Tuberous Sclerosis Complex

Literature and regulatory information updated: 4 October 2026.

Bourneville disease: TSC1-related and TSC2-related tuberous sclerosis complex, somatic mosaicism and TSC2/PKD1 contiguous gene syndrome (autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis)

0. Initial Reference Table

1. Introduction

Tuberous sclerosis complex is a multisystem genetic disorder with autosomal dominant inheritance, characterised by the development of hamartomas: tumour-like lesions that are generally benign and composed of tissues native to the organ in abnormal proportions or architecture, affecting the brain, skin, kidneys, heart, lungs, retina and other organs, and frequently associated with epilepsy and intellectual disability [1, 9]. The disease may manifest at any age, from fetal life to late adulthood, and is distinguished by markedly variable expression: the same genotype may produce subtle cutaneous signs in a parent and infantile spasms with severe developmental delay in a child [9, 31]. The most frequent presentation remains epilepsy in early childhood, particularly infantile spasms, although a growing proportion of diagnoses follows the detection of cardiac rhabdomyomas on routine obstetric ultrasound [9].

The first description is usually attributed to Friedrich von Recklinghausen, who in 1862 described the post-mortem findings in a newborn with cardiac tumours and cerebral sclerosis. Recognition of the entity is nevertheless credited to Désiré-Magloire Bourneville, who in 1880 published the case of a girl with epilepsy, hemiplegia and intellectual disability whose brain showed hardened, “tuberous” convolutions, which he termed sclérose tubéreuse des circonvolutions cérébrales [2, 32, 33]. Vogt's classic triad (1908), comprising seizures, intellectual disability and “adenoma sebaceum”, dominated diagnosis for decades, until the demonstration of patients with normal intelligence and forms with few symptoms, particularly by Manuel Gómez at the Mayo Clinic, led to adoption of the term “complex” and formulation of weighted diagnostic criteria [33]. Gómez's criteria were revised at the 1998 consensus conference, which introduced the distinction between major and minor criteria and the categories of definite, probable and possible diagnosis [11, 34], and again at the 2012 international conference, which added the genetic criterion [35]. The 2021 revision, which forms the basis of this article, retained the 2012 structure with two changes: “multiple cortical tubers and/or radial migration lines” replaced the generic term “cortical dysplasias”, and sclerotic bone lesions were reinstated as a minor criterion [15].

The molecular era began with demonstration of locus heterogeneity, with linkage to 9q34 and 16p13. The TSC2 gene was identified in 1993 by the European Chromosome 16 Tuberous Sclerosis Consortium, through deletions in patients with tuberous sclerosis and polycystic kidney disease [6], and TSC1 was cloned in 1997 by van Slegtenhorst and colleagues [5]. Discovery that hamartin and tuberin form a complex that activates the GTPase activity of RHEB and thereby inhibits mTOR [8] transformed TSC into a paradigm of precision medicine: the mTOR inhibitors everolimus and sirolimus now constitute targeted, approved treatments for SEGA, renal angiomyolipoma, refractory focal seizures, LAM and, by topical administration, facial angiofibromas [1, 18, 22, 24].

Prevalence is approximately 1 in 10,000 individuals [9, 11], and birth incidence has been estimated at up to 1 in 5,800 live births [2, 12]. Central nervous system manifestations, including TSC-associated neuropsychiatric disorders (TAND), constitute the principal cause of morbidity, whereas renal disease is the principal cause of mortality [1, 16]. This article presents the molecular basis, manifestations by organ system, the 2021 criteria, recommended surveillance by system and treatment, with doses from official prescribing information; EEG-guided preventive epilepsy treatment (EPISTOP and PREVeNT trials) is presented briefly.

2. Molecular Genetics and Pathophysiology

2.1 Genes, proteins and the mTOR pathway

TSC1, at 9q34.13, encodes hamartin, and TSC2, at 16p13.3, encodes tuberin [1, 2]. The two proteins associate in a tumour-suppressor heterodimer, to which a third subunit (TBC1D7) binds, forming the TSC complex [36]. Tuberin is the catalytic subunit: its GAP domain accelerates hydrolysis of GTP bound to the small GTPase RHEB, maintaining it in an inactive state; GTP-bound RHEB is the direct activator of mTORC1 [8]. Hamartin, the non-catalytic component, stabilises tuberin and protects it from ubiquitination and proteasomal degradation, also functioning as an HSP90 co-chaperone [36]. The complex integrates signals from growth factors (through the PI3K–AKT pathway, which phosphorylates and inhibits tuberin, and the ERK and RSK kinases), cellular energy (through LKB1–AMPK, which activates tuberin during energy deficiency), the Wnt–GSK3 pathway and amino acid availability [9, 36]. mTORC1 is a central regulator of cell growth and proliferation: it promotes protein translation (through phosphorylation of S6 kinase and 4E-BP1), ribosome biogenesis, lipid synthesis and stress resistance, and inhibits autophagy [9, 36]. Rapamycin (sirolimus) and its derivatives, the rapalogues, inhibit mTORC1 by blocking binding of the accessory protein raptor to mTOR, explaining their action on TSC lesions [1, 9].

2.2 Two-hit mechanism and origin of lesions

TSC is dominant at the individual level and recessive at the cellular level. All cells in the patient carry an inactivating germline variant in one allele of TSC1 or TSC2 (first hit), and focal lesions, such as angiomyolipomas, SEGAs, rhabdomyomas and LAM cells, result from somatic inactivation of the second allele (second hit), through loss of heterozygosity, a point variant or an epigenetic alteration [9, 36]. This model explains the mosaic distribution of lesions and their variable number. Cortical tubers, however, do not always demonstrate a second hit, and haploinsufficiency is thought to contribute to diffuse changes in neuronal connectivity and myelination, helping explain why TAND and epilepsy do not correlate linearly with the number of visible lesions [2, 36]. Haploinsufficiency of TSC1 or TSC2 dysregulates mTORC1 activity and, in association with other pathway proteins, determines abnormal brain development [2].

