Clinical characteristics.

COMP-related pseudoachondroplasia (COMP-PSACH) is characterized by normal length at birth and normal facies. 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, leading to a moderately severe form of disproportionate short-limb short stature. Joint pain during childhood, particularly in the large joints of the lower extremities, is common. Degenerative joint disease is progressive; approximately 50% of individuals with COMP-PSACH eventually require hip replacement surgery.

Diagnosis/testing.

The diagnosis of COMP-PSACH can be made on the basis of clinical findings and radiographic features. Identification of a heterozygous pathogenic variant in COMP on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Analgesics for joint pain; encourage physical activities that do not cause excessive wear and/or damage to the joints; osteotomy for lower limb malalignment; rarely, surgery for scoliosis; C1-C2 fixation for symptoms and radiographic evidence of cervical spine instability; attention to and social support for psychosocial issues related to short stature for affected individuals and their families.

Surveillance: Assess growth at each visit throughout childhood. Regular examinations for evidence of symptomatic joint hypermobility and/or lower limb malalignment, kyphoscoliosis, degenerative joint disease, and neurologic manifestations, particularly spinal cord compression secondary to odontoid hypoplasia. Assess for psychosocial issues annually or at each visit.

Agents/circumstances to avoid: In those with odontoid hypoplasia, extreme neck flexion and extension should be avoided.

Genetic counseling.

COMP-PSACH is inherited in an autosomal dominant manner. Some individuals diagnosed with COMP-PSACH have an affected parent. A proband diagnosed with COMP-PSACH may have the disorder as the result of a de novo pathogenic variant. Each child of an individual with COMP-PSACH and a reproductive partner with normal bone growth has a 50% chance of inheriting the COMP pathogenic variant and having COMP-PSACH. Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with COMP-PSACH may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. Once the COMP pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

COMP-related pseudoachondroplasia (COMP-PSACH) should be suspected in individuals with the following clinical findings and radiographic features.

Clinical findings

• Normal length at birth
• Normal facies
• Waddling gait, recognized at the onset of walking
• Decline in growth rate to below the standard growth curve by approximately age two years, leading to moderately severe disproportionate short-limb short stature
• Moderate brachydactyly
• Ligamentous laxity and joint hyperextensibility, particularly in the hands, knees, and ankles
• Mild myopathy reported for some individuals
• Restricted extension at the elbows and hips
• Valgus, varus, or windswept deformity of the lower limbs
• Mild scoliosis
• Lumbar 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 individuals

Radiographic features

• 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 individuals
• Significant brachydactyly; short metacarpals and phalanges that show small or cone-shaped epiphyses and irregular metaphyses; small, irregular carpal bones
• Anterior 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 (see Figure 1).

Figure 1.

Radiographs of a prepubertal child showing the changes typical of pseudoachondroplasia

Establishing the Diagnosis

The diagnosis of COMP-PSACH is established in a proband with the abovementioned clinical and radiographic features. The diagnosis is ideally confirmed on radiographs obtained in prepubertal individuals. At a minimum, AP views of the hips, knees, hands, and wrists and a lateral view of the spine are required (see Figure 1). Identification of a heterozygous pathogenic (or likely pathogenic) variant in COMP by molecular genetic testing (see Table 1) establishes the diagnosis if clinical features are inconclusive.

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants.

Molecular genetic testing approaches can include a single-gene testing or use of multigene panel:

• Single-gene testing. Sequence analysis of COMP is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• A multigene panel that includes COMP and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

COMP-related pseudoachondroplasia (COMP-PSACH) 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]. To date, more than 500 individuals have been identified with COMP-PSACH. The following description of the phenotypic features associated with this condition is based on these reports.

Growth. Affected individuals are generally of normal length at birth. Typically, the growth rate falls below the standard growth curve by approximately age two years, leading to moderately severe disproportionate short-limb short stature. Growth curves for COMP-PSACH have been developed [Horton et al 1982]. Mean adult height is 116 cm for females and 120 cm for males [McKeand et al 1996].

Facies. Head size and shape are normal, without dysmorphic features.

Gait. Often the presenting feature is a waddling gait, recognized at the onset of walking.

Extremities. COMP-PSACH is a short-limb form of dwarfism with all limb segments equally affected (rhizo-, meso-, and acromelia). Individuals have moderate brachydactyly. Ligamentous laxity and joint hyperextensibility is present particularly in the hands, knees, and ankles. Extension at the elbows may be limited, and the elbows and knees may appear large. Valgus, varus, or windswept deformity of the lower limbs is common.

Some individuals have mild myopathy.

Scoliosis/lordosis can be observed in childhood and may persist into adulthood; severity is variable and there are no effective treatments.

