Pseudoachondroplasia

A number sign (#) is used with this entry because of evidence that pseudoachondroplasia (PSACH) is caused by heterozygous mutation in the gene encoding cartilage oligomeric matrix protein (COMP; 600310) on chromosome 19p13.

Multiple epiphyseal dysplasia-1 (EDM1; 132400) is an allelic disorder with a similar, but milder, phenotype.

Description

Pseudoachondroplasia is an autosomal dominant osteochondrodysplasia characterized by disproportionate short stature, deformity of the lower limbs, brachydactyly, loose joints, and ligamentous laxity. Vertebral anomalies, present in childhood, usually resolve with age, but osteoarthritis is progressive and severe. PSACH and EDM1 comprise a clinical spectrum with phenotypic overlap between mild forms of PSACH and EDM1 (summary by Briggs and Chapman, 2002).

Clinical Features

Maroteaux and Lamy (1959) first clearly delineated this disorder under the designation 'pseudoachondroplastic spondyloepiphyseal dysplasia.'

Hall and Dorst (1969) reported a family with a severe form of pseudoachondroplasia with apparent autosomal recessive inheritance. A brother and sister had marked shortening of the limbs, but the parents were reportedly unaffected. However, the brother subsequently fathered a child who had a mild form of pseudoachondroplasia, suggesting autosomal dominant inheritance. Hall et al. (1987) concluded that the 1 of the parents of the originally affected brother and sister had gonadal mosaicism. Furthermore, Hall et al. (1987) noted that the father he had a congenital anomaly of one elbow, which showed incomplete extension, and likely reflected carrier status.

Pseudoachondroplasia is one of the most frequent skeletal dysplasias (Kopits et al., 1974). Affected individuals appear normal at birth, and growth retardation is seldom recognized until the second year of life or later, at which time the body proportions resemble those of persons with achondroplasia (ACH; 100800). However, unlike achondroplasia, the head circumference and facies are normal. Deformities of the lower limbs range from genu varum to genu valgum to a 'wind-swept' deformity; ligamentous laxity contributes to the leg deformities. The fingers are short and do not show the trident configuration typical of achondroplasia. There is incomplete extension at the elbows and ulnar deviation of the wrists. Radiologically, all tubular bones are short with widened metaphyses and fragmentation and irregularities of the developing epiphyses. The epiphyses of the hips and phalanges are small. In childhood, platyspondyly is characteristic, with anterior tonguing due to delayed ossification of the annular epiphyses. However, the vertebrae become more normal in appearance after puberty. Kopits et al. (1974) described a 12-year-old patient with pseudoachondroplasia who had chronic compression myelopathy of the cervical cord due to habitual atlantoaxial dislocation.

Khungar et al. (1993) reported a 7-year-old girl with PSACH who was originally diagnosed with vitamin-D dependent rickets (see, e.g., 264700). She was well until 1 year of age, when mild bowing of the legs became apparent. At age 3.5 years, she had short stature, short limbs, normal head and facies, waddling gait, genu varum, lumbar lordosis, and fixed flexion deformity of the elbows. Radiographs showed generalized epiphyseal and metaphyseal irregularities with metaphyseal flaring and spurring, as well as anterior and central beaking and flattening of the vertebral bodies. There was also delayed maturation of the pelvic bones.

Rimoin et al. (1994) reported a large family in which multiple members spanning 5 generations had a chondrodysplasia inherited in an autosomal dominant pattern. Affected individuals appeared to be of normal size and appearance at birth. Onset appeared within the first years of life, with waddling gait, short limbs, and short stature. Other features included joint pain in early childhood and severe progressive osteoarthropathy. Many affected individuals required total hip replacement in the third and fourth decades. The radiographic presentation resembled pseudoachondroplasia in childhood and multiple epiphyseal dysplasia in adults, suggesting a spectrum of disease within the same family. Small epiphyses and hypoplastic acetabulum were apparent by age 2 years. Affected adults had short stature, brachydactyly, and epiphyseal and metaphyseal abnormalities. Vertebral anomalies were worse in childhood, but appeared to resolve over time. Ultrastructural examination of resting cartilage showed markedly dilated endoplasmic reticulum in chondrocytes. Genetic analysis excluded mutations in 7 cartilage-related genes.