2.3 Mutational spectrum and diagnostic yield

In series of patients with a clinical diagnosis, a pathogenic variant is identified in 75% to 90% of cases [1, 2, 37]. In the series by Dabora and colleagues (224 index cases), variants were identified in 83%: 138 small TSC2 variants, 20 large TSC2 rearrangements and 28 small TSC1 variants; the predominance of TSC2 reflects the larger gene size and an intrinsically higher mutation rate [9, 37]. Among more than 10,000 individuals with an identified variant, approximately 26% of probands had a TSC1 variant and 74% a TSC2 variant [1]. TSC2 predominates in sporadic (simplex) cases, whereas in familial cases the ratio between the two genes is close to 1:1 [1, 38].

Table adapted from GeneReviews (proportion of pathogenic variants identified by each method) [1].

TSC1 variants are predominantly small deletions and insertions and nonsense variants, detected by sequencing; TSC2 variants include, besides point variants and small indels, a substantial fraction of exon or whole-gene deletions and rearrangements requiring targeted deletion and duplication analysis, for example by MLPA (multiplex ligation-dependent probe amplification) [1, 39]. Kozlowski and colleagues identified 54 large deletions or duplications in TSC1 and TSC2 by MLPA and estimated that somatic mosaicism for large rearrangements may affect 5% of patients with normal sequencing results [2, 39]. A negative blood result therefore does not exclude the diagnosis: somatic mosaicism should be considered, and testing other tissues (tumours, saliva, skin, hair follicles) with high-coverage sequencing capable of detecting low variant allele fractions is indicated; when a variant of uncertain significance may affect splicing, messenger RNA sequencing should be considered [1, 15]. A variant is considered pathogenic for the genetic criterion only if it clearly inactivates hamartin or tuberin function (frameshifting indels, nonsense variants), prevents protein synthesis (large genomic deletions) or has a demonstrated effect in functional studies; other variants do not satisfy the genetic criterion [1, 15].

2.4 Genotype–phenotype correlations

TSC2 variants are associated with a more severe phenotype than TSC1 variants [1, 37]. Dabora and colleagues showed that sporadic patients with a TSC1 variant had, on average, fewer seizures, a lower frequency of moderate to severe intellectual disability, fewer subependymal nodules and cortical tubers, less severe renal involvement and facial angiofibromas and, according to Smith's, no retinal hamartomas [2, 9, 37]. Subsequent studies confirmed greater risks of multiple angiomyolipomas (> 4), renal neoplasia, significant developmental delay at 24 months, intellectual disability, low intelligence quotient, autism spectrum disorder (ASD), infantile spasms, cardiac rhabdomyomas and facial angiofibromas in TSC2 variant carriers [1, 40]. Even after adjustment for intellectual disability, TSC2-TSC is associated with a higher rate of self-injurious behaviour [1].

Some missense variants of TSC2 are associated with milder, often familial disease: p.Arg622Trp, p.Arg905Gln, p.Ser1036Pro, p.Arg1200Trp, p.Gln1503Pro, p.Gly1579Ser and p.Arg1713His (NM_000548.5), as well as c.4255_4256delCA, which creates a cryptic splice donor site and produces the in-frame deletion p.Gln1419_Ser1449del instead of the expected premature termination codon [1]. Variants in the carboxy-terminal region of tuberin may be associated with a higher incidence or severity of LAM in women, and renal cystic disease may be more severe with small TSC2 variants [1]. These correlations guide counselling but do not alter the surveillance schedule, which is the same for both genes [15].

2.5 TSC2/PKD1 contiguous gene syndrome

PKD1, responsible for approximately 77% of autosomal dominant polycystic kidney disease (ADPKD), lies immediately adjacent to TSC2 at 16p13.3, in a tail-to-tail orientation [41, 42]. Deletions removing both genes produce a contiguous gene syndrome, described by Brook-Carter and colleagues in 1994, in which the TSC phenotype coexists with severe polycystic kidney disease, usually evident in utero or in early childhood, with enlarged kidneys, a radiological appearance of advanced ADPKD and progression to end-stage kidney disease in late childhood or early adulthood [1, 9, 42]. Consugar and colleagues characterised the breakpoints of these rearrangements and showed that deletions affecting only the 3′ end of PKD1 may be associated with milder cystic disease [43]. Patients with this syndrome are also exposed to extrarenal ADPKD complications, such as hepatic cysts and saccular intracranial aneurysms [1, 2]. Numerous renal cysts in a patient with TSC, or multiple cysts associated with seizures or hypomelanotic macules in a patient with suspected ADPKD, should prompt investigation for a contiguous deletion [9, 41].

