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5例Kallmann综合征患者的临床及遗传学分析
陈娇, 袁珂, 何敏菲, 王春林, 陈春, 方燕兰, 朱建芳, 梁黎
中国当代儿科杂志 ›› 2018, Vol. 20 ›› Issue (11) : 925-929.
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5例Kallmann综合征患者的临床及遗传学分析
Clinical and genetic features of Kallmann syndrome: an analysis of 5 cases
Kallmann综合征（KS）是一类罕见的儿科疾病，主要表现为嗅觉功能缺陷和低促性腺激素性腺功能减退。本文报道的5例KS患者就诊年龄为6月龄至19岁，男4例、女1例，均表现为低促性腺激素性腺功能减退，其中3例伴嗅觉功能缺陷（2例MRI发现嗅球发育不良），1例伴唇腭裂，1例婴儿期表现为小阴茎、隐睾、右肾缺如。5例患者染色体核型均正常，其父母临床表型均正常，1例的伯父自幼有第二性征发育不全伴嗅觉障碍。高通量测序发现2例存在已报道的FGFR1基因杂合错义突变，分别是c.1097C > T（p.P366L）、c.809G > C（p.G270A）；1例存在KAL1基因的新发移码突变：c.1877_1887/p.S627Tfs*6，该缺失突变碱基序列移码并产生截短蛋白，蛋白结构明显改变，具有高度致病性。KS临床和遗传异质性大，可伴不完全显性遗传，基因检测有助于诊断。
Kallmann syndrome (KS) is a rare pediatric disease with major manifestations of olfactory dysfunction and hypogonadotropic hypogonadism. Five children (4 boys and 1 girl) with KS reported in this article were aged between 6 months and 19 years at the time when they attended the hospital. All the children had the clinical manifestation of hypogonadotropic hypogonadism; in addition, three children had olfactory dysfunction (two were found to have olfactory bulb dysplasia on magnetic resonance imaging), one had cleft lip and palate, and one had micropenis and cryptorchidism with right renal agenesis during infancy. All the five children had normal karyotype and their parents had normal clinical phenotypes. The uncle of one child had underdeveloped secondary sexual characteristics and olfactory disorder since childhood. High-throughput sequencing found two known heterozygous missense mutations in the FGFR1 gene, i.e., c.1097C > T(p.P366L) and c.809G > C(p.G270A), in two children. One child had a novel frameshift mutation, c.1877_1887/p.S627Tfs*6, in the KAL1 gene; this deletion mutation caused a frameshift in base sequence and produced truncated proteins, which led to a significant change in protein structure, and thus it was highly pathogenic. It is concluded that KS has great clinical and genetic heterogeneity and can be accompanied by incomplete dominant inheritance and that gene detection helps with the diagnosis of this disease.
Kallmann综合征 / 基因 / 低促性腺激素性腺功能减退 / 儿童
Kallmann syndrome / Gene / Hypogonadotropic hypogonadism / Child
[1] Kim SH. Congenital hypogonadotropic hypogonadism and Kallmann syndrome:Past, present, and future[J]. Endocrinol Metab (Seoul), 2015, 30(4):456-466.
[2] Boehm U, Bouloux PM, Dattani MT, et al. Expert consensus document:European consensus statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment[J]. Nat Rev Endocrinol, 2015, 11(9):547-564.
[3] Pitteloud N, Meysing A, Quinton R, et al. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes[J]. Mol Cell Endocrinol, 2006, 254-255:60-69.
[4] Trarbach EB, Costa EM, Versiani B, et al. Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia[J]. J Clin Endocrinol Metab, 2006, 91(10):4006-4012.
[5] Dodé C, Fouveaut C, Mortier G, et al. Novel FGFR1 sequence variants in Kallmann syndrome, and genetic evidence that the FGFR1c isoform is required in olfactory bulb and palate morphogenesis[J]. Hum Mutat, 2007, 28(1):97-98.
[6] Teixeira L, Guimiot F, Dodé C, et al. Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions[J]. J Clin Invest, 2010, 120(10):3668-3672.
[7] Dodé C, Hardelin JP. Kallmann syndrome[J]. Eur J Hum Genet, 2009, 17(2):139-146.
[8] de Castro F, Esteban PF, Bribián A, el a1.The adhesion molecule anosmin-1 in neurology:Kallmann syndrome and beyond[J]. Adv Neurobiol, 2014, 8:273-292.
[9] FrancoB, Guioli S, Pragliola A, et al. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules[J]. Nature, 1991, 353(6344):529-536.
[10] Costa-Barbosa FA, Balasubramanian R, Keefe KW, et al. Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes[J]. J Clin Endocrinol Metab, 2013, 98(5):E943-E953.
[11] Quinton R, Duke VM, Robertson A, et al. Idiopathic gonadotrophin deficiency:genetic questions addressed through phenotypic characterization[J]. Clin Endocrinol(Oxf), 2001, 55(2):163-174.
[12] Salenave S, Chanson P, Bry H, el a1. Kallmann's syndrome:a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations[J]. J Clin Endocrinol Metab, 2008, 93(3):758-763.
[13] Nie M, Xu H, Chen R, el a1. Analysis of genetic and clinical characteristics of a Chinese Kallmann syndrome cohort with ANOS1 mutations[J]. Eur J Endocrinol, 2017, 177(4):389-398.
[14] Hu Y, Bouloux PM. Novel insights in FGFR1 regulation:lessons from Kallmann syndrome[J]. Trends Endocrinol Metab, 2010, 21(6):385-393.
[15] Miraoui H, Dwyer AA, Sykiotis GP, et al. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism[J]. Am J Hum Genet, 2013, 92(5):725-743.
[16] Pitteloud N, Acierno JS Jr, Meysing AU, et al. Reversible Kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene[J]. J Clin Endocrinol Metab, 2005, 90(3):1317-1322.
[17] Pitteloud N, Meysing A, Quinton R, et a1. Mutations in fibroblast growth factor receptor l cause Kallmann syndrome with a wide spectrum of reproductive phenotypes[J]. Mol Cell Endocrinol, 2006, 254-255:60-69
[18] 王伟. Kallmann综合征研究进展及儿科早期诊断[J]. 临床儿科杂志, 2008, 26(12):1010-1012.
[19] Koenigkam-Santos M, Santos AC, Versiani BR, el a1. Quantitative magnetic l-esonance imaging evaluation of the olfactory system in Kallmann syndrome:correlation with a clinical smell test[J]. Neuroendocrinology, 2011, 94(3):209-217.
[20] Zhang Z1, Sun X, Wang C, el a1. Magnetic resonance imaging findings in Kallmann syndrome:14 cases and review of the literature[J]. J Comput Assist Tomogr, 2016, 40(1):39-42.
[21] Kaplan JD, Bernstein JA, Kwan A, el a1. Clues to an early diagnosis of Kallmann syndrome[J]. Am J Med Genet A, 2010, 152A(11):2796-2801.
国家自然科学基金面上项目（11571309）。
