Summary
Clinical characteristics.
Pseudoachondroplasia 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 pseudoachondroplasia eventually require hip replacement surgery.
Diagnosis/testing.
The diagnosis of pseudoachondroplasia 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; osteotomy for lower-limb malalignment; C1-C2 fixation for symptoms and radiographic evidence of cervical spine instability; rarely, surgery for scoliosis; attention to and social support for psychosocial issues related to short stature for affected individuals and their families.
Prevention of secondary complications: Encourage physical activities that do not cause excessive wear and/or damage to the joints.
Surveillance: Regular examinations for evidence of symptomatic lower limb malalignment, kyphoscoliosis, symptomatic joint hypermobility, degenerative joint disease, and neurologic manifestations, particularly spinal cord compression secondary to odontoid hypoplasia.
Agents/circumstances to avoid: In those with odontoid hypoplasia, extreme neck flexion and extension should be avoided.
Genetic counseling.
Pseudoachondroplasia is inherited in an autosomal dominant manner. Some individuals diagnosed with pseudoachondroplasia have an affected parent; the proportion of pseudoachondroplasia resulting from a de novo pathogenic variant is unknown. Each child of an individual with pseudoachondroplasia and a reproductive partner with normal bone growth has a 50% chance of inheriting the pathogenic variant and having pseudoachondroplasia. Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with pseudoachondroplasia may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. Prenatal testing for pregnancies at increased risk for pseudoachondroplasia is possible if the pathogenic variant in the family is known.
Clinical Characteristics
Clinical Description
Pseudoachondroplasia 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].
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. 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].
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. Pseudoachondroplasia is a short-limb form of dwarfism. 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 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 pseudoachondroplasia 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 Genetics, Normal gene product.)
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 pseudoachondroplasia
phenotype.
Pathogenic
missense variants in nucleotides encoding the fourth and fifth (of 8 total) type III calcium-binding repeats (i.e., T3
4 and T3
5) showed significant association with the MED compared to the pseudoachondroplasia
phenotype.
Pathogenic
missense variants in nucleotides encoding the sixth through eighth type III calcium-binding repeats (i.e., T3
6, T3
7, and T3
8) were significantly associated with the pseudoachondroplasia
phenotype.
The majority of pathogenic
in-frame deletions, insertions, or indels lead to pseudoachondroplasia (n=74; 82%), whereas a smaller proportion cause MED (n=16; 18%); however, in several instances, the same
pathogenic variant was reported to cause both pseudoachondroplasia 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].
Most type III calcium-binding repeats have both an N- and C-type motif (see
Molecular Genetics,
Normal gene product). Specific
missense variants that result in pseudoachondroplasia (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 pseudoachondroplasia 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.
Pseudoachondroplasia was referred to as pseudoachondroplastic dysplasia in the old literature.
Prevalence
No firm data on the prevalence of pseudoachondroplasia are available; it is estimated at 1:30,000 (see Genetics Home Reference).
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members. This section is not meant to address all personal, cultural, or
ethical issues that individuals may face or to substitute for consultation with a genetics
professional. —ED.
Risk to Family Members
Parents of a proband
Some individuals diagnosed with pseudoachondroplasia have an
affected parent.
A
proband with pseudoachondroplasia may have the disorder as the result of a
de novo
COMP pathogenic variant. The proportion of cases caused by 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 pseudoachondroplasia, a
COMP pathogenic variant had arisen
de novo [
Kennedy et al 2005a].
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 pseudoachondroplasia, the risk to the sibs is 50%.
If both parents have pseudoachondroplasia, their offspring have a 25% chance of having average stature, a 50% chance of having pseudoachondroplasia, 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 which the authors felt was more typical of MED [
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 pseudoachondroplasia because of the possibility of parental
germline mosaicism. Parental germline mosaicism for a
COMP pathogenic variant has been reported [
Hall et al 1987,
Ferguson et al 1997], but the frequency is unknown and the empiric risk to sibs of a proband has not been determined.