To delineate the natural history of PSACH at all ages, McKeand et al. (1996) collected questionnaire information on 79 affected individuals. The phenotype was not distinct or more severe in familial cases as compared with new mutation cases. In addition, there were no differences in the number of orthopedic complications, operations, or number of offspring between these 2 groups. Less than half of affected adults reported having total hip replacement surgery. Extraskeletal complications were generally uncommon. Premature osteoarthritis was a major health problem.

Delot et al. (1999) reported a girl with typical PSACH diagnosed at 3 years of age. She presented with rhizomelic shortening of her upper and lower extremities, marked joint laxity of the hands, knees, and ankles, a slightly decreased range of motion at the elbows, and height well below the 5th percentile. She had a waddling gait, experienced marked joint pain throughout childhood, and underwent numerous osteotomies for both genu varum and genu valgum deformities. Radiologic findings were typical. Electron microscopy of cartilage showed the presence of lamellar inclusions of the rough endoplasmic reticulum. These inclusions were also present in tendon tissue and were thought to be related to the loose jointedness.

Double-Heterozygosity Phenotypes

Langer et al. (1993) presented a 7.5-year-old girl with achondroplasia and pseudoachondroplasia. Her mother had achondroplasia and her father had pseudoachondroplasia. Langer et al. (1993) outlined the radiographic manifestations of these conditions and compared the findings in this patient to those of achondroplastic and pseudoachondroplastic patients of similar ages. The authors concluded that Fairbank MED (a mild form of EDM1; see 132400) may be the mildest form of pseudoachondroplasia, a conclusion that was also suggested by linkage studies.

Woods et al. (1994) described a family in which the father had pseudoachondroplasia and the mother had achondroplasia. Two daughters were doubly affected and a son had achondroplasia only. At birth, the 2 daughters appeared to have achondroplasia. Later, the development of a fixed lumbar gibbus, unusual radiographic changes in the spine, increasing joint laxity of the hands, and characteristic gait and hand posture made the appearance of pseudoachondroplasia apparent.

Flynn and Pauli (2003) described another case with radiologic findings virtually identical to those described by Langer et al. (1993) and Woods et al. (1994). They commented that the fact that all the probands were initially thought to have achondroplasia alone was not surprising, since pseudoachondroplastic features usually are not identifiable until after 2 years of age. The patient described by Langer et al. (1993) developed lumbar spinal stenosis at age 7.5 years. Both sibs in the report of Woods et al. (1994) had sufficiently severe stenosis of the foramen magnum to cause high cervical myelopathy requiring decompression.

Unger et al. (2001) reported a child with double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita (SEDC; 183900). The child inherited pseudoachondroplasia from his mother and spondyloepiphyseal dysplasia congenita from his father. Mutations in the COMP gene (600310.0014) and the COL2A1 gene (120140.0035) were confirmed by molecular analysis. The child had clinical and radiographic findings that were more severe than either disorder alone.

Inheritance

Pseudoachondroplasia is considered an autosomal dominant disorder due to inheritance patterns and the finding of heterozygous mutations in the COMP gene (Hecht et al., 1995).

Wynne-Davies et al. (1986) reviewed 10 families with dominant inheritance of pseudoachondroplasia and 6 families with presumed recessive inheritance. They concluded that there are no clearly distinguishing clinical or radiologic features between the 2 forms.

Mosaicism

Pseudoachondroplasia with presumed autosomal recessive inheritance in the family reported by Hall and Dorst (1969) was later concluded to be due to germline mosaicism (Hall et al., 1987; Ferguson et al., 1997). Furthermore, a heterozygous COMP mutation (600310.0004) was identified in this family (Hecht et al., 1995). Hall et al. (1987) reviewed pseudoachondroplasia pedigrees previously reported as compatible with autosomal recessive inheritance and concluded that most or all are instances of gonadal mosaicism for the autosomal dominant mutation. Ferguson et al. (1997) reached the same conclusion.

Early somatic mutation was proposed as the explanation for the findings in a 22-year-old patient reported by Fryns and van den Berghe (1986) who had a chondrodysplasia resembling pseudoachondroplasia and involving almost exclusively the right side of the body. The authors noted that germinal mosaicism has been proposed as an explanation for a number of dominant disorders that occur in 2 or more affected children of normal parents. Examples include achondroplasia, split-hand deformity (183600), and osteogenesis imperfecta congenita (OIC; 166210).

