In addition to hypogonadotropic hypogonadism, 44.4% (8/18) patients exhibited other clinical deformities, including dental agenesis (3/18, 16.7%), hearing loss (3/18, 16.7%), and hand malformation (2/18, 11.1%). hCG/hMG therapy was effective in promoting sexual development in IHH patients with FGFR1, FGF8, and FGF17 mutations.
In a clinical sense, recognizing those IHH genes and associated phenotypes may improve our diagnostic capabilities by enabling us to prioritize the screening of particular gene(s) such as synkinesia (ANOS1), dental agenesis (FGF8/FGFR1) and hearing loss (CHD7).
Currently, the fibroblast growth factor receptor 1 (FGFR1) gene is the only known autosomal dominant cause of KS, which is also associated with synkinesia, midfacial defects, and dental agenesis.
Heterozygous FGFR1 mutations were found in three of seven unrelated nIHH probands with normal MRI of the olfactory system: (i) G237S in an nIHH female and a KS brother; (ii) (P722H and N724K) in an nIHH male missing two teeth and his mother with isolated hyposmia; and (iii) Q680X in a nIHH male with cleft lip/palate and missing teeth, his brother with nIHH, and his father with delayed puberty.
The results suggest the following: 1) KAL1 mutations might be more prevalent in the Japanese patients than previously estimated in the Caucasian patients and can be associated with apparently normal olfactory function; 2) FGFR1 mutations account for approximately 10% of KS patients, as previously reported in the Caucasian patients, and can result in HH and olfactory dysfunction-only phenotype; and 3) renal aplasia, which is characteristic of KAL1 mutations, and cleft palate and dental agenesis, which are characteristic of FGFR1 mutations, can occur in patients without KAL1 and FGFR1 mutations.