Handbook of Genetic Counseling/Neurofibromatosis - Type 1-3

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Neurofibromatosis Type 1

Genetic Etiology

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  • 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


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

Diagnostic Criteria

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  • 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

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  • 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

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  • 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

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  • 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


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  • 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

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  • 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

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  • 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

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  • 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


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  • 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.


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The information in this outline was last updated in 2001.