Hypochondroplasia

Hypochondroplasia (HCH) is a type of skeletal dysplasia with similar features to achondroplasia (though features are milder). It is caused by pathogenic variants in the FGFR3 gene, and children may present with disproportionate short stature. A skeletal survey may not be diagnostic until the patient is over two years old.

Classically, HCH presents at the age of two as limb-to-trunk disproportion.

Though often mild and not detected in infancy, HCH has been reported antenatally (even de novo cases), with prenatal scans demonstrating a short femur or shortened long bones in some cases.

Clinical features are variable and typically include:

• shortening of the proximal (rhizomelia) or middle (mesomelia) segments of the limbs;
• short stature (often two to three standard deviations (2–3SD) below the mean, though it can be milder) or normal stature with limb-trunk disproportion;
• relative macrocephaly;
• joint laxity (often mild); and
• broad hands and feet with brachydactyly (short digits).

Less common features include:

• lumbar lordosis or scoliosis;
• mild to moderate intellectual disability;
• temporal lobe epilepsy; and
• acanthosis nigricans.

Medical complications (such as obstructive sleep apnoea, spinal stenosis, tibial bowing and adult-onset osteoarthritis) may occur, but are less common than in achondroplasia.

Radiological findings can include:

• brachydactyly;
• shortened fetal long bones with metaphyseal flare;
• shortened squared ilia;
• short and broad femoral neck; and
• narrowed inferior lumbar interpedicular distances.

HCH is caused by a pathogenic variant in one copy of the FGFR3 gene. Several other conditions, including achondroplasia and Muenke syndrome, can be caused by pathogenic variants in this gene. There are two common variants (c.1620C>A and c.1620C>G) that cause approximately 60% of all cases of HCH.

Targeted FGFR3 c.1620 testing for HCH is available within the National Genomic Test Directory; alternatively, testing can be performed as part of a broader test for skeletal dysplasias. For further information about genomic testing, see Presentation: Clinical suspicion of hypochondroplasia and  Presentation: Child with suspected skeletal dysplasia.

HCH is an autosomal dominant condition. It commonly occurs as a result of a de novo pathogenic variant. If a parent has HCH, there is a 50% chance of each of their children being affected. If parents do not have the FGFR3 pathogenic variant (which is detectable from a blood sample), there would be an estimated chance of recurrence in 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 HCH is complex and should be delivered via a multidisciplinary team, with monitoring of growth, development and musculoskeletal and neurological features.

For clinicians

• GeneReviews: Hypochondroplasia
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• OMIM: 146000 Hypochondroplasia (HCH)
• 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 335. DOI: 10.1093/med/9780199557509.001.0001
• Sabir AH, Sheikh J, Singh A and others. ‘Earlier detection of hypochondroplasia: A large single-center UK case series and systematic review’. American Journal of Medical Genetics Part A 2021: volume 185, issue 1, pages 73–82. DOI: 10.1002/ajmg.a.61912

For patients

• Restricted Growth Association
• Little People UK: Hypochondroplasia