Achondroplasia

Achondroplasia is a skeletal dysplasia recognisable at birth. Cardinal clinical features include disproportionate short stature with rhizomelic shortening of the limbs, macrocephaly, a characteristic facies with frontal bossing and midface retrusion, exaggerated lumbar lordosis, limited elbow extension and rotation, genu varum, brachydactyly, and a trident configuration of the hands; excess mobility of the knees, hips, and most other joints is common. Average adult height is 129.9 ± 6.25 cm in men and 122.4 ± 5.9 cm in women. Clinical presentation is consistent across affected individuals, although severity of complications varies. Intelligence lies in the average range unless hydrocephalus or other central nervous system complications occur. Other complications include obstructive sleep apnoea, recurrent otitis media, and spinal stenosis, which may require surgical decompression in a substantial proportion of patients.

The estimated birth prevalence is 1 in 26,000 to 1 in 28,000 live births.

Achondroplasia is caused by heterozygous gain-of-function variants in FGFR3 (4p16.3), which accounts for more than 99 % of cases. FGFR3 encodes fibroblast growth factor receptor 3, a transmembrane tyrosine kinase that acts as a negative regulator of endochondral bone growth. Two recurrent variants, c.1138G>A and c.1138G>C (both p.Gly380Arg), underlie nearly all cases and cause constitutive receptor activation; the resulting excess inhibitory signalling slows proliferation and differentiation of growth-plate chondrocytes. The recurrent variant arises almost exclusively on the paternally derived allele during spermatogenesis, and its frequency rises with advancing paternal age, reflecting clonal expansion of mutation-bearing spermatogonial clones in the ageing male germline.

Achondroplasia is inherited in an autosomal dominant manner. About 80% of affected individuals carry a de novo variant, with the remainder having an affected parent; each child of an affected individual has a 50% risk of inheriting the variant. When both parents are unaffected, the empirical recurrence risk for a further child is low but not zero, because the paternally arising variant can be present as germ-cell (gonadal) mosaicism in an unaffected father; rare sibling recurrences are attributed to this mechanism.

The diagnosis of achondroplasia can be established in an individual with characteristic clinical and radiographic features. Molecular genetic testing of FGFR3 can be used to confirm the diagnosis in individuals with atypical findings or diagnostic uncertainty.

Main differential diagnoses include:

• Hypochondroplasia: milder disproportionate short stature with less pronounced craniofacial features, often not recognised until childhood; FGFR3 (autosomal dominant)
• : severe, usually neonatally lethal short-limbed dysplasia with extreme limb shortening and bowed femora; FGFR3 (autosomal dominant)
• Pseudoachondroplasia: disproportionate short stature with a normal craniofacial appearance and normal findings at birth, presenting in early childhood; COMP (autosomal dominant)
• SADDAN: severe short stature with developmental delay and acanthosis nigricans; FGFR3 (autosomal dominant)
• Cartilage-hair hypoplasia: short-limb short stature with metaphyseal dysplasia and fine sparse hair; RMRP (autosomal recessive)

• Identification of the underlying FGFR3 pathogenic variant confirms the molecular diagnosis, clarifies the genetic aetiology, provides the basis for accurate genetic counselling and enables predictive testing.
• A confirmed molecular diagnosis can support condition-specific surveillance and clinical management, including assessment for craniocervical junction compression in infancy and monitoring for complications such as spinal stenosis; specific measures are determined by the treating physicians in consultation with the affected individual and their family.

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