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At a glance

Phakomatoses are multisystem disorders that primarily affect the skin and the CNS. Part of the RASopathies. Neurofibromatosis (NF) Type I (NF-I), also called von Recklinghausen disease, is a rare genetic disorder characterized by the development of multiple neurofibromas of the nerves and skin. The presence of café-au-lait spots on the skin of the trunk and other regions, as well as freckling, particularly in the axillary region and in the inguinal area is a characteristic. Often evident by age 1 year, the café-au-lait spots tend to increase in size and number over time. At birth or early childhood, plexiform neurofibromas may be present. Benign tumor-like nodules of the colored regions of the eyes (Lisch nodules) may be present.

Synonyms

Type I: Neurofibromatosis von Recklinghausen; Fibromatosis Molluscum Multiplex; Elephantiasis Neuromatoses; von Recklinghausen disease; Legius Syndrome.

Classification

Neurofibromatosis is more a spectrum of disorders classified as follows (Riccardi):

  • NF-I, or Peripheral NF: It is best known as von Recklinghausen neurofibromatosis (VRNF).

  • NF-II, or Central NF: It is bilateral acoustic neuroma NF (BANF).

  • NF-III: It appears to combine at least some features of Types I and II.

  • NF-IV: It represents a heterogeneous category (Lisch nodules in the iris are absent).

  • NF-V, or Segmental NF: It is restricted in its involvement of the body.

  • NF-VI: It manifests primarily as café-au-lait spots without neurofibromas.

  • NF-VII: It is a late-onset variety.

  • NF-NOS and NF1-Like (Legius Syndrome): They represent forms of NF that do not appear to fit into categories I to VII of this classification.

Incidence

Approximately 1:3,000 in the general population. One million patients estimated in 1987 worldwide. NF-I = 1:4,000, NF-II = 1:50,000 in the general population.

Genetic inheritance

Usually autosomal dominant, but heterogenic (half of probands represent new mutations). The NF-I defect is on chromosome 17q11.2, and NF-II is caused by mutations of the NF2 gene on chromosome 22q12. Approximately 50% of cases of NF1 are familial, and the remaining cases occur sporadically. NF1 gene produces neurofibromin, which is considered a tumor-suppressor gene-controlling cell proliferation, differentiation, and interaction. NF2 gene produces merlin or schwannomin. Mutations in the SPRED1 gene on chromosome 15q13.2 are responsible for the NF1-like (Legius) Syndrome. Differential diagnosis is difficult due to significant phenotypic overlap. Café-au-lait spots may appear in syndromes as different as Bannayan-Riley-Ruvalcaba, Jaffe-Campanacci, ☞LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and deafness), and ☞Tuberous Sclerosis.

Pathophysiology

The NF1 gene encodes for the protein neurofibromin, which acts as a guanine triphosphatase (GTPase)-activating protein (GAP) and is important in cell growth and signaling pathways, participating in downregulating the tumor-suppressing RAS-MAPK pathway. The NF2 gene encodes for the protein merlin (also known as schwannomin), a ...

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