2.6 Isolated somatic lesions: these are not TSC

Isolated tumours without other TSC features, such as SEGAs, renal angiomyolipomas, cardiac rhabdomyomas, pulmonary LAM, perivascular epithelioid cell tumours (PEComas), urothelial and hepatocellular carcinomas, may contain a somatic TSC1 or TSC2 variant absent from the germline, in which case the predisposition is not hereditary [1]. In a study of isolated hepatic angiomyolipomas, 10 of 12 had a somatic TSC2 variant with a low allele fraction [1]. Sporadic LAM results from somatic TSC2 variants, with the same variant in angiomyolipoma and pulmonary cells, supporting the concept of benign metastasis of LAM cells [44]; rare cases of a germline TSC1 variant with a phenotype limited to LAM have been described [45]. In focal cortical dysplasia type II, paired brain and saliva sequencing identified cerebral somatic TSC1 or TSC2 variants in 5 of 40 MTOR-negative patients, all with mTOR hyperactivation; these are non-hereditary variants restricted to the malformed cortex and do not imply TSC [4]. In oncology, the 2022 World Health Organization classification recognises renal tumours with TSC1/TSC2 variants or mTOR pathway activation as a molecular subgroup, and variants in these genes are rare in sporadic chromophobe carcinoma [46].

3. Clinical Spectrum and Manifestations by Organ System

3.1 Overview

TSC may affect any organ, but manifestations are concentrated in the skin, brain, kidneys, heart, lungs and retina [1]. The following table summarises the frequencies of the main manifestations; differences between sources reflect cohort age, ascertainment method (hospital series, registry or population study) and widespread use of surveillance magnetic resonance imaging (MRI).

3.2 Skin

The skin is affected in virtually all patients [1]. Hypomelanotic macules are usually the first cutaneous manifestation, present at birth or appearing in early childhood; they occur in approximately 95% of patients by age 5 years [9]. They are oval, lanceolate (“ash leaf”) or “fingerprint” shaped, usually measure 1 to 5 cm, occur predominantly on the trunk and limbs, and most patients have fewer than six [2, 48]. A Wood's lamp (360 nm ultraviolet light) facilitates their visualisation, particularly in fair skin [9]. Approximately 0.8% of healthy newborns have similar macules, rarely more than three; in a healthy population, 6% of children and 4% of adults younger than 45 years had an isolated macule, fewer than 1% had multiple lesions and no individual without TSC had more than three [9, 48, 49]. GeneReviews discourages the term “ash-leaf spots” because macules may have any shape or size and shape does not alter their diagnostic value [1]. Confetti lesions are numerous scattered hypopigmented macules measuring 1 to 3 mm, particularly on the limbs, with frequencies ranging from 3% in children to 58% across all patients [1, 2]. White hair patches (poliosis) and café-au-lait macules may also occur [11]. For the criteria, poliosis counts as a hypomelanotic macule [14].

Facial angiofibromas (formerly “adenoma sebaceum”, an inappropriate term because lesions have no sebaceous component) are rarely evident before age 2 years and may only appear in middle age; they occur in 75–85% of patients, in a “butterfly” distribution over the nose, nasolabial folds and malar regions, and also on the chin, with colour ranging from pink to red, yellowish or brownish [1, 2, 9]. They are present in 50% of children by age 5 years [2]. They differ from acne through the absence of sebaceous gland involvement and infection and their persistence at the same location, although both conditions may coexist [9]. They are the most disfiguring skin lesions, without medical severity [1, 2]. A fibrous cephalic plaque is a smooth, raised, skin-coloured or yellowish-brown waxy lesion, measuring a few millimetres to several centimetres, on the forehead (look beneath the fringe), usually appearing in late childhood [9]. A shagreen patch is a thickened connective tissue naevus with an “orange-peel” texture, usually in the lumbosacral region slightly lateral to the midline, appearing between childhood and puberty and present in approximately half of young adults [2, 9]. Ungual fibromas (Koenen tumours) are pink or red nodules emerging from the corner of the nail bed, causing nail grooves; they are usually multiple, more frequent on the feet, where they may bleed following trauma, and occur in up to 88% of adults [9, 11]. The French PNDS (French National Diagnosis and Care Protocol), based on a reference series, gives lower overall frequencies (hypomelanotic macules in approximately two-thirds, angiofibromas in 60%, shagreen patch in 25%, fibrous cephalic plaque and ungual fibromas in approximately 15% each and confetti lesions in 10%), a difference that mainly reflects the age of the cohorts, because several lesions appear only in adolescence or adulthood [14]. The same document considers the fibrous cephalic plaque, present from birth and more often described in girls, probably the most specific skin lesion of TSC; it notes that angiofibromas bleed on contact and become more visible with sun exposure, and that ungual fibromas may be complicated by recurrent paronychia and, when subungual, be mistaken for warts and treated as such [14]. Folliculocystic hamartomas and acrochordons (molluscum pendulum) are also described [14].

3.3 Central nervous system: structural lesions

Cortical tubers are areas of cortical dysplasia with loss of lamination, dysmorphic neurones and giant cells; they are observed in approximately two-thirds of cases on computed tomography (CT) and approximately 95% on MRI, with FLAIR (fluid-attenuated inversion recovery) sequences showing them best because they suppress the signal from fluid adjacent to the ventricles [9, 50]. Most patients have 1 to 10 tubers, and patients with intellectual disability have significantly more tubers than those with normal intelligence [9]. White matter radial migration lines, reflecting hypomyelination and heterotopia, are visible in approximately 20% of MRI examinations [9]. Subependymal nodules (SENs) lie along the walls of the lateral ventricles and adjacent to the caudate nucleus, are frequently calcified and clearly visible on CT; they are the most diagnostically informative cerebral lesions and occur in approximately 80% of patients [1, 9]. In infants younger than 18 months, whose myelination is incomplete, MRI may demonstrate tubers poorly and CT may be preferable when clinical suspicion is strong, weighing specificity, radiation and availability; MRI performed before 15 months may need to be repeated later [9, 51].