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 COMP-PSACH 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 generally necessary.

Genotype-Phenotype Correlations

A systematic analysis of the relationship between genotype and phenotype has been performed on 300 reported COMP pathogenic variants resulting in PSACH and/or autosomal dominant multiple epiphyseal dysplasia (MED) [Briggs et al 2014]. The following are correlations from this study. (For repeat and domain structure, see Molecular Pathogenesis.)

• Pathogenic missense variants of nucleotides encoding either the N- or C-type motifs within each of the type III calcium-binding domains showed no significant association with either the MED or the PSACH phenotype.
• Pathogenic missense variants in nucleotides encoding the fourth and fifth (of 8 total) type III calcium-binding repeats (i.e., T3₄ and T3₅) showed significant association with the MED compared to the PSACH phenotype.
• Pathogenic missense variants in nucleotides encoding the sixth through eighth type III calcium-binding repeats (i.e., T3₆, T3₇, and T3₈) were significantly associated with the PSACH phenotype.
• The majority of pathogenic in-frame deletions, insertions, or indels were associated with PSACH (n=74; 82%), whereas a smaller proportion were associated with MED (n=16; 18%); however, in several instances, the same pathogenic variant was reported to cause both PSACH and MED [Briggs et al 2014].

Correlations from prior studies:

• Individuals with a pathogenic variant in the seventh type III calcium-binding repeat are reported to have more severe short stature than those with pathogenic variants in the other type III repeats [Mabuchi et al 2003].
• Individuals heterozygous for the common p.Asp473del pathogenic variant, present in approximately 30% of affected individuals, have a consistent, typical form of PSACH and are severely short [Mabuchi et al 2003]. In contrast, the insertion of an adjacent Asp (GAC) codon (p.Asp473dup) results in mild MED [Délot et al 1999, Zankl et al 2007, Jackson et al 2012].
• Most type III calcium-binding repeats have both an N- and C-type motif (see Molecular Genetics). Specific missense variants that result in PSACH (as opposed to MED) affect residues in the C-type motif, whereas missense variants in the N-type motif generally result in MED [Jackson et al 2012]. In-frame deletions are found equally between the N-type and C-type motifs [Jackson et al 2012] and can cause both PSACH and MED.

Penetrance

Penetrance is 100%.

Nomenclature

In the past, four subtypes of pseudoachondroplasia, including dominant and recessive forms, were recognized under the term pseudoachondroplasia. The current classification recognizes a single, dominantly inherited phenotype referred to as COMP-related pseudoachondroplasia [Unger et al 2023].

COMP-PSACH was referred to as pseudoachondroplastic dysplasia in older literature.

Prevalence

No firm data on the prevalence of COMP-PSACH are available; it is estimated at 1:30,000 (see MedlinePlus).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with COMP-related pseudoachondroplasia (COMP-PSACH), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for COMP-PSACH.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

In the small fraction of individuals with odontoid hypoplasia, extreme neck flexion and extension should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

For females with COMP-PSACH, delivery by cesarean section is often necessary because of the small size of the pelvis. Cesarean delivery should be considered on a case-by-case basis.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Growth hormone treatment is ineffective in COMP-PSACH [Kanazawa et al 2003].

Mode of Inheritance

COMP-related pseudoachondroplasia (COMP-PSACH) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with COMP-PSACH have an affected parent.
• A proband diagnosed with COMP-PSACH may have the disorder as the result of a de novo pathogenic variant. The proportion of probands who have a de novo pathogenic variant has not been accurately determined, but a study by Kennedy and colleagues indicated that in at least 22% of individuals with molecularly confirmed COMP-PSACH, a COMP pathogenic variant had arisen de novo [Kennedy et al 2005a].
• If the proband appears to be the only affected family member (i.e., a simplex case), evaluation of the parents of the proband is recommended in order to evaluate their genetic status and inform recurrence risk assessment; recommended evaluations include physical examination, radiographs, and molecular genetic testing. (Molecular genetic testing may detect parental somatic mosaicism for the COMP pathogenic variant.)
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. Germline mosaicism for a COMP pathogenic variant has been reported [Hall et al 1987, Ferguson et al 1997]; the frequency is unknown.
    * A parent with somatic and germline mosaicism for a COMP pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If one parent of the proband has COMP-PSACH, sibs have a 50% chance of inheriting the COMP pathogenic variant and having COMP-PSACH.
• If both parents have COMP-PSACH, sibs of the proband have a 25% chance of having average stature, a 50% chance of having COMP-PSACH, and a 25% chance of having biallelic COMP pathogenic variants and severe pseudoachondroplasia [Tariq et al 2018]. Severe pseudoachondroplasia has been reported in two individuals from a consanguineous family who were found to have homozygous pathogenic COMP variants. (Note: Other family members with heterozygous variants had a mild pseudoachondroplasia phenotype that the authors felt was more typical of multiple epiphyseal dysplasia [Tariq et al 2018].)
• If the parents are clinically unaffected, the recurrence risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for COMP-PSACH because of the possibility of parental germline mosaicism [Hall et al 1987, Ferguson et al 1997].

