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 ... 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).
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) ... 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.
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 ... 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.
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 ... 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.
The diagnosis of pseudoachondroplasia can be made on the basis of clinical findings and radiographic features. Although typical forms [Maroteaux & Lamy 1959, McKusick & Scott 1971] and mild forms [Maroteaux et al 1980, Rimoin et al 1994] of pseudoachondroplasia are recognized, the spectrum of clinical severity is continuous....
DiagnosisClinical DiagnosisThe diagnosis of pseudoachondroplasia can be made on the basis of clinical findings and radiographic features. Although typical forms [Maroteaux & Lamy 1959, McKusick & Scott 1971] and mild forms [Maroteaux et al 1980, Rimoin et al 1994] of pseudoachondroplasia are recognized, the spectrum of clinical severity is continuous.Clinical findingsNormal length at birthNormal faciesWaddling gait, recognized at the onset of walkingTypically, decline in growth rate to below the standard growth curve by approximately age two years, leading to moderately severe disproportionate short-limb short statureModerate brachydactylyLigamentous laxity and joint hyperextensibility, particularly in the hands, knees, and anklesMild myopathy has been reported for some individualsRestricted extension at the elbows and hipsValgus, varus, or windswept deformity of the lower limbsMild scoliosisLumbar lordosis (~50% of affected individuals)Joint pain during childhood, particularly in the large joints of the lower extremities; may be the presenting symptom in mildly affected individualsRadiographic diagnosis of pseudoachondroplasia is ideally made based on radiographs obtained in prepubertal individuals. At a minimum, AP views of the hips, knees, and hands and wrists and a lateral view of the spine are required (see Figure 1). Findings include the following: FigureFigure 1. Radiographs of a prepubertal child showing the changes typical of pseudoachondroplasia Delayed epiphyseal ossification with irregular epiphyses and metaphyses of the long bones (consistent)Small capital femoral epiphyses, short femoral necks and irregular, flared metaphyseal borders; small pelvis and poorly modeled acetabulae with irregular margins that may be sclerotic, especially in older individualsSignificant brachydactyly; short metacarpals and phalanges that show small or cone shaped epiphyses and irregular metaphyses; small, irregular carpal bonesAnterior beaking or tonguing of the vertebral bodies on lateral view. This distinctive appearance of the vertebrae normalizes with age, emphasizing the importance of obtaining in childhood the radiographs to be used in diagnosis (Figure 1).Molecular Genetic TestingGene. COMP, encoding cartilage oligomeric matrix protein, is the only gene in which mutations are known to cause pseudoachondroplasia [Briggs et al 1995, Hecht et al 1995, Briggs & Chapman 2002].Clinical testingSequence analysis of selected exons. All mutations characterized to date have been sequence variants found in the exons encoding the eight type III calcium-binding repeats (exons 8-14) or the carboxyl-terminal globular domain (exons 14-19). If mutations are not identified in these exons, sequence analysis of the remaining exons can be considered; recently novel sequence variants have been identified in exons 5 and 7 in individuals with pseudoachondroplasia (or the related disease, multiple epiphyseal dysplasia (MED) (see Genetically Related Disorders), but their pathogenicity has not been fully confirmed [Jackson et al 2012]. Table 1. Summary of Molecular Genetic Testing Used in PseudoachondroplasiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityCOMPSequence analysisp.Asp473del 2~30%ClinicalSequence variants 3 in exons 1-19 4100% 5Sequence analysis / mutation scanning of select exons 6Sequence variants 3 in the select exons 8-19 7>96% 5Deletion / duplication analysis 8Exonic and/or whole-gene deletionsVery rare 91. The ability of the test method used to detect a mutation that is present in the indicated gene2. Approximately 30% of individuals with pseudoachondroplasia [Briggs et al 1998, Briggs & Chapman 2002, Mabuchi et al 2003] have the same recurrent mutation, p.Asp473del, deletion of a single GAC (c.1417_1419delGAC) codon within a run of five consecutive GAC codons in exon 13 [Hecht et al 1995], corresponding to the seventh type III calcium-binding repeat domain of the protein.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. Mutations are either missense (~65%) small in-frame deletions (~30%) or deletions/insertions (~5%); typically sequence analysis does not detect exonic or whole-gene deletions/duplications.5. Jackson et al [2012]6. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.7. Exons sequenced may vary by laboratory. 8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.9. Mabuchi et al [2003]Interpretation of test resultsFor issues to consider in interpretation of sequence analysis results, click here.In a simplex case (i.e., a single occurrence in a family), analysis of parental DNA can be used to distinguish polymorphisms from the causative mutation.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. A recent analysis of COMP mutations identified in 35 individuals with pseudoachondroplasia demonstrated that they are distributed in seven exons in the following order of prevalence: 13, 14, 9/10, 18, and 11/16 [Kennedy et al 2005a, Jackson et al 2012].Because of the prevalence of the p.Asp473del mutation, analysis of exon 13 may be carried out first. If no disease causing mutation is found in exon 13, sequence analysis of exons 8-19 may be pursued next. Note that several mutations have been detected in exons 1-7, but their pathogenicity remains unclear [Jackson et al 2012]. Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersCOMP mutations have been reported in skeletal disorders ranging from pseudoachondroplasia at the severe end of the spectrum to autosomal dominant multiple epiphyseal dysplasia that may resemble precocious osteoarthropathy at the mild end.Multiple epiphyseal dysplasia (MED) (see Multiple Epiphyseal Dysplasia, Dominant and Differential Diagnosis). Approximately 65% of individuals with molecularly confirmed autosomal dominant MED are heterozygous for a COMP mutation [Jackson et al 2012]. Mutations in COMP are believed to alter the structure and/or function of the cartilage oligomeric matrix protein [Briggs & Chapman 2002]. As in pseudoachondroplasia, the mutations causing MED have been found in the exons encoding the Type III calcium-binding repeats (~85%) and the carboxyl-terminal globular domain (~15%).