Subependymal giant cell astrocytoma (SEGA) is a slowly growing glioneuronal tumour arising from a subependymal nodule, typically in the head of the caudate nucleus, adjacent to the foramen of Monro [9]. Frequency varies between sources: 5–15% in SGRT, approximately 10% in Smith's, 10–15% in the Oxford Desk Reference and up to 25% in MRI surveillance series, such as the TOSCA registry (24.4%) [1, 2, 9, 11, 47]. Peak incidence occurs between late childhood and adolescence [9]. Symptomatic presentation results from obstructive hydrocephalus, with headache, vomiting, worsening seizures or acute neurological deterioration [1, 9]. Malignant transformation of periventricular nodules is rare [2]. Children with SEGA have almost twice the likelihood of ASD [1]. The French PNDS adds imaging and natural history details: subependymal nodules measure 1 to 10 mm and may grow slowly; before 3 months of age, nodules and tubers are hyperintense on T1 and hypointense on T2, the pattern subsequently reversing; SEGA, histologically identical to the nodule, is distinguished by its location near the foramen of Monro and by its growth potential, greater when it is poorly calcified and enhances intensely with gadolinium, and it rarely appears after 20 years of age; it is not epileptogenic, but may worsen pre-existing epilepsy as it grows [14]. Raised intracranial pressure due to SEGA may develop insidiously, with sleep disturbance, school difficulties, worsening behaviour or atypical headaches, and without papilloedema [14]. In presurgical evaluation, epileptogenic tubers tend to show increased diffusion, normal or increased perfusion on ASL (arterial spin labeling) and increased alpha-methyltryptophan uptake on positron emission tomography, whereas the remaining tubers are hypoperfused and hypometabolic [14].

3.4 Epilepsy

Epilepsy occurs in approximately 80% of patients (83.5% in TOSCA), and the best estimate in familial cases is 62%, lower than in sporadic cases, partly because of the smaller proportion of TSC2 variants [9, 47]. Up to 75% of patients develop seizures before age 2 years, often in the first months of life [1, 9]. Focal seizures with or without impaired awareness, tonic and generalised tonic–clonic seizures, atonic and myoclonic seizures, and infantile spasms occur, with patterns changing throughout early childhood [9]. TSC is the most frequent autosomal dominant cause of epilepsy with developmental delay and accounts for approximately 25% of infantile spasm cases [51]. The electroencephalogram (EEG) is abnormal in 87% of patients and may show hypsarrhythmia [2]. Two-thirds develop drug-resistant epilepsy, and 85% of children with seizures continue to have them at age 5 years [1, 9]. Epileptiform EEG activity frequently precedes clinical seizures, providing the rationale for serial EEG surveillance in infants [1, 15]. Early onset and treatment resistance are strongly associated with developmental delay, ASD and psychiatric disorders [1]. The data compiled in the French PNDS place epilepsy in 60–90% of patients, with onset in the first year of life in two-thirds, epileptic spasms in 30–40% (diagnosed mainly between 3 and 6 months and often preceded by subtle focal seizures), TSC in 7–25% of infants with West syndrome, progression to Lennox–Gastaut syndrome in 25–30% and drug resistance (failure of two appropriate antiseizure medications) in 60–75% [14]. Hypsarrhythmia is less frequent than with other causes of spasms, and the response to vigabatrin is better than with other aetiologies, without preventing the later appearance of other seizure types [14]. In 8–12% of adults with TSC, epilepsy begins in adulthood, sometimes after 60 years of age, usually focal, unifocal and less severe, with intellectual disability less frequent, although with the usual neuropsychological disorders; there is no evidence that routine EEG in adults predicts the onset of seizures [14].

3.5 TSC-associated neuropsychiatric disorders (TAND)

TAND denotes the interrelated behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC [1, 52]. More than 90% of children and adults will have at least one TAND during their lifetime, yet only approximately 20% receive assessment and intervention [1]. Data analysis identified seven natural clusters: scholastic, neuropsychological, autism-like, dysregulated behaviour, hyperactivity/impulsivity, mood/anxiety and eating/sleep, alongside the psychosocial level [1, 27].

Intellectual disability. Prevalence is estimated at 44% to 64% [1, 53]. More than 50% of patients have normal intelligence, and intellectual disability is unusual in those who have never had seizures [9]. Children with seizures during the first 2 years, particularly infantile spasms, are more likely to have intellectual disability, and seizure onset after age 5 years is rarely associated with learning difficulties unless non-convulsive status epilepticus occurs [9]. In a small series, estimated intelligence quotient fell from 92 before spasms to 73 when spasms lasted less than 1 month and 62 when they lasted more than 1 month [1]. Between 36% and 58% of children have academic difficulties requiring intervention [1]. Cognitive deterioration is unusual except in association with very frequent seizures or status epilepticus [2].

ASD. Prevalence is estimated at 16% to 61% (approximately 25% in the Oxford Desk Reference and 40% in Smith's), while more broadly defined pervasive developmental disorders affect 50–86% [1, 2, 9, 54]. TSC is found in approximately 1% of children with autism [54]. ASD signs may appear from age 9 months, and classification at 12 months predicts diagnosis at 2 years using ADOS-2 (Autism Diagnostic Observation Schedule, Second Edition) [1]. Tubers in the fusiform gyrus are associated with a 3.7-fold higher ASD risk, and males have a higher risk [1].

