NORD gratefully acknowledges Jacqueline T. Hecht, PhD, Professor and Division Head, Pediatric Research Center and Vice Chair for Research, Leah L. Lewis Distinguished Chair, Department of Pediatrics, McGovern Medical School, UTHealth, Associate Dean for Research, UTHealth School of Dentistry, for assistance in the preparation of this report.
Pseudoachondroplasia (PSACH) is a short-limbed dwarfing condition characterized by disproportionate short stature, attractive face and early onset osteoarthritis; intelligence is normal. There is marked laxity in the fingers, wrists, elbows and knees. Joint pain is common at all ages; osteoarthritis occurs in early adulthood and affects all the joints. Scoliosis or abnormal curvature of the spine is an occasional complication. Pseudoachondroplasia is caused by a mutation in the cartilage oligomeric matrix protein or COMP gene and is transmitted in an autosomal dominant pattern. Thirty percent of cases are familial with an affected parent transmitting the condition, while 70% occur as a random, new (de novo) mutation in COMP with no previous family history.
Pseudoachondroplasia was first described in 1959 by Drs. Maroteaux and Lamy and was originally believed to be a type of spondyloepiphyseal dysplasia. While four different forms were previously differentiated based on severity and inheritance pattern, pseudoachondroplasia is now considered a single, distinct disorder caused by mutations in the COMP gene.
Pseudoachondroplasia shows variable expression with the severity varying within and between families. Infants with pseudoachondroplasia have normal birth parameters and cannot be distinguished from unaffected newborns since birth length and weight are normal. Generally, the first sign is diminished linear growth starting between 9 to 12 months with length and eventually height falling approximately two years behind the standard growth curve. Disproportionate short stature becomes more apparent with age. Affected children usually begin to walk between 12- 18 months but the gait is abnormal and described as ‘waddling’ reflecting underlying skeletal abnormalities involving the hips. The face is attractive and has been described as angular. Disproportionate shortening of the arms and legs become apparent between 3-5 years of age. The hands and feet are short with the fingers and toes showing dramatic shortening and laxity. All the joints exhibit extreme laxity except the elbows which may have limited extension. The joint laxity at the knees contributes to the lower extremity deformities that include bowing (genu varum) or knock knee (genu valgum) deformities. Sometimes bowing can occur in one leg and a knock knee deformity in the other. Surgical correction is generally required but should be delayed to get maximum sustainable correction.
Spinal abnormalities are common and include: 1) scoliosis or S-shaped spinal curve, 2) exaggerated lumbar lordosis, which is an abnormal inward curvature of the lower portion of the spine and 3) kyphosis, which is abnormal front-to-back (or outward) curvature of the spine so that the spine is abnormally rounded at the top. Underdevelopment (hypoplasia) of the small, tooth-like projection (odontoid) at the top of the spine occurs infrequently. Odontoid hypoplasia causes instability in the neck region (cervical instability), which increases the risk of spinal injury (cervical myelopathy). This complication often requires surgical fusion of the upper spine.
Pain, a common and universal complaint, starts in early childhood and is exacerbated by exercise. Activities that stress the joints should be avoided. This includes all contacts sports and trampoline. Early joint pain may reflect an inflammatory process related to the underlying chondrocyte pathology. Osteoarthritis in early adulthood is a universal finding usually developing into chronic joint pain (arthralgia). The hips, ankles, shoulder, elbows and wrists are particularly affected. Degenerative joint disease is progressive and ultimately may require surgery starting with hip replacement followed by other joint replacements. Symptomatic treatment with anti-inflammatory medications is used for pain management with varying degrees of success.
Final adult height on average is 3’8” (116 cm) in women and 3’9” for men (120 cm) but this can vary as some individuals may attain a height of 4’10”. Intelligence and life expectancy are unaffected and most individuals raise families and lead productive, active and full lives.
Mutations in the COMP gene are known to cause pseudoachondroplasia. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a gene mutation occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. COMP mutations specifically affect chondrocytes in the growth centers, which are the cells that specify for linear growth.
Approximately 70% of cases occur as a new (sporadic or de novo) mutation, which means that in the majority of cases, the gene mutation occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. In that case, the disorder is usually not inherited from or “carried” by a unaffected parent. However, once the mutation has occurred, it is transmitted by dominant inheritance from either an affected mother or father to their child. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disorder. 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 child.
A few families showed recurrence in what appeared to be autosomal recessive inheritance. Mutational analysis revealed that these cases were the result of parental germline mosaicism for a COMP mutation. As a result, one or more of the parent’s children may inherit the germ cell gene COMP mutation, leading to pseudoachondroplasia, while the parent does not have this disorder because the mutation is not present in sufficient number of body cells. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation versus the percentage that do not. There is no test for germline mutation prior to pregnancy. Testing during a pregnancy for familial cases with a known mutation is available and should be discussed with a genetic specialist.
The exact birth prevalence pf pseudoachondroplasia is unknown, but estimated to be 1 in 50,000-100,000. Males and females are equally affected.
The diagnosis of pseudoachondroplasia is based upon identification of characteristic clinical and radiographic findings, detailed patient history, and mutational testing. The diagnosis is rarely made at birth because short stature is not present. The distinctive features develop over time, and this sets it apart from other short stature conditions.
Clinical Testing and Workup
A complete set of x-rays (radiographs) can help to establish a diagnosis by revealing abnormal growth centers (epiphyses) and other characteristic skeletal findings. The diagnosis is made clinically and by reviewing the radiographs. More advanced imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans can be used later to assess skeletal health, particular in advance of surgery to correct skeletal malformations. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.
Genetic counseling helps families understand the genetics and natural history of pseudoachondroplasia as well as providing psychosocial support. Sequencing of the COMP gene confirms the diagnosis and is commercially available. Prenatal diagnosis for pregnancies at increased risk for pseudoachondroplasia is accomplished by chorionic villus sampling or amniocentesis if the COMP gene mutation has been identified in an affected family member.
Treatments are directed toward the specific symptoms as they become apparent and usually require the coordinated efforts of a team of specialists. The team includes geneticist, pediatrician, specialists in treating skeletal disorders (orthopedic surgeons), neurologists, physical and occupational therapists and other healthcare professionals who will systematically and comprehensively plan needed treatments.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of painful symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
Pain medications may be beneficial in treating pain associated with joint disease. Physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), is beneficial.
In some patients, surgery may be necessary to achieve better positioning and to increase the range of motion in certain joints. Surgery may be necessary to treat malformation of the hips and, in some individuals, total hip replacement surgery (total hip arthroplasty) may be necessary. Surgical procedures may be recommended to treat abnormalities of the knees and lower legs. Osteotomy, a surgical procedure in which bone is cut to change the alignment, is common in pseudoachondroplasia to treat improper alignment of bones of the lower legs.
In some children, spinal abnormalities may require surgical intervention. Abnormal curvature of the spine, e.g. scoliosis, usually does not require surgery, but in severe cases, surgery has been effective. More serious spinal problems such as cervical instability may require spinal fusion.
Currently there are no investigational therapies for pseudoachondroplasia.
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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., short stature, skeletal abnormalities, etc.)
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