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