Pseudoachondroplasia is characterized by disproportionate short-limb short stature. Intrafamilial and interfamilial variability are observed....
Natural HistoryPseudoachondroplasia is characterized by disproportionate short-limb short stature. Intrafamilial and interfamilial variability are observed.Natural history is well documented [Wynne-Davies et al 1986, McKeand et al 1996]. Affected individuals are generally of normal length at birth. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, the growth rate falls below the standard growth curve by approximately age two years. Growth curves for pseudoachondroplasia have been developed [Horton et al 1982]. Mean adult height is 116 cm for females and 120 cm for males [McKeand et al 1996].Pseudoachondroplasia is a short-limb form of dwarfism. Head size and shape are normal, without dysmorphic features. Extension at the elbows may be limited, and the elbows and knees may appear large. Scoliosis/lordosis can be observed in childhood and may persist into adulthood.Osteoarthritis of the upper extremities and the spine may occur in early adult life. Degenerative joint disease is progressive and approximately 50% of individuals with pseudoachondroplasia eventually require hip replacement surgery.Odontoid hypoplasia is not a common finding but does sometimes occur. Cervical spine instability can result, but C1-C2 fixation is not commonly necessary.
A systematic analysis of the relationship between gene mutation and phenotype has not been performed. In particular there is little correlation between the type and location of a mutation and the resulting phenotype, with the following notable exceptions:...
Genotype-Phenotype CorrelationsA systematic analysis of the relationship between gene mutation and phenotype has not been performed. In particular there is little correlation between the type and location of a mutation and the resulting phenotype, with the following notable exceptions:Individuals with mutations in the seventh type III calcium binding repeat are reported to have more severe short stature than those with mutations in the other type III repeats [Mabuchi et al 2003]. Individuals heterozygous for the common p.Asp473del mutation, present in approximately 30% of affected individuals, have a consistent, typical form of the disorder and are severely short [Mabuchi et al 2003]. In contrast, the insertion of a GAC codon at the same region p.Asp473dup results in mild MED [Délot et al 1999, Zankl et al 2007, Jackson et al 2012]. Specific missense mutations that result in pseudoachondroplasia (as opposed to MED) affect residues in the C-type motif of the type III calcium binding repeats, whereas missense mutations in the N-type motif of the type III repeats generally result in MED [Jackson et al 2012]. In-frame deletions are found equally between the N-type and C-type motifs of the type III repeats [Jackson et al 2012] and can cause both pseudoachondroplasia and MED.A range of intrafamilial variability has been observed, indicating that there are modifiers of phenotypic expression. Interfamilial variability is much wider, likely reflecting mutation-specific determinants of phenotypic severity as well as the effect of genetic modifiers.
