Accessible Requires Authentication Published by De Gruyter September 15, 2017

Molecular genetic and clinical delineation of 22 patients with congenital hypogonadotropic hypogonadism

Kohei Aoyama, Haruo Mizuno, Tatsushi Tanaka, Takao Togawa, Yutaka Negishi, Kei Ohashi, Ikumi Hori, Masako Izawa, Takashi Hamajima and Shinji Saitoh



Congenital hypogonadotropic hypogonadism (CHH) is classified as Kallmann syndrome (KS) with anosmia/hyposmia or normosmic (n)CHH. Here, we investigated the genetic causes and phenotype-genotype correlations in Japanese patients with CHH.


We enrolled 22 Japanese patients with CHH from 21 families (18 patients with KS and 4 with nCHH) and analyzed 27 genes implicated in CHH by next-generation and Sanger sequencing.


We detected 12 potentially pathogenic mutations in 11 families, with three having a mutation in ANOS1 (X-linked recessive); three and four having a mutation in FGFR1 and CHD7, respectively (autosomal dominant); and one having two TACR3 mutations (autosomal recessive). Among four patients with KS carrying a CHD7 mutation, one had perceptive deafness and two had a cleft lip/palate.


The frequency of CHH genes in the Japanese was compatible with previous reports, except that CHD7 mutations might be more common. Furthermore, partial phenotype-genotype correlations were demonstrated in our cohort.

Corresponding author: Haruo Mizuno, MD, PhD, Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-Ku, Nagoya, 467-8601, Japan, Phone: +81-52-853-5311, Fax: +81-52-842-3449


We wish to thank the individuals and their families for their participation in this study, as well as the clinicians for providing patient samples and information. We thank the Core Laboratory, Nagoya City University Graduate School of Medical Sciences, and also Ms. Masami Banno, Ms. Yumiko Sato and Ms. Naomi Ogasawara (our laboratory staff).

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


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Received: 2017-1-23
Accepted: 2017-7-31
Published Online: 2017-9-15
Published in Print: 2017-10-26

©2017 Walter de Gruyter GmbH, Berlin/Boston