Spranger et al. (2005) described a brother and sister with a severe form of pseudoachondroplasia in whom no mutation was found in the COMP gene. Although parental gonadal mosaicism was a possibility, the authors suggested that the sibs may have had a disorder resulting from a defect of an extracellular matrix protein other than COMP. They stated that the disorder should be suspected in patients with unusually severe dwarfism, severe epimetaphyseal abnormalities, and persistent platyspondyly.

Population Genetics

Pseudoachondroplasia affects at least 1 in 20,000 individuals (Tufan et al., 2007).

Diagnosis

Mabuchi et al. (2004) presented evidence that plasma COMP levels are significantly decreased in patients with COMP mutations compared with controls (P less than 0.0001). In addition, plasma COMP levels were significantly decreased in multiple epiphyseal dysplasia (MED) patients carrying mutations in COMP relative to those who lacked COMP mutations (P = 0.001). These results indicated that measuring the level of circulating COMP may be an easier, more rapid, and cost-efficient method for diagnosing pseudoachondroplasia and particularly for diagnosing MED.

Tufan et al. (2007) found that plasma COMP levels were significantly reduced in 3 adult women from 1 PSACH family, aged 80, 60, and 36, compared to a control group of 21 adults. Radiographs from the 36-year-old woman showed short-limbed dwarfism with generalized epiphyseal and metaphyseal involvement and 'uncertain' vertebral changes. The diagnosis of PSACH was confirmed by genetic analysis. Tufan et al. (2007) concluded that plasma COMP levels are a reliable means of diagnosing PSACH.

Mapping

In the large family with a mild form of pseudoachondroplasia reported by Rimoin et al. (1994), Briggs et al. (1993) found linkage to markers on chromosome 19. Haplotype analysis delineated a 6.3-cM interval between D19S199 and D19S222 in the pericentric region of chromosome 19. The authors noted the since EDM1 had been mapped to the same region (Oehlmann et al., 1994), the 2 disorders could be allelic. Hecht et al. (1993) demonstrated linkage between typical pseudoachondroplasia and DNA markers on chromosome 19 in 9 unrelated multigenerational families with PSACH. As indicated by Hecht et al. (1995) and Briggs et al. (1995), the location of the PSACH gene is 19p13.1-p12.

Molecular Genetics

In patients with pseudoachondroplasia, Hecht et al. (1995) and Briggs et al. (1995) demonstrated heterozygous mutations in the COMP gene (see, e.g., 600310.0001-600310.0004 and 600310.0018). Briggs et al. (1995) suggested that the accumulation of material in the rough endoplasmic reticulum of chondrocytes in PSACH and some cases of multiple epiphyseal dysplasia represents structurally abnormal COMP. Since COMP is also expressed in tendon, the presence of abnormal COMP in this tissue explains the loose joints that are a consistent feature of pseudoachondroplasia.

Ikegawa (1998) reported a 15-year-old boy with PSACH who had a heterozygous de novo mutation in the COMP gene (600310.0010). In this boy, Ikegawa et al. (1998) had first observed a de novo interstitial deletion in chromosome 11q: del(11)(q21q22.2), suggesting that this deletion may contain a candidate PSACH gene; however, the deletion was later considered not to be causative of the disorder.

In a girl with typical PSACH, Delot et al. (1999) identified a heterozygous expansion of a trinucleotide repeat in the COMP gene (600310.0011).

Reviews

Jackson et al. (2012) conducted a 7-year study (2003-2007) of 130 patients with pseudoachondroplasia or suspected multiple epiphyseal dysplasia and provided a detailed review of the clinical diagnoses and molecular findings in these patients compared to previously reported patients. For most patients referred with a diagnosis of PSACH, the diagnosis was confirmed and they were found to have a mutation in the COMP gene (27 of 28 patients). Jackson et al. (2012) concluded that the classic form of PSACH is relatively straightforward to diagnose, provided there is sufficient clinical and radiographic information.

Pathogenesis

Maynard et al. (1972) identified unique rough surfaced inclusions in the endoplasmic reticulum in chondrocytes isolated from patients with pseudoachondroplasia.

