped into syndromes according to the combination and severity of symptoms accompanying the basic bone disorder, and according to the apparent mode of inheritance. (For more information on this disorder, choose "Osteogenesis Imperfecta" as your search term in the Rare Disease Database.)

Non-syndromal congenital bowing of legs is a condition in which the long bones of the legs are bowed but no other abnormalities are present.

Standard Therapies

Diagnosis
Diagnosis is based on clinical examination, x-rays of vertebrae, hips, chest, legs and feet, ultrasound of kidneys and echocardiogram of the heart. DNA analysis of blood can confirm a mutation in the SOX9 gene.

Treatment
Treatment of respiratory problems consists of mechanical or physical breathing assistance such as positive end expiratory pressure (PEEP). Orthopedic medical care including surgery may help alleviate some of the more serious bone deformities. The bowed tibiae usually straighten spontaneously.

It may be appropriate to reassign the sex of a male with female genitalia to be female.

Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

The Titanium Rib Project is underway to implant expandable ribs in children with disorders involving missing, underdeveloped, or otherwise malformed rib cages and/or chest walls. Birth defects, fused ribs, or hypoplastic chests may be improved using the titanium ribs that can be expanded as the child grows. More research is needed to determine the long-term safety and effectiveness of these artificial ribs. People who are interested may have their physicians contact:

Robert Campbell, M.D.
Santa Rosa Children's Hospital
519 West Houston Street
San Antonio, TX 78207
(210) 704-2988

NORD does not promote, endorse, or encourage participation in any specific medical research study. This information is presented to further scientific understanding that could lead to the prevention, treatment, and/or cure of rare disorders. NORD recommends that anyone interested in participating in a clinical research program seek the advice or counsel of his or her own personal physician(s).

Research on birth defects and their causes is ongoing. The National Institutes of Health (NIH) is sponsoring the Human Genome Project which is aimed at mapping every gene in the human body and learning why they sometimes malfunction. It is hoped that this new knowledge will lead to prevention and treatment of genetic disorders in the future.

References

Opitz JM. Campmomelic Syndrome. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:706-7.

McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Entry Number; 114290: Last Edit Date: 10/17/02.

TEXTBOOKS
Jones KL, Ed. Smith’s Recognizable Patterns of Human Malformation, 4th Ed. W.B. Saunders Co. 1988. Pp.296.

Buyse ML, Ed. Birth Defects Encyclopedia. Blackwell Scientific Publications. 1990. Pp. 252-3.

ARTICLES
Houston CS, Opitz JM, Spranger JW, et al. The campomelic syndrome: review, report of 17 cases, and follow-up on the currently 17 year old boy first reported by Martesux et al in 1971. Aam J Med Genet. 1983;15:3-28.

MacPherson RI, et al. Campomelic dysplasia. Pediatr Radiol. 1989;20:90-3.

Foster JW Dominquez-Stelich MA, Guioli S, et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature. 1994;37:525-530.

Mansour S, Hall, CM, Pembrey ME, et al. A clinical and genetic study of campomelic dysplasia. J Med Genet. 1995;32:415-420.

Wunderle VM, Crither R, Hastie N, et al. Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia. Proc Natl Acad Sci USA. 1998;95:10649-10654.

Olney PN, Kean LS, Graham D, et al. Campolmelic syndrome and deletion of SOX9. Am J Med Genet. 1999;84:20-24.