Differential DiagnosisMultiple epiphyseal dysplasiasDominant multiple epiphyseal dysplasia (MED) presents early in childhood, usually with pain in the hips and/or knees after exercise. Affected children complain of fatigue during long walking. Waddling gait may be present. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints. The diagnosis of dominant MED is based on the clinical and radiographic presentation in the proband and other family members. In the initial stage of the disorder, often before the onset of clinical symptoms, radiographs show delayed ossification of the epiphyses of the long tubular bones. With the appearance of the epiphyses, the ossification centers are small with irregular contours, usually most pronounced in the hips and/or knees. The tubular bones may be mildly shortened. The spine is by definition normal, although Schmorl bodies and irregular vertebral end plates may be observed. Mutations in one of five genes cause autosomal dominant MED: COMP, COL9A1, COL9A2, COL9A3, and MATN3. However, in approximately 20% of all samples analyzed from clinically confirmed cases, a mutation cannot be identified in any of the five genes above [Zankl et al 2007]. Moreover, differences in ascertainment, diagnosis, and genetic testing have suggested previously that up to 50% of individuals with MED do not have a mutation in one of the five known genes [Unger et al 2001, Jakkula et al 2005, Kennedy et al 2005a].Recessive multiple epiphyseal dysplasia (EDM4/rMED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have some abnormal finding at birth including clubfoot, cleft palate, clinodactyly, or (rarely) cystic ear swelling. Onset of articular pain is variable but usually occurs in late childhood. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished, with the median height shifting from the 50th to the tenth percentile; range is 150-180 cm. Functional disability is mild or absent. EDM4/rMED is diagnosed on clinical and radiographic findings. SLC26A2 (DTDST) is the only gene known to be associated with EDM4/rMED. Diagnosis can be confirmed by molecular genetic testing of SLC26A2.Other forms of spondyloepimetaphyseal dysplasia (SEMD). Many different skeletal dysplasias have abnormalities of the spine, metaphyses, and epiphyses apparent on x-ray. For example, Spranger et al [2005] described a severe form of SEMD with some radiographic similarity to pseudoachondroplasia but without a COMP mutation. Generally, a complete genetic skeletal survey can distinguish these phenotypes from pseudoachondroplasia.Another resource to help diagnose skeletal dysplasias using radiographic images is available online (registration or subscription required). Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with pseudoachondroplasia, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with pseudoachondroplasia, the following evaluations are recommended:Measurement of height and plotting on growth chart, preferably disorder-specific growth chartEvaluation by history and physical examination for skeletal manifestations, including arthritis“Genetic” skeletal survey including: AP views of the hips, knees and hands, as well as lateral views of the knees and spineEvaluation of the cervical vertebrae because of the serious potential clinical complications associated with cervical spine instability [Shetty et al 2007]. This can be assessed by flexion/extension MRI, especially in persons with neurologic symptoms suggestive of cord compression. Assessment of ligamentous laxity and its clinical implicationsMedical genetics consultationTreatment of ManifestationsJoint pain may be controlled with analgesics, but no systematic studies have evaluated the effectiveness of various forms of pain control in pseudoachondroplasia.Osteotomy to treat the lower limb malalignment is common during childhood. The need for subsequent revision is also common, which most likely reflects the severe joint instability that can be present in some affected individuals [Hunter 1999, Li et al 2007]. Very few examples of extended limb lengthening have been reported for pseudoachondroplasia; thus, the outcome of this procedure in pseudoachondroplasia is not known. The need for surgical treatment of scoliosis is uncommon but may be effective in severe situations. Surgical methods are standard.In persons with neurologic symptoms and radiographic evidence of cervical spine instability or cord compression, C1-C2 fixation is the recommended surgical procedure. Awareness of psychosocial issues related to short stature, including stigmatization and discrimination, is important in caring for the individual. Social support organizations, including the Little People of America and other similar organizations in other countries (see Resources), may be of great benefit in providing information to affected individuals and their families.Prevention of Secondary ComplicationsThe articular cartilage of individuals with pseudoachondroplasia is likely to be severely disrupted; therefore, directing the individual toward physical activities that do not accelerate joint degeneration will be beneficial.SurveillanceAffected individuals should be examined regularly for the following by a medical geneticist and/or orthopedist familiar with the phenotype:Evidence of degenerative joint disease manifesting as joint pain or by radiographsSymptomatic lower limb malalignmentEvidence of kyphoscoliosisSymptoms related to joint hypermobilityNeurologic manifestations, particularly spinal cord compression secondary to odontoid hypoplasiaAgents/Circumstances to AvoidIn the small fraction of individuals with odontoid hypoplasia, extreme neck flexion and extension should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management For females with pseudoachondroplasia, delivery by cesarean section is often necessary because of the small size of the pelvis. