Loss-of-Function SOX10 Mutation in a Patient with Kallmann Syndrome, Hearing Loss, and Iris Hypopigmentation

Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder consisting of hypogonadotropic hypogonadism and anosmia. KS is occasionally associated with deafness. Recently, mutations in SOX10, a well-known causative gene of Waardenburg syndrome (WS) characterized by deafness, skin/hair/iris hypopigmentation, Hirschsprung disease, and neurological defects, have been identified in a few patients with KS and deafness. However, the current understanding of the clinical consequences of SOX10 mutations remains fragmentary.

A Japanese male patient presented with sensory deafness, blue irises, and anosmia, but no hair/skin hypopigmentation, Hirschsprung disease, or neurological abnormalities. He showed no pubertal sex development at 15.1 years of age. Blood examinations revealed low levels of FSH and testosterone.

Molecular analysis detected a de novo p.Leu145Pro mutation in SOX10, which has previously been reported in a patient with WS and Hirschsprung disease. The mutation was predicted to be probably damaging. The mutant protein barely exerted in vitro transactivating activity.

These results highlight the significance of SOX10 haploinsufficiency as a genetic cause of KS with deafness. Importantly, our data imply that the same SOX10 mutations can underlie both typical WS and KS with deafness without skin/hair hypopigmentation, Hirschsprung disease, or neurological defects.