The diagnostic criteria for NFI have been formulated by the National Institutes of Health (NIH) Consensus Development Conference on NF,³ and include six or more café-au-lait macules (CALM), two or more neurofibromas of any type or one or more pleximorm neurofibroma, two or more Lisch nodules, distinct osseous lesions and a first-degree relative with NFI. If two or more of these signs are present, the diagnosis is NFI. Although direct sequencing could be used to detect the causative mutation for individuals who meet these diagnostic criteria for NFI, molecular testing is generally not necessary.

Patients with NFI manifest clinically with cutaneous, ophthalmological, musculoskeletal and/or neurological symptoms.^4,5 The cutaneous and ocular manifestations are the most common and typically are CALM, axillary freckling and Lisch nodules. CALM are apparent in 99% of patients and are usually present at birth. Musculoskeletal abnormalities include bone abnormalities, such as skeletal dysplasia (particularly sphenoid wing dysplasia), scoliosis and tibial pseudarthrosis. The neurological manifestations of NFI are variable and may be due to brain, spine or peripheral nerve tumours, epilepsy, macrocephaly, hydrocephalus, meningoceles and/or peripheral neuropathy.

Neurofibromas in NFI manifest as cutaneous neurofibromas, subcutaneous neurofibromas, nodular plexiform neurofibromas and diffuse plexiform neurofibromas.⁶ In contrast with cutaneous neurofibromas, plexiform neurofibromas may undergo malignant transformation. Both NFI and NFII patients are at increased risk of developing intra-cranial tumours; however, the tumour types are quite different. Brain tumours that have a higher incidence in NFI patients than in the general population are gliomas, ependymosmas, meningiomas and primitive neuroectodermal tumours (PNETs). Gliomas are typically lowgrade and involve the optic pathways, hypothalamus, cerebellum, brainstem and spinal cord.

Optic pathway tumours usually involve the anterior visual pathways and occur in 11–19% of patients. Almost half are asymptomatic at diagnosis, while in the others the symptoms are related to the location of the tumours along the optic pathways. The initial management of optic pathway gliomas is follow-up with serial neuroimaging and ophthalmological examinations. These tumours may have a more indolent natural history and are less aggressive than optic gliomas in patients without NFI.^4,5,7 Tumours involving the intra-orbital segment of the optic nerve cause progressive proptosis, papilledema and optic atrophy. Those involving the chiasm may extend to the hypothalamus and third ventricle and lead to severe endocrine disturbances and/or hydrocephalus. In cases of significant proptosis or visual loss, and particularly for unilateral tumours located anterior to the optic chiasm, surgical removal is an option. Residual tumour or regrowth after incomplete removal may be treated with chemotherapy (in children <5 years) or radiotherapy.

NFI patients may present with vascular complications. Strokes occur in approximately 1% of patients and the most common cause is the occlusion of the carotid or middle cerebral artery.¹ NFI has a significant effect on learning and cognition. Areas of signal hyperintensity on transverse relaxation (T2)-weighted magnetic resonance images (MRIs) – the ‘unidentified bright objects’ – are observed in 60–70% of children with NFI, but the relationship between unidentified bright objects and cognitive dysfunction remains controversial. Psychiatric disorders occur in 33% of patients, which is a much higher frequency compared with the general population.