Neurofibromatosis (overview) Q85.0

Author: Prof. Dr. med. Peter Altmeyer

All authors of this article

Last updated on: 29.10.2020

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Synonym(s)

M. Recklinghausen; neurofibromatosis generalisata; NF; Recklinghausen disease; Recklinghausen M.

History
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Akenside, 1768; Tilesius von Tilenau, 1793; Smith, 1849; von Recklinghausen, 1882

Definition
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Group of hereditary, autosomal-dominantly inherited or spontaneously mutated neuroectodermal systemic diseases in which 8 types can currently be distinguished from a clinical and genetic point of view (see Table 1). The main symptom is neurofibroma.

Classification
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  • Type I Peripheral neurofibromatosis, also called classical or cutaneous NF, 85% of all cases. Autosomal dominant inherited defect of the NFI gene (Neurofibromatosis-1 gene; gene locus: 17q11.2). It is characterized by cafe-au-lait spots and visible neurofibromas.
  • Type II central neurofibromatosis, uni- or bilateral acoustic neuroma (hearing loss often the first symptom at 20-30 years of age); café-au-lait spots only in about 50% of cases, no Lisch nodules. In this form of neurofibromatosis an autosomal dominant mutation of both alleles in the NFII gene (Neurofibromatosis-2 gene; gene locus: 22q12.2) with consecutive disruption of the expression of the tumor suppressor protein Merlin (acronym for Moesin-Ezrin-Radixin like protein) also called Schwannomin (see below).
  • Type III Central-peripheral neurofibromatosis (palmo-plantar neurofibromatosis)
  • Type IV Atypical neurofibromatosis (heterogeneous group). Autosomal-dominantly inherited inversions on gene locus 12q21-12q24.2.
  • Type V Segmental neurofibromatosis, very rare, somatic mutation
  • Type VI Familial-intestinal neurofibromatosis (multiple café-au-lait spots without neurofibromas)
  • Type VII Neurofibromatosis Pheochromocytoma Duodenal Carcinoid System (NPDC)
  • Type VIII Neurofibromatosis-Noonan syndrome (syn. Watson syndrome), complex form of peripheral neurofibromatosis (NF type I) with the clinical phenotype of Noonan syndrome (short stature, ptosis, midface hypoplasia, pterygium colli, learning disabilities and muscle hypotension). Autosomal dominant inherited defect of the NFNS gene (neurofibromatosis-noonan syndrome gene; gene locus: 17q11.2) with consecutive defect of neurofibromin.

Occurrence/Epidemiology
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Incidence: 30-40 patients/100,000 inhabitants; about 1 child affected/2,500-3,300 births. In about 50% of cases a new mutation is probable.

Manifestation
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Pigmentation spots appear from birth or in childhood, tumours mainly during puberty. Men are more frequently affected than women.

Localization
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Whole integument, especially the hull.

Clinical features
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The clinical picture varies according to the type of expression of neurofibromatosis (see table).

  • Pigmentary spots: café-au-lait spots, axillary freckling, pigmentation of the oral mucosa.
  • Nevi: melanocytic nevi, hemangiomas and lymphangiomas, lentigines, nevi spili.
  • Single or numerous, pea-sized or monstrous, skin-coloured to bluish, broad or stalked papules or nodules (neurofibromas), possibly with wrinkling or as dewlap-like formations, cutis laxa. Bell-button phenomenon: subcutaneous tumours which protrude like hernia through the skin can be pushed back with one finger.
  • Skeleton: Kyphoscoliosis, pointed foot, cystic dilatations, thickenings and extensions of the tubular bones.
  • Eyes: Lisch nodules, characteristic of NF1, do not occur in NF2, NF3 and NF4. For the diagnosis of NF1 s. Table 2.

Histology
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According to the neurofibroma.

Diagnosis
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Diagnosis is likely to be made on 2 or > 2 applicable criteria:
  • At least 6 café-au-lait stains (before puberty: > than 0.5 cm in diameter, then > 1.5 cm in diameter)
  • Axillary or inguinal pigmentation (axillary freckling)
  • At least 2 neurofibromas or 1 plexiform neurofibroma.
  • A first-degree relative with peripheral neurofibromatosis.
  • At least 2 Lisch nodules.
  • Bone lesions.

