The Clinical Manifestation And Mutation Study Of NF1 Gene On Segmental Neurofibromatosis

Background Neurofibromatosis type 1(NF1)is a common autosomal dominant disorder.The clinical manifestation of NF1 is cutaneous cafe-au-lait spots,skin fold freckling,neurofibromas,iris hamartomas(Lisch nodules),neuroglioma,learning disabilities,epilepsy,skeletal anomalies and so on.Segmental neurofibromatosis(SNF)is a rare variant of NF1,is clinically characterized by typical features of NF1 limited to specific body regions.NF1 gene is mapped on chromosome 17q11.2,encoding neurofibromin.NF1 is considered to be a tumor-suppressor gene,which mainly negatively regulates Ras signal pathway by NF1 gene transcript called neurofibromin,participating in the growth and differentiation of cell and tumor formation.To date,about 2600 mutations in the NF 1 gene have been recorded on The Human Gene Mutation Database,the types of mutations in which included missense,synonymy,nonsense,splicing,insertion,deletion,repeat mutations.Most mutations could cause truncation protein.A lot of researches on NF1 gene mutations were carried out at home and abroad,the genotype/phenotype correlations are still indeterminate.Objective To identify NF1 gene mutations in one baby girl with SNF,who presented with cafe-au-lait macules distributed diffusedly over the right side of head and face,and exophthalmos of the right eye,expand database of NF1 gene mutation and provide a foundation of genetic consultation,prenatal diagnosis,genetic diagnosis in NF1.And to further illustrate the correlations of genotype and phenotype in neurofibromatosis type 1 on the basis of research results.Methods We collected the blood samples of the patient with SNF and her parents.Genomic DNA was extracted from peripheral blood.All the coding exons of NF 1 gene were amplified by polymerase chain reaction and products analyzed by direct sequencing.The images and data of magnetic resonance imaging(MRI)and ophthalmological examination were collected.Results(1)Clinical findings:A large area of well-demarcated,smoothing caf6-au-lait macule was distributed diffusedly over the right side of the head and face,trunk and limbs.The exophthalmos of the right eye was found accompanied with palpebral and corneal edema.The eyesight of her right eye was found decreased obviously.The power of the griping of her left hand was weaker than that of the right hand.MRI demonstrated cavernous malformation with remote hemorrhage and brain atrophy in the right hemisphere and diencephalon.MRI also indicated exophthalmos,slightly thickened right optic nerve and enlarged and deformed vitreous in her right eye.Ophthalmological examination showed an increased IOP and a clinical diagnosis of secondary glaucoma was made by the ophthalmologist.(2)NF1 mutations identifications and analysis direct DNA sequencing revealed six point mutations in exon 13,one point mutation in exonl8,one heterozygous deletion mutation in exon 30 and two point mutations in 3’ untranslated regions.They are c.1400C>T、c.1448A>G、c.1458A>G、c.1461A>G、c.1466A>G、c.1513A>G、c.2034G>A、chrl7:31248997-/G、chrl7:31376357 G>A、chrl7:31376421 C>G.Apart from the mutation c.1466A>G encoding p.Tyr489Cys reported previously,the other nine were first reported.Four missense mutations including p.Thr467Ile,p.Asp483Gly,p.Tyr489Cys and p.Lys505Glu,which encoded by c.1400C>T,c.1448A>G,c.1466A>G and c.1513A>G in the mRNA of NF1,were predicted to be damaging by PolyPhen.CONCLUSION These mutations c.1400C>T,c.1448A>G,c.1458A>G,c.1461A>G,c.1466A>G,c.1513A>G,c.2034G>A,chrl7:31248997-/G,chrl7:31376357 G>A,chrl7:31376421 C>G extend the database of known mutations in NF1 gene,may be pathogenic cause for this SNF case,and may be associated with unilateral exophthalmos,unilateral caf6-au-lait macules,cerebral cavernous malformation and unilateral atrophy in the brain.