NeurologyTier 2Disease (DEADMAN)

Neurofibromatosis type 1

Description

Autosomal dominant neurocutaneous (phakomatosis) tumour-predisposition syndrome
NF1 gene, chromosome 17q11.2 -> neurofibromin (a RAS-GAP, i.e. a tumour suppressor)
- Loss of neurofibromin -> unopposed RAS-MAPK signalling -> tumour growth
- Explains why MEK inhibitors work

Core manifestations

Cafe-au-lait macules - earliest sign, present from infancy
Skinfold freckling (Crowe sign) - axillary, inguinal, neck, sub-mammary
Cutaneous neurofibromas - appear around puberty, increase in pregnancy
Plexiform neurofibromas - congenital, diffuse, can be disfiguring; the lesions that transform
Lisch nodules - iris hamartomas, slit-lamp, by age ~20 in >90%
Optic pathway glioma - childhood, usually indolent pilocytic astrocytoma
Bone dysplasia - sphenoid wing, tibial bowing/pseudarthrosis

Neurofibromas + cafe-au-lait macules + Lisch nodules together are present in virtually all adults with NF1.

NF1 vs NF2 (now "NF2-related schwannomatosis")

	NF1	NF2
Gene	NF1, 17q (neurofibromin)	NF2, 22q (merlin)
Frequency	1:2,500-3,000	1:25,000-33,000
Skin	Cafe-au-lait, freckling, neurofibromas	Few skin lesions, schwannomas
Eye	Lisch nodules, optic glioma	Juvenile posterior subcapsular cataract, retinal hamartoma
Tumours	Neurofibroma, MPNST, optic glioma, phaeo	Bilateral vestibular schwannoma, meningioma, ependymoma
Presentation	Childhood skin/learning	Young adult hearing loss, tinnitus, imbalance

Epidemiology

~1 in 2,500-3,000 births - commonest autosomal dominant neurocutaneous disorder
M=F
Autosomal dominant with ~100% penetrance but highly variable expressivity (even within a family)
~50% are de novo mutations - a negative family history does not argue against the diagnosis
- NF1 has one of the highest spontaneous mutation rates of any human gene
Mosaic/segmental NF1 occurs - manifestations confined to one body region

Aetiopathogenesis

NF1 (17q11.2), very large gene -> high mutation rate
Neurofibromin = GTPase-activating protein
- Normally: accelerates RAS-GTP -> RAS-GDP (inactive)
- Loss -> RAS stays GTP-bound -> RAS/MAPK and mTOR activation -> proliferation
Tumour suppressor, two-hit mechanism
- Germline first hit in every cell; somatic second hit in a Schwann cell precursor -> neurofibroma
Neurofibroma composition: Schwann cells (the NF1-/- clone) + fibroblasts, mast cells, perineurial cells
Malignant transformation of plexiform neurofibroma -> MPNST
- Additional hits: CDKN2A, TP53, SUZ12/EED (PRC2)
Genotype-phenotype correlation is poor, with exceptions: whole-gene deletion -> severe phenotype, more neurofibromas, higher MPNST risk; p.Met992del -> cafe-au-lait only, no neurofibromas

Diagnosis

Diagnostic criteria - >=2 required

(Revised international criteria; a pathogenic NF1 variant or a parent with NF1 now counts as a criterion.)

	Criterion
1	>=6 cafe-au-lait macules - >5 mm prepubertal, >15 mm postpubertal
2	Freckling in axilla, groin, neck or sub-mammary folds
3	>=2 neurofibromas of any type, or >=1 plexiform neurofibroma
4	Optic pathway glioma
5	>=2 Lisch nodules (slit-lamp) or >=2 choroidal abnormalities on OCT/NIR imaging
6	Distinctive bony lesion - sphenoid wing dysplasia, anterolateral tibial bowing, pseudarthrosis of a long bone
7	Heterozygous pathogenic NF1 variant (VAF ~50% in unaffected tissue)
8	Parent with NF1 meeting the criteria

A child with a parent with NF1 needs only one other criterion
Cafe-au-lait + freckling without other features in a child - consider Legius syndrome (SPRED1): no neurofibromas, no Lisch nodules, no tumour risk. Genetic testing distinguishes them

Examination

Skin: count and measure cafe-au-lait macules; >6 warrants full assessment; examine folds for freckling; palpate for cutaneous and subcutaneous neurofibromas
Eyes: visual acuity, colour vision, fields, fundoscopy (optic glioma), slit-lamp (Lisch nodules)
Spine: kyphoscoliosis
Blood pressure - renal artery stenosis and phaeochromocytoma
Neuro: focal deficits, cognitive/learning assessment
Growth, head circumference (macrocephaly), pubertal status

Investigations

No routine whole-body imaging in asymptomatic adults - clinical surveillance
Whole-body MRI where plexiform burden is high or MPNST risk assessment needed
New, rapidly growing, or newly painful nodule, or new neurological deficit -> urgent MRI +/- FDG-PET (SUVmax) -> biopsy
Plasma free metanephrines if hypertensive, paroxysmal symptoms, or before surgery/pregnancy
Renal artery imaging if hypertensive and young

Management

No cure. Management is lifelong structured surveillance plus treatment of individual complications.