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherGrowth hormone treatment is ineffective in pseudoachondroplasia [Kanazawa et al 2003].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Pseudoachondroplasia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCOMP19p13.11Cartilage oligomeric matrix proteinCOMP homepage - Mendelian genesCOMPData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Pseudoachondroplasia (View All in OMIM) View in own window 177170PSEUDOACHONDROPLASIA; PSACH 600310CARTILAGE OLIGOMERIC MATRIX PROTEIN; COMPNormal allelic variants. The coding sequence of COMP is organized into 19 exons distributed over approximately 8.5 kilobases of genomic DNA. A frequent single-nucleotide normal variant predicts a p.Asn386Asp substitution.Pathologic allelic variants. All individuals with pseudoachondroplasia appear to have COMP mutations [Jackson et al 2012]. Furthermore, all of the mutations predict an alteration in the primary structure of the protein, with the majority found in the exons encoding the eight type III calcium-binding repeats of the protein (~85%; exons 8-14). Mutations in the exons encoding the carboxyl-terminal globular domain have mostly been found in the remaining affected individuals (~15%; exons 14-19). A mutation in exon 7 has been identified but pathogenesis has not been fully resolved [Jackson et al 2012]. Approximately 30% of individuals have the same mutation: deletion of a single aspartic acid codon (p.Asp473del) within a run of five consecutive GAC (Asp encoding) codons in exon 13 [Hecht et al 1995, Briggs & Chapman 2002], corresponding to the seventh type III calcium-binding repeat domain of the protein. Most of the remaining individuals have a diverse range of single amino-acid substitution mutations, small in-frame deletions, duplications or indels. Interestingly, unlike the type III mutations, the carboxyl terminal domain (CTD) mutations (exons 14-19) appear to cluster in 3 distinct regions and affect only a limited number of residues. These mutation clusters include p.Thr529Ile, p.Glu583Lys, p.Thr585Met, p.Thr585Arg, p.Thr585Lys, p.His587Arg, and [p.Gly719Ser; p.Gly719Asp] and point to an important role for these residues in the structure and/or function of COMP [Briggs et al 1998, Deere et al 1998, Hecht et al 1998, Deere et al 1999, Mabuchi et al 2001, Kennedy et al 2005a, Kennedy et al 2005b, Jackson et al 2012].A single in-frame exon deletion and a single mutation predicting synthesis of a truncated protein have also been characterized, but not analyzed in-depth [Mabuchi et al 2003].Table 2. Selected COMP Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change (Alias 1)Reference SequencesNormalc.1156A>Gp.Asn386AspNM_000095.2 NP_000086.2Pathologicc.1417_1419delGACp.Asp473del (p.469delD)c.1417_1419dupGACp.Asp473dupc.1747G>Ap.Glu583Lysc.1754C>Tp.Thr585Metc.1754C>Gp.Thr585Argc.1754C>Ap.Thr585Lysc.1760A>Gp.His587Argc.1679A>Gp.Thr527Alac.1586C>Tp.Thr529Ilec.2155G>Ap.Gly719Serc.2156G>Ap.Gly719AspSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. Cartilage oligomeric matrix protein (COMP) is a 757-amino acid protein [Newton et al 1994] composed of an amino-terminal coiled-coil domain, four type II (EGF-like) repeats, eight type III (calmodulin-like calcium binding) repeats, and a carboxyl-terminal globular domain. It is a 550-kd homopentameric adhesive glycoprotein found predominantly in the cartilage extracellular matrix [Hedbom et al 1992]. COMP is also found in tendon, ligament, and muscle. It is the fifth member of the thrombospondin protein family and is also known as thrombospondin 5 (TSP5). COMP is a modular, multifunctional structural protein. The type III repeats bind calcium cooperatively and the carboxyl-terminal globular domain interacts with both fibrillar (types I, II, and III) and non-fibrillar (type IX) collagens.Abnormal gene product. Mutations in the exons encoding the type III repeats of COMP result in the misfolding of the mutant protein and its retention in the rough endoplasmic reticulum (rER) of chondrocytes. This protein retention results in ER stress that ultimately causes increased cell death in vitro [Chen et al 2000, Maddox et al 2000, Unger & Hecht 2001, Kleerekoper et al 2002]. Three transgenic mouse models of the common p.Asp473del (p.Asp469del) COMP mutation have been generated to study disease mechanisms in vivo [Schmitz et al 2008, Posey et al 2009, Suleman et al 2012]. Although there are some model-specific differences in the disease pathology and genetic pathways affected, all three models confirm that mutant COMP is retained in the ER of chondrocytes causing premature cell death. The retained protein in cartilage samples from patients can have a diagnostic lamellar appearance by transmission electron microscopy [Maynard et al 1972]. The effect of mutations in the exons encoding the C-terminal domain of COMP is not fully resolved, but these mutations are not thought to prevent the secretion of mutant COMP in vitro [Spitznagel et al 2004, Schmitz et al 2006]. Furthermore, they are believed to affect collagen fibrillogensis in cell culture models [Hansen et al 2011]. A mouse model of mild pseudoachondroplasia with the c.1754C>T (p.Thr585Met) mutation has also provided insight into disease mechanisms in vivo. Mutant COMP protein is efficiently secreted from the rER of chondrocytes and elicits a classic unfolded protein response (UPR). This ultimately results in decreased chondrocyte proliferation and increased and dysregulated apoptosis [Piróg-Garcia et al 2007]. Interestingly, mild myopathy has been characterized in this mouse model, originating from an underlying tendon and ligament pathology that is a direct result of structural abnormalities in the collagen fibril architecture [Piróg et al 2010].