Pseudoachondroplasia

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2021-01-18

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COMP, COL9A2, COL9A3, COL9A1, SCN8A, MATN3, ACAN, FGFR3, SPARC, P4HB, GLS, DCN, EPHA3, DMD, CANX, HAPLN1, COL10A1, COL2A1, MMRN1

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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.

Diagnosis

Suggestive Findings

Pseudoachondroplasia 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 (Figure 1).

Figure 1.

Radiographs of a prepubertal child showing the changes typical of pseudoachondroplasia

Establishing the Diagnosis

The diagnosis of pseudoachondroplasia is established in a proband with the above 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 variant in COMP by molecular genetic testing (see Table 1) establishes the diagnosis if clinical features are inconclusive.

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

Single-gene testing. Sequence analysis of COMP detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.
Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
A multigene panel that includes COMP and other genes of interest (see Differential Diagnosis) may be considered. 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. Thus, a panel should be chosen that is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.

Table 1.

Molecular Genetic Testing Used in Pseudoachondroplasia

Gene ¹	Test Method	Proportion of Probands with a Pathogenic Variant ² Detectable by This Method
COMP	Sequence analysis ³	>99% ⁴
COMP	Gene-targeted deletion/duplication analysis ⁵	Very rare ⁶

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Jackson et al [2012]
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6.: Mabuchi et al [2003]

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., T3₄ and T3₅) 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., T3₆, T3_7, and T3₈) 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].
Individuals heterozygous for the common p.Asp473del (often referred to as p.Asp469del) pathogenic variant, 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 an adjacent Asp (GAC) codon (p.Asp473del [p.Asp469dup]) 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, 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).

Differential Diagnosis

Multiple epiphyseal dysplasias

Autosomal dominant multiple epiphyseal dysplasia 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 but is less consistent than in pseudoachondroplasia. Adult height is either in the lower range of normal or mildly shortened but in general greater than in pseudoachondroplasia. 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. Arthritis typically develops at an older age and is less severe than in pseudoachondroplasia. The diagnosis of autosomal 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.
A pathogenic variant in one of five genes causes autosomal dominant MED: COMP, COL9A1, COL9A2, COL9A3, and MATN3. However, in approximately 10%-20% of all samples analyzed from individuals with clinically confirmed MED, a pathogenic variant cannot be identified in any of these five genes [Zankl et al 2007, Jackson et al 2012].
Jackson et al [2012] reported pathogenic missense variants in COL2A1 in two individuals with suspected MED for whom there were limited clinical data and radiographic images on which to base an unambiguous diagnosis [Jackson et al 2012]. Both pathogenic variants were in exon 50 and resulted in a glycine substitution (Gly1179Arg and Gly1176Val). A recurrent missense variant (Gly1170Ser) in this exon has also been consistently associated with dominant Legg-Calvé-Perthes disease (LCPD) [Liu et al 2005] while other COL2A1 pathogenic variants, such as p.Gly393Ser [Kannu et al 2011] and p.Gly717Ser [Miyamoto et al 2007], have also been associated with LCPD and avascular necrosis of the femoral head.
Autosomal recessive multiple epiphyseal dysplasia (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 (e.g., clubfoot, clinodactyly, or rarely, cystic ear swelling) not seen in pseudoachondroplasia. Onset of articular pain is variable but usually occurs in late childhood – typically later in onset and of lower severity than in pseudoachondroplasia. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished and ranges from 150 to 180 cm. Functional disability is mild or absent. Autosomal recessive MED is diagnosed on clinical and radiographic findings and is caused by biallelic pathogenic variants in SLC26A2 or CANT1 (OMIM 617719).

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 pathogenic variant. Generally, a complete genetic skeletal survey can distinguish these phenotypes from pseudoachondroplasia.

Another resource to help diagnose skeletal dysplasias using radiographic images, dREAMS, is available online (registration or subscription required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with pseudoachondroplasia, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

Height measurement and plotting of growth on a disorder-specific growth chart
Evaluation by history and physical examination for skeletal manifestations, ligamentous laxity, and 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 potentially serious clinical complications associated with cervical spine instability [Shetty et al 2007], which can be assessed by flexion/extension radiographs or cervical spine MRI examination, especially in persons with neurologic symptoms suggestive of cord compression
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Table 2.

Treatment of Manifestations in Individuals with Pseudoachondroplasia

Manifestation	Treatment	Considerations/Other
Joint pain	Analgesics	No systematic studies have evaluated effectiveness of various forms of pain control in pseudoachondroplasia.
Lower limb malalignment	Osteotomy	Common during childhood Subsequent revision commonly needed (most likely due to severe joint instability that can be present in some affected individuals) ¹
Neurologic symptoms & radiographic evidence of cervical spine instability or cord compression	C1-C2 fixation
Scoliosis	Surgery	Surgical treatment of scoliosis is rarely needed but may be effective in severe presentations.
Short stature	Extended limb lengthening	Very few examples of extended limb lengthening reported for pseudoachondroplasia Outcome of procedure in pseudoachondroplasia not known
Psychosocial issues related to short stature, incl stigmatization & discrimination	Awareness Referral to resources	Awareness is important in caring for the individual. Social support organizations incl the Little People of America & similar organizations in other countries (see Resources) may be of great benefit in providing information to affected individuals & families.

1.: Hunter [1999], Li et al [2007]

Prevention of Secondary Complications

The 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.

Surveillance

Affected individuals should be examined regularly for the following by a clinical geneticist and/or orthopedist familiar with the phenotype:

Symptomatic lower limb malalignment
Evidence of kyphoscoliosis
Symptoms related to joint hypermobility
Evidence of degenerative joint disease manifesting as joint pain or by radiographs
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.

Pregnancy Management

For females with pseudoachondroplasia, 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 www.ClinicalTrialsRegister.eu 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 pseudoachondroplasia [Kanazawa et al 2003].