1. 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

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

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

4. 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

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

6. Café-au-lait
Freckles

7. Plexiform Neurofibroma
Dermal Neurofibromas
Plexiform Neurofibroma

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

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

10. 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.

11. Molecular basis of NF1

12. 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 del ATT) on exon 17
Absence of Dermal neurofibromas

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

14. 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

15. 75% of families have an interfamilial difference in clinical features
NF1

16. NF1+/-
mpnst
p53

17. NF1+/-
p53 +/-
p53
NF1
p53
NF1
NF1+/-
p53+/-

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

19. 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.

20. 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

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

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

23. 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

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

25. 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:
Heim RA, Silverman LM, Farber RA, Kam-Morgan LNW, Luce MC. Screening for truncated NF1 proteins. Nature Genet. 8: , 1994. 
Trovo-Marqui AB, Tajara EH. Neurofibromin: a general outlook. Clin. Genet. 70: 1-13, 2006. 

26. Thank you