Elsevier

The Lancet Neurology

Volume 6, Issue 4, April 2007, Pages 340-351
The Lancet Neurology

Review
Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective

https://doi.org/10.1016/S1474-4422(07)70075-3Get rights and content

Summary

Historically, neurofibromatosis 1 (NF1) has been inextricably linked with neurofibromatosis 2 (NF2). Both are inherited autosomal-dominant neurocutaneous disorders that have high de novo mutation rates and carry a high risk of tumour formation. However, they are clinically and genetically distinct diseases and should be considered as seperate entities. NF1 is a common disease that mainly affects the skin and peripheral nervous system and causes characteristic bony dysplasia. By contrast, NF2 is a rare disorder with a relative paucity of skin manifestations and high-grade malignancy is unusual. Neurological symptoms are the predominant problem and the cardinal sign is bilateral vestibular schwannomas. In this Review, I discuss the pertinent diagnostic, clinical, and genetic symptoms of NF1 and NF2. I also examine the current views on the pathogenesis of these neurocutaneous disorders in the wake of advances in molecular genetics and the development of mouse models of disease.

Introduction

Previously, neurofibromatosis 1 (NF1) was referred to as von Recklinghausen's disease and neurofibromatosis 2 (NF2) was termed bilateral acoustic or central neurofibromatosis.1, 2 Both disorders were independently documented in the historical literature. Mark Akenside provided a convincing account of NF1 when “in the year of 1761, a man about threescore years of age came to St. Thomas' Hospital…He had been accustomed during the greater part of his life to a constant succession of wens [tumours] that shot out in several places on his head, trunk, arms and legs: which indisposition he inherited from his father.”3 In 1822, NF2 was described in a young baker who presented to the Scottish surgeon James Wishart with progressive deafness affecting both ears. He succumbed to septicaemia after surgery for a cranial tumour. Post-mortem identified multiple tumours of the dura mater and brain in addition to bilateral tumours of the eighth nerve.4

Despite these early descriptions, NF1 and NF2 were not demarcated or defined as separate diseases until the end of the twentieth century.5 Recent progress in molecular biology, advances in neuroimaging, and the development of mouse models have provided an insight into the pathogenesis of these complex disorders and the prospect of drug treatment. In this Review, I discuss the current diagnostic and clinical features of NF1 and NF2 and the management of its complications. This Review will highlight the molecular advances that have permitted a biological approach to targeted therapies for tumours and the development of clinical trials.

Section snippets

Epidemiology and differential diagnosis

NF1 has a birth incidence of one in 2500 to one in 3000 and a minimum prevalence of one in 4–5000.6 The National Institute of Health (NIH) Consensus Development Conference formulated the current diagnostic criteria and proposed the name neurofibromatosis 1 (NF1; panel 1).5 Macrocephaly and stature at 10th–25th percentile are not diagnostic of the disorder, but are common minor disease characteristics.7

The conspicuous loophole in the NIH diagnostic stipulations is that café au lait patches may

Epidemiology and differential diagnosis

NF2 has a birth incidence of about one in 25 000 and an annual incidence of one in 2 355 000.86 The discrepancy between birth incidence and incidence of newly diagnosed symptomatic patients arises because many individuals do not develop clinical problems until adulthood and others die. The diagnostic prevalence of NF2 was reported in 1992 as one in 210 000, but is likely to be higher because patients' survival has increased and modern neuroimaging and genetic testing allows early diagnosis of

Conclusions

NF1 and NF2 are tumour predisposition syndromes, but undoubtedly they are distinct clinical and genetic disorders. The time is ripe to rename NF2, to indicate that the hallmark tumours are schwannomas and meningiomas. Progress in molecular biology and the burgeoning of mouse models offer the hope of understanding the pathogenesis of neurofibromas, schwannomas, and optic pathway gliomas, while enhancing our understanding of sporadic tumour formation. The task of twenty first century clinicians

Search strategy and selection criteria

The references were obtained between July and October, 2006, by consulting all publications in English and French on PubMed from 1980 to 2006, and the historical literature references were taken from the authors' doctoral thesis. Search terms were “NF1”, “NF2”, “neurofibroma”, “schwannoma”, “gastrointestinal stromal tumour”, “glomus tumour”, “neurofibromin”, and “merlin”.

References (119)

  • Y Verlinsky et al.

    Preimplantation diagnosis for neurofibromatosis

    Reprod Biomed Online

    (2002)
  • J Trofatter et al.

    A novel moesin-esrin-radixin-like gene is a candidate for the neurofibromatosis 2 tumour suppressor

    Cell

    (1993)
  • S Tsukita et al.

    ERM family: from cytoskeleton to signal transduction

    Curr Opin Cell Biol

    (1997)
  • FD von Recklinghausen

    Über die multiplen fibrome der haut und ihre Beziehung zu den multiplen neuromen

    (1882)
  • R Henneberg et al.

