Clinical Diagnosis

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.

Clinical findings

• Normal length at birth

• Normal facies

• Waddling gait, recognized at the onset of walking

• Typically, 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

• 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 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 a lateral view of the spine are required (see Figure 1). Findings include the following:

Figure

Figure 1. Radiographs of a prepubertal child showing the changes typical of pseudoachondroplasia

• Delayed epiphyseal ossification and 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 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 (Figure 1).

Molecular Genetic Testing

Gene. COMP, encoding the cartilage oligomeric matrix protein, is the only gene in which mutation is known to cause pseudoachondroplasia [Briggs et al 1995, Hecht et al 1995, Briggs & Chapman 2002].

Clinical testing

• Sequence analysis of selected exons. All mutations characterized to date have been structural mutations found in the exons encoding the eight calmodulin-like calcium-binding repeats (exons 8-14) or the carboxyl-terminal globular domain (exons 15-19). If mutations are not identified in these exons, sequence analysis of the remaining exons can be considered:

  • 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 calmodulin-like calcium-binding repeat domain of the protein.

  • Most remaining affected individuals have missense mutations. Other types of mutations are rare.

• Sequence analysis of the entire coding region. This approach should detect virtually all mutations, although mutations in exons 1-7 have not been identified in any previous cases.

Table 1. Summary of Molecular Genetic Testing Used in Pseudoachondroplasia

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
COMP	Sequence analysis	p.Asp473del	~30%	Clinical
		Missense and small in-frame deletions	~70%

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

Interpretation of test results

• For 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.

Testing Strategy

To confirm the diagnosis in a proband. Because of the prevalence of the p.Asp473del mutation, analysis of the exon encoding this residue can be carried out first, followed by analysis of the remaining exons.

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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

COMP mutations have been reported in skeletal disorders ranging from pseudoachondroplasia at the severe end of the spectrum to dominant multiple epiphyseal dysplasia (adMED) that may resemble precocious osteoarthropathy at the mild end.

Multiple epiphyseal dysplasia (MED) (see Multiple Epiphyseal Dysplasia, Dominant and Differential Diagnosis). About 25%-35% of individuals with autosomal dominant MED are heterozygous for a COMP structural mutation (a change in the amino acid sequence of the COMP protein resulting from a missense change or a small deletion or duplication within the gene) [Briggs & Chapman 2002]. As in pseudoachondroplasia, the mutations causing MED have been found in the exons encoding the calmodulin-like calcium-binding repeats and the carboxyl-terminal globular domain.

Natural History

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]. 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 half 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.

Pregnancy. For females with pseudoachondroplasia, delivery by cesarean section is often necessary because of the small size of the pelvis.

Genotype-Phenotype Correlations

A systematic analysis of the relationship between gene mutation and phenotype has not been carried out. However, individuals heterozygous for the common p.Asp473del mutation, present in approximately 30% of the individuals, have a consistent, typical form of the disorder [Mabuchi et al 2003].

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.

Penetrance

Penetrance is 100%.

Anticipation

Anticipation has not been observed in families with pseudoachondroplasia.

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.

Prevalence

No firm data are available for the prevalence of pseudoachondroplasia.

Evaluations Following Initial Diagnosis

To 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 chart

• Evaluation 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 spine.

• Evaluation 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 implications

Treatment of Manifestations

Joint 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 deformities is common during childhood. The need for subsequent revision is also common [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 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 (see Resources) may be of great benefit in providing information to affected individuals and their families.

Prevention of Secondary Complications

Directing the individual toward physical activities that preserve the joints may be beneficial.

Surveillance

Affected 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 radiographs

• Symptomatic genu varus/valgus

• Neurologic manifestations, particularly spinal cord compression secondary to odontoid hypoplasia

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.

Therapies Under Investigation

Search 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.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

International Skeletal Dysplasia Registry
Cedars-Sinai Medical Center
Phone: 800-233-2771 (toll-free)
Fax: 310-423-0462
Web: cedars-sinai.edu

Other

Growth hormone treatment is ineffective in pseudoachondroplasia [Kanazawa et al 2003].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Pseudoachondroplasia is inherited in an autosomal dominant manner.

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 gene mutation. The proportion of cases caused by de novo mutations has not been estimated.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include physical examination and radiographs. If a COMP mutation has been identified in the proband, molecular genetic testing of the parents is available and could detect somatic mosaicism for the mutation in one of the parents. Awareness of the possibility that somatic mosaicism for the mutation could be detected in the unaffected parent is important.

