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Clinical Assessment and Mutation Analysis of Kallmann Syndrome 1 (KAL1) and Fibroblast Growth Factor Receptor 1 (FGFR1, or KAL2) in Five Families and 18 Sporadic Patients

National Research Institute for Child Health and Development (N.S., N.K., M.K., T.O.), Tokyo 154-8567; Keio University School of Medicine (T.H., N.H.), Tokyo 160-8582; Toki General Hospital (S.K.), Gifu 509-5122; International Medical Center of Japan (S.M.), Tokyo 113-8655; Kushiro City General Hospital (A.S.), Kushiro 085-0822; Mishuku Hospital (Y.S.), Tokyo 153-0051; Sapporo Medical University (M.Y.), Sapporo 060-8556; Chiba National Hospital (T.Y.), Chiba 260-8606; Niigata Graduate School of Medical and Dental Sciences (K.N.), Niigata 951-8510; Hyogo Prefectural Kobe Children’s Hospital (D.H.), Hyogo 654-0081; Tokyo Metropolitan Kiyose Children’s Hospital (Y.H.), Tokyo 204-8567; Kanagawa Children’s Medical Center (K.T.), Kanagawa 232-8555; and National Center for Child Health and Development (Y.N., R.H., T.T.), Tokyo 154-8535, Japan

Address all correspondence and requests for reprints to: N. Sato or T. Ogata, Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo 154-8567, Japan. E-mail: naoko{at}nch.go.jp or tomogata{at}nch.go.jp.

We report on the clinical and molecular findings in 25 males and three females with Kallmann syndrome (KS) aged 10–53 yr. Ten males were from five families, and the remaining 15 males and three females were apparently sporadic cases. Molecular studies were performed for Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, also known as KAL2) by sequence analysis for all the coding exons, by PCR-based deletion analysis, and by fluorescence in situ hybridization (FISH) analysis, showing six novel and two recurrent intragenic KAL1 mutations in seven familial and four sporadic male cases and two novel intragenic FGFR1 mutations in two sporadic male cases. In addition, submicroscopic deletions at Xp22.3 involving VCX-A, STS, KAL1, and OA1 were identified in three familial cases and one sporadic male case affected by a contiguous gene syndrome. Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in two males and right-side dominant renal lesion in seven males, in addition to variable degrees of hypogonadotropic hypogonadism (HH) in all the 15 males and olfactory dysfunction in 13 males. The two males with FGFR1 mutations had HH and anosmia and lacked other features. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in one female, cleft palate in one male, cleft palate and perceptive deafness in one male, and dental agenesis and perceptive deafness in one male, in addition to a variable extent of HH and olfactory dysfunction.

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.

This work was supported by grants for Child Health and Development (13C-1 and 14C-1) from the Ministry of Health, Labor, and Welfare, by a grant from the Foundation for Growth Science, and by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture (15591150).

Abbreviations: FISH, Fluorescence in situ hybridization; FGFR1, fibroblast growth factor receptor 1; hCG, human chorionic gonadotropin; HH, hypogonadotropic hypogonadism; KAL1, Kallmann syndrome 1; KS, Kallmann syndrome; MRI, magnetic resonance imaging; T, testosterone; WAP, whey acidic protein.

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