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Neurofibromatosis types 1 and 2 (NF1 and NF2), tuberous sclerosis complex (TSC1 and TSC2), and von Hipple-Lindau disease (VHL) are neurocutaneous disorders that are loosely classified as phakomatoses. Neurocutaneous conditions are also discussed in Chapter 578.

The phakomatoses are generally autosomal dominant conditions that show a consistent pattern of abnormal growth of various tissues, and each affected individual has unique and unpredictable manifestations. The variability of clinical expression of cutaneous manifestations and tumors distinguishes each of these disorders, and this variability has multiple causes, including modifier loci, somatic mutation, and simple stoichiometry in cells with haploinsufficiency of the respective neurocutaneous gene. Somatic mutation leading to inactivation of the normal neurocutaneous gene allele, termed second hits or loss of heterozygosity (LOH), in individuals who have a constitutional mutation is a common theme and suggests that genes causing neurocutaneous disorders fit the paradigm of tumor suppressors. Characterization of these genes has led to the identification of biochemical pathways involved in intracellular growth signaling pathways; this information led to the development of novel therapeutic regimens strategically targeted to the regulation of growth of benign tumors associated with these conditions.

Clinical Aspects

Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disorder, affecting approximately 1 in 3000 people worldwide. The hallmark features of NF1, café au lait spots and benign cutaneous neurofibromas, typically arise in early childhood and adolescence, respectively. Approximately two thirds of individuals with NF1 have manifestations that generally do not require clinical intervention, whereas the remaining one third display myriad medical complications which are unpredictable, both in timing and severity.

Even though NF1 has been recognized as von Recklinghausen disease by the medical community since the 19th century, both its variability and age dependence of clinical manifestations made it essential to develop a well-accepted set of clinical criteria to establish the diagnosis (eTable 182.1).1-3 The typical clinical manifestations allow the diagnosis to be established in children by 10 years.4 By virtue of full penetrance in the adult population, diagnosis of NF1 is more straightforward in familial cases because it requires only one physical manifestation in addition to an affected first-degree relative. In sporadic cases, NF1-related associations that are not part of the diagnostic criteria sometimes appear prior to the development of a second diagnostic sign.

eTable 182.1. Diagnostic Criteria for Neurofibromatosis 1 (NF1)

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