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NeurofibromatosisType 1 (NF1)
Von Recklinghausen Disease
By: Dr. Mahmoud Almutadares, House officer at KAU, MBBS
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
Optic Glioma
Lisch Nodules
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
5-10% >90%
Large 17q11 deletions
More sever phenotype
Intragenic Mutations
No clear-cut allele-phenotype correlations
3-bp frame deletion (c.2970-2972 del ATT) on exon 17
Absence of Dermal neurofibromas
No apparentinfluence
of the NF1 gene
1132 Individuals from 313 families
Cohort Family Studies
Trial Patients Families MZ Twins Siblings Parent-offspring 2nd
degree3rd
degreeTrial Patients Families MZ Twins Siblings Parent-offspring 2nd
degree3rd
degreeEaston et al
1993 175 48 6 76 60 54 43
Trial Patients Families MZ Twins Siblings Parent-offspring 2nd
degree3rd
degreeEaston 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
degree3rd
degreeEaston et al
1993 175 48 6 76 60 54 43
Szudek et al 2000 904 373 ALL
Sabbagh et al 2009 275 ALL
NF175% of families have an interfamilial difference in clinical features
NF1+/-
p53
MPNST
NF1+/- p53 +/-
NF1+/-
p53+/-
p53p53
NF1 NF1
p53p53
NF1 NF1
NF1 expression
level
CH11
Nstr1
Nstr2
11q12-13
5p13-15
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
1. Generate hypothesis and identifying candidate genes:– Understanding the biochemical function of NF1
2. Identifying variants (SNPs) near these genes3. Genotyping these variants in a populations
NF1+/-
NF1+/-
NF1-/- NF1+/-Miss MatchRepair Gene
MLH1MSH6PMS2MSH2
> Dermal Neurofibroma
PlexiformNeurofibroma
NF1+/+
SKP NF1+/-
NF1+/+ NF1+/+
Males and Non-Pregnant Females
Pregnant Females
NF1+/-
NF1+/-
NF1-/-
5% expressed estrogen receptors75% expressed progesterone receptors
• 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