ADHD, behaviour and mood. Attention deficit hyperactivity disorder (ADHD) occurs in 21–52% (43–59% for disruptive disorders with hyperactivity or attention deficit, according to Oxford), aggression in 13–58%, self-injurious behaviour in 27–41%, anxiety in 9–48% and depression in 6–43% [1, 9]. Sleep disorders are very frequent, particularly when epilepsy is poorly controlled [9]. Untreated TAND contributes significantly to poorer prognosis and quality of life [1]. In the TOSCA registry, cited by the French PNDS, neuropsychological assessment of 885 patients showed normal IQ in 44.4%, mild intellectual disability in 28.1%, moderate in 15.1%, severe in 9.3% and profound in 3.1%; across the more than 2,000 patients in the registry, formal diagnoses were ASD in 21%, ADHD in 19%, anxiety disorder in 9% and depression in 6%, whereas behavioural symptoms were much more frequent (hyperactivity 45%, impulsivity 42%, anxiety 33%, mood lability 30%, aggression 24%, sleep disorders 44%), with school difficulties in approximately 60% and neuropsychological deficits in 55% [14]. The gap between formal diagnoses and symptoms is consistent with the under-identification of TAND. Hyperactive and impulsive symptoms predominate in children, and anxious-depressive and hallucinatory symptoms in adults [14]. The PNDS distinguishes two populations with different needs: children with epilepsy beginning in the first year, often with spasms, at high risk of intellectual disability and of impaired social interaction when there is drug resistance; and patients with later-onset or rapidly controlled epilepsy, or without epilepsy, with preserved cognition, in whom the challenge is to identify specific cognitive deficits that compromise schooling and employment [14].

3.6 Kidneys

Renal disease is the principal cause of early death in TSC; approximately 80% of children have an identifiable renal lesion at a mean age of 10.5 years [1, 2, 55]. Five lesion types are described: benign angiomyolipoma (70%), epithelial cysts (20–30%), oncocytoma (< 1%), malignant angiomyolipoma (epithelioid, < 1%) and renal cell carcinoma (< 3%) [1]. Angiomyolipomas comprise abnormal blood vessels, smooth muscle and mature adipose tissue; they are usually multiple and bilateral and increase in number and size with age, being present in 17%, 42%, 65% and 92% of patients aged under 2, 2–5, 9–14 and 14–18 years, respectively [9, 56]. They may be asymptomatic or cause loin pain, haematuria, potentially fatal intrarenal or retroperitoneal haemorrhage (Wunderlich syndrome) and, through replacement of the parenchyma, chronic kidney disease progressing to end-stage disease [1, 9]. Bleeding risk increases with size (above 3.5–4 cm) and intratumoural aneurysms [2, 11]. Renal cysts are present from early childhood, are usually few and do not appear to increase in number with age except in contiguous gene syndrome [9, 41]; their epithelial lining comprises hypertrophic and hyperplastic eosinophilic cells [1]. Renal cell carcinoma develops in 2–5% of patients, with a typical age at diagnosis of 28 to 30 years, much earlier than sporadic forms; fat-poor angiomyolipomas may be indistinguishable from carcinoma on imaging, and immunohistochemistry (HMB-45 positivity in angiomyolipoma, cytokeratin in carcinoma) is recommended [1]. TSC is among the predisposition syndromes responsible for the 5–10% of renal carcinomas with a germline variant [46]. Hypertension may occur as a complication of renal disease [2]. The French PNDS (French National Diagnosis and Care Protocol) estimates renal involvement in 80% of adults, with angiomyolipomas usually identified at around 10 years of age and growing faster from that age, particularly before and during puberty, an effect attributed to oestrogen [14]. Risk factors for rupture identified in observational studies are a diameter above 4 cm, intratumoural aneurysms larger than 5 mm and oestrogen exposure (pregnancy, hormonal treatment); 70–80% of angiomyolipomas larger than 4 cm become symptomatic (pain, loin heaviness, urinary compression, haematuria), and the reported rupture rate is 5–6% per year [14]. Renal cysts, outside the TSC2/PKD1 syndrome, occur in 30–45% and usually do not progress; renal carcinomas are mainly clear cell, with papillary forms and oncocytomas described, and may arise from adolescence; nephrolithiasis is inconstant; end-stage kidney disease requiring dialysis is rare [14]. Angiomyolipomas belong to the PEComa family and co-express smooth muscle and melanocytic markers (HMB-45); the absence of visible fat on imaging does not exclude the diagnosis [14, 29].

3.7 Heart

Cardiac rhabdomyomas occur in approximately 50% of patients and 30–50% of fetuses with TSC; they are largest in the neonatal period, may be detected on second- or third-trimester ultrasound (usually not before the third) and regress spontaneously with age [1, 2, 9]. In the absence of outflow tract obstruction at birth, they rarely cause subsequent problems except arrhythmias, attributed to cellular remnants persisting after regression [1]. Arrhythmias include Wolff–Parkinson–White syndrome, due to accessory atrioventricular conduction pathways, which may cause death in childhood [11, 57]. In the German surveillance cohort, rhabdomyomas were associated with arrhythmias in 25.6% of patients with a rhabdomyoma [13]. Aortic coarctation and aortic aneurysms have also been described [11]. Rhabdomyomas are usually detected between 20 and 30 weeks of gestation, grow until the end of pregnancy and, after regression, persist as remnants; large tumours may obstruct the outflow or inflow tracts and cause heart failure from fetal life, and arrhythmias (atrial or ventricular hyperexcitability, supraventricular or ventricular tachycardias) are reportedly more frequent with large tumours; bundle branch blocks have no clinical consequence, and symptomatic sinus bradycardia and atrioventricular block are exceptional [14]. Aneurysms of the aorta and medium-sized arteries are exceptional and often recognised only at rupture, a frequency that does not justify systematic screening; the initial echocardiogram and chest and abdominal imaging performed for other reasons are opportunities to look for them [14].

