Transcript Neurofibromatosisx

Neurofibromatosis
Type 1 (NF1)
Von Recklinghausen Disease
By: Dr. Mahmoud Almutadares,
House officer at KAU, MBBS
Objectives
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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
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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
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Short statured
Café-au-lait (CAL) spots
Freckling
Lisch Nodules
Neurofibromas
Optic gliomas
Café-au-lait
Freckles
Dermal
Neurofibromas
Plexiform
Neurofibroma
Lisch Nodules
Optic Glioma
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%
Intragenic Mutations
Large 17q11
deletions
More sever
phenotype
No clear-cut allele-phenotype
correlations
3-bp frame deletion (c.29702972 del ATT) on exon 17
Absence of Dermal neurofibromas
1132 Individuals
from 313 families
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
Sabbagh et al
2009
275
ALL
ALL
75% of
families have
an
interfamilial
difference in
clinical
features
p53
p53
NF1
NF1
p53
p53
NF1
NF1
NF1
expression
level
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 genes
3. Genotyping these variants in a populations
MLH1
MSH6
PMS2
MSH2
> Dermal
Neurofibroma
SKP NF1+/-
Males and Non-Pregnant
Females
Pregnant Females
5% expressed estrogen receptors
75% 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
•CDKN2A-CDNK2B-ARF
•ANRIL
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