Neurofibromatosis Type 1 (NF1) Von Recklinghausen Disease 4/1/2017 Neurofibromatosis Type 1: An Approach Neurofibromatosis Type 1 (NF1) Von Recklinghausen Disease By: Dr. Mahmoud Almutadares, House officer at KAU, MBBS Dr. Mahmoud Almutadares

Objectives Epidemiology of NF1 Neurofibromin gene Clinical features of NF1 Molecular basis of NF1 Gene strategies to identify modifier genes

Epidemiology Birth incidence: 1:2500 Prevalence of 1:4000 Autosomal Dominant with variable expression

Neurofibromin 1 Located in 17q11.2 Approximately 350kb and contains 61 exons A tumor suppressor gene. Encodes for Neurofibromin Over 300 different mutations reported worldwide

Clinical Features Short statured Café-au-lait (CAL) spots Freckling Lisch Nodules Neurofibromas Optic gliomas

Café-au-lait Freckles

Plexiform Neurofibroma Dermal Neurofibromas Plexiform Neurofibroma

Neurofibromatosis Type 1: An Approach 4/1/2017 Neurofibromatosis Type 1: An Approach Lisch Nodules Optic Glioma Dr. Mahmoud Almutadares

Distinctive osseous lesion such as sphenoid dysplasia or cortical thinning of long bones

Expressivity Expressivity is the variations in a phenotype among individuals carrying a particular genotype, it is analogous to the severity of a condition in clinical medicine. Variable expressivity occurs when a phenotype is expressed to a different degree among individuals with the same genotype.

Molecular basis of NF1

No clear-cut allele-phenotype correlations 5-10% >90% Intragenic Mutations Large 17q11 deletions No clear-cut allele-phenotype correlations More sever phenotype 3-bp frame deletion (c.2970-2972 del ATT) on exon 17 Absence of Dermal neurofibromas

No apparent influence of the NF1 gene 1132 Individuals from 313 families No apparent influence of the NF1 gene

Cohort Family Studies Trial Patients Families MZ Twins Siblings Parent-offspring 2nd degree 3rd degree Easton et al 1993 175 48 6 76 60 54 43 Szudek et al 2000 904 373 ALL Sabbagh et al 2009 275 Trial Patients Families MZ Twins Siblings Parent-offspring 2nd degree 3rd degree Easton et al 1993 175 48 6 76 60 54 43 Szudek et al 2000 904 373 ALL Trial Patients Families MZ Twins Siblings Parent-offspring 2nd degree 3rd degree Easton et al 1993 175 48 6 76 60 54 43 Trial Patients Families MZ Twins Siblings Parent-offspring 2nd degree 3rd degree

75% of families have an interfamilial difference in clinical features NF1

NF1+/- mpnst p53

NF1+/- p53 +/- p53 NF1 p53 NF1 NF1+/- p53+/-

NF1 expression level Nstr1 11q12-13 ch11 5p13-15 Nstr2 8q22-24

Gene strategies to identify modifier genes Approach scanning the whole genome Approach focusing on candidate genes Number of variants are generally small. However, detailed understanding of the candidate gene product.

Candidate gene approach Generate hypothesis and identifying candidate genes: Understanding the biochemical function of NF1 Identifying variants (SNPs) near these genes Genotyping these variants in a populations

> Dermal Neurofibroma NF1+/- NF1-/- Miss Match Repair Gene NF1+/- MLH1 MSH6 PMS2 MSH2 Plexiform Neurofibroma > Dermal Neurofibroma NF1+/-

Males and Non-Pregnant Females NF1+/+ SKP NF1+/- NF1+/+ NF1+/+ Males and Non-Pregnant Females Pregnant Females

NF1-/- NF1+/- NF1+/- 5% expressed estrogen receptors 75% expressed progesterone receptors NF1+/- NF1 patients typically develop dermal neurofibromas around puberty Increased potential for malignant transformation of plexiform neurofibromas with pregnancy

Whole genomic gene approach Pasmant et al CDKN2A-CDNK2B-ARF ANRIL Tag SNPs In 1105 subjects (306 families): Allele T of SNP rs2151280 was strongly associated with plexiform neurofibromas

Refrences Nelson Textbook of pediatric, 19th edition Oxford Handbook of Clinical Medicine, 8th edition Pasmant E, Vidaud M, Vidaud D, Wolkenstein P. Neurofibromatosis type 1: from genotype to phenotype. J Med Genet 2012;49:483-489 Heim RA, Silverman LM, Farber RA, Kam-Morgan LNW, Luce MC. Screening for truncated NF1 proteins. Nature Genet. 8: 218-219, 1994.  Trovo-Marqui AB, Tajara EH. Neurofibromin: a general outlook. Clin. Genet. 70: 1-13, 2006. 

Thank you