# Handbook of Genetic Counseling/Neurofibromatosis - Type 1-3

Neurofibromatosis Type 1

## Genetic Etiology

* Mode of inheritance:
** Autosomal dominant
** 50% of cases represent a new mutation
* Chromosome location:
** The gene for NF1 is located at chromosome 17q11.2
** The gene is very large, which is consistent with the large mutation rate
* Penetrance:
** High- but wide variability in expression

## Incidence

* NF1 is estimated to affect 1/3,500 people in the population

## Diagnostic Criteria

* NF1 is present in an individual who has two or more of the following signs:
** Six or more café au lait macules >5 mm in prepubertal individuals or >15 mm after puberty
** Two or more neurofibromas of any type, or one+ plexiform neurofibromas
** Freckling in the axilla or inguinal regions
** A tumor of the optic pathway (optic glioma)
** Two or more Lisch nodules
** Long bone bowing (w/ or w/o pseudarthrosis)
** A first-degree relative with NF1 by the above criteria

## Clinical Features

* Clinical features are extremely variable both between and within families
* Skin:
** Café-au-lait spots in ~94% of patients
** Axillary or inguinal freckling- common after 3 years of age
** Xanthogranulomas (2-5%)
* Eye:
** Optic glioma (often present at birth; occurs in 10-15% of patients)
** Lisch nodules- pigmented iris hamartomas (100% after the age of 20)
* Neurological:
** Neurofibromas- benign tumors arising from nerve cells that can occur anywhere in the body and are often associated with the skin.
** Plexiform neurofibromas- tumors along nerve bundle tracts, can be large and usually appear at birth or early in childhood (occur in ~25%)
** Malignant peripheral nerve sheath tumors arise in ~2-4% of individuals
** Headaches occur in >10% of patients
** Seizures and/or EEG abnormalities occur in ~20%
** Hydrocephalus occurs in ~5% of individuals
** Sensorineural hearing loss occurs in ~5% of patients
** Precocious puberty (2-5%)
* Orthopedic:
** Scoliosis
** Hypoplastic bowing of lower legs, with pseudoarthrosis at birth
** Short stature
** Macrocephaly
* Cognitive:
** Developmental delay
** Learning disabilities- hyperactivity and/or speech problems occur in 50%
** Mental retardation (8% of patients)
* Other-occasional:
** Syndactyly
** Glaucoma
** Ptosis
** Pruritis

## Risk of Occurrence/Recurrence

* The risk for an affected individual to have a child with NF1 is 50%
* The risk for each additional pregnancy is also 50%

## Natural History and Life Span

* Infancy:
** Café-au-lait spots
** Long bone bowing
** Developmental delay
** Optic glioma
** Plexiform neurofibroma
* Childhood:
** Neurofibromas
** Freckling patterns
** Learning disabilities
** Scoliosis
** Hypertension
* Adolescence:
** Worsening of existing condition
** Rarely malignant peripheral nerve sheath tumors develop
* Adulthood:
** Increase in neurofibromas
** Hypertension
** If other symptoms have not developed, they may do so at this time
* Decreased lifespan has been associated with the following features:
** Malignant peripheral sheath tumors
** Acute hydrocephalus
** Severe seizure
** Progressive spinal plexiform neurofibromas

## Testing

* Families with two or more affected individuals can use linkage analysis to identify carriers of the abnormal gene NF1
* Sporadic cases require direct mutational analysis of the gene, if presymptomatic testing is desired
* FISH can be used to detect microdeletions of chromosome 17q11.2
* Individuals with large deletions tend to have mental retardation and an increased tumor burden (approximately 5% of individuals with NF1 have whole gene deletions)

## Management and Treatment Options

* Individuals should be placed on surveillance programs
* Treatment includes treating the symptoms as they occur
** Learning difficulties: appropriate school placement, IEP
** Dermal neurofibromas: surgically remove if they are symptomatic
** Early recognition of long bone bowing can be accompanied with braces (which may help prevent fractures)
** MRI's should be scheduled to screen for optic gliomas
** Ophthalmologic exam to look for Lisch nodules
** Bracing for scoliosis
** Meds for seizures and headaches

## Differential Diagnosis

* Overlap primarily lies in cutaneous features, especially café-au-lait spots
** Consider: Russell-Silver, Bloom, Noonan, and Watson syndromes.
* For neurofibromas, consider:
** Bannayan-Riley-Ruvalcaba syndrome, Carney syndrome, Proteus syndrome etc.

## Additional Psychosocial Issues

* Risk for increased emotional and social problems
* Self-esteem issues associated with cosmetic concerns
* Reproductive concerns
* For parents, guilt issues as well as blame issues

## References

* Jones KL (1997). Smith's Recognizable Patterns of Human Malformation. Philadelphia: W.B. Saunders Company.
* Viskochil D, Chapter 14. (2001). Management of Genetic Syndromes. Ed. Allanson JE, Cassidy SB. New York: Wiley-Liss, Inc.

## Notes

The information in this outline was last updated in 2001.