Abstract：
To date, over 200 families with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and over 600 families with Birt-Hogg-Dubé (BHD) syndrome have been reported, with low incidence. Here, we describe a patient with suspected rare HLRCC complicated by BHD syndrome. The proband (II1) had characteristic cutaneous leiomyoma-like protrusions on the neck and back, a left renal mass and multiple right renal, liver and bilateral lung cysts. Three family members (I1, II2, II3) had a history of renal cancer and several of the aforementioned clinical features. Two family members (II1, II3) diagnosed with fumarate hydratase (FH)-deficient papillary RCC via pathological biopsy carried two heterozygous variants: FH (NM_000143.3) missense mutation c.1189G>A (p.Gly397Arg) and FLCN (NM_144997.5) frameshift mutation c.1579_1580insA (p.Arg527Glnfs*75). No family member carrying a single variant had renal tumours. In HEK293T cells transfected with mutant vectors, mRNA and protein expression after FLCN p.Arg527Glnfs*75 and FH p.Gly397Arg mutations were significantly lower than those in wild-type (WT) cells. Cell immunofluorescence showed altered protein localisation and reduced protein expression after FLCN p.Arg527Glnfs*75 mutation. The FH WT was uniformly distributed in the cytoplasm, whereas FH protein expression was reduced after the p.Gly397Arg mutation and scattered sporadically with altered cell localisation. Patients with two variants may have a significantly increased penetrance of RCC.
摘要：
迄今为止,已经报道了200多个遗传性平滑肌瘤和肾细胞癌（HLRCC）的家庭和600多个Birt-Hogg-Dubé（BHD）综合征的家庭，发病率低。这里,我们描述了1例疑似罕见HLRCC并发BHD综合征的患者.先证者（II1）在颈部和背部有特征性的皮肤平滑肌瘤样突起，左肾肿块和多发性右肾，肝和双侧肺囊肿。三个家族成员（I1，II2，II3）有肾癌病史和几个上述临床特征。通过病理活检诊断为富马酸水合酶（FH）缺陷型乳头状RCC的两个家族成员（II1，II3）携带两个杂合变体：FH（NM_000143.3）错义突变c.189G>A（p。Gly397Arg）和FLCN（NM_144997.5）移码突变c.1579_1580insA（p。Arg527Glnfs*75）。没有携带单个变体的家庭成员患有肾肿瘤。在用突变载体转染的HEK293T细胞中，FLCNp.Arg527Glnfs*75和FHp.Gly397Arg突变后的mRNA和蛋白表达显著低于野生型(WT)细胞。细胞免疫荧光显示FLCNp.Arg527Glnfs*75突变后蛋白质定位改变和蛋白质表达降低。FHWT在细胞质中均匀分布，而FH蛋白表达在p.Gly397Arg突变后降低，并随细胞定位改变而零星分散。具有两种变体的患者可能具有显著增加的RCC的外显率。
