Pseudoachondroplasia is an inherited disorder of bone growth. It is a genetic autosomal dominant disorder which is linked to mutations in the COMP gen located on chromosome 19. It is generally not discovered until 2–3 years of age, since growth is normal at first. Pseudoachondroplasia is usually first detected by a drop of linear growth in contrast to peers, a waddling gait or arising lower limb deformities. Pseudoachondroplasia (also known as PSACH, pseudoachondroplastic dysplasia, and pseudoachondroplastic spondyloepiphyseal dysplasia syndrome) is an osteochondrodysplasia that results in mild to severely short stature due to the inhibition of skeletal growth primarily in the limbs. Though similarities in nomenclature may cause confusion, pseudoachondroplasia should not be confused with achondroplasia, which is a clinically and genetically distinct skeletal dysplasia. Pseudoachondroplasia is caused by a heterozygous mutation in the gene encoding cartilage oligomeric matrix protein (COMP). Mutation in the COMP gene can also cause multiple epiphyseal dysplasia. Despite the radioclinical similarities between pseudoachondroplasia and multiple epiphyseal dysplasia, the latter is less severe.
Signs and symptoms Disproportionate short stature, deformity of the lower limbs, short fingers, and ligamentous laxity give pseudoachondroplasia its distinctive features. The average height of adult males with the condition is around 120 centimeters (3 ft, 11 in), while adult females are typically around 116 cm (3 ft, 9in). Affected individuals are not noticeably short at birth. Patients with pseudoachondroplasia present with gait abnormalities, lower limb deformity, or a delayed growth rate that characteristically appear at age 2–3 years. Disproportionate short stature is characterized by shortening of proximal limb segments (humeri and femora) also called rhizomelic shortening. Other known clinical features include, genu valgum/varum, brachydactyly (short fingers), supple flexion deformity of the hips, knees, hyperlordosis of lumbar spine, rocker bottom feet and broadening of the metaphyseal ends of long bones especially around the wrists, knees and ankles. Patients with pseudoachondroplasia have normal intelligence and craniofacial features (ie, patients are normocephalic) .
Genetics Pseudoachondroplasia is inherited in an autosomal dominant manner, though one case of a very rare autosomal recessive form has been documented. The offspring of affected individuals are at 50% risk of inheriting the mutant allele. Prenatal testing by molecular genetic examination is available if the disease-causing mutation has been identified in an affected family member (Hecht et al. 1995).
Pathophysiology COMP is an extracellular calcium binding protein directly involved in chondrocyte migration and proliferation. It is observed at a high frequency in chondrocytes in developing bone and tendon. In pseudochondroplasia, COMP is not secreted, but instead collects in the chondrocytes, ultimately poisoning and killing them. Though some chondrocytes do manage to survive, growth is significantly reduced, resulting in the characteristically short limbs and seemingly unaffected face and torso of those inflicted with the disorder (OMIM 2008). Mutations in COMP result in a phenotypic spectrum that varies from pseudochondroplasia (at the most extreme end) to multiple epiphyseal dysplasia or MED (a genetically similar, though milder skeletal dysplasia). Studies conducted by Hetch et al. suggest that type IX collagen, a collagen active specifically in the construction of cartilage, plays a key role in pseudoachondroplasia. The researchers found that IX collagen was amassed within the pseudoachondroplasia chondrocytes. This discovery suggests that the pathogenesis of pseudoachondroplasia involves the interactions of the mutant COMP gene products with specific cartilage components, such as type IX collagen, and that it is not solely the result of the effects of mutant molecules on the production and secretion of COMP (OMIM 2008).
Molecular biology The COMP gene is located on chromosome 19p13.1; its precise locus is P49747. COMP contains 19 exons. The cartilage oligomeric matrix protein is 757 aa (OMIM 2008). COMP protein is found in the extracellular matrix, a complex web of proteins and other molecules that form in the spaces between the cells that make up ligaments and tendons. It is also found near chondrocytes (cartilage-forming cells). Chondrocytes play a vital role in osteogenesis (the formation of bone), particularly in the spine, hips, and limbs where osteogenesis begins with the formation of cartilage, which is then calcified and transformed into bone. We do not yet fully understand the normal function of COMP protein, though it is believed to play a part in cellular growth, division and apoptosis (self-destruction) of cells, as well as participating in the regulation of cell movement and attachment (OMIM 2008). Nearly 60 mutations in the COMP gene have been identified in individuals with pseudoachondroplasia. However, the mutation responsible for the most common allele is a deletion of one codon within a very short triplet repeat (GAC), in which the 469th amino acid, an aspartic acid, is deleted (OMIM 2008).
Diagnosis
Exact diagnosis remains widely built on precise history taking, with the characteristic clinical and radiographic skeletal features. Genetic diagnosis is based on DNA sequencing. Because plasma COMP levels are significantly reduced in patients with COMP mutations, such as pseudoachondroplasia, measuring plasma COMP levels has become a reliable means of diagnosing this and pathopysiologically similar disorders.
Skeletal radiography Accurate assessment of plain radiographic findings remains an important contributor to diagnosis of pseudoachondroplasia. It is noteworthy that vertebral radiographic abnormalities tend to resolve over time. Epiphyseal abnormalities tend to run a progressive course. Patients usually suffer early-onset arthritis of hips and knees. Many unique skeletal radiographic abnormalities of patients with pseudoachondroplasia have been reported in the literature.
… excerpt ends here. Continue reading the full article.
