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

Naoko Sato, Noriyuki Katsumata, Masayo Kagami, Tomonobu Hasegawa, Naoaki Hori, Setsuyo Kawakita, Shigeru Minowada, Aki Shimotsuka, Yoshimasa Shishiba, Masato Yokozawa, Toshiyuki Yasuda, Keisuke Nagasaki, Daiichiro Hasegawa, Yukihiro Hasegawa, Katsuhiko Tachibana, Yasuhiro Naiki, Reiko Horikawa, Toshiaki Tanaka, Tsutomu Ogata

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Abstract

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.

Original languageEnglish
Pages (from-to)1079-1088
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume89
Issue number3
DOIs
Publication statusPublished - 2004 Mar

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Kallmann Syndrome
Receptor, Fibroblast Growth Factor, Type 1
Mutation
Exons
Genes
Fluorescence
Hypogonadism
Cleft Palate
Deafness
Tooth

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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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. / Sato, Naoko; Katsumata, Noriyuki; Kagami, Masayo; Hasegawa, Tomonobu; Hori, Naoaki; Kawakita, Setsuyo; Minowada, Shigeru; Shimotsuka, Aki; Shishiba, Yoshimasa; Yokozawa, Masato; Yasuda, Toshiyuki; Nagasaki, Keisuke; Hasegawa, Daiichiro; Hasegawa, Yukihiro; Tachibana, Katsuhiko; Naiki, Yasuhiro; Horikawa, Reiko; Tanaka, Toshiaki; Ogata, Tsutomu.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 89, No. 3, 03.2004, p. 1079-1088.

Research output: Contribution to journalArticle

Sato, N, Katsumata, N, Kagami, M, Hasegawa, T, Hori, N, Kawakita, S, Minowada, S, Shimotsuka, A, Shishiba, Y, Yokozawa, M, Yasuda, T, Nagasaki, K, Hasegawa, D, Hasegawa, Y, Tachibana, K, Naiki, Y, Horikawa, R, Tanaka, T & Ogata, T 2004, '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', Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 3, pp. 1079-1088. https://doi.org/10.1210/jc.2003-030476
Sato, Naoko ; Katsumata, Noriyuki ; Kagami, Masayo ; Hasegawa, Tomonobu ; Hori, Naoaki ; Kawakita, Setsuyo ; Minowada, Shigeru ; Shimotsuka, Aki ; Shishiba, Yoshimasa ; Yokozawa, Masato ; Yasuda, Toshiyuki ; Nagasaki, Keisuke ; Hasegawa, Daiichiro ; Hasegawa, Yukihiro ; Tachibana, Katsuhiko ; Naiki, Yasuhiro ; Horikawa, Reiko ; Tanaka, Toshiaki ; Ogata, Tsutomu. / 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. In: Journal of Clinical Endocrinology and Metabolism. 2004 ; Vol. 89, No. 3. pp. 1079-1088.
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abstract = "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.",
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T1 - 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

AU - Sato, Naoko

AU - Katsumata, Noriyuki

AU - Kagami, Masayo

AU - Hasegawa, Tomonobu

AU - Hori, Naoaki

AU - Kawakita, Setsuyo

AU - Minowada, Shigeru

AU - Shimotsuka, Aki

AU - Shishiba, Yoshimasa

AU - Yokozawa, Masato

AU - Yasuda, Toshiyuki

AU - Nagasaki, Keisuke

AU - Hasegawa, Daiichiro

AU - Hasegawa, Yukihiro

AU - Tachibana, Katsuhiko

AU - Naiki, Yasuhiro

AU - Horikawa, Reiko

AU - Tanaka, Toshiaki

AU - Ogata, Tsutomu

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N2 - 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.

AB - 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.

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