Rhizomelic chondrodysplasia punctata
Rhizomelic chondrodysplasia punctata
Rhizomelic chondrodysplasia punctata is a rare, severe, inherited disease. The main features are limb shortening, bone and cartilage abnormalities visible on x ray, abnormal facial appearance, severe mental retardation, profound psychomotor retardation, and cataracts. Skeletal abnormalities can be seen prenatally. Most affected persons die in infancy. No treatments are available.
Rhizomelic chondrodysplasia punctata (RCDP) is caused by an abnormal protein in a part of the cell called the peroxisome. The inside of the cell contains compartments (called "organelles") that perform specific functions. The peroxisome functions in many metabolic processes, especially those involving lipids (fats) and hydrogen peroxide. Multiple peroxisomes are in almost every human cell. RCDP is one of many peroxisomal disorders, as well as a metabolic disorder.
Three other conditions are also called "chondrodysplasia punctata." These conditions are different from RCDP. They have almost the same name because it describes a feature that is present in all four conditions. However, the causes, features, and patterns of inheritance of the other chondrodysplasia punctata conditions are different from those of RCDP.
Rhizomelic chondrodysplasia punctata is an autosomal recessive condition. This means that it occurs in both males and females, and often affects people who have no family history of the condition. Humans have two copies of every gene , one maternally and one paternally inherited. Autosomal recessive conditions occur when a person has two abnormal copies of the same gene. People who have one abnormal copy and one normal copy of a particular gene are unaffected; they are called "carriers." An affected person has inherited two abnormal RCDP genes, one from each carrier parent. The risk for the carrier parents to have another affected child is then 25% with each pregnancy.
In 1997, the gene that causes RCDP was identified. The gene is called PEX7 and it is on chromosome 6. Fifteen genes involved in the synthesis of peroxisomes have been identified in humans. These genes are called PEX genes, and the proteins they code for are called peroxins. Disorders caused by abnormalities of peroxin proteins are often called "peroxisomal biogenesis" disorders.
The PEX7 gene codes for a peroxisomal component that helps transport other important proteins into the peroxisome. The proteins to be transported contain a signal, called "PTS2" (peroxisome targeting sequence 2) that is recognized by the receptor on the peroxisome. When PEX7 is abnormal, the receptor that usually recognizes and helps transport the PTS2 proteins is abnormal. Thus, the abnormality of this one receptor has a cascade effect on many other proteins.
Rhizomelic chondrodysplasia punctata is quite rare. It occurs in fewer than 1/100,000 births. The incidence of peroxisomal biogenesis disorders is approximately 1/50,000 births; RCDP accounts for fewer than one fifth of these.
Signs and symptoms
"Rhizomelic" refers to shortening of the bones near the center of the body (the bones of the thighs and upper arms more so than the bones of the forearms and lower legs). "Chondro" refers to cartilage and "dysplasia" to abnormal development. "Punctata" refers to specific abnormalities seen on radiological studies such as x ray. The ends of the bones near joints appear to be spotted. The spots represent dense, abnormal cartilage. The spots are also called "punctate calcifications." Other abnormalities include frozen joints (called contractures), abnormal facial features, cataracts, hearing loss, severe mental retardation, and profound psychomotor retardation. People with RCDP may also have other bone abnormalities, small heads, coarse and sparse hair, and dry, red skin.
The proximal shortening of the bones causes short stature, which is apparent before birth. Growth after birth is retarded as well. The rhizomelic shortening is severe, and occurs to the same degree on both sides of the body. The stippling (spotting) of the bones mainly involves the ends of the bones near the hip, knee, elbow, and shoulder. "Severe" mental retardation describes cognitive deficits worse than those of typical Down syndrome . Some researchers have described degeneration of brain tissue after birth. Researchers are not sure of the reason for this; it may be due to toxic effects of excess phytanic acid. Cataracts are symmetrical and occur in both eyes. The abnormal facial features have been called "koala bear facies." Facial features include a broad forehead and a saddle nose.
A subset of people with RCDP do not have some of the typical symptoms, such as shortening of proximal bones and/or severe mental retardation. The diagnosis in these individuals was confirmed to be RCDP. Therefore, the spectrum of features in RCDP is variable; some people are much more mildly affected than is typical. These differences in severity appear to be associated with different mutations in the PEX7 gene.