Offspring of a proband

• Each child of an individual with COMP-PSACH and a reproductive partner with normal bone growth has a 50% chance of inheriting the COMP pathogenic variant and having COMP-PSACH.
• Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with COMP-PSACH may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals may be distinct from those of the parents [Unger et al 2001, Flynn & Pauli 2003].
• If both partners have a dominantly inherited bone growth disorder, offspring have a 25% chance of having the maternal bone growth disorder, a 25% chance of having the paternal bone growth disorder, a 25% chance of having average stature and bone growth, and a 25% chance of having double heterozygosity for the two disorders.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members are at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with COMP-PSACH.

Prenatal Testing and Preimplantation Genetic Testing

Once the COMP pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Cartilage oligomeric matrix protein (COMP) is composed of an amino-terminal coiled-coil domain, four type II (EGF-like) repeats, eight consecutive type III (calmodulin-like calcium-binding) repeats, and a carboxyl-terminal globular domain. The type III motifs typically are composed of both an N- and a C-type motif, although the third and fifth type III repeats lack the N-type motif. COMP is a homopentameric adhesive glycoprotein found predominantly in the cartilage extracellular matrix [Hedbom et al 1992]. COMP is also found in tendon, ligament, and muscle. 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 nonfibrillar (type IX) collagens.

Pathogenic variants in the exons encoding the type III repeats of COMP result in the misfolding of the mutated 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, Coustry et al 2012]. The retained protein in cartilage samples from individuals with COMP-related pseudoachondroplasia (COMP-PSACH) can have a diagnostic lamellar appearance by transmission electron microscopy [Maynard et al 1972].

The effect of pathogenic variants in the exons encoding the C-terminal globular domain of COMP is not fully resolved, but these pathogenic variants are not thought to prevent the secretion of mutated COMP in vitro [Spitznagel et al 2004, Schmitz et al 2006]. Furthermore, they are believed to affect collagen fibrillogenesis in cell culture models [Hansen et al 2011].

All individuals with pseudoachondroplasia appear to have COMP pathogenic variants [Jackson et al 2012]. Furthermore, all of the pathogenic variants 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). Pathogenic variants in the exons encoding the carboxyl-terminal globular domain have mostly been found in the remaining affected individuals (~15%; exons 14-19). Two variants in exons 7 and 8 encoding a type II repeat have been identified, but their pathogenesis has not been fully resolved [Jackson et al 2012, Briggs et al 2014].

Approximately 30% of individuals have the same pathogenic variant: deletion of a single aspartic acid codon p.Asp473 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 of the protein. Most of the remaining individuals have a diverse range of single amino-acid substitution variants, small in-frame deletions, duplications, or indels. Interestingly, unlike the pathogenic variants in nucleotides of the type III repeats, pathogenic variants within the carboxyl-terminal domain (exons 14-19) appear to cluster in three distinct regions and affect only a limited number of residues. These variant clusters include p.Thr529Ile, p.Glu583Lys, p.Thr585Met, p.Thr585Arg, p.Thr585Lys, p.His587Arg, p.Gly719Ser, and 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].

Evidence suggests that pathogenic variants in exons 7 and 8 encoding the type II repeats may be an uncommon cause of COMP-PSACH [Jackson et al 2012, Briggs et al 2014].

A single in-frame exon deletion and a single pathogenic variant predicting synthesis of a truncated protein have also been characterized but not analyzed in depth [Mabuchi et al 2003].

Mechanism of disease causation. Dominant-negative

Author History

Michael D Briggs, PhD (2013-present)
Daniel H Cohn, PhD; University of California, Los Angeles (2004-2013)
Michael J Wright, MB, ChB, MSc, FRCP (2013-present)

Revision History

• 30 November 2023 (sw) Comprehensive update posted live
• 16 August 2018 (sw) Comprehensive update posted live
• 16 July 2015 (me) Comprehensive update posted live
• 28 February 2013 (me) Comprehensive update posted live
• 13 April 2010 (me) Comprehensive update posted live
• 11 December 2006 (me) Comprehensive update posted live
• 20 August 2004 (ca) Review posted live
• 6 April 2004 (dc) Original submission

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