In studies of 4 patients with PSACH, Stanescu et al. (1982) found an accumulation of a noncollagenous protein in the rough endoplasmic reticulum of chondrocytes and absence of proteoglycans in the cartilage. The accumulated material stained with antibodies against the core proteins of proteoglycans. The authors suggested that an abnormally synthesized or processed protein core was not properly transferred to the Golgi system. Byers (1989) interpreted immunohistochemical studies as suggesting that the stored material in pseudoachondroplasia cells is probably a proteoglycan core protein. The authors suggested that an abnormality in the synthesis or secretion of the core protein was the defect in the mouse mutation called cartilage matrix deficiency, symbolized cmd/cmd (Kimata et al., 1981), and in nanomelia in chickens (Stirpe et al., 1987).

Maroteaux et al. (1991) pointed out that the inclusions are characteristic of, but not specific for, pseudoachondroplasia since similar but smaller inclusions are found in the Fairbank type of multiple epiphyseal dysplasia (see Stanescu et al., 1993).

Maddox et al. (2000) showed that a mutation in the thrombospondin type 3 repeat domains of COMP resulting in pseudoachondroplasia profoundly reduced calcium binding affinity compared with wildtype and resulted in a highly altered conformation of the protein.

Dinser et al. (2002) developed a cell culture model of pseudoachondroplasia by expressing mutant COMP in bovine primary chondrocytes. They showed that mutant COMP exerts its deleterious effects through both intra- and extracellular pathogenic pathways. Overexpression of mutant COMP led to a dose-dependent decrease in cellular viability. The secretion of mutant COMP was markedly delayed, presumably due to a prolonged association with chaperones in the endoplasmic reticulum. The extracellular matrix lacked organized collagen fibers and showed amorphous aggregates formed by mutant COMP. Thus, pseudoachondroplasia appeared to be an endoplasmic reticulum storage disease, most likely caused by improper folding of mutant COMP. The growth failure of patients with pseudoachondroplasia may be explained by an increased cell death of growth-plate chondrocytes. Dominant interference of the mutant protein with collagen fiber assembly could contribute to the observed failure of the extracellular matrix of cartilage and tendons.

Nomenclature

Hall and Dorst (1969) originally suggested a classification of pseudoachondroplastic spondyloepiphyseal dysplasia into 4 types, 2 dominant (formerly designated types I and III) and 2 recessive (formerly designated types II and IV). Types I and II were considered to be phenotypically milder than types III and IV (Khungar et al., 1993). However, subsequent reports and genetic elucidation have shown that the disorder is a homogeneous autosomal dominant disorder that results almost exclusively from mutations in the COMP gene (Briggs and Chapman, 2002).

Autosomal dominant type III of Hall and Dorst (1969) was probably the form that Maroteaux and Lamy (1959) described in their original description, although they referred to 'formes' of pseudoachondroplasia.

The designation 'pseudoachondroplastic dysplasia' was suggested in the so-called Paris nomenclature (McKusick and Scott, 1971). 'Pseudoachondroplasia' has become the most frequently used designation.

History

In families with PSACH, Hecht et al. (1992) excluded linkage with the genes for cartilage link protein (HAPLN1; 115435) and type II collagen (COL2A1; 120140).

Animal Model

Riser et al. (1980) found pseudoachondroplasia in the miniature poodle, in which it is an autosomal recessive disorder.

PSACH and EDM1 patients often have a mild myopathy characterized by mildly increased plasma creatine kinase levels, a variation in myofiber size and/or small atrophic fibers. Pirog et al. (2010) studied skeletal muscle, tendon, and ligament in a mouse model of mild PSACH harboring a T585M mutation. T585M-mutant mice exhibited a progressive muscle weakness associated with an increased number of muscle fibers with central nuclei at the perimysium and at the myotendinous junction. Collagen fibril diameters in the mutant tendons and ligaments were thicker, and tendons became more lax in cyclic strain tests. Pirog et al. (2010) hypothesized that the myopathy in PSACH-MED may originate from underlying tendon and ligament pathology that may be a direct result of abnormalities in collagen fibril architecture.

Using homologous recombination, Suleman et al. (2012) generated a knockin mouse model carrying the common D469del mutation in the COMP gene (600310.0004), which is found in approximately one-third of patients with PSACH. Microarray analysis identified expression changes in groups of genes implicated in oxidative stress, cell cycle regulation, and apoptosis, consistent with the chondrocyte pathology. Suleman et al. (2012) suggested that a novel form of chondrocyte stress triggered by the expression of mutant COMP is central to the pathogenesis of PSACH.