3.8 Lungs

Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm characterised by proliferation of atypical smooth muscle cells (LAM cells) in the pulmonary parenchyma and lymphatic vessels, with formation of thin-walled cysts [1, 28]. It predominantly affects women, with a mean age at diagnosis in TSC of 28 years, and is estimated to affect 30–40% of women with TSC, or up to 80% by age 40 years with systematic CT; cysts consistent with LAM have been described in 10–12% of men [1]. Smith's reports LAM in 40% of women of reproductive age [2]. Most patients are asymptomatic; symptomatic disease manifests as progressive dyspnoea, spontaneous recurrent pneumothorax, chylothorax, dry cough and haemoptysis [1, 11]. Only 5–10% of women with TSC-associated LAM progress to respiratory failure [1]. Multifocal micronodular pneumocyte hyperplasia (MMPH), a nodular proliferation of type II pneumocytes, occurs in up to 40–58% of patients of both sexes, with or without LAM, and rarely has clinical consequences [1]. The natural history data compiled in the French PNDS documents refine these figures: in a cohort of 101 women with TSC, 7% had more than three cysts on CT before 21 years of age and 81% after 40; only 63% of women with CT abnormalities developed symptoms, and 12.5% died of LAM without mTOR inhibitor treatment [14]. Lung cysts have been described in 10–30% of men with TSC, but symptomatic LAM in men is exceptional [14, 29]. LAM causes airflow obstruction and reduced carbon monoxide diffusing capacity, which is often affected before FEV1; FEV1 declines on average by 75–135 mL/year, compared with 20–30 mL/year in healthy adults, and in a cohort of 43 untreated patients the decline was −17 ± 3 mL/month before and −3 ± 3 mL/month after menopause [14, 29]. The decline was considered slower in TSC-associated LAM, but the LAM PNDS attributes this difference mainly to the screening of asymptomatic patients and recommends the same follow-up intervals in both forms [29]. Without treatment, chronic respiratory failure develops on average approximately 10 years after symptom onset; pneumothorax occurs in 57% of patients, with a recurrence rate of the order of 70%, and serum VEGF-D has prognostic value [14, 29]. Bone mineral density is reduced in 70% of patients [29]. The TSC PNDS estimates MMPH in 28–71% of patients of both sexes; it does not occur in sporadic LAM, presents as ground-glass micronodules of 1 to 5 mm, has no physiological or prognostic consequence, and should be distinguished from other causes of ground-glass nodules, such as lepidic adenocarcinoma [14, 29].

3.9 Eyes

Retinal astrocytic hamartomas occur in 30–50% of patients, are frequently multiple and bilateral and take several forms: the commonest are flat, smooth, oval, semitransparent lesions matching the fundus colour; less frequent are the classic “mulberry” lesions, which are raised, opaque, multinodular and calcified, usually adjacent to the optic disc [1, 9]. They are almost always asymptomatic but may impair vision if they affect the macula and, rarely, cause retinal detachment or neovascular glaucoma [2, 9]. Retinal achromic patches were found in 34% of patients, compared with a population incidence of 1:20,000 [1]. Other ocular abnormalities include iris depigmentation, strabismus, optic atrophy, visual field defects (including those induced by vigabatrin) and cataracts [11]. The French PNDS classifies astrocytic hamartomas as type 1 (flat and translucent, approximately 50%), type 2 (exophytic, multinodular and calcified, “mulberry”, 15–25%, with prevalence increasing with age) and type 3 (intermediate, 15–25%, possibly a transitional stage); they are bilateral and multiple in approximately 40%, are located at the posterior pole, along the temporal arcades and around the optic nerve, and on optical coherence tomography (OCT) arise in the nerve fibre layer, with optically empty spaces, which also allows subclinical lesions to be detected [14]. They are usually congenital and change little, although new lesions have been documented; complications (macular epiretinal membrane, vitreous haemorrhage, exudation with retinal detachment) are exceptional and often self-limiting [14]. The same document describes achromic patches in 10–39% of patients, compared with approximately 6% of the general population in one of the studies cited, a reference value that differs from that given by GeneReviews; they generally measure approximately 0.5 mm, are located in the mid-periphery and do not progress [1, 14].

3.10 Other organs

Extrarenal angiomyolipomas, particularly hepatic (10–15%) and pancreatic, occur more frequently in patients with renal angiomyolipomas [1]; hepatic hamartomas are present in 25% and rarely have clinical significance [9]. Neuroendocrine tumours, particularly pancreatic tumours, are increasingly identified on surveillance abdominal MRI; the most frequent functioning tumours are insulinomas, but gastrinomas, glucagonomas and tumours producing ACTH and growth hormone have been described; they are more associated with TSC2, occur earlier and have no clear evidence of greater aggressiveness than sporadic tumours [1]. Smith's additionally lists pituitary and parathyroid adenomas, parathyroid hyperplasia, hypothyroidism, thyroid adenomas, precocious puberty, lymphoedema and hamartomatous rectal polyps [2]. Sclerotic bone lesions, particularly in the posterior vertebral elements, increase in number and size with age and have no clinical consequences despite being a minor criterion [1]; phalangeal bone cysts with periosteal thickening were described in 66% in older radiological series [2]. In the mouth, dental enamel pits increase susceptibility to caries and intraoral fibromas, particularly gingival fibromas, may appear after trauma or as an effect of some antiseizure medications [1, 9]; enamel pits may occur in healthy individuals and therefore have limited specificity in isolation [9]. The French PNDS stresses that sclerotic bone lesions, particularly in the vertebrae and limb girdles, may be mistaken for metastases (from renal tumours or other primaries) when discovered incidentally; in adults they do not usually take up technetium on scintigraphy, but may do so in children and young adults while they are developing; cranial hyperostoses and chordomas are exceptional [14]. It adds adrenal angiomyolipomas in approximately a quarter of patients, almost never haemorrhagic, papillary thyroid adenomas without dysfunction, congenital lymphoedema, localised hypertrophies and hemihypertrophy; neuroendocrine tumours are not hamartomas and do not count as a diagnostic criterion [14].

