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.