Offspring of a proband
Each child of an individual with pseudoachondroplasia and a reproductive partner with normal bone growth has a 50% chance of inheriting the
COMP pathogenic variant and having pseudoachondroplasia.
Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with pseudoachondroplasia 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, the 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, his or her family members are at risk.
Prenatal Testing and Preimplantation Genetic Diagnosis
Once the COMP pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
Molecular Genetics
Information 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 Databases
View in own window
Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Gene structure. The coding sequence of COMP is organized into 19 exons distributed over approximately 8.5 kb of genomic DNA. For a detailed summary of gene and protein information, see Table A, Gene.
Benign variants. A frequent single-nucleotide benign variant predicts a p.Asn386Asp substitution.
Pathogenic variants. 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 (often referred to as p.Asp469del) 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, and [p.Gly719Ser; p.Gly719Asp] (see ) 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 pseudoachondroplasia [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].
Table 3.
View in own window
| Variant Classification | DNA Nucleotide Change | Predicted Protein Change
(Alias 1) | Reference Sequences |
|---|
| Benign | c.1156A>G | p.Asn386Asp | NM_000095.2
NP_000086.2 |
| Pathogenic | c.1417_1419delGAC | p.Asp473del 2, 3
(Asp469del) |
| c.1417_1419dupGAC | p.Asp473dup 2, 3
(Asp469dup) |
| c.1586C>T | p.Thr529Ile |
| c.1747G>A | p.Glu583Lys |
| c.1754C>T | p.Thr585Met |
| c.1754C>G | p.Thr585Arg |
| c.1754C>A | p.Thr585Lys |
| c.1760A>G | p.His587Arg |
| c.2155G>A | p.Gly719Ser |
| c.2156G>A | p.Gly719Asp |
Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
- 2.
Commonly referred to in the literature as p.Asp469del and p.Asp469dup, respectively
- 3.
Note: The reference sequence NP_000086.2 has five tandem Asp residues, the first at residue 469 and the last at residue 473 (i.e., 469-AspAspAspAspAsp-473). Standard nomenclature has a rule that assigns a change (deletion or duplication of an Asp residue) in a single amino acid stretch of tandem repeats to the most C-terminal position. Thus, the standard nomenclature is p.Asp473del or p.Asp473dup.
Normal 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 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. Domain structure of COMP is summarized by Briggs et al [2014]. COMP 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. 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 pseudoachondroplasia 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].
Three transgenic mouse models of the human COMP variant p.Asp469del () were generated to study disease mechanisms in vivo [Schmitz et al 2008, Posey et al 2009, Posey et al 2012, Suleman et al 2012]. Although there are some model-specific differences in the disease pathology and genetic pathways affected, all three models confirm that variant (often referred to as p.Asp469del) COMP is retained in the ER of chondrocytes, causing premature cell death in the growth plate [Briggs et al 2015].
An orthologous mouse model of mild pseudoachondroplasia () has also provided insight into disease mechanisms in vivo. This mutated COMP protein is efficiently secreted from the rER of chondrocytes and elicits a classic unfolded protein response. This ultimately results in decreased chondrocyte proliferation and increased and dysregulated apoptosis [Piróg-Garcia et al 2007].
Analysis of the cartilage proteome from two mouse models of pseudoachondroplasia (orthologous to human and p.Asp473 (often referred to as p.Asp469del) show common and discrete disease signatures [Bell et al 2013]. Most notably there are genotype-specific changes in the extractability of a range of cartilage proteins, confirming that mutated COMP protein exerts a dominant-negative effect on cartilage structure and function and that this is likely to contribute to pseudoachondroplasia pathology and early-onset osteoarthritis [Bell et al 2013, Briggs et al 2015].
A mild myopathy has been characterized in two mutated COMP mouse models (orthologous to the human p.Thr585Met and p.Asp473del (p.Asp469del), 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, Piróg et al 2013].
