Educational draft · awaiting clinical reviewThe full textbook explains uncertainty but does not replace live national or local guidance, specialist advice, or current prescribing information.
Neurofibromatosis and tuberous sclerosis
Paediatrics and child health · UK scope · Sources checked 27 Aug 2026 · Clinical review pending
Overview
Differentiate neurofibromatosis type 1, NF2-related schwannomatosis and tuberous sclerosis complex, recognise neurological, visual, renal and tumour emergencies, and coordinate lifelong syndrome-specific surveillance and targeted care.
Neurofibromatosis and tuberous sclerosis are autosomal dominant tumour-predisposition disorders with high variability and frequent de novo occurrence. NF1 is associated with café-au-lait macules, intertriginous freckling, neurofibromas, plexiform lesions, ocular signs, distinctive bone lesions, learning needs and selected tumours. NF2-related schwannomatosis centres on vestibular and other schwannomas, meningiomas, ependymomas and juvenile cataract. Tuberous sclerosis complex produces hamartomas and developmental disease across the brain, kidney, skin, heart, eye and lung. The skin can reveal hidden organ risk, but formal criteria and age matter.
In NF1, pigmentary signs often appear before tumours. Count and measure café-au-lait macules, examine axillary and inguinal areas, inspect for cutaneous or plexiform neurofibromas, measure blood pressure and assess growth, puberty, spine, limbs, development and vision. Diagnostic criteria should be applied rather than relying on gestalt. Young children with only pigmentary features may meet criteria later or have Legius syndrome, so review and genomic testing can be more appropriate than premature certainty.
Surveillance in a child with NF1 is clinical and purposeful. Visual acuity, colour or field assessment where developmentally possible, pupils, ocular alignment and fundoscopy seek optic pathway dysfunction. Routine MRI solely to find an asymptomatic optic pathway glioma can create anaesthetic and incidental-finding harms without improving outcomes. Image promptly for declining vision, proptosis, focal signs, atypical early puberty or another clinical indication. Ask at every review about painful or rapidly changing plexiform lesions and examine any reported change.
NF2-related disease may begin with hearing change, tinnitus, imbalance, facial weakness, a peripheral nerve mass, meningioma or ocular finding. Because mosaicism is common in apparently isolated presentations, a negative blood result does not end specialist assessment. Surveillance is coordinated through a specialist service and can include audiology, ophthalmology and serial brain and spinal imaging. Management balances hearing preservation, neurological function, tumour control and treatment morbidity; surgery, radiotherapy and targeted systemic therapy require expert case selection.
Tuberous sclerosis often presents prenatally with cardiac rhabdomyoma, in infancy with hypomelanotic macules or spasms, or later through seizures, development, skin or renal findings. Examine skin with appropriate light, characterise seizures and confirm the full diagnostic feature set. In an asymptomatic person without a subependymal giant cell astrocytoma, consensus surveillance uses brain MRI every one to three years until age twenty-five; a childhood SEGA that persists needs periodic adult imaging. Renal imaging for angiomyolipoma and cystic disease continues every one to three years throughout life, while blood pressure and estimated GFR are assessed at least annually.
Seizure timing is critical. Families of infants with TSC need education about brief clustered flexion or extension events and rapid access to EEG. The 2021 international consensus advises EEG in an asymptomatic infant approximately every six weeks until twelve months and every three months until twenty-four months; symptoms or an abnormal tracing can require prolonged video EEG sooner. NICE recommends vigabatrin for infantile spasms caused by TSC, with response assessed promptly. Other epilepsies follow the epilepsy guideline, and persistent seizures may require ketogenic diet, surgery or mTOR-targeted treatment through a tertiary team.
Targeted mTOR inhibition can shrink a growing subependymal giant cell astrocytoma or renal angiomyolipoma and can reduce refractory focal seizures in selected TSC patients. It is not a general preventive tonic. Specialist teams define indication, dose and trough target and monitor infection, mouth ulcers, blood count, renal and liver function, lipids, glucose, proteinuria and lung toxicity. Surgery, embolisation and other interventions remain important according to lesion, bleeding risk and organ function.
Genetic counselling explains a one-in-two transmission probability for a heterozygous affected parent while emphasising that severity cannot be predicted from the parent's course. Test parents when a child appears to have a de novo result, including assessment for subtle or mosaic disease where appropriate. Provide syndrome-specific emergency information, educational and psychological support, transition to adult multisystem care and a named coordinator so separate specialties do not duplicate imaging or leave surveillance gaps.
