成纤维细胞生长因子受体1基因突变导致的卡尔曼综合征四例临床特点以及治疗转归

Clinical features and treatment outcome of four patients with Kallmann syndrome caused by fibroblast growth factor receptor-1 gene mutation

目的探讨因成纤维细胞生长因子受体1(FGFR1)基因突变而导致卡尔曼综合征(KS)患者的临床特点以及治疗转归,加深对疾病认识。方法对30例KS或嗅觉正常的特发性低促性腺激素性性腺功能减退(nIHH)患者行靶向二代测序,发现因FGFR1突变致KS患者4例,对其临床资料、实验室及影像学检查以及治疗转归等进行回顾性研究。结果4例患者均为男性,就诊年龄为11岁至22岁,均表现为小阴茎,伴嗅觉缺陷。其中2例有隐睾手术史;3例有唇腭裂手术史;较为严重的1例患者除唇腭裂、隐睾外,合并有身材矮小、耳畸形及牙齿发育不全。4例患者均存在FGFR1杂合突变,其中2例为点突变(p.Y374X;p.E670K),2例为移码突变(p.S346Yfs*61;p.S723*fs*1)。1例青年期就诊的患者GnRH脉冲泵治疗后可成功生育。结论因FGFR1突变导致KS的患者临床表现复杂,除嗅觉障碍外,在男性患者中主要表现为小阴茎、小睾丸和青春期发育延迟。唇腭裂等特征有助于早期识别,而明确诊断依赖于基因检测。脉冲式GnRH泵可使患者取得满意疗效,但起始治疗的年龄应根据患者的情况慎重考虑。

Objective To investigate the clinical features and treatment outcome of Kallmann syndrome(KS)caused by fibroblast growth factor receptor-1(FGFR1)gene mutation in 4 patients.Methods Targeted next-generation sequencing(NGS)was performed on thirty KS and normosmic idiopathic hypogonadotropic hypogonadism(nIHH)patients.FGFR1 mutation was identified in four KS patients.The clinical data,laboratory and imaging examinations,and treatment outcome were retrospectively analyzed.Results Four male patients,aging from 11 to 22 years old,presented as micropenis,and with olfactory dysfunction.Among them,two had history of cryptorchidism,three had history of cleft lip and palate repair surgery.The most severe patient presented with short stature,left microtia and dental agenesis.FGFR1 heterozygous mutation was identified in all four patients,two were point mutation(p.Y374X;p.E670K),and the other was frameshift mutation(p.S346Yfs*61;p.S723*fs*1).One patient,who started treatment of the pulsatile GnRH pump during his youth,succeeded in having two babies.Conclusion Patients with Kallmann syndrome caused by FGFR1 mutation presents complex clinical manifestations.Besides dysosmia,micropenis,microrchidia,and delayed pubertal development are the main clinical manifestations in male patients.Symptoms such as cleft lip and palate are helpful for early recognition.Genotyping analysis is crucial to confirm the diagnosis.The pulsatile GnRH pump can produce satisfactory therapeutic effect,but the age of initiating therapy should be carefully considered.