Neurofibromatosis and tuberous sclerosis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

NF1, NF2-related schwannomatosis and TSC are autosomal dominant disorders with high new-variant rates and variable expression. A parent may therefore have subtle signs while a child is more severely affected, and a clinically unaffected family history does not rule out disease. Diagnosis uses recognised clinical criteria supported by molecular testing, but variants of uncertain significance do not independently establish the diagnosis. Mosaic disease can produce segmental or milder features and may require specialised tissue or high-sensitivity analysis.

NF1 involves skin, peripheral nerves, vision, skeleton, vessels, cognition and endocrine systems. Important complications include optic pathway glioma, plexiform neurofibroma, malignant peripheral nerve sheath tumour, scoliosis, tibial dysplasia, hypertension from essential disease, renal artery stenosis or phaeochromocytoma, and learning or attention difficulties. NF2-related schwannomatosis is anatomically different: progressive hearing loss, tinnitus or imbalance from vestibular schwannomas may accompany multiple meningiomas, spinal ependymomas and neuropathy.

TSC produces hamartomas in multiple organs. Neurological morbidity comes from epilepsy, intellectual or learning disability, autism, sleep and behavioural disorders and growing SEGAs. Renal angiomyolipomas can enlarge or bleed; cystic disease can impair function; pulmonary lymphangioleiomyomatosis affects mainly women; and cardiac rhabdomyomas are particularly relevant antenatally and in infancy. Surveillance and treatment use a specialist TSC team, with surgery, embolisation, antiseizure therapy and mTOR inhibitors selected for specific indications.

Key points

NF1 is an autosomal dominant RAS–MAPK tumour-predisposition disorder caused by pathogenic NF1 variants and characterised by café-au-lait macules, flexural freckling, neurofibromas and multisystem complications.
Plexiform neurofibromas can cause disfigurement, pain and neurological compromise; new persistent pain, rapid growth, hard texture or deficit raises malignant peripheral nerve sheath tumour.
NF2-related schwannomatosis typically causes bilateral vestibular schwannomas, meningiomas, ependymomas, peripheral nerve tumours and early cataracts rather than the cutaneous neurofibroma burden of NF1.
Tuberous sclerosis complex arises from TSC1 or TSC2 dysfunction and mTOR activation, producing cortical tubers, subependymal nodules, epilepsy, neuropsychiatric features, skin lesions and renal, lung and cardiac disease.
Hypomelanotic ash-leaf macules, facial angiofibromas, shagreen patches and ungual fibromas are diagnostic clues in TSC, but a Wood lamp and age-aware examination may be needed.
Infantile spasms in TSC require urgent EEG and specialist treatment, with vigabatrin favoured in the current NICE epilepsy pathway because delay harms development.
A subependymal giant-cell astrocytoma can obstruct the foramen of Monro and cause hydrocephalus; new headache, vomiting, visual change or regression needs urgent brain imaging.
Both conditions require coordinated genetic counselling and organ-specific surveillance; a normal early childhood assessment does not end follow-up because manifestations are age dependent.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

NF1 pathogenic variants

Autosomal-dominant loss of neurofibromin increases RAS–MAPK signalling, producing pigmentary change, neurofibromas and diverse tumour susceptibility across organ systems.

NF2-related schwannomatosis

Pathogenic NF2 variants impair merlin tumour suppression and cause bilateral vestibular schwannomas, meningiomas, ependymomas and peripheral nerve tumours.

Tuberous sclerosis complex

Loss of TSC1 or TSC2 function activates mTOR signalling, leading to hamartomas and dysplastic lesions across brain, skin, kidney, lung and heart.

De novo and mosaic disease

New or mosaic pathogenic variants can produce variable or segmental manifestations without an affected parent, complicating recognition and recurrence counselling.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Tumour-suppressor loss
A germline pathogenic variant removes one protective copy in susceptible cells, with further molecular events allowing abnormal proliferation.
2
Dysregulated growth signalling
Excess RAS–MAPK or mTOR activity promotes nerve-sheath tumours, cortical malformation, hamartoma and organ-specific dysplasia across affected organs.
3
Age-dependent lesion accumulation
Tumours and organ manifestations emerge at different life stages, so a normal early assessment does not remove future surveillance need.
4
Network and organ dysfunction
Lesions cause seizures, hydrocephalus, hearing loss, pain, renal bleeding, respiratory disease and neuropsychiatric impairment according to location.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

NF1 pigmentary phenotype

Multiple café-au-lait macules and axillary or inguinal freckling often appear early, while Lisch nodules and cutaneous neurofibromas increase with age.

