PDF(Pubmed)
Abstract：
The fibroblast growth factor receptors comprise a family of related but individually distinct tyrosine kinase receptors. Within this family, FGFR2 is a key regulator in many biological processes, e.g., cell proliferation, tumorigenesis, metastasis, and angiogenesis. Heterozygous activating non-mosaic germline variants in FGFR2 have been linked to numerous autosomal dominantly inherited disorders including several craniosynostoses and skeletal dysplasia syndromes. We report on a girl with cutaneous nevi, ocular malformations, macrocephaly, mild developmental delay, and the initial clinical diagnosis of Schimmelpenning-Feuerstein-Mims syndrome, a very rare mosaic neurocutaneous disorder caused by postzygotic missense variants in HRAS, KRAS, and NRAS. Exome sequencing of blood and affected skin tissue identified the mosaic variant c.1647=/T > G p.(Asn549=/Lys) in FGFR2, upstream of the RAS signaling pathway. The variant is located in the tyrosine kinase domain of FGFR2 in a region that regulates the activity of the receptor and structural mapping and functional characterization revealed that it results in constitutive receptor activation. Overall, our findings indicate FGFR2-associated neurocutaneous syndrome as the accurate clinical-molecular diagnosis for the reported individual, and thereby expand the complex genotypic and phenotypic spectrum of FGFR-associated disorders. We conclude that molecular analysis of FGFR2 should be considered in the genetic workup of individuals with the clinical suspicion of a mosaic neurocutaneous condition, as the knowledge of the molecular cause might have relevant implications for genetic counseling, prognosis, tumor surveillance and potential treatment options.
摘要：
成纤维细胞生长因子受体包括相关但各自不同的酪氨酸激酶受体家族。在这个家庭中,FGFR2是许多生物过程中的关键调节剂，例如，细胞增殖，肿瘤发生，转移,和血管生成。FGFR2中的杂合激活非镶嵌种系变体与许多常染色体显性遗传性疾病有关，包括几种颅骨滑膜病和骨骼发育不良综合征。我们报道了一个皮肤痣的女孩，眼部畸形,大头畸形,轻度发育迟缓,和Schimmelpenning-Feuerstein-Mims综合征的初步临床诊断，由HRAS的合子后错义变异引起的非常罕见的马赛克神经皮肤疾病，KRAS,和NRAS。血液和受影响的皮肤组织的外显子组测序鉴定了RAS信号传导途径上游FGFR2中的镶嵌变体c.1647=/T>Gp.(Asn549=/Lys)。该变体位于FGFR2的酪氨酸激酶结构域中的调节受体活性的区域中,并且结构作图和功能表征显示其导致组成型受体激活。总的来说,我们的研究结果表明，FGFR2相关的神经皮肤综合征是报告个体的准确临床分子诊断，从而扩大FGFR相关疾病的复杂基因型和表型谱。我们得出的结论是，在对临床怀疑为马赛克神经皮肤疾病的个体进行遗传检查时，应考虑对FGFR2进行分子分析。因为分子原因的知识可能对遗传咨询有相关的影响，预后,肿瘤监测和潜在的治疗选择。
