FGFR3基因R248C突变致不成比例矮小伴特殊面容和黑棘皮病一例及文献复习

Craniofacial features with disproportionate short stature and acanthosis nigricans caused by a R248C mutation in FGFR3:A case report and literature review

目的:分析1例成纤维细胞生长因子受体3(fibroblast growth factor receptor 3,FGFR3)基因突变所致不成比例矮小伴特殊面容和黑棘皮病患者的临床表型,并分析其临床表型与基因型间的相关性。方法:患儿为男性,13岁,表现为类克鲁宗综合征(类Crouzon综合征)面容、严重身材矮小(不匀称性矮小)和全身严重黑棘皮病。收集其临床资料,并进行生化、糖脂代谢、内分泌激素水平检测,同时行皮肤病理、骨X线片等检查。抽取患儿及父母全血提取基因组DNA进行全外显子测序及DNA Sanger测序验证,同时复习相关文献进行综合分析。结果:实验室检验结果显示,其存在不伴高血糖的轻度胰岛素抵抗,而生长激素水平正常;影像学检查未提示其存在软骨发育不良和(或)不全、短头畸形及面中部发育不良等表现,但有轻度脊柱侧凸;皮肤病理活检结果提示表皮乳头瘤样增生,符合黑棘皮病病理表现。对患者及父母进行全外显子测序,发现该患者存在FGFR3基因的新发突变(NM00142:c.742C>T;Chr4:1803564;p.R248C),经美国医学遗传学与基因组学学会指南(2015)评估,该位点为致病突变。结论:本文首次报道了由于经典型FGFR3 R248C突变而表现出类克鲁宗综合征面容、轻微骨骼发育不良和进行性加重的黑棘皮病的特殊表型病例,建议当医师发现患者表现为身材矮小或特殊面容,尤其是伴有早发黑棘皮病时,需考虑进行FGFR3基因突变检测。

Objectives:To analyze the correlation between clinical phenotype and genotype in a patients presenting with Crouzon-like facial appearance,disproportionate short stature and acanthosis nigricans(AN)caused by fibroblast growth factor receptor 3 gene(FGFR3)mutation.Methods:The 13-year-old boy presented craniofacial dysmorphic features,with disproportionate short stature and severe acanthosis nigricans.The clinical data was retrieved and the laboratory parameters of glucose and lipid metabolism,and endocrine hormone were acquired.The results of skin pathology and bone X-ray examination were analyzed.The DNA sample was extracted from peripheral blood withdrawn from the proband and family members for whole-exome sequencing(WES)and Sanger sequencing.Results:Laboratory examination revealed normal hormone level and slight insulin resistance without hyperglycemia.Skeletal survey showed no evidence of midface hypoplasia,brachycephaly or achondroplasia.Skin biopsy identified cutaneous papillomatosis consistent with the manifestations of AN.A spontaneous mutation(NM00142:c.742 C>T;Chr4:1803564;p.R248 C)was identified in FGFR3 by whole-exome sequencing,a causative gene established by American College of Medical Genetics and Genomics(ACMG)guidelines.Conclusions:The report described for the first time a case presenting Crouzon-like facial appearance with mild skeletal dysplasia and progressive acanthosis nigricans caused by classical R248 C mutation in FGFR3.Sequencing of FGFR3 should be considered in patients with short stature or subtle dysmorphic features,especially accompanied by signs of early onset AN.