Note: If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

• If the disease-causing mutation identified in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. The risk to the sibs of the proband depends on the probability of germline mosaicism in a parent of the proband and the spontaneous mutation rate of COMP. Germline mosaicism for a COMP mutation 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 mutation 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 of a proband. 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.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as pseudoachondroplasia that do not affect intellect and have some treatment available are not common. 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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Briggs MD, Chapman KL. Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum Mutat. 2002;19:465–78. [PubMed: 11968079]
2. Briggs MD, Hoffman SM, King LM, Olsen AS, Mohrenweiser H, Leroy JG, Mortier GR, Rimoin DL, Lachman RS, Gaines ES. et al. Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nat Genet. 1995;10:330–6. [PubMed: 7670472]
3. Briggs MD, Mortier GR, Cole WG, King LM, Golik SS, Bonaventure J, Nuytinck L, De Paepe A, Leroy JG, Biesecker L, Lipson M, Wilcox WR, Lachman RS, Rimoin DL, Knowlton RG, Cohn DH. Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum. Am J Hum Genet. 1998;62:311–9. [PMC free article: PMC1376889] [PubMed: 9463320]
4. Ferguson HL, Deere M, Evans R, Rotta J, Hall JG, Hecht JT. Mosaicism in pseudoachondroplasia. Am J Med Genet. 1997;70:287–91. [PubMed: 9188668]
5. Flynn MA, Pauli RM. Double heterozygosity in bone growth disorders: four new observations and review. Am J Med Genet. 2003;121A:193–208. [PubMed: 12923858]
6. Hall JG, Dorst JP, Rotta J, McKusick VA. Gonadal mosaicism in pseudoachondroplasia. Am J Med Genet. 1987;28:143–51. [PubMed: 3314506]
7. Hecht JT, Nelson LD, Crowder E, Wang Y, Elder FF, Harrison WR, Francomano CA, Prange CK, Lennon GG, Deere M. et al. Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nat Genet. 1995;10:325–9. [PubMed: 7670471]
8. Hedbom E, Antonsson P, Hjerpe A, Aeschlimann D, Paulsson M, Rosa-Pimentel E, Sommarin Y, Wendel M, Oldberg A, Heinegard D. Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage. J Biol Chem. 1992;267:6132–6. [PubMed: 1556121]
9. Horton WA, Hall JG, Scott CI, Pyeritz RE, Rimoin DL. Growth curves for height for diastrophic dysplasia, spondyloepiphyseal dysplasia congenita, and pseudoachondroplasia. Am J Dis Child. 1982;136:316–9. [PubMed: 6803579]
10. Hunter AG. Perceptions of the outcome of orthopedic surgery in patients with chondrodysplasias. Clin Genet. 1999;56:434–40. [PubMed: 10665662]
11. Kanazawa H, Tanaka H, Inoue M, Yamanaka Y, Namba N, Seino Y. Efficacy of growth hormone therapy for patients with skeletal dysplasia. J Bone Miner Metab. 2003;21:307–10. [PubMed: 12928832]
12. Li QW, Song HR, Mahajan RH, Suh SW, Lee SH. Deformity correction with external fixator in pseudoachondroplasia. Clin Orthop Relat Res. 2007;454:174–9. [PubMed: 16957646]
13. Mabuchi A, Manabe N, Haga N, Kitoh H, Ikeda T, Kawaji H, Tamai K, Hamada J, Nakamura S, Brunetti-Pierri N, Kimizuka M, Takatori Y, Nakamura K, Nishimura G, Ohashi H, Ikegawa S. Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Genet. 2003;112:84–90. [PubMed: 12483304]
14. Maroteaux P, Lamy M. Pseudo-achondroplastic forms of spondylo-epiphyseal dysplasias. Presse Med. 1959;67:383–6. [PubMed: 13633894]
15. Maroteaux P, Stanescu R, Stanescu V, Fontaine G. The mild form of pseudoachondroplasia. Identity of the morphological and biochemical alterations of growth cartilage with those of typical pseudoachondroplasia. Eur J Pediatr. 1980;133:227–31. [PubMed: 7389735]
16. Maynard JA, Cooper RR, Ponseti IV. A unique rough surfaced endoplasmic reticulum inclusion in pseudoachondroplasia. Lab Invest. 1972;26:40–4. [PubMed: 4333078]
17. McKeand J, Rotta J, Hecht JT. Natural history study of pseudoachondroplasia. Am J Med Genet. 1996;63:406–10. [PubMed: 8725795]
18. McKusick VA, Scott CI. A nomenclature for constitutional disorders of bone. J Bone Joint Surg Am. 1971;53:978–86. [PubMed: 5557608]
19. Newton G, Weremowicz S, Morton CC, Copeland NG, Gilbert DJ, Jenkins NA, Lawler J. Characterization of human and mouse cartilage oligomeric matrix protein. Genomics. 1994;24:435–9. [PubMed: 7713493]
20. Rimoin DL, Rasmussen IM, Briggs MD, Roughley PJ, Gruber HE, Warman ML, Olsen BR, Hsia YE, Yuen J, Reinker K. et al. A large family with features of pseudoachondroplasia and multiple epiphyseal dysplasia: exclusion of seven candidate gene loci that encode proteins of the cartilage extracellular matrix. Hum Genet. 1994;93:236–42. [PubMed: 7907311]
21. Shetty GM, Song HR, Unnikrishnan R, Suh SW, Lee SH, Hur CY. Upper cervical spine instability in pseudoachondroplasia. J Pediatr Orthop. 2007;27:782–7. [PubMed: 17878785]
22. Spranger JW, Zabel B, Kennedy J, Jackson G, Briggs M. A disorder resembling pseudoachondroplasia but without COMP mutation. Am J Med Genet A. 2005;132A:20–4. [PubMed: 15551305]
23. Unger S, Korkko J, Krakow D, Lachman RS, Rimoin DL, Cohn DH. Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita. Am J Med Genet. 2001;104:140–6. [PubMed: 11746045]
24. Wynne-Davies R, Hall CM, Young ID. Pseudoachondroplasia: clinical diagnosis at different ages and comparison of autosomal dominant and recessive types. A review of 32 patients (26 kindreds). J Med Genet. 1986;23:425–34. [PMC free article: PMC1049780] [PubMed: 3783619]

Revision History

• 13 April 2010 (me) Comprehensive update posted live

• 11 December 2006 (me) Comprehensive update posted to live Web site

• 20 August 2004 (ca) Review posted to live Web site

• 6 April 2004 (dc) Original submission