三例散发I型神经纤维瘤病患者NF1基因突变检测

目的：对三例散发I型神经纤维瘤病(neurofibromatosis type 1,NF1)患者进行NFl基因检测。方法：提取3例患者及5名正常家系成员和100例无NF1家族史的正常人外周血DNA。PCR扩增NF1基因全部外显子及侧翼序列,经纯化后采用Sanger测序法对目标基因区域进行测序。结果：患者1,患者2和患者3分别检测到39号外显子发生碱基G缺失（c.5635 delG）,47号外显子大片段碱基缺失（c.7041～7062+4del）,21号外显子发生碱基A、C缺失（c.2714-2715delAC）。患者家属及100例正常对照均未检测到上述突变。结论：本研究在3例NFl患者中发现NFl基因3种新突变。     

三例散发Ⅰ型神经纤维瘤病NF1基因突变检测

目的:对3例Ⅰ型神经纤维瘤病(neurofibromatosis type1,NF1)患者及其家系进行致病基因突变检测。方法:应用目标序列捕获高通量测序技术对3例Ⅰ型神经纤维瘤病患者进行测序。患者检测出可疑突变类型后,应用多重连接探针扩增技术(multiplex ligation-dependent probe amplification,MLPA)及Sanger测序技术对患者及其家系成员进行突变位点验证。并采用SIFT、PolyPhen_2、Mutation Taster和GERP++软件对致病性不明的位点进行致病性预测。结果:3例Ⅰ型神经纤维瘤病患者分别检测到1个NF1基因变异:NF1基因整体杂合缺失、c.4064delC和Exon14_36del。其中c.4064delC与Exon14_36del未见文献报道,为新发突变。结论:本研究中3例Ⅰ型神经纤维瘤病患者中发现3个NF1基因突变,其中2个为新发突变,扩充了NF1基因突变位点。     

三例散发I型神经纤维瘤病NF1基因突变检测

目的：对3例I型神经纤维瘤病(neurofibromatosis type1, NF1)患者及其家系进行致病基因突变检测。方法：应用目标序列捕获高通量测序技术对3例I型神经纤维瘤病患者进行测序。患者检测出可疑突变类型后,应用多重连接探针扩增技术（multiplex ligation-dependent probe amplification, MLPA）及Sanger测序技术对患者及其家系成员进行突变位点验证。并采用SIFT、PolyPhen_2、Mutation Taster和GERP++软件对致病性不明的位点进行致病性预测。结果：3例I型神经纤维瘤病患者分别检测到1个NF1基因变异：NF1基因整体杂合缺失、c.4064delC和Exon14_36del。其中c.4064delC与Exon14_36del未见文献报道,为新发突变。结论：本研究中3例I型神经纤维瘤病患者中发现3个NF1基因突变,其中2个为新发突变,扩充了NF1基因突变位点。     

I型神经纤维瘤病NF1基因突变检测

目的：检测I型神经纤维瘤病患者的NF1基因突变。方法：提取I型神经纤维瘤病1家系、1例散发患者及200名正常对照外周血DNA,PCR扩增NF1基因全部外显子及侧翼序列并进行Sanger测序。结果：在家系的先证者及其母亲外周血DNA中检测到NF1基因c.3975-2 A〉T突变,其他家系成员未发现突变位点;在散发病例中检测到c.3619delA突变,为国际上首次报道。结论： I型神经纤维瘤病具有遗传基因异质性。     

RASA1 mutation in a family with capillary malformation–arteriovenous malformation syndrome: A discussion of the differential diagnosis

We describe a family who presented with several scattered, vascular, cutaneous lesions and was found to have a novel mutation in RASA1, diagnostic of capillary malformation–arteriovenous malformation syndrome. Our patient was initially given a presumptive clinical diagnosis of hereditary hemorrhagic telangiectasia. Capillary malformation–arteriovenous malformation syndrome shares several features with hereditary hemorrhagic telangiectasia and hereditary benign telangiectasia, but it can be distinguished clinically according to its morphologic appearance and distribution of cutaneous vascular lesions, the presence of internal fast‐flow lesions, and genetic analysis.     

Identification of a missense mutation causing exon skipping in a neurofibromatosis type 1 patient

Neurofibromatosis type 1 (NF1), caused by germ line mutations of the NF1 tumor‐suppressor gene, is one of the most common autosomal dominant disorders. Here, we reported a NF1 patient with the mutation NF1 c.4367+1G>C. This sequence change locates at the first nucleotide of NF1 intron 32 within the consensus splice site. Compared with NF1 c.4367G>C predicted to potentially damage the wild‐type donor site at c.4367, the NF1 c.4367+1G>C potentially abolishes this wild‐type donor site by in silico analysis. In vitro minigene assay revealed that the NF1 c.4367+1G>C may cause exon 32 skipping. Our result provides further evidence for its clinical significance of NF1 c.4367+1G>C in clinical practise.     

Review of 52 cases with Hailey–Hailey disease identified 25 novel mutations in Chinese Han population

Hailey–Hailey disease (HHD) is a rare autosomal dominant inherited keratosis caused by mutations in ATP2C1. The aim of our study was to identify and analyze the features of the mutations in HHD. We examined 52 Chinese Han cases which were diagnosed as HHD based on their clinical and histological findings. Genomic DNA polymerase chain reaction and direct sequencing of ATP2C1 were performed from peripheral blood samples of the patients and 100 unrelated healthy controls. Twenty‐five novel mutations and 14 recurrent mutations were identified, including 11 (28.2%) missense mutations, nine (23.1%) frame‐shift deletion mutations, eight (20.5%) nonsense mutations, seven (17.9%) splicing mutations and four (10.3%) frame‐shift insertion mutations. Together with ours, all 209 mutations showed a uniform distribution without hotspots or clusters. In addition, there is no specific genotype–phenotype correlation in HHD. Our findings update the spectrum of mutations in ATP2C1.     

