Neurofibromatosis type 1 (NF1)

What it is

NF1 is caused by inactivating variants in the NF1 gene, which encodes neurofibromin. Neurofibromin normally accelerates the conversion of active RAS-GTP to inactive RAS-GDP, dampening RAS-MAPK signalling. When one NF1 allele is lost, RAS-MAPK signalling is mildly over-active in every cell; cancers and most clinical lesions occur when the second allele is also lost in a specific cell lineage (the classic 'two-hit' tumour-suppressor model). This single biological insight explains why MEK inhibitors — which work downstream of RAS — are effective in many NF1-related tumours.

NF1 is autosomal dominant with complete penetrance but extraordinarily variable expressivity, even within a single family. About half of children with NF1 have an affected parent; the other half carry a new (de novo) variant.

Diagnosis (2021 revised criteria)

The 2021 international consensus revised the long-standing NIH 1988 criteria. Diagnosis now requires either A) two or more of the seven clinical features, B) one of these features plus an affected parent, or C) a pathogenic NF1 variant in genetic testing (now accepted as a stand-alone criterion):

• Six or more café-au-lait macules (>5 mm pre-pubertal, >15 mm post-pubertal)
• Axillary or inguinal freckling (Crowe sign)
• Two or more neurofibromas (or one plexiform neurofibroma)
• Optic pathway glioma
• Two or more Lisch nodules (iris hamartomas) or two or more choroidal anomalies on OCT
• Distinctive osseous lesion (sphenoid dysplasia, tibial pseudarthrosis, long-bone bowing)
• Heterozygous pathogenic variant in NF1 in a normal tissue (now sufficient alone)

Surveillance — the heart of paediatric NF1 care

Because NF1 manifestations evolve over decades, children need structured lifelong follow-up. Modern paediatric NF1 clinics offer the following:

• Yearly blood pressure (renal artery stenosis and phaeochromocytoma)
• Yearly ophthalmology with formal visual acuity and visual fields from age 1; particular vigilance for optic pathway gliomas, which usually present age 1–7
• Annual paediatrician review for growth, puberty, scoliosis, learning and behaviour
• Whole-body MRI as a one-off in the late teens to identify internal plexiform neurofibromas, with risk-stratification follow-up
• Cognitive and educational assessment at school entry and at any concern, with an Education Health Care Plan (in the UK) or Individualised Education Program (in the US)
• Mental-health screening at every clinic visit for adolescents
• Breast cancer surveillance in women from age 30, including annual MRI

Treatment by manifestation

There is no curative treatment for NF1 itself. Treatment is targeted at specific manifestations:

• Plexiform neurofibromas — selumetinib (Koselugo) FDA-approved 2020 and EMA 2021 for children ≥2 years with symptomatic, inoperable plexiform neurofibromas. SPRINT Phase 2 showed durable ~70% volume reductions. Mirdametinib (Gomekli) FDA-approved 2025 with paediatric data — first MEK inhibitor with adult AND paediatric approval together
• Optic pathway gliomas — usually low-grade pilocytic astrocytomas; treated only if vision is threatened. First-line is carboplatin/vincristine chemotherapy; second-line increasingly MEK inhibitors (selumetinib, trametinib, binimetinib) with strong recent evidence. Radiotherapy is now generally avoided in NF1 because of vasculopathy and secondary tumour risk
• Cognitive and learning support — at school entry: cognitive assessment; tailored support; lamotrigine and methylphenidate are useful where ADHD coexists. Lovastatin trials in NF1 cognition were negative; targeted MAPK-pathway trials for cognition are ongoing
• Cutaneous neurofibromas — laser, electrosurgery or surgical removal for cosmetic concern; large or symptomatic dermal neurofibromas may benefit from MEK inhibitors
• Scoliosis and tibial pseudarthrosis — orthopaedic management; bone-modifying agents in selected cases
• Hypertension — annual blood pressure; investigate renovascular and phaeochromocytoma causes when found
• Malignant peripheral nerve sheath tumours (MPNST) — wide local excision and chemoradiation; MEK + mTOR combinations under investigation. Survival improves substantially with early recognition

Prognosis

Most people with NF1 lead full lives. Life expectancy is reduced on average by 8–15 years compared with the unaffected population, largely from cancer-related causes — though modern surveillance and MEK inhibitors are expected to narrow this gap meaningfully in the coming decade. Quality of life is strongly determined by the cognitive and educational support a child receives in the early years, far more than by the visible skin features.

How an educational review can help

NF1 families face a long list of competing surveillance recommendations and rapidly evolving treatment options. An educational review can place a child against the 2021 revised criteria, summarise the modern surveillance schedule, explain when MEK inhibitors are indicated and where the trials are at, and help you prepare focused questions for your treating team and your NF1 specialist clinic.

It is an educational second opinion — not a diagnosis, treatment or prescription — and it does not replace the care of your child's own clinicians.