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.