3.11 Differences by sex

Females tend to have milder neurological disease, with less impulsivity, hyperactivity, ASD and ADHD, but greater vulnerability to pulmonary (LAM) and renal disease [1, 2, 16]. SGRT reports a slight male predominance and a higher frequency of angiomyolipomas in women [11].

4. Clinical Recognition and Warning Signs

Recognition of TSC depends on age because manifestations emerge in a predictable temporal sequence: cardiac rhabdomyomas in fetuses and newborns, hypomelanotic macules and infantile spasms in infants, facial angiofibromas from preschool age, shagreen patches between childhood and puberty, ungual fibromas and angiomyolipomas from adolescence, and LAM in adult women [1, 2, 9]. In the German prospective surveillance cohort, median age at diagnosis was 6 months; the most frequent presentations were central nervous system involvement (73.3%, almost always seizures), skin involvement (58.1%, with hypomelanotic macules in 92%) and cardiac rhabdomyomas (half of patients, detected on prenatal ultrasound in 22.1%) [13].

History-taking should include a three-generation pedigree with targeted enquiry about TSC, infantile spasms, epilepsy, learning difficulties and facial angiofibromas, seizure history and a detailed developmental and behavioural history [9]. Physical examination should include the entire skin with a Wood's lamp, the forehead beneath the fringe, the lumbosacral region, all fingernails and toenails, the oral cavity and teeth, blood pressure and fundus examination [9, 51]. In a child with epilepsy and developmental delay, a retinal phakoma and hypomelanotic macules are specific warning signs [51]. In settings with limited genetic diagnostic resources, cutaneous manifestations are particularly useful clinical markers [60].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 2021 international diagnostic criteria

TSC may be diagnosed through genetic or clinical criteria [15]. The genetic criterion is identification, in DNA from normal tissue, of a pathogenic TSC1 or TSC2 variant, defined as one that clearly inactivates protein function, prevents protein synthesis or whose effect has been established through functional testing; this is sufficient for a definite diagnosis regardless of clinical manifestations, because these develop over time [1, 15]. A variant of uncertain significance neither establishes nor excludes the diagnosis, and 10–25% of patients have no variant identified by conventional testing, so a normal result does not exclude TSC [1, 15].

Definite clinical diagnosis: 2 major criteria, or 1 major with ≥ 2 minor criteria. Possible diagnosis: 1 major criterion, or ≥ 2 minor criteria. *The isolated combination of LAM and angiomyolipomas, without other manifestations, does not satisfy the criteria for a definite diagnosis [1, 9, 15].

The evolution of the criteria is relevant when reading the literature and teaching texts. The 1998 criteria, still reproduced in SGRT, included cortical tubers, subependymal nodules and migration lines as separate criteria, recognised definite, probable (1 major and 1 minor) and possible (1 major or ≥ 2 minor) diagnoses, and considered bone cysts, hamartomatous rectal polyps and gingival fibromas minor criteria [11, 34]. The 2012 criteria added the genetic criterion, removed the “probable” category, grouped cortical abnormalities under “cortical dysplasias”, defined numerical thresholds and removed bone cysts [9, 35]. The 2021 criteria retained this structure with the two changes already mentioned [15]. In practice, isolated “cortical dysplasia”, even when multiple, should not be counted simultaneously with migration lines as two major criteria.

The French TSC PNDS (French National Diagnosis and Care Protocol) reproduces the 2021 criteria and adds, for variants of uncertain effect, supporting arguments for pathogenicity (consistent segregation in the family, absence from population databases, previous description in patients), which do not replace the functional demonstration required by the genetic criterion [14]. It diverges on one point: it states that the appearance of facial angiofibromas in adulthood counts only as a minor criterion, because they may correspond to Birt–Hogg–Dubé syndrome or multiple endocrine neoplasia type 1; this rule is not part of the 2021 criteria, but it justifies biopsy and differential diagnosis when angiofibromas appear in an adult without other signs [14, 15]. The LAM PNDS also reproduces, in an annex, the 2012 criteria, with “cortical dysplasias” as a single criterion and without sclerotic bone lesions [29, 35].

5.2 Genetic testing

The recommended strategy is simultaneous sequencing of TSC1 and TSC2 with targeted deletion and duplication analysis (MLPA or targeted microarray), either alone or within a multigene panel including differential diagnostic genes when TSC suspicion is less certain [1]. Panels limit identification of variants of uncertain significance and findings unrelated to the phenotype; exome or genome sequencing may be used when the presentation is non-specific [1, 51]. In patients with a clinical diagnosis and negative blood testing, somatic mosaicism should be investigated in DNA from lesional tissue (angiofibroma, ungual fibroma, angiomyolipoma) using high-coverage sequencing [1, 15]. In a Brazilian series of 116 patients with a definite clinical diagnosis, pathogenic alterations were identified in 91% (17% in TSC1 and 83% in TSC2), 35 of them previously unreported, and functional assessment of TORC1 activity allowed seven TSC2 variants to be reclassified [61]. Genetic testing also has predictive value in relatives (section 8) and enables prenatal and preimplantation diagnosis [1]. SGRT reported approximately 300–350 distinct variants known at that time; LOVD databases now record thousands of variants in both genes [1, 11]. The French PNDS recommends offering testing to all patients with a definite or possible diagnosis, estimates the sensitivity of conventional techniques at approximately 85% and notes that, in low allele fraction mosaicism detected in a single tissue, it may be difficult to exclude an artefact; mosaicism is not systematically associated with milder disease, although it is more frequent in forms with little or no neurological involvement, so the recommended surveillance is the same as for complete forms [14]. When a variant of uncertain significance is found in the proband, testing the asymptomatic parents is useful, because de novo occurrence supports pathogenicity, whereas its presence in an asymptomatic parent is difficult to interpret and may require testing of other relatives and a complete clinical assessment of that parent [14].

