Paeds · genetics-dysmorphology-and-metabolism
Neurofibromatosis type 1 and type 2
Also known as NF1 · von Recklinghausen disease · NF2 · MISME syndrome · Bilateral acoustic neurofibromatosis · Phakomatoses · RASopathy
A fellowship approach to neurofibromatosis type 1 and type 2: recognise the child with multiple cafe-au-lait macules and freckling as NF1 until proven otherwise, confirm clinically with the NIH criteria and molecularly with NF1 sequencing, build multidisciplinary surveillance around optic glioma, plexiform neurofibroma and learning difficulty, and separate NF2 entirely as a chromosome-22 disorder of bilateral vestibular schwannomas and meningiomas managed in a specialist tumour clinic.
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Target exams
Red flags
- Six or more cafe-au-lait macules in any child, especially with axillary or inguinal freckling — apply the NIH diagnostic criteria for NF1
- A plexiform neurofibroma that is painful, rapidly growing, or changing in texture — suspect malignant peripheral nerve sheath tumour
- A child with NF1 reporting visual decline, proptosis, or precocious puberty — investigate optic pathway glioma urgently
- An adolescent or young adult with progressive unilateral or bilateral hearing loss and tinnitus — evaluate for vestibular schwannoma and consider NF2
- Hypertension in a child with NF1 — exclude renal artery stenosis and phaeochromocytoma before attributing it to essential causes
- Early-onset or juvenile cataracts alongside cranial nerve signs — a recognised first presentation of NF2
- A first-degree relative of a confirmed case who has not had genetic assessment — cascade testing is mandatory for both conditions
Life stages
Care settings
Clinical exam formats
Board mappings
- NIH diagnostic criteria for neurofibromatosis type 1
- Recognition of cafe-au-lait macules and freckling
- Indications for NF1 genetic testing
- NF1 and NF2 molecular genetics and tumour spectrum
- Multidisciplinary surveillance and MEK-inhibitor therapy
- Distinguishing Legius syndrome and the schwannomatoses
- Assessing a child with suspected neurofibromatosis
- Genetic counselling of an autosomal-dominant tumour syndrome
- Coordinating ophthalmology, oncology and developmental support
- Long case of a child with cafe-au-lait macules and learning difficulty
- Counselling a family on NF1 versus NF2 and reproductive risk
- Genetic causes of neurodevelopmental disability and tumour predisposition
- Communication in lifelong chronic genetic disease
- Safeguarding and transition to adult care
- Neurofibromatosis type 1 genetics and diagnostic criteria
- Neurofibromatosis type 2 and the schwannomatoses
- Optic pathway glioma and plexiform neurofibroma management
- Skin and dysmorphology examination of the child with NF1
- Counselling on genetic testing and surveillance results
- Neurofibromatosis type 1 and type 2
- Evaluation of the child with cafe-au-lait spots
- Genetic counselling and cascade family testing
- Neurofibromatosis type 1
- Phakomatoses and tumour-predisposition syndromes
- Multidisciplinary care of chronic genetic disease
- Optic pathway glioma surveillance
- Multidisciplinary care of inherited tumour syndromes
The mark-winning candidate keeps three layers in view at once. The first is the child in front of you: their skin, their vision, their learning, their blood pressure, and the tumours that are and are not there. The second is the molecular mechanism: a lost tumour suppressor that fails to brake cell growth, neurofibromin in NF1 and merlin in NF2, working through completely different pathways. The third is the family: an autosomal-dominant condition with 50 per cent transmission means every first-degree relative deserves assessment and counselling. [1] [3]
Overview & Definition
Neurofibromatosis type 1 is an autosomal-dominant disorder caused by loss-of-function variants in the NF1 gene on chromosome 17q11.2, which encodes neurofibromin, a protein that switches off active RAS and restrains cell proliferation. When neurofibromin is absent, the RAS-MAPK pathway runs unchecked in Schwann cells, melanocytes and glia, producing the cafe-au-lait macules, freckling, neurofibromas and optic pathway gliomas that define the condition. NF1 is the commonest of the phakomatoses and a member of the RASopathies, a family of developmental disorders linked by dysregulated RAS signalling. [1] [10]
Neurofibromatosis type 2 is a clinically and genetically distinct disorder caused by variants in the NF2 gene on chromosome 22q12.2, which encodes merlin (also called schwannomin), a cytoskeletal tumour suppressor that maintains contact-dependent growth inhibition. Loss of merlin drives the growth of bilateral vestibular schwannomas together with meningiomas, spinal ependymomas and peripheral neuropathy. NF2 is roughly ten times rarer than NF1 and is managed as a tumour-predisposition syndrome rather than a dysmorphic one, because the skin findings are minimal and the cognitive profile is usually normal. [2] [3]
The clinical distinction matters because patients and families often assume the two conditions are grades of the same disease. They are not. NF1 brings developmental, dermatological and learning problems that dominate childhood; NF2 brings progressive hearing, balance and cranial-nerve loss that dominates adolescence and young adulthood. Confirming which gene is involved sets the surveillance schedule, the treatment options and the reproductive counselling, and it removes a great deal of needless fear. [2] [4]
References10ShowHide
- [1]Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ. Neurofibromatosis type 1. Nat Rev Dis Primers, 2017.PMID 28230061
- [2]Asthagiri AR, Parry DM, Butman JA, Kim HJ, Tsilou ET, Zhuang Z, Lonser RR. Neurofibromatosis type 2. Lancet, 2009.PMID 19476995
- [3]Plotkin SR, Wick A. Neurofibromatosis and Schwannomatosis. Semin Neurol, 2018.PMID 29548054
- [4]Plotkin SR, Messiaen L, Legius E, et al. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: an international consensus recommendation. Genet Med, 2022.PMID 35674741
- [5]Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med, 2021.PMID 34012067
- [6]Evans DG, Mostaccioli S, Pang D, et al. ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis. Eur J Hum Genet, 2022.PMID 35361920
- [7]Fisher MJ, Loguidice M, Gutmann DH, et al. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro-oncology, 2012.PMID 22474213
- [8]Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med, 2020.PMID 32187457
- [9]Ferner RE, Bakker A, Elgersma Y, et al. From process to progress-2017 International Conference on Neurofibromatosis 1, Neurofibromatosis 2 and Schwannomatosis. Am J Med Genet A, 2019.PMID 30908866
- [10]Williams VC, Lucas J, Babcock MA, et al. Neurofibromatosis type 1 revisited. Pediatrics, 2009.PMID 19117870