Handbook of Genetic Counseling/Neurofibromatosis - Type 1-3
Neurofibromatosis Type 1
Genetic Etiology
edit- 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
edit- NF1 is estimated to affect 1/3,500 people in the population
Diagnostic Criteria
edit- 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
edit- 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
edit- 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
edit- 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
edit- 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
edit- 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
edit- 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
edit- 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
edit- 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
editThe information in this outline was last updated in 2001.