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