Abstract
Hypochondroplasia (HCH) is a rare autosomal dominant skeletal dysplasia condition caused by FGFR3 mutations leading to disproportionate short stature. Classically HCH presents in toddlers or school-age children, as limb-to-trunk disproportion and is often mild and easily overlooked during infancy. We report experiences from a single-center UK HCH-cohort of 31 patients, the rate of antenatal HCH detection in our cohort (13/31, 41.9%) and describe relevant case-data for this subset of 13 patients. Inclusion criteria were patients with confirmed molecular HCH diagnosis (by age 3 years) and presenting with short long-bones or large head size on antenatal ultrasound scan. We then conducted a systematic literature review using PUBMED and MEDLINE, analyzing patients with HCH and related antenatal findings. Antenatally suspected (with subsequent molecular confirmation) HCH has been reported 15 times in the literature (2004-2019). Key markers (consistent in both groups) included reduced; femur length, humeral length and increased; biparietal diameter and head circumference. HCH is increasingly detected both antenatally and in infancy, contrary to previous descriptions. This is likely due to greater HCH awareness, improved imaging, and easier molecular testing. Thus, one should consider HCH outside the classical presenting period. Studying the natural history of younger patients with HCH is important with the advent of several targeted FGFR3 therapies currently in trials for Achondroplasia, that may soon be trialed in HCH.
Highlights
Hypochondroplasia (HCH), a rare genetic disorder, is a relatively common skeletal dysplasia (SD) condition caused by activating heterozygous mutations of the fibroblast growth factor receptor (FGFR3) gene (Bober, Bellus, Nikkel, & Tiller, 1999)
Knowing how early and in what way HCH presents in the unselected population is important, as some clinicians may discount the possibility of HCH in a child aged less than 2–3 years old based on the classical reported age of presentation
We have tried to ascertain those patients with molecularly confirmed HCH in both the reported literature and our large cohort of HCH patients, where HCH was detected antenatally or soon after birth, without a prior family history
Summary
The recent literature, demonstrates that HCH is clinically detectable earlier, even antenatally. This literature is often biased by patients with HCH with family history, priming clinicians to look for clinical features, rather than reflecting the earliest HCH detection in an unselected population. It does not reflect the unselected HCH presentation in the background population. Further bias includes patients reported without molecular confirmation of HCH, which considering the phenotypic overlap with other short stature conditions, creates doubt about the diagnostic accuracy or “purity” of the reports. On analysis of the local cohort, we further identify patients with HCH that are both molecularly confirmed and clinically diagnosed antenatally and report the antenatal detection rate of HCH for the first time
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