SickKids

Paediatric Laboratory Medicine
Paediatric Laboratory Medicine
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Achondroplasia/Hypochondroplasia

Background
Who should be tested?
Testing Methodology
Potential Outcomes and Interpretation of Test Results
Cautions
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Background

Achondroplasia (ACH) is characterized by abnormal bone growth that results in short stature with disproportionately short arms and legs, a large head, and characteristic facial features. Intelligence and life span are usually unaffected, although medical complications in infancy from compression of the spinal cord and/or upper airway obstruction may occur. Hypochondroplasia (HCH) is also characterized by short stature with disproportionately short arms and legs. The skeletal features are very similar to achondroplasia but usually tend to be milder. Medical problems common to achondroplasia (e.g., airway obstruction, spine compression) occur less frequently in hypochondroplasia but deficits in mental capacity may be more common.

Both achondroplasia and hypochondroplasia are autosomal dominant disorders caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene located on chromosome 4 (4p16.3). Since the disease is dominant, all individuals who have a mutated copy of the FGFR3 gene will be affected. Although the same gene causes these two conditions, different changes occur in the gene. Two mutations in the FGFR3 gene account for more than 99 per cent of achondroplasia cases. Two different mutations in the FGFR3 gene account for approximately 70 per cent of hypochondroplasia cases. Mutations accounting for the remaining 30 per cent of HCH patients have not yet been identified.

The majority of individuals with achondroplasia or hypochondroplasia have parents who are not affected and have average stature. In these cases, the disorder is due to a new mutation or genetic change, and the parents are at low risk of having another affected child. A person with ACH or HCH whose partner is average-sized has a 50 per cent or 1 in 2 chance of having children with the same condition. When both parents are affected, they have a 75 per cent chance their children will be affected. The severity of the disorder in these children will vary, depending on the type and number of mutations inherited.

Who should be tested?

  • individuals clinically suspected of being affected with achondroplasia or hypochondroplasia
  • pregnancies at risk due to abnormal ultrasound findings or a family history of ACH/HCH

Testing Methodology

Direct Mutation Analysis, Achondroplasia: Samples are analyzed using a PCR assay for the following mutations in the FGFR3 gene: c.1138G>A (p.Gly380Arg, c.1138G>C (p.Gly380Arg) and c.1123G>T (p.Gly375Cys).

Direct Mutation Analysis, Hypochondroplasia: Samples are analyzed using a PCR assay for the following mutations in the FGFR3 gene: c.1620C>A (p.Asn540Lys), c.1620C>G (p.Asn540Lys), c.1619A>C (p.Asn540Thr) and c.1612A>G (p.Iso538Val).

Test Sensitivity: The mutations indicated above account for 99 per cent of the mutations seen in individuals affected with achondroplasia, and 70 per cent of the mutations seen in individuals with hypochondroplasia.

For example, of 10 people with achondroplasia, this test is able to confirm the diagnosis in virtually all of them. Of 10 people with hypochondroplasia, this test is able to identify seven.

A very small fraction of people with achondroplasia do not have the common mutations listed above, but have different mutations in the FGFR3 gene. These mutations are not detected by the diagnostic procedures currently used by the Molecular Genetics Laboratory.

Mutations in FGFR3 other than those listed above, as well as mutations in other genes, may account for approximately 30 per cent of hypochondroplasia cases. These mutations are not detected by the diagnostic procedures currently in place in the Molecular Genetics Laboratory. Therefore, the absence of an FGFR3 mutation does not rule out a diagnosis of hypochondroplasia.

Potential Outcomes & Interpretation of Test Results

FGFR3 Gene Mutation
allele 1/ allele 2

Explanation

none detected / none detected

  • This result does not support a diagnosis of achondroplasia or hypochondroplasia.

mutation detected (G380R or G375C)/ none detected

  • This result confirms a diagnosis of achondroplasia.

mutation detected (N540K/T or I538V)/ none detected

  • This result confirms a diagnosis of hypochondroplasia.

Cautions

  • Current molecular testing will not detect all possible mutations in this gene. A negative result does not rule out the possibility that the individual is affected with ACH or HCH.
  • Test results should be interpreted in the context of clinical findings, family history and other laboratory data.
  • Other mutation combinations are possible, in addition to those listed above. These combinations are very rare and usually result in a more serious phenotype.
  • This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

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