NF1 tumour warning

A plexiform neurofibroma that becomes rapidly larger, persistently painful, firm or neurologically symptomatic needs urgent sarcoma and NF specialist assessment.

NF2-related pattern

Bilateral hearing loss, tinnitus, imbalance, facial weakness or multiple meningiomas in a young person suggests vestibular schwannomas within NF2-related schwannomatosis.

TSC skin pattern

Three or more hypomelanotic macules, facial angiofibromas, a shagreen patch or multiple ungual fibromas should trigger a multisystem TSC assessment.

TSC epilepsy pattern

Focal seizures, infantile spasms or developmental plateau may be the earliest neurological manifestation and require prompt EEG and specialist treatment.

TSC organ pattern

Renal angiomyolipomas or cysts, cardiac rhabdomyoma, pulmonary lymphangioleiomyomatosis and retinal hamartomas support the diagnosis beyond brain and skin.

Red flags requiring action

Rapid growth, unremitting night pain, hard change or neurological deficit in an NF1 tumour requires urgent assessment for malignant peripheral nerve sheath tumour.
Acute headache, vomiting, papilloedema or declining cognition in TSC may reflect SEGA-related obstructive hydrocephalus and needs emergency imaging.
New or clustered infantile spasms, status epilepticus or developmental regression requires urgent paediatric neurology assessment.
Flank pain, hypotension or falling haemoglobin in TSC raises bleeding renal angiomyolipoma and needs emergency renal and interventional review.
Severe or paroxysmal hypertension in NF1 requires prompt evaluation for renal vascular disease or phaeochromocytoma before routine escalation alone.
Sudden hearing or facial-nerve deterioration in NF2-related schwannomatosis requires expedited neuro-otology and imaging review.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Clinical diagnostic criteria and pedigreeFirst step
Why
Identify the characteristic, age-dependent features and inheritance pattern of NF1, NF2-related schwannomatosis or TSC.
Interpretation and limitations
Count and characterise lesions accurately and examine parents when consented; one café-au-lait macule or one cortical lesion is not a syndromic diagnosis.
02
NHS germline genomic testing
Why
Confirm NF1, NF2, TSC1, TSC2 or another schwannomatosis diagnosis and enable familial testing.
Interpretation and limitations
Use the current Genomic Test Directory and consider mosaic analysis; a negative blood test may not exclude mosaic clinical disease, while a VUS is not predictive.
03
MRI brain and spine
Why
Assess symptomatic tumours and perform syndrome-specific surveillance for vestibular schwannoma, meningioma, ependymoma, cortical lesions or SEGA.
Interpretation and limitations
Imaging frequency and contrast use depend on age, genotype, prior findings and specialist protocol; avoid screening scans that are not recommended for the specific disorder.
04
EEG
Why
Confirm infantile spasms, classify focal or generalised seizures and assess unexplained developmental change in TSC.
Interpretation and limitations
Hypsarrhythmia supports infantile spasms but treatment should not wait for prolonged delay when the clinical pattern is convincing and urgent specialist review is available.
05
Renal imaging and renal function
Why
Detect and follow TSC angiomyolipomas, cysts, bleeding risk, renal growth and chronic kidney disease.
Interpretation and limitations
MRI is often used for surveillance to avoid repeated radiation; size, aneurysmal change, growth and symptoms guide embolisation or mTOR treatment.
06
Audiology and ophthalmology
Why
Monitor vestibular schwannoma-related hearing and identify optic pathway, retinal, Lisch nodule or cataract features.
Interpretation and limitations
Age, communication and cognitive needs determine the method; reported hearing or visual function can underestimate progressive objective loss.
07
Blood pressure and cause-directed endocrine tests
Why
Detect hypertension and investigate renal artery stenosis or catecholamine-secreting tumour when NF1 features support them.
Interpretation and limitations
Measure pressure reliably at each review and use specialist biochemical preparation for metanephrines; do not biopsy a suspected phaeochromocytoma.
08
Pulmonary assessment in TSC
Why
Identify lymphangioleiomyomatosis in adults at risk through symptoms, lung function and specialist-directed imaging.
Interpretation and limitations
New exertional breathlessness, pneumothorax or chylous effusion warrants respiratory review; surveillance is tailored by sex, age and findings.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Legius and pigmentary syndromes

