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 ACH caused by the Gly380Arg variant exhibit similar clinical presentations and can easily be confused, variants associated with ACH are also considered.

References

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