Pseudoachondroplasia (PSACH) is a short-limbed dwarfing condition characterized by disproportionate short stature, joint laxity, attractive face and early onset osteoarthritis. Joint laxity is marked in the fingers, wrists and elbows and knees. Joint pain is common at all ages with osteoarthritis occurring at an early age and affecting all the joints. Abnormal curvature of the spine (scoliosis) is an occasional complication. Intelligence is normal. 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. Also, although previously considered to be composed of at least four different forms, differentiated by severity and inheritance pattern, it has now considered a single, distinct disorder caused by mutations in the COMP gene.
Pseudoachondroplasia is a highly variable disorder. The specific symptoms and severity vary greatly, even among members of the same family (Unger, 2001). Affected individuals may not have all of the symptoms discussed below.
Infants with pseudoachondroplasia are of normal length and have normal facial features at birth. The initial signs of the disorder occur around the age of 2 or 3 years. Affected infants may have a ‘waddling’ manner of walking (abnormal gait) that occurs because of underlying skeletal abnormalities involving the hips. In addition, around the age of two, linear growth rate slows, eventually falling approximately two years behind the standard growth curve. Short stature becomes more apparent with age. The face is angular and extremely attractive. Final adult often ranges between 3.8 feet (116 cm) in women to 3.9 feet for men (120 cm).
Pseudoachondroplasia is classified as a form of short-limbed dwarfism, in which the arms and legs are abnormally short in comparison to the body. Hands and feet appear short and wide and the fingers may be short and stubby. Abnormal looseness or instability (laxity) of certain joints, predominantly those in the hands, may also occur. Affected joints may exhibit hypermobility, in which the joints are able to move beyond the normal range of movement. Hypermobility can affect the hands, knees, and ankles. Conversely, the elbows may be limited in range of motion (incomplete elbow extension).
Delayed development of the epiphyses or ‘heads’ of the long bones of the legs (femurs) may result in malformation of the hips (hip dysplasia). Affected individuals may also have bowed legs (genu varum) or ‘knock knees’ (genu valgum), a condition in which the legs bend inward so that when a person is standing the knees will touch even if the ankles and feet are not. Sometimes bowing can occur in one leg and a knock knee deformity in the other.
Spinal abnormalities are common and include abnormal curvature of the spine. Affected individuals may exhibit exaggerated lumbar lordosis, which is defined as abnormal inward curvature of the lower portion of the spine; kyphosis, which is defined as abnormal front-to-back (or outward) curvature of the spine so that the spine is abnormally rounded at the top; and mild to moderate scoliosis, which is defined as abnormal sideways curvature of the spine.
Affected individuals also experience early onset of inflammation, pain and stiffness in affected joints (early-onset arthritis) that can develop into chronic joint pain (arthralgia). The hips, upper arms and spine are particularly affected by early-onset arthritis. Degenerative joint disease is progressive and ultimately may require surgery such as hip replacement surgery.
Underdevelopment (hypoplasia) of the small, tooth-like projection (odontoid) at the top of the spine can occur. As a result, in rare cases, instability in the neck region may develop (cervical instability), which can increase the risk of spinal injury (cervical myelopathy). This complication may require surgery.
Intelligence is unaffected. There may be delays in attaining certain developmental milestones such as crawling and walking because of the underlying skeletal abnormalities.
Pseudoachondroplasia is caused by a mutation in the COMP gene (Hecht, 1995). It is the only gene known to cause the disorder. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene 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, which are the cells that specify linear growth.
Approximately 70% of cases occur as a new (sporadic or de novo) mutation, which means that in nearly all cases the gene mutation has 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 healthy parent. However, once the mutation has occurred, it would then be passed on through dominant inheritance (where a trait is transmitted from either an affected mother or father to their child).
Genetic disorders are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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 child.
Investigators have determined that the COMP gene is located on the short arm (p) of chromosome 19 (19p13.11). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further subdivided into many bands that are numbered.
Some cases of pseudoachondroplasia occur because of germline mosaicism. In germline mosaicism, some of a parent’s reproductive cells (germ cells) carry the COMP gene mutation, while other germ cells contain normal COMP genes. The other cells in the parent’s body do not have the mutation, so these parents are unaffected. As a result, one or more of the parent’s children may inherit the germ cell gene COMP mutation, leading to the development of pseudoachondroplasia, while the parent does not have this disorder because the mutation is not present in sufficient number of cells. Germline mosaicism may be suspected when apparently unaffected parents have more than one child with the same autosomal dominant genetic condition. 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 is available and should be discussed directly with a genetic specialist.
Pseudoachondroplasia affects males and females in equal numbers. The exact prevalence of the disorder is unknown, but estimated to occur in 1 in 30,000-60,000 people in the general population.
A diagnosis of pseudoachondroplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The diagnosis is rarely made at birth because growth deficiency is not yet apparent and other distinctive features develop over time.
Clinical Testing and Workup
A complete set of x-rays (radiographs) can help to establish a diagnosis by revealing abnormal 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.
Molecular genetic testing can confirm a diagnosis of pseudoachondroplasia. Molecular genetic testing can detect mutations in the COMP gene known to cause the disorder, but it is only available as a diagnostic service at specialized laboratories.
Prenatal diagnosis in pregnancies with an increased risk of pseudoachondroplasia is possible by chorionic villus sampling or amniocentesis if the specific gene mutation has been identified in a family member.
Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists in diagnosing and treating skeletal disorders (orthopedists and orthopedic surgeons), neurologists, rheumatologists, physical therapists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well. Pseudoachondroplasia while causing physical issues does not usually reduce life expectancy. Intelligence is unaffected and most individuals raise families and lead productive, active and full lives.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of certain 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 cases, 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 cases, 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 shorten, lengthen or change the alignment, is common in children with 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 or the implanting of a rod to stabilize the spine. This rod, known as a ‘growing rod’, can treat a spinal deformity, but allows for the continued and controlled growth of the spine.
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