Café-au-lait macules and freckling without neurofibromas or typical NF1 tumours may indicate another RAS-pathway condition such as Legius syndrome.

Other schwannomatosis

Multiple painful schwannomas without bilateral vestibular tumours can reflect non-NF2 schwannomatosis requiring distinct genomic assessment and surveillance.

Sporadic tumour syndromes

An isolated schwannoma, meningioma or renal lesion does not establish a multisystem inherited condition; age, multiplicity and family history guide testing.

Other neurocutaneous disorders

Vascular birthmarks, calcification or different seizure–skin patterns may indicate Sturge–Weber or another mosaic neurocutaneous disorder rather than TSC.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01NF1Child with pigmentary signsFirst stepA child has multiple café-au-lait macules, flexural freckling or a parent with confirmed NF1.

1Document lesion number, size and distribution and examine skin, eyes, growth, development, spine, limbs, neurology and blood pressure.
2Refer to paediatrics or an NF/genetics service for clinical criteria review and genomic testing where it will clarify diagnosis or family planning.
3Arrange age-appropriate vision, developmental, skeletal and pressure surveillance and educate the family about painful or rapidly changing tumours.
4Avoid routine whole-body imaging unless the specialist pathway indicates it; investigate symptoms and known lesions with the appropriate modality.

02TSCPossible multisystem TSCSkin, brain, seizure, cardiac or renal features raise tuberous sclerosis complex.

1Perform skin and neurological examination, developmental and behavioural assessment, blood pressure and a three-generation pedigree.
2Coordinate brain, renal, cardiac, eye and age-appropriate lung assessment and arrange TSC1/TSC2 testing through clinical genetics.
3Classify and treat seizures urgently and review SEGA, renal angiomyolipoma and pulmonary findings with the relevant specialist teams.
4Create one shared surveillance schedule with named responsibility so organ follow-up is not fragmented across services.

03SPASMSInfantile spasms in TSCAn infant with known or suspected TSC develops clusters of brief flexor, extensor or mixed spasms or developmental regression.

1Obtain urgent paediatric neurology assessment and EEG while documenting cluster timing, video evidence, development and current antiseizure medicines.
2Start vigabatrin promptly under the NICE specialist pathway for TSC-related infantile spasms, with dosing and response review directed by the paediatric team.
3Assess cessation of clinical spasms and EEG response rapidly and add or change therapy if the specified early response is not achieved.
4Monitor vision and adverse effects, provide emergency seizure advice and continue developmental and early-intervention support.

04TUMOURChanging tumour syndrome lesionPain, rapid enlargement, new deficit, hydrocephalus symptoms or organ bleeding suggests a complicated lesion.

1Treat airway, seizure, haemodynamic or intracranial-pressure emergencies and obtain urgent imaging of the symptomatic anatomical region.
2Refer to the relevant NF, TSC, sarcoma, neurosurgical, renal or interventional multidisciplinary team rather than arranging isolated biopsy.
3Use surgery, embolisation or a genotype- and indication-specific targeted therapy according to pathology, resectability and current commissioning.
4Define objective response, toxicity surveillance and a plan for recurrence or progression before treatment begins.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Provides first-line antiseizure treatment for TSC-related infantile spasms, where early spasm control supports developmental outcome.

Vigabatrin

For infantile spasms associated with TSC, use the paediatric specialist weight-based regimen and rapid titration specified by NICE and the current product information; this is not an adult self-start medicine.

Specialist monitoring is required for visual-field toxicity, sedation, movement disorder and MRI signal changes; review response promptly and do not continue ineffective treatment without a plan.