Key points
NF1 is diagnosed from age-dependent combinations of pigmentary, ocular, bony, tumour, genetic and family criteria; one café-au-lait macule is not diagnostic.
Regular clinical visual assessment is more useful than routine screening brain MRI for an asymptomatic young child with NF1; image when visual, neurological or endocrine findings create concern.
NF2-related schwannomatosis should be considered with bilateral vestibular schwannoma, multiple meningiomas, ependymoma, cataract or characteristic nerve tumours, particularly at a young age.
Tuberous sclerosis diagnosis integrates major and minor features such as multiple hypomelanotic macules, angiofibromas, cortical tubers, subependymal nodules, renal angiomyolipomas and cardiac rhabdomyomas.
For asymptomatic TSC, obtain brain MRI every one to three years until age twenty-five and renal imaging every one to three years lifelong, shortening intervals when lesions or symptoms warrant.
Measure blood pressure and estimated GFR and screen TSC-associated neuropsychiatric disorders at least annually, alongside age-appropriate skin, eye, cardiac, dental and lung assessment.
In an asymptomatic infant with TSC, the 2021 consensus advises EEG about every six weeks to twelve months and every three months from twelve to twenty-four months, with urgent testing for suspicious events.
Aetiology
01
NF1 tumour suppressor loss
A heterozygous pathogenic NF1 variant reduces neurofibromin regulation of RAS signalling; many cases are de novo and expression varies within families.
02
NF2 pathway disruption
Pathogenic NF2 variation causes schwannoma, meningioma and ependymoma predisposition; mosaic disease may present regionally and be absent from routine blood testing.
03
TSC complex loss
Pathogenic TSC1 or TSC2 variation disrupts hamartin-tuberin inhibition of mTOR, allowing hamartomatous growth across brain, kidney, heart, skin, lung and eye.
Pathophysiology
1
RAS signalling excess
Reduced neurofibromin increases proliferation and survival signals in susceptible neural-crest and vascular tissues, producing pigmentary signs, neurofibromas and tumour risk.
2
Second-hit tumour formation
Somatic loss of the remaining functional tumour-suppressor allele within a cell clone contributes to focal tumour development and variable organ burden.
3
mTOR activation
Loss of the TSC protein complex removes restraint from cellular growth pathways, generating cortical tubers, subependymal lesions, angiomyolipomas and other hamartomas.
4
Network developmental disruption
Abnormal cortical development and early epilepsy alter learning, autism, behaviour and sleep in tuberous sclerosis beyond the size of visible lesions.
Clinical features and red flags
NF1 pigmentary pattern
Multiple age-sized café-au-lait macules with axillary or inguinal freckling support NF1 suspicion, particularly with another diagnostic feature.
NF1 tumour warning
A plexiform lesion with sustained pain, accelerated growth, hardening or neurological deficit raises possible malignant change.
NF2-related pattern
Young-onset vestibular schwannoma, multiple meningiomas, ependymoma, cataract or several schwannomas should prompt specialist genomic classification.
TSC skin pattern
Three or more hypomelanotic macules, facial angiofibromas, shagreen patch or ungual fibromas are important age-dependent diagnostic features.
TSC organ pattern
Cortical tubers, subependymal lesions, bilateral renal angiomyolipomas and cardiac rhabdomyomas form a recognisable multisystem combination.
Red flags requiring action
Persistent pain, rapid enlargement, hardening or new weakness around an NF1 plexiform neurofibroma raises concern for malignant peripheral nerve sheath tumour and needs urgent specialist imaging.
New visual loss, proptosis, squint, abnormal colour vision or early puberty in a child with NF1 may indicate a clinically significant optic pathway or hypothalamic lesion.
Clusters of infantile spasms, developmental plateau or regression in a baby with tuberous sclerosis require urgent EEG-linked specialist treatment.
Investigations
01Formal clinical diagnostic criteriaFirst step
Why
Integrate age-dependent skin, eye, tumour, bone and organ features reproducibly.
Interpretation and limitations
A partial phenotype may need longitudinal review, and a molecular diagnosis can confirm disease before all features emerge.
02Syndrome-directed genomic testing
Why
Identify NF1, NF2, TSC1, TSC2 or related pathogenic variation for classification and family testing.
Interpretation and limitations
Negative blood testing does not exclude tissue-limited mosaicism; deletion and mosaic analysis may require tailored methods.
