Neurofibromatosis type 1 (NF1)

Description

Autosomal dominant tumour-predisposition syndrome - NF1 gene (neurofibromin, a Ras-GTPase-activating protein, tumour suppressor)
Multisystem: skin, nervous system, bone, eye, vasculature
Distinct from NF2 (bilateral vestibular schwannomas, different gene/chromosome)

~1 in 2500-3000
Autosomal dominant, full penetrance by adulthood but highly variable expressivity (including within families)
~50% new (de novo) mutations

NF1 gene (chr17) -> neurofibromin -> negative regulator of Ras signalling
Loss of function -> unchecked Ras/MAPK pathway activation -> tumour predisposition (neurofibromas, gliomas, GIST, leukaemia)
One of the largest human genes - high spontaneous mutation rate

Clinical criteria (revised) - 2 or more required

>=6 café-au-lait macules (>5mm prepubertal, >15mm postpubertal)
>=2 neurofibromas of any type, or 1 plexiform neurofibroma
Axillary/inguinal freckling (Crowe sign)
Optic pathway glioma
>=2 Lisch nodules (iris hamartomas) - or choroidal abnormalities on newer criteria
Distinctive osseous lesion - sphenoid dysplasia, tibial pseudarthrosis/bowing
First-degree relative with NF1 (by these criteria)
Heterozygous pathogenic NF1 variant

Genetic testing - confirms atypical/isolated presentations, informs reproductive counselling

Surveillance (annual, MDT)

Growth + puberty - monitor for precocious puberty (optic pathway glioma)
Vision - annual ophthalmology to school age (optic glioma screening), Lisch nodules
Skin/soft tissue - monitor neurofibromas for rapid growth/pain -> malignant peripheral nerve sheath tumour (MPNST) transformation (~8-13% lifetime risk in plexiform NF)
BP - annual, screen for renal artery stenosis and phaeochromocytoma
Skeletal - scoliosis surveillance, tibial dysplasia
Learning - screen for ADHD/learning difficulties (very common, often the most functionally limiting feature)

Targeted therapy

MEK inhibitor (selumetinib) - for symptomatic, inoperable plexiform neurofibromas - shrinks tumour, improves pain/function
Surgery for symptomatic/disfiguring lesions or malignant transformation
Genetic counselling - autosomal dominant, 50% offspring risk

Optic pathway glioma (~15%, usually low-grade, mostly young children)
Plexiform neurofibromas -> MPNST risk
Phaeochromocytoma, GIST, juvenile myelomonocytic leukaemia (rare but characteristic)
Learning difficulties/ADHD (very common, >50%)
Renal artery stenosis -> secondary hypertension
Scoliosis, sphenoid wing dysplasia, tibial pseudarthrosis
Vasculopathy (NF1 vasculopathy - stenoses, aneurysms, moyamoya-like)

Life expectancy modestly reduced overall, mainly from MPNST and vasculopathy
Number/burden of café-au-lait macules and cutaneous neurofibromas increases with age
Plexiform neurofibromas present from birth/early childhood, grow fastest in childhood
Lifelong surveillance needed - malignancy and vascular risk persist into adulthood

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