Inhibits mTOR signalling for selected growing SEGA, renal angiomyolipoma or treatment-resistant TSC epilepsy under commissioned specialist care.

Everolimus

Use a specialist-calculated oral dose for the licensed TSC indication, adjusted to drug concentration, body size, organ function, interacting medicines and treatment response.

Monitor stomatitis, infection, blood count, lipids, glucose, renal and liver function and interactions; withhold around serious infection or surgery according to the specialist protocol.

Can reduce tumour volume and morbidity in selected NF1 plexiform neurofibromas when surgery is not feasible.

Targeted MEK inhibition for NF1

Use only the licensed paediatric or adult regimen for an eligible symptomatic inoperable plexiform neurofibroma through the specialist NF multidisciplinary service.

Confirm indication and commissioning and perform product-specific cardiac, ophthalmic, skin, gastrointestinal and laboratory monitoring; it is not treatment for a suspected malignant transformation.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Malignant peripheral nerve-sheath tumour

An NF1 plexiform neurofibroma can transform, with new persistent pain, rapid growth, hard texture or neurological deficit requiring urgent assessment.

Seizures and obstructive hydrocephalus

TSC cortical lesions cause epilepsy, while a subependymal giant-cell astrocytoma can block ventricular flow and raise intracranial pressure.

Renal and pulmonary morbidity

TSC angiomyolipomas can bleed or impair kidneys, and pulmonary lymphangioleiomyomatosis causes progressive respiratory disease in susceptible adults.

Hearing, vision and cognitive disability

Vestibular tumours, optic pathway lesions and epilepsy-associated neurodevelopmental difficulties can substantially restrict communication, education and independence.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Measure blood pressure regularly in NF1 and TSC and investigate severe, refractory or symptomatic elevation for syndrome-specific causes.
Track growth, puberty, school progress, behaviour, attention, autism features and family support in children rather than monitoring tumours alone.
Follow known plexiform or intracranial tumours with clinical and imaging intervals set by the specialist team and urgently review new pain or deficit.
In TSC, maintain a shared brain, seizure, renal, lung, cardiac, skin, dental and eye surveillance schedule across the lifespan.
In NF2-related schwannomatosis, monitor hearing, balance, facial function, ophthalmic health and brain and spinal tumour burden.
For vigabatrin, mTOR or MEK treatment, complete the exact visual, cardiac, infection, laboratory and interaction checks required by the product and service.
Review genetic and reproductive counselling when an adolescent reaches decision-making age or family plans change.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Manifestations are age dependent

A young child may meet pigmentary NF1 criteria years before neurofibromas appear, so absence of adult signs does not weaken an otherwise compatible early diagnosis.

NF2 has new nomenclature

NF2-related schwannomatosis distinguishes the syndrome from NF1 and places it within the genetically defined schwannomatosis group.

White macules need contrast

Hypomelanotic TSC lesions can be difficult to see in pale skin and may be detected more clearly with a Wood lamp.

TSC behaviour is clinical disease

TSC-associated neuropsychiatric difficulties require active screening and intervention rather than being treated as an inevitable social consequence.

Mosaicism changes recurrence discussion

A post-zygotic variant can produce segmental signs and a negative routine blood test, while reproductive risk depends on whether germ cells are involved.

Pain can be oncological information

Persistent new pain in a previously stable NF1 tumour is a biological warning and should not be managed indefinitely with analgesia alone.

11Common pitfallsFrequent interpretation and management errors.

01
Do not confuse NF1 with NF2-related schwannomatosis; their hallmark tumours, surveillance and counselling differ.
02
Do not reassure a patient with NF1 about a rapidly growing painful mass without urgent malignant transformation assessment.
03
Do not wait for repeated developmental loss before treating suspected infantile spasms in TSC.
04
Do not interpret one café-au-lait macule, one renal cyst or one nonspecific MRI focus as diagnostic of a tumour-predisposition syndrome.
05
Do not use a variant of uncertain significance for predictive testing or declare a child unaffected because manifestations have not yet emerged.
06
Do not fragment TSC surveillance so that renal, lung or behavioural disease is missed while seizures receive attention.
07
Do not begin an mTOR or MEK inhibitor without a specialist indication, baseline checks and objective monitoring plan.