Chapter 141. The Neurofibromatoses

Robert Listernick; Joel Charrow

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Neurofibromatosis Type 1 at a Glance

Autosomal dominant condition with incidence of 1 in 3,000 live births.
Diagnosed clinically if two major features are present (see Table 141-1).
Cutaneous neurofibromas:
- Softer than the surrounding connective tissue and protrude just above the skin surface or lie just under the skin with an overlying violaceous hue.
Subcutaneous neurofibromas:
- Arise from peripheral nerves, both under the skin and deep in the viscera.
- Generally much harder.
Plexiform neurofibromas:
- Generally present at birth or apparent during the first several years of life.
- May lead to disfigurement, blindness (secondary to amblyopia, glaucoma, or proptosis), loss of limb function, or organ dysfunction by compression of vital structures.
Segmental neurofibromatosis type 1 (NF-1):
- Manifestations of NF-1, usually limited to one area of the body.
- Occurs as result of a postconceptional mutation in the NF-1 gene, leading to somatic mosaicism.

Table 141-1 Diagnostic Criteria for NF-1 (Two or More Required for Diagnosis)

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Table 141-1 Diagnostic Criteria for NF-1 (Two or More Required for Diagnosis)

Six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals, and over 15 mm in postpubertal individuals
Two or more neurofibromas of any type or one plexiform neurofibroma
Freckling in the axillary or inguinal regions
Optic glioma
Two or more iris Lisch nodules
A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudarthrosis
A first-degree relative (parent, sibling, or offspring) with NF-1 by the above criteria

The “modern age” of neurofibromatosis began in 1981, with Riccardi's detailed clinical descriptions of the features and natural history of von Recklinghausen disease and the subsequent description of “central neurofibromatosis with bilateral acoustic neuroma.” With the availability of gene-based diagnosis, several distinct clinical syndromes have been identified: (1) neurofibromatosis type 1 (NF-1), also known as von Recklinghausen disease; (2) neurofibromatosis type 2 (NF-2), whose cardinal feature is the development of bilateral vestibular schwannomas; (3) segmental or mosaic NF-1; (4) Legius syndrome (SPRED1 mutation) leading to autosomal dominant transmission of café-au-lait spots, intertriginous freckling and macrocephaly; and (5) schwannomatosis. Both NF-1 and NF-2 occur equally in all ethnic groups. NF-1 occurs at an incidence of 1 in 3,000 live births, whereas NF-2 is much less common with an estimated incidence of 1 in 40,000 live births.

Genetics

NF-1 is inherited in an autosomal dominant fashion. Although the expressivity of NF-1 varies considerably, even among individuals in the same family who are genotypically identical, the disorder is considered to be 100% penetrant. Thus, apparent skipping of NF-1 between generations may be the result of misdiagnosis, nonpaternity, or the occurrence of a new mutation in the grandchild. Although a large number of NF1 mutations have been described, only two genotype-phenotype correlations have been noted. Individuals who have deletions of the entire NF1 gene have an increased risk ...

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