Differential diagnosis
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Complication(s)
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Neurofibromas also occur on internal organs, spinal and cranial nerve roots with neurological symptoms.

Therapy
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  • Dermatologically relevant are especially café-au-lait stains and neurofibromas. Cosmetically disturbing or painful, rapidly growing tumours are excised. Important in the treatment is the regular comprehensive examination of the patient and his relatives at least once a year in order to detect the development of new tumours early! Otherwise genetic counselling, prenatal diagnostics is theoretically possible for the peripheral NF and the central NF (type II).
  • Remember! Regular neurological, ophthalmological and ENT medical examinations are required!

Progression/forecast
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Quoad vitam cheap. Increase of tumours during life in number and size. In 5% sarcomatous degeneration with metastasis ( neurofibrosarcoma).

Tables
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Symptoms of peripheral type neurofibromatosis (type I)

Main symptoms

at least 6 Café-au-lait stains > 1,5cm(85%
); Start: from the age of 1 year

Neurofibromas (≤ 2) or a plexiform neurofibroma
(100%); Start: childhood/puberty

Lisch nodules = pigmented Irish armartomas; ≥ 2 (93%) (slit lamp examination!); Start: childhood

Freckle-like pigmentation axillary (axillary freckling
) or inguinal (70%); Start: from the age of 3 years

Side symptoms and complications

Learning disability (29.8%)

Mental disability (3.2%)

Seizures (4.2%)

hydrocephalus (2.1%)

Neurogenic malignancies, CNS or peripheral (4.4-5.2%)

Optic glioma (0.7%)

Premature or delayed onset of puberty (2.1%) Scoliosis (5.2%)

Pseudoarthroses (2.1%)

Hemihypertrophy (4.7%)

Gastrointestinal neurofibromas (2.1%)

Renal artery stenoses (2.1%)

Neurofibromatosis von Recklinghausen (NF1) can be diagnosed when 2 or more of the main symptoms are present

Note(s)
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According to the Knudson hypothesis, type II neurofibromatosis requires the mutation of both alleles of the NF-2 gene in order to develop tumours. This is the case with autosomal dominant inheritance.

If only 1 allele is affected, either due to a germ cell mutation or a de novo mutation ("first hit"), tumour development can occur in the course of life from cells that lose the physiological function of the remaining, normal(wild-type) NF2 allele ("second hit").

Literature
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  1. Akenside M (1768) Observations on cancers. Med Trans Coll Phys Lond 1: 64
  2. Chiasson-MacKenzie C et al (2015) NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin. J Cell Biol 211:391-405.

  3. Dugoff L et al (1996) Neurofibromatosis type 1 and pregnancy. At J Med Genet 66: 7-10
  4. Hirata D et al (2003) of Recklinghausen disease in a patient with X-linked agammaglobulinemia. Internal Med 41: 1039-1043
  5. Okazaki M et al (2003) The mechanism of epidermal hyperpigmentation in cafe-au-lait macules of neurofibromatosis type 1 (von Recklinghausen's disease) may be associated with dermal fibroblast-derived stem cell factor and hepatocyte growth factor. Br J Dermatol 148: 689-897
  6. Smith RW (1849) Pathology, Diagnosis and Treatment of Neuroma. Hodges & Smith, Dublin
  7. Ruiz Villaverde R et al (2003) Phacomatosis pigmentovascularis and Lisch nodules. Relationship between Von Recklinghausen and phakomatosis pigmentovascularis? J Eur Acad Dermatol Venereol 17: 53-55
  8. Tilesius of Tilenau WG (1793) Historia pathologica singularis entis turpitudinus. Jo Godofredi Rheinhardi viri 50 Annorum. SL Crusins, Leipzig
  9. By Recklinghausen FD (1882) On multiple fibromas of the skin and their relation to multiple neuroma. In: Studies in honour of Rudolph Virchow, August Hirschwald, Berlin
  10. Walther MM et al (2003) from Recklinghausen's disease and pheochromocytomas. J Urol 162:1582-1586

Disclaimer

Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

Authors

Last updated on: 29.10.2020