Service d'ORL et de Chirurgie Cervico-Faciale and CESEM, UMR, Paris-Descartes School of Medicine, Paris V University, Paris, France.
Eur J Endocrinol. 2012 Dec 10;168(1):31-7. doi: 10.1530/EJE-12-0578. Print 2013 Jan.
Isolated congenital anosmia (ICA) is a rare phenotype defined as absent recall of any olfactory sensations since birth and the absence of any disease known to cause anosmia. Although most cases of ICA are sporadic, reports of familial cases suggest a genetic cause. ICA due to olfactory bulb agenesis and associated to hypogonadotropic hypogonadism defines Kallmann syndrome (KS), in which several gene defects have been described. In KS families, the phenotype may be restricted to ICA. We therefore hypothesized that mutations in KS genes cause ICA in patients, even in the absence of family history of reproduction disorders.
In 25 patients with ICA and olfactory bulb agenesis, a detailed phenotype analysis was conducted and the coding sequences of KAL1, FGFR1, FGF8, PROKR2, and PROK2 were sequenced.
Three PROKR2 mutations previously described in KS and one new PROK2 mutation were found. Investigation of the families showed incomplete penetrance of these mutations.
This study is the first to report genetic causes of ICA and indicates that KS genes must be screened in patients with ICA. It also confirms the considerable complexity of GNRH neuron development in humans.
孤立性先天性嗅觉缺失症（ICA）是一种罕见的表型，定义为自出生以来对任何嗅觉感觉均无记忆，且不存在任何已知导致嗅觉缺失的疾病。尽管大多数 ICA 病例为散发性，但家族病例报告提示存在遗传原因。由于嗅球发育不全并伴有促性腺激素释放激素缺乏的 ICA 定义为 Kallmann 综合征（KS），其中已描述了几种基因缺陷。在 KS 家族中，表型可能仅限于 ICA。因此，我们假设 KS 基因的突变会导致患者出现 ICA，即使他们没有家族生殖障碍病史。
在 25 名 ICA 合并嗅球发育不全的患者中，进行了详细的表型分析，并对 KAL1、FGFR1、FGF8、PROKR2 和 PROK2 的编码序列进行了测序。
发现了三个先前在 KS 中描述的 PROKR2 突变和一个新的 PROK2 突变。对这些家庭的调查显示，这些突变存在不完全外显率。
本研究首次报道了 ICA 的遗传原因，并表明 KS 基因必须在 ICA 患者中进行筛查。它还证实了人类 GnRH 神经元发育的复杂性。
