neurofibromatosis type 1 (nf1) von recklinghausen disease
DESCRIPTION
Neurofibromatosis Type 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. - PowerPoint PPT PresentationTRANSCRIPT
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NeurofibromatosisType 1 (NF1)
Von Recklinghausen Disease
By: Dr. Mahmoud Almutadares, House officer at KAU, MBBS
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Objectives
• Epidemiology of NF1• Neurofibromin gene• Clinical features of NF1• Molecular basis of NF1• Gene strategies to identify modifier genes
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Epidemiology
• Birth incidence: 1:2500• Prevalence of 1:4000• Autosomal Dominant with variable expression
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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
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Clinical Features
• Short statured• Café-au-lait (CAL) spots• Freckling• Lisch Nodules• Neurofibromas• Optic gliomas
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Café-au-lait
Freckles
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Plexiform Neurofibroma
Dermal Neurofibromas
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Optic Glioma
Lisch Nodules
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Distinctive osseous lesion such as sphenoid dysplasia or cortical thinning of long bones
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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.
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Molecular basis of NF1
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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
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No apparentinfluence
of the NF1 gene
1132 Individuals from 313 families
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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
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NF175% of families have an interfamilial difference in clinical features
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NF1+/-
p53
MPNST
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NF1+/- p53 +/-
NF1+/-
p53+/-
p53p53
NF1 NF1
p53p53
NF1 NF1
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NF1 expression
level
CH11
Nstr1
Nstr2
11q12-13
5p13-15
8q22-24
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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.
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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
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NF1+/-
NF1+/-
NF1-/- NF1+/-Miss MatchRepair Gene
MLH1MSH6PMS2MSH2
> Dermal Neurofibroma
PlexiformNeurofibroma
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NF1+/+
SKP NF1+/-
NF1+/+ NF1+/+
Males and Non-Pregnant Females
Pregnant Females
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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
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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
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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.
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Thank you