Achondroplasia (FGFR3 gene): causes, inheritance and recurrence

Achondroplasia is a skeletal dysplasia, a condition of abnormal bone and cartilage growth. The Restricted Growth Association explains that the name means no cartilage, which is misleading: it is really a condition of one gene, FGFR3, that results in abnormal cartilage formation. People have an average-sized trunk and shorter arms and legs, which is called disproportionate short stature, and in the RGA's experience most people with restricted growth conditions have normal intelligence and normal life expectancy.

The NHS Genomics Education Programme lists the clinical features, which vary from person to person: height two to three standard deviations below average, shortening of the upper arm and thigh segments (rhizomelia), a relatively large head, a prominent forehead with a flattened mid-face and nasal bridge, bowed legs, short broad hands and feet, and a trident hand shape. The condition is often noticed first because of the short stature.

Several health issues are looked for, including compression at the junction between skull and spine, obstructive sleep apnoea, middle ear problems, kyphosis in infancy, lumbar lordosis when walking begins, and spinal stenosis. Management is by a multidisciplinary team that monitors growth, development and musculoskeletal and neurological features.

FGFR3 makes a receptor on the surface of cartilage cells that acts as a brake on bone growth. The Restricted Growth Association explains that this receptor normally limits the conversion of cartilage into bone, particularly in the long bones, and in achondroplasia the change makes it overly active. That interferes with bone growth and produces the pattern of short limbs.

Nearly everyone with achondroplasia carries one of just two changes at the same position in the gene, so testing is straightforward. The NHS Genomics Education Programme says a targeted FGFR3 hotspot test is available within the National Genomic Test Directory, or the gene can be tested as part of a broader skeletal dysplasia panel. Other conditions, including hypochondroplasia and Muenke syndrome, can result from different changes in the same gene, and the RGA describes hypochondroplasia as a milder condition that is caused by a different change in FGFR3.

Achondroplasia is autosomal dominant, so one changed copy of FGFR3 is enough. In practice, most affected children are born to parents of average height. The Restricted Growth Association says many children with disproportionate short stature have average-height parents and the genetic condition occurred spontaneously, and the NHS Genomics Education Programme says achondroplasia commonly occurs as a result of a de novo variant.

When neither parent has the variant, the chance of another affected child is estimated to be less than 1%. It is not zero because a parent could carry the variant in a proportion of egg or sperm cells without having it in the rest of their body, which is germline mosaicism. The programme also notes that increasing paternal age may have an effect on the chance of a new change.

When a parent has achondroplasia, each child has a 50% chance of inheriting the changed gene and so of having the condition. A genetic counsellor can talk through what this means for a couple, including options for testing in pregnancy.

The NHS Genomics Education Programme says achondroplasia may be diagnosed before or after birth. The programme has separate testing pathways for a pregnancy in which a skeletal dysplasia is suspected and for a baby in whom achondroplasia is suspected after birth. X-ray features include short tubular bones, narrowing of the spinal canal in the lower back and characteristic changes in the pelvis, and a targeted genetic test confirms the diagnosis.

Because the same genetic test can be done in pregnancy or after birth, families should ask their local clinical genetics service which route applies to them. The RGA offers information for parents and a network of members.

The Restricted Growth Association is a UK charity for people affected by restricted growth and describes restricted growth as a final adult height of 4 feet 10 inches or less due to a medical condition. It provides medical information on the types of dwarfism and information for parents.

Health care centres on watching for the complications listed above. The NHS Genomics Education Programme says care is multidisciplinary and involves monitoring of growth, development and musculoskeletal and neurological features.