Although suspicion of RCDP is raised by the physical and radiographic features, the diagnosis is made by laboratory testing. People with RCDP have very specific biochemical abnormalities, i.e. abnormal levels of particular substances in bodily fluids. These abnormalities are due to the underlying defect in the peroxisome. The specific abnormalities are: 1) deficient plasmalogen synthesis with very low plasmalogen levels in red blood cells, 2) inability to process (oxidize) phytanic acid leading to elevated levels of phytanic acid in the blood, and 3) an unprocessed form of peroxisomal thiolase. Phytanic acid levels are normal at birth and increase to at least ten times normal by one year of age. Some experts recommend that confimatory studies be performed on cells obtained by skin biopsy.
The biochemical studies diagnostic of RCDP can be performed prenatally on cells obtained by chorionic villus sampling (CVS) or amniocentesis . CVS is usually performed at 10–12 weeks of pregnancy and amniocentesis is usually performed after 15 weeks of pregnancy. RCPD may be suspected in a fetus based on ultrasound findings.
Each feature of RCDP is seen in many other conditions, for example rhizomelic limb shortening is seen in other conditions that cause dwarfism. Chondrodysplasia punctata is seen in many inherited conditions but can also be caused by prenatal exposure to the anticoagulant drug, Warfarin. Doctors who specialize in diagnosing rare genetic conditions use subtle differences between the symptoms of these conditions to narrow their search for the suspected diagnosis. Many peroxisomal disorders have abnormal very long chain fatty acids (VLCFAs); VLCFA levels are normal in RCDP.
Two rare conditions cannot be distinguished from RCDP by physical symptoms. These conditions involve specific abnormalities of plasmalogen synthesis. RCDP is caused by abnormal peroxisome synthesis, which leads to multiple biochemical abnormalities including deficient plasmalogen synthesis. In contrast, these two conditions each affect only one protein. The proteins affected are dihydroxyacetone phosphate acyltransferase (DHAPAT) and alkyl dihydroxyacetone phosphate synthase. People with deficiencies in these two proteins have normal thiolase and normal phytanic acid levels.
RCDP is the only condition known to be caused by abnormal PEX7 gene. Genetic testing is another method to confirm the diagnosis. A doctor who specializes in medical genetics can determine whether this testing is available clinically.
Treatment and management
The only treatments for RCDP are supportive therapies to treat symptoms. People with RCDP, especially those who are less severely affected, benefit from symptomatic support of various specialties such as ophthalmology and physical therapy. Dietary restrictions or supplements have shown promise in the treatment of some peroxisomal disorders. The enormous obstacle in the severe conditions is that many of the abnormalities develop before birth and are irreversible. The multiple biochemical abnormalities of RCDP also complicate treatment efforts. Some researchers have tried to improve the function of the deficient metabolic process. This treatment, if it works, will probably benefit mildly affected patients more than the typically severely affected person with RCDP.
The underlying cause of the severe mental retardation is not well understood. Some abnormalities of nerve tissue have been described. In many peroxisomal disorders similar to RCDP the nerve tissue migrates abnormally before birth. This abnormal migration is not present in RCDP. It appears that in RCDP the nerve tissue does not differentiate properly once it has migrated to the correct location in the body.
The prognosis for the typical individual with RCDP, who is severely affected, is death in infancy. Most affected infants die in the first two years of life. However, exceptions have reported in the medical literature. Individuals who lived past the age of 10 years have been reported. For atypical, mildly affected patients, prognosis is variable.
Scientists' understanding of peroxisomal disorders, and of the peroxisome itself, increased enormously in the last five years. Developing effective treatments of RCDP is a great challenge. But having a better understanding of the underlying cause is the first step. This has also increased awareness of RCDP, probably leading to more accurate diagnoses and higher clinical suspicion. A correct diagnosis is critical in providing accurate recurrence, prognosis, and prenatal diagnosis information.
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International Patient Advocacy Association. 800 Bellevue Way NE, Suite 400, Bellvue, WA 98004. (425) 462-4037 or (310) 229-5750 or (800) 944-7823 x4037. [email protected] <http://www.vanpelt-ipaa.com>.
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>.
Rhizomelic Chondrodysplasia Punctata (RCP) Family Support Group. 137 25th Ave., Monroe, WI 53566.
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Michelle Queneau Bosworth, MS, CGC