A new COL3A1 mutation in Ehlers–Danlos syndrome type IV

The vascular type of the Ehlers–Danlos syndrome (Ehlers–Danlos syndrome type IV, EDS IV; OMIM #130050) is a rare connective tissue disorder with autosomal dominant transmission caused by mutations in the COL3A1 gene resulting in increased fragility of connective tissue with arterial, intestinal, and uterine ruptures and premature death. We present a 28‐year‐old female who in addition to typical EDS IV symptoms had severe peripheral artery occlusive disease (PAOD) and subtotal stenosis of the abdominal aorta. COL3A1 sequencing resulted in detection of an as yet undescribed mutation in exon 36 at position 2465 leading to a nucleotide replacement (c.2465G>C; p.G822A). Ultrastructural analysis of a skin biopsy revealed abnormal morphology and distribution of dermal collagen fibres. We conclude that PAOD is a possible manifestation of EDS IV and that further research is required to define its true prevalence among patients with EDS IV and its molecular pathology including genotype–phenotype correlation.     

Novel mutations in Chinese Han patients with tuberous sclerosis complex: Case series and review of the published work

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomas in multiple organ systems. This study was performed in one familial and two sporadic cases with TSC. Two novel mutations (c.1884_1887delAAAG and c.5266A>G) and two previously reported mutations (c.4258_4261delTCAG and c.1960G>C) were identified by direct DNA sequencing. Of the four mutations, c.1884_1887delAAAG and c.1960G>C were found in a family and identified in the same allele by TA cloning sequencing. However, c.1960G>C was reported to be non‐pathogenic. Furthermore, correlations between genotypes and phenotypes of Chinese Han patients since 2014 were performed by paired χ²‐tests in our published work review, which has not been reported. The results showed that patients with TSC2 mutations had a higher frequency of mental retardation and there were no significant differences of seizures and skin lesions with TSC1 mutations. Genetically, they had a higher frequency of familial inheritance.     

Anthropometric characteristics and comorbidities in Japanese patients with neurofibromatosis type 1: A single institutional case–control study

Neurofibromatosis type 1 (NF1) is a well‐known genetic disorder characterized by café‐au‐lait spots and neurofibromas, but many other clinical characteristics and associated comorbidities also have been reported. This study aimed to characterize NF1 further by investigating its association with anthropometric characteristics and other diseases. We performed a case–control study of 227 NF1 patients (101 male, 126 female) and a randomly selected age‐ and sex‐matched control group of 681 non‐NF1 patients (303 male, 378 female) who visited our institution in Japan. We examined adult (≥20 years) height and body mass index (BMI), and, in the total sample, allergic diseases (bronchial asthma [BA], atopic dermatitis [AD] and allergic rhinitis) and other respiratory cardiovascular and psychiatric disorders. In adults, the mean BMI was lower in the NF1 group than in the control group, and was significantly statistically different among men (P = 0.0238). In the whole sample, the prevalences of BA (P = 0.0184), AD (P = 0.0144) and valvular heart disease (P = 0.0166) were significantly greater in the NF1 group than in the control group. To date, no similar research on the BMI or the prevalence of allergic disease in NF1 patients has been reported. Our results suggest that NF1 patients tend to have lower BMI and may have alterations in specific metabolic pathways and altered allergic immunity.     

Genotype‐phenotype correlation in type 1 neurofibromatosis: pMet992del mutation and milder disease

A few genotype‐phenotype correlations have been described in type 1 neurofibromatosis. One deletion, p.Met992del, seems to be responsible for a mild form of the condition, in which there is absence of externally visible neurofibromas. We report a mother and a son with this mutation.     

Coexistence of neurofibromatosis 1 and chiari type I malformation: an unusual association

Neurofibromatosis 1 (NF-1) is a relatively common, autosomally dominant disorder, comprised of characteristic skin lesions. NF-1 is also associated with a variety of cerebral dysplasias. We describe a patient with both NF-1 and Chiari type I malformation. The frequency of this correlation depends on the magnetic resonance imaging (MRI) findings in patients with NF-1, because some cases of Chiari malformations are asymptomatic. Awareness and further observation of this unusual association are required, and Chiari type I malformation should be added to the differential diagnosis of the central nervous system dysplasias in patients affected by NF-1.     

1型神经纤维瘤病NF1基因突变检测

目的 检测1例1型神经纤维瘤病(NF1)患者NF1基因的突变.方法 采用PCR和DNA测序法检测1例NF1患者、2例直系亲属及100例无亲缘关系的正常人NF1基因突变.结果 在NF1患儿中检测到1个移码突变c.3822delC,患者直系亲属及100例无亲缘关系的正常对照均未检测到上述突变.结论 在该例NF1患儿中新发现1个NF1基因移码突变c.3822delC不是罕见的单核苷酸多态性,可能是致病突变,通过影响NF1基因的功能致病.     

Topical sirolimus as an effective treatment for a deep neurofibroma in a patient with neurofibromatosis type I

A 14‐year‐old boy with neurofibromatosis type I (NF1) presented with a painful neurofibroma on his right palm. The lesion was treated with topical sirolimus, resulting in decreased size and pain and improvement in motor function of his hand. This case demonstrates the efficacy of topical sirolimus in the management of neurofibromas in NF1.