HYPOCHONDROPLASIA

Hypochondroplasia (HCH) is an autosomal-dominantly inherited syndrome characterized by disproportionate short stature, primarily due to rhizomelic shortening of the limbs, similar to achondroplasia. However, the symptoms are generally much milder than those observed in achondroplasia and other FGFR3-related disorders. In HCH patients, there is no deformity of the tibia, the fibula is not elongated, and the growth curves overlap with those of normal children.

The disease is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene (FGFR3) that lead to either direct activation or dimerization of the receptor, resulting in its constitutive activation (gain-of-function).

The dysregulation of enchondral ossification, which results in growth inhibition, occurs through various signal transduction pathways. In about 60% of patients, the most common variant causative for HCH is Asn540Lys.

Since severe cases of HCH caused by the Asn540Lys variant and mild cases of achondroplasia caused by the Gly380Arg variant exhibit similar clinical presentations and can easily be confused, variants associated with achondroplasia are also considered.

References

Arenas et al. 2018, J Pediatr Endocrinol Metab 31:1279 / Ornitz et Legeai-Mallet 2017, Dev Dyn 246:291 / Massart et al. 2015, Pharmacogenomics 16:1965 / Pinto et al. 2014, Horm Res Paediatr 82:355 / Heuertz et al. 2006, Eur J Hum Genet 14:1240 / Zabel 2004, medgen 16:8 / Van Esch et al. 2004, Genet Counsel 15:375 / Wilkin 2001 in: The Metabolic & Molecular Basis of Inherited Disease 5379 / Vajo et al. 2000, Endocr Rev 21:23 / Shiang et al. 1994, Cell 78:335 / Rousseau et al. 1994, Nature 371:252