A. Annual surveillance - the core of care

Full skin examination - new, painful, hard or rapidly enlarging lesion is the MPNST question
Blood pressure at every visit (renal artery stenosis, phaeochromocytoma, coarctation)
Ophthalmology - annual to age ~8 (optic glioma window), then symptom-driven
Spine examination for scoliosis, especially through growth
Developmental/cognitive and school progress in children; mood in adults
Pubertal assessment (precocious puberty -> optic chiasmal glioma)

B. By problem

Plexiform neurofibroma, symptomatic and inoperable - MEK inhibitor (selumetinib; mirdametinib) produces durable partial responses
- Toxicity: rash, paronychia, diarrhoea, reduced ejection fraction, retinopathy/RVO, raised CK
- Baseline + serial echo and ophthalmic assessment
Cutaneous neurofibromas - excision, laser or electrodesiccation for cosmesis or irritation; recur
MPNST - wide local excision with negative margins is the only curative treatment; radiotherapy for local control; chemotherapy (doxorubicin/ifosfamide) with modest benefit
Optic pathway glioma - observation if asymptomatic; chemotherapy (carboplatin/vincristine) if progressive vision loss. *Avoid radiotherapy - moyamoya and second malignancy*
Scoliosis - bracing, surgery for dystrophic curves
Tibial pseudarthrosis - orthopaedic, high non-union rate
Hypertension - always exclude a secondary cause before labelling essential
Learning and behaviour - ~50-70% have learning difficulties, ~40% ADHD; educational support, stimulant medication
Breast cancer - lifetime risk ~4-5x; annual MRI screening from age 30-50, plus mammography

C. Genetic counselling

Autosomal dominant, 50% transmission risk; expressivity cannot be predicted
Offer prenatal/preimplantation genetic diagnosis
Test parents - ~50% are de novo, but mosaic parents exist
Pregnancy: neurofibromas enlarge; higher hypertension and pre-eclampsia risk - obstetric-medicine input

Avoid

Radiotherapy where avoidable - NF1 tissue is radiosensitive for second malignancy and moyamoya
Labelling a new nerve-territory pain as "just a neurofibroma"

Associations

Malignant peripheral nerve sheath tumour - arises in plexiform neurofibromas, lifetime risk ~8-13%
Optic pathway and other gliomas; brainstem glioma; juvenile myelomonocytic leukaemia; rhabdomyosarcoma; GIST; breast cancer
Phaeochromocytoma (~1-5%), renal artery stenosis, coarctation, moyamoya, cerebral aneurysm
Lung cysts and bullae; diffuse lung disease
Retinal hamartomas; choroidal abnormalities
Skeletal: rib notching, erosive bony defects, sphenoid wing dysplasia, tibial bowing/pseudarthrosis, scoliosis, osteopenia, short stature, macrocephaly
Neurodevelopmental: learning disability, ADHD, autism spectrum, epilepsy
Aqueductal stenosis -> hydrocephalus
Unidentified bright objects (UBOs) on T2 MRI - benign, fade with age, not tumours

Natural history & complications

Age-ordered emergence: cafe-au-lait (infancy) -> freckling (early childhood) -> optic glioma (<8 yrs) -> Lisch nodules (adolescence) -> neurofibromas (puberty onwards)
Neurofibroma burden increases through adult life; accelerates in pregnancy
Life expectancy reduced by ~8-15 years - driven by malignancy and vasculopathy

MPNST - the dominant prognostic issue

Lifetime risk ~8-13% (vs ~0.001% general population)
Warning features: new or increasing pain, especially at night; rapid growth; change to hard texture; new neurological deficit
5-year survival ~20-50%; complete resection is the only reliable determinant
A plexiform neurofibroma that starts hurting is MPNST until imaged

Other complications

Disfigurement and its psychosocial impact - a major driver of quality of life
Vasculopathy: renovascular hypertension, moyamoya, stroke, aneurysm
Scoliosis, fracture, pseudarthrosis, osteoporosis
Chronic pain, pruritus
Cognitive and educational underachievement
Hydrocephalus from aqueductal stenosis

Transition from paediatric to adult services is where surveillance is most often lost

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