Achondroplasia

Achondroplasia (ACH) is a type of skeletal dysplasia caused by pathogenic variants in the FGFR3 gene. It is inherited in an autosomal dominant pattern and is the most common cause of disproportionate short stature, which is the feature that affected children often present with.

Clinical features of ACH are variable. They include:

• disproportionate short stature (two to three standard deviations (2–3SD) below the mean);
• shortening of the proximal (rhizomelia) segments of the limbs;
• relative macrocephaly;
• characteristic facies (frontal bossing, midface retrusion, depressed nasal bridge);
• bowed legs;
• broad hands and feet with brachydactyly (short digits); and
• trident hand configuration.

Complications of ACH can include:

• craniocervical junction compression;
• obstructive sleep apnoea;
• middle ear dysfunction;
• thoracolumbar kyphosis (usually in infancy);
• lumbar lordosis (when walking begins); and
• spinal stenosis.

Radiographic features may include:

• short tubular bones;
• rhizomelia;
• narrowing of the interpedicular distance of the caudal spine;
• vertebral scalloping posteriorly;
• square ilia and horizontal trident acetabula;
• proximal femoral radiolucency;
• short, constricted femoral necks;
• proximal fibula elongation; and
• mild generalised metaphyseal changes.

ACH is caused by a pathogenic variant in one copy of the FGFR3 gene. Several other conditions, including hypochondroplasia and Muenke syndrome, can be caused by pathogenic variants in this gene. About 99% of patients with ACH have one of two pathogenic variants: 98% have the c.1138G>A (p.Gly380Arg) variant, and 1% have the c.1138G>C (p.Gly380Arg) variant.

Targeted FGFR3 c.1138 ‘hotspot’ testing for ACH is available within the National Genomic Test Directory; alternatively, testing can be performed as part of a broader test for skeletal dysplasias. For information about genomic testing, see Presentation: Clinical suspicion of achondroplasia (postnatal), Presentation: Clinical suspicion of hypochondroplasia and Presentation: Child with suspected skeletal dysplasia.

ACH is an autosomal dominant condition that commonly occurs as a result of a de novo pathogenic variant. If a parent of an affected individual has ACH, there is a 50% chance of them having another affected child. If neither parent has the FGFR3 pathogenic variant, there would be an estimated chance of recurrence for future children of less than 1% (due to the possibility of constitutional (germline) mosaicism in the parents). Increasing paternal age may also have an effect.

Management of children with ACH is complex and should be delivered via a multidisciplinary team, with monitoring of growth, development and musculoskeletal and neurological features.

For clinicians

• Achondroplasia.expert
• Central Manchester University Hospitals: Personal Child Health Record (PCHR) insert for babies born with achondroplasia (PDF, 22 pages)
• GeneReviews: Achondroplasia
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• OMIM: 100800 Achondroplasia (ACH)
• Skeletal Dysplasia Management Consortium: Best practice guidelines
• Skeletal Dysplasia Group (promotes teaching and research)
• US National Library of Medicine: ClinicalTrials.gov database

References:

• Firth HV, Hurst JA. ‘Oxford Desk Reference Clinical Genetics and Genomics, second edition’. Oxford University Press 2017: page 334. DOI: 10.1093/med/9780199557509.001.0001

For patients

• Restricted Growth Association UK
• Little People UK: Achondroplasia