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
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
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DOI：
10.1210/jc.2003-030476
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发表时间：
2004-03-01
影响因子：
5.8
通讯作者：
Ogata, T
中科院分区：
文献类型：
--
作者：
Sato, N;Katsumata, N;Ogata, T
我们报告了25名男性和3名女性10-53岁Kallmann综合征(KS)的临床和分子表现。10名男性来自5个家庭，其余15名男性和3名女性显然是散发性病例。对Kallmann综合征1(KAL1)和成纤维细胞生长因子受体1(FGFR1，又称KAL2)进行了所有编码外显子的序列分析、基于PCR的缺失分析和荧光原位杂交(FISH)分析，在7例家族性和4例散发性男性病例中发现了6个新的和2个复发的KAL1基因内突变，在2个散发性男性病例中发现了2个新的基因内突变。此外，在3个家族性病例和1个受邻近基因综合征影响的散发性男性病例中，发现了涉及VCX-A、STS、KAL1和OA1的Xp22.3亚显微缺失。对15例KAL1基因突变男性的临床评估显示，2例男性嗅觉功能正常或接近正常，7例男性右侧显性肾损害，此外15例男性均有不同程度的性腺激素减退(HH)，13例男性嗅觉障碍。两名携带FGFR1突变的男性患有高血压和嗅觉障碍，缺乏其他特征。在其余11例无明显KAL1或FGFR1突变的患者中，临床特征包括1例女性右肾发育不全，1例男性腭裂，1例男性腭裂和感觉性耳聋，1例男性牙齿发育不全和感觉性耳聋，以及不同程度的HH和嗅觉功能障碍。结果表明：1)KAL1突变在日本患者中可能比先前估计的在高加索患者中更普遍，并可能与明显正常的嗅觉功能有关；2)FGFR1突变约占KS患者的10%，正如先前在高加索患者中所报道的那样，并可导致HH和嗅觉功能障碍的表型；3)以KAL1突变为特征的肾发育不全和以FGFR1突变为特征的腭裂和牙齿发育不全可发生在没有KAL1和FGFR1突变的患者中。
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.