03Ophthalmological and audiological assessment
Why
Detect NF1 optic dysfunction or NF2-related hearing and ocular disease early.
Interpretation and limitations
Serial functional change guides imaging and intervention more reliably than an incidental lesion alone.
04Brain and spinal MRI
Why
Evaluate symptomatic NF disease and conduct specialist tumour or TSC subependymal surveillance.
Interpretation and limitations
For asymptomatic TSC, brain MRI is repeated every one to three years until age twenty-five; new pressure or focal symptoms override routine timing.
05Renal imaging and function
Differential diagnosis
01
Legius syndrome
SPRED1-related disease causes café-au-lait macules and freckling without the typical NF1 neurofibroma, Lisch-nodule or tumour spectrum.
02
Constitutional mismatch repair deficiency
Biallelic mismatch-repair disease can combine pigmentary lesions with childhood malignancy and requires urgent genomic distinction because cancer risk differs profoundly.
03
Schwannomatosis spectrum
Multiple schwannomas from NF2, SMARCB1 or LZTR1 mechanisms overlap clinically, while vestibular involvement, pain pattern, pathology and mosaicism refine classification.
04
Other hypopigmentation disorder
Isolated ash-leaf-like macules, vitiligo, hypomelanosis of Ito and nevus depigmentosus can resemble TSC skin findings without its multisystem criteria.
05
Sporadic organ lesion
A single cardiac rhabdomyoma, renal angiomyolipoma, seizure or subependymal nodule may be isolated and needs assessment against formal diagnostic criteria.
Management
01ClassifyConfirm the syndrome patternFirst stepPigmentary, tumour, seizure, cardiac or renal features suggest a neurocutaneous disorder.+
1Document skin findings, development, neurology, vision, hearing, blood pressure and a three-generation pedigree.
2Apply current syndrome criteria and arrange mechanism-appropriate genomic testing through specialist services.
3Complete baseline organ assessment without indiscriminate imaging that lacks a syndrome-specific purpose.
1Stabilise seizures, haemorrhage, raised pressure, hypertension or other immediate physiology promptly.
2Contact the relevant specialist pathway and obtain targeted imaging or EEG without waiting for routine review.
Complications
01
Neurological morbidity
Epilepsy, spasms, hydrocephalus, learning disability, autism, attention difficulty and mental-health problems can dominate daily life and developmental outcome.
02
Vision and hearing loss
Optic pathway glioma threatens vision in NF1, while bilateral vestibular schwannomas and other tumours cause hearing and balance impairment in NF2-related disease.
03
Malignant transformation
An NF1 plexiform neurofibroma can transform into malignant peripheral nerve sheath tumour, signalled by persistent pain, altered consistency, growth or deficit.
04
Renal and vascular injury
TSC angiomyolipoma can bleed or impair kidney function; NF1 and TSC both associate with hypertension through distinct renal or vascular mechanisms.
05
Psychosocial burden
Visible lesions, uncertainty, repeated imaging, learning needs, pain and inherited risk affect schooling, independence, relationships and family wellbeing.
Monitoring and follow-up
For NF1, review growth, puberty, development, school, blood pressure, skin and plexiform symptoms with age-appropriate visual surveillance.
For NF2-related disease, maintain specialist hearing, eye, neurological and brain-spine tumour surveillance with function-centred outcome recording.
For TSC, record six-weekly EEG to twelve months and three-monthly EEG to twenty-four months in asymptomatic infants unless the specialist plan changes for clinical findings.
Continue brain MRI every one to three years to age twenty-five, renal imaging every one to three years lifelong, and at least annual blood pressure, estimated GFR and TAND screening.
Compare lesion size and symptoms against previous studies rather than reacting to a single report without trajectory.
Monitor targeted treatment toxicity and adherence using the specific drug protocol, including infection and interaction review.
At transition, transfer original molecular results, imaging history, unresolved lesions, emergency warnings and the next due surveillance dates.
Special situations
Age changes diagnostic sensitivity
Pigmentary signs can precede tumours in NF1, while TSC and NF2 manifestations accumulate at different times, making planned reassessment essential.
Mosaic disease hides in blood
A localised or mild phenotype can reflect postzygotic variation that routine blood analysis fails to detect at validated depth.
Function outranks image anxiety
Tumour presence alone does not always mandate treatment; visual, hearing, neurological, renal and pain outcomes guide proportionate intervention.
TAND needs active screening
Tuberous-sclerosis-associated neuropsychiatric difficulties are common yet easily missed when appointments focus only on MRI and kidneys.