    Über centrale neurofibromatose und die Geschwülste des Kleinhirnbrückenwinkels (Acusticusneurome)

    Arch F Psychiatr

    (1903)
  • M Akenside

    Observations on cancers

    Med Trans Coll Phys Lon

    (1768)
  • JH Wishart

    Case of tumours in the skull, dura mater, and brain

    Edinburgh Med Surg J

    (1822)
  • Arch Neurol

    (1988)
  • SM Huson et al.

    A genetic study of von Recklinghausen neurofibromatosis in south east Wales: prevalence, fitness, mutation rate, and effect of parental transmission on severity

    J Med Genet

    (1989)
  • SM Huson et al.

    Von Recklinghausen neurofibromatosis: clinical and population study in South East Wales

    Brain

    (1988)
  • BR Korf

    Diagnostic outcome in children with multiple café au lait spots

    Paediatrics

    (1992)
  • LM Messiaen et al.

    Exhaustive mutation analysis of the NF1gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects

    Hum Mutat

    (2000)
  • BR Korf et al.

    The Phakamatoses

  • M Poyhonen et al.

    Hereditary spinal neurofibromatosis: a rare form of NF1?

    J Med Genet

    (1997)
  • M Ruggieri et al.

    The clinical and diagnostic implications of mosaicism in the neurofibromatoses

    Neurology

    (2001)
  • D Viskochil et al.

    Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus

    Cell

    (1990)
  • MR Wallace et al.

    Type 1 neurofibromatosis gene: identification of a larger transcript disrupted in three NF1 patients

    Science

    (1990)
  • D Viskochil et al.

    The gene encoding the oligodendrocyte-myelin glycoprotein is embedded within the neurofibromatosis type 1 gene

    Mol Cell Biol

    (1991)
  • CM Johannessen et al.

    The NF1 tumour suppressor critically regulates TSC2 and m TOR

    Proc Natl Acad Sci USA

    (2005)
  • KN North et al.

    Cognitive function and academic performance in neurofibromatosis. 1: consensus statement from the NF1 Cognitive Disorders Task Force

    Neurology

    (1997)
  • SL Hyman et al.

    The nature and frequency of cognitive deficits in children with neurofibromatosis type 1

    Neurology

    (2005)
  • VF Mautner et al.

    Treatment of ADHD in neurofibromatosis type 1

    Dev Med Child Neurol

    (2002)
  • DP DiPaolo et al.

    Neurofibromatosis type 1: pathologic substrate of high-signal-intensity foci in the brain

    Radiology

    (1995)
  • RE Ferner et al.

    The nature and evolution of increased intensity T2 weighted lesions and their relationship to intellectual impairment

    J Neurol Neurosurg Psychiatry

    (1993)
  • RM Costa et al.

    Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1

    Nature

    (2002)
  • MR Johnson et al.

    Detailed analysis of the oligodendrocyte myelin glycoprotein gene in four patients with neurofibromatosis 1 and primary progressive multiple sclerosis

    J Neurol Neurosurg Psychiatry

    (2000)
  • TL Rosser et al.

    Cerebrovascular abnormalities in a population of children with neurofibromatosis type 1

    Neurology

    (2005)
  • BR Korf et al.

    Patterns of seizures observed in association with neurofibromatosis type1

    Epilepsia

    (1993)
  • AK Afifi et al.

    Ventriculomegaly in neurofibromatosis 1: association with Chiari type 1 malformation

    Neurofibromatosis

    (1988)
  • A. Créange et al.

    Neurological complications of neurofibromatosis type 1 in adulthood

    Brain

    (1999)
  • R Listernick et al.

    Late-onset optic pathway tumours in children with neurofibromatosis 1

    Neurol

    (2004)
  • ML Bajenaru et al.

    Natural history of neurofibromatosis 1-associated optic nerve glioma in mice

    Ann Neurol

    (2005)
  • RJ Packer et al.

    Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas

    J Neurosurg

    (1997)
  • B Dasgupta et al.

    Proteomic analysis reveals hyper-activation of the mammalian target of rapacmycin pathway in neurofibromatosis 1-associated human and mouse brain tumours

    Cancer Res

    (2005)
  • K Lisch

    Ueber beteiligung der augen, inbesondere das Vorkommen von irisknotchen bei der neurofibromatose (Recklinghausen)

    Z Augenheilkunde

    (1936)
  • ML Lubs et al.

    Lisch nodules in neurofibromatosis 1

    N Engl J Med

    (1991)
  • A Richetta et al.

    Lisch nodules of the iris in neurofibromatosis type 1

    J Eur Acad Dermatol Venereol

    (2004)
  • T Yasunari et al.

    Frequency of choroidal abnormalities in neurofibromatosis type 1

    Lancet

    (2000)
  • L Dugoff et al.

    Neurofibromatosis type 1 and pregnancy

    Am J Med Genet

    (1996)
  • M Lammert et al.

    Do hormonal contraceptives stimulate growth of neurofibromas: a survey of 59 patients

    BMC Cancer

    (2005)
  • Cited by (379)

    • Integumentary system

      2023, Multi-system Imaging Spectrum associated with Neurologic Diseases
    • Establishment of an epithelioid sarcoma PDCs and PDX to evaluate drug sensitivity

      2022, Biochemical and Biophysical Research Communications
    View all citing articles on Scopus
    View full text