Pain can be oncological
A new persistent pain pattern within an NF1 plexiform lesion warrants examination and urgent expert evaluation even before obvious enlargement.
Common pitfalls
01
Diagnosing NF1 from one or two isolated café-au-lait macules.
02
Ordering repeated screening MRI for asymptomatic NF1 without a defined indication.
03
Missing infantile spasms because each individual movement is brief.
04
Treating every visible TSC lesion while ignoring function and treatment toxicity.
05
Assuming a negative blood test excludes mosaic neurocutaneous disease.
06
Allowing separate specialty surveillance plans to conflict or leave gaps.
Practice
Two practice questions
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Question 1 of 2
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Paediatrics and child healthOriginal SBA
Incomplete NF1 phenotype
A healthy three-year-old has five café-au-lait macules but no freckling, neurofibroma, ophthalmic, bony or family criterion. What is the most appropriate interpretation and plan?
Sources and review status6 sources · checked 27 Aug 2026 · clinical review pending+
Sources
Sources and review status
National guidance is shown before implementation-dependent detail. Typical adult dose examples remain subject to patient factors, contraindications and the live BNF or specialist protocol. Source check completed 27 Aug 2026; clinical approval remains outstanding.
New persistent pain or rapid growth in an NF1 lesion, visual deterioration, pressure symptoms, renal bleeding or infantile spasms requires urgent syndrome-aware escalation.
Confirm the molecular diagnosis when it changes family testing or classification, while recognising that blood testing may miss mosaic disease and cannot predict severity precisely.
Headache, vomiting, somnolence, papilloedema or focal deficit in tuberous sclerosis can reflect obstructive hydrocephalus from a subependymal giant cell astrocytoma.
Flank pain, haematuria, falling haemoglobin or shock in tuberous sclerosis can indicate bleeding from a renal angiomyolipoma and requires emergency renal imaging and stabilisation.
Severe headache, neurological deficit or marked hypertension in NF1 warrants urgent assessment for vascular disease, renal artery stenosis, phaeochromocytoma or intracranial pathology.
Renal imaging continues every one to three years lifelong, with blood pressure and estimated GFR at least annually and closer review for lesion growth or symptoms.
06Developmental and neuropsychiatric profile
Why
Identify learning, autism, attention, mood, sleep and adaptive support needs.
Interpretation and limitations
Use a TAND screen at least annually and complete formal evaluation at key developmental stages or whenever concerns emerge.
3Compare with prior organ studies and document the exact new symptom, tempo and functional consequence.
03SurveilUse a syndrome-specific calendarNF1, NF2-related schwannomatosis or TSC is established.+
1For TSC, schedule brain MRI every one to three years to age twenty-five and renal imaging every one to three years lifelong.
2Measure TSC blood pressure and estimated GFR and complete TAND screening at least annually, with infant EEG at consensus intervals.
3Coordinate imaging and functional review across teams and make one clinician responsible for tracking completion and response.
04TreatMatch intervention to consequenceA lesion grows, causes symptoms or reaches a syndrome-specific treatment threshold.+
1Discuss surveillance, surgery, embolisation, epilepsy care or targeted systemic treatment in the specialist multidisciplinary team.
2Define intended benefit and functional outcome before exposing the child to treatment toxicity.
3Continue unaffected-organ surveillance and communicate new treatment implications to primary and emergency care.
Key medicines and prescribing safety2 treatments · regimens, roles and cautions+
NICE-recommended treatment for infantile spasms when tuberous sclerosis is the underlying cause.
Vigabatrin for TSC-associated infantile spasms
Specialist paediatric treatment is given orally in two divided daily doses, commonly beginning around 50 mg/kg/day and titrating quickly according to clinical and EEG response up to the protocol maximum, often 100 to 150 mg/kg/day.
Urgently document baseline development and vision context, then monitor sedation, hypotonia, seizure and EEG response, MRI signal change and cumulative exposure because irreversible visual-field toxicity is a major concern.
Controls selected growing TSC lesions or refractory seizures through inhibition of overactive mTOR signalling.
Everolimus for selected TSC manifestations
The specialist calculates an indication-specific oral dose using body surface area or the licensed regimen and adjusts it to measured trough concentration; fixed general paediatric dosing is inappropriate.
Before and during treatment assess infection, vaccination, mouth ulceration, blood count, renal and liver function, glucose, lipids, proteinuria, respiratory symptoms and CYP3A interactions; plan interruption around serious infection or procedures.