5.3 Initial assessment after diagnosis

Following diagnosis, the 2021 consensus recommends a multisystem baseline assessment, which also documents additional criteria [1, 15]:

In infants, echocardiography is particularly useful because rhabdomyomas are frequent at this age and may support the diagnosis; in young adult women, baseline high-resolution chest CT and pulmonary function tests are recommended [9]. Renal ultrasound may identify the small minority of infants with TSC2/PKD1 syndrome [9], but MRI is preferable for angiomyolipoma surveillance because it better characterises fat-poor lesions and avoids radiation [15].

The French PNDS adds to the baseline assessment: in children, abdominal (hepatorenal) ultrasonography when MRI would require general anaesthesia, completed by MRI if the child is prepubertal or has an angiomyolipoma larger than 30 mm, and routine abdominal MRI in adults; abdominal MRI in the same anaesthetic session as brain MRI; estimation of GFR from creatinine or cystatin C and measurement of albuminuria and urinary creatinine in a spot sample, which serve as a baseline if everolimus is later prescribed; kidney-protection advice (diet, preservation of venous access, avoidance of non-steroidal anti-inflammatory drugs) and explanation of warning signs (loin pain, haematuria); an electrocardiogram in all patients, because pre-excitation and conduction defects influence the choice and dose of psychotropic drugs; Holter monitoring in patients with rhabdomyomas; echocardiography unnecessary in adults without cardiac symptoms or history; ophthalmological examination with acuity, refraction, alignment, intraocular pressure, slit lamp and dilated fundoscopy, with retinal photography; a gynaecology consultation in women, because of the contraindication to oestrogens; and optional bone radiography or scintigraphy [14]. Brain MRI requires sedation or general anaesthesia in children and in patients with intellectual disability; if this is not possible, CT or transfontanellar ultrasonography are suboptimal alternatives [14]. Vascular anomalies, gastrointestinal polyps, bone cysts and endocrinopathies do not justify systematic assessment in the absence of symptoms [14].

5.4 Prenatal diagnosis following suspicion

Detection of a cardiac rhabdomyoma on routine second- or third-trimester ultrasound, outside targeted prenatal diagnosis, is associated with a TSC probability of 39–86% (Gamzu and colleagues), 50–80% according to Smith's and 90–95% when rhabdomyomas are multiple [1, 2, 9, 58]. Fetal MRI may demonstrate cortical tubers and subependymal nodules and strengthen the diagnosis, and genetic testing may be performed on chorionic villi or amniotic fluid [1, 62]. In fetuses at 50% risk without a known familial variant, the sensitivity of high-resolution ultrasound is unknown, and cardiac tumours are rarely detected before the third trimester [1]. The French PNDS gives close but not identical estimates: a TSC probability of 30–40% (approximately 50% in the genetic counselling section) for a single isolated rhabdomyoma, and close to 100% for multiple rhabdomyomas, considering that two rhabdomyomas establish the diagnosis [14]. It recommends referral to a multidisciplinary prenatal diagnosis centre (CPDPN) to assess cerebral involvement by fetal MRI in the third trimester, notes that a normal fetal MRI does not exclude the diagnosis and that the neurological prognosis cannot be predicted before birth, except in severe malformations of gyration, and indicates that amniocentesis for urgent variant testing, discussed case by case, has a turnaround time of 3 to 4 weeks, and that the diagnosis may remain uncertain (single rhabdomyoma with negative testing or a variant of uncertain significance) [14]. In France, termination of pregnancy for medical reasons may be discussed at the CPDPN [14].

5.5 Diagnostic algorithm

The practical algorithm can be summarised in four steps. First, when a warning sign is present (section 4), apply the 2021 clinical criteria using Wood's lamp skin examination, fundus examination, brain MRI, echocardiography (up to age 18 years) and abdominal MRI. Second, test TSC1 and TSC2 through sequencing and deletion and duplication analysis; identification of a pathogenic variant establishes the diagnosis even without complete clinical criteria. Third, if blood testing is negative and clinical suspicion persists, investigate mosaicism in lesional tissue and, if a variant of uncertain significance potentially affects splicing, study RNA. Fourth, if numerous renal cysts are present, assess whether the deletion extends to PKD1 [1, 9, 15].

5.6 Genetic testing limitations and report content

TSC1 and TSC2 sequencing with deletion and duplication analysis detects a variant in 75–90% of patients with a clinical diagnosis, and the remaining fraction should not be interpreted as lacking a genetic cause [1, 15]. In a study of 53 patients without a variant identified by conventional methods, next-generation sequencing covering the entire genes found a variant in 45 (85%): 58% were mosaics, 40% were intronic variants outside routinely analysed regions, 38% had allele fractions below 5%, and two were identified only in skin tumour biopsies [63]. The report should therefore state coverage of intronic and regulatory regions, the method and resolution of copy number analysis, read depth and mosaicism detection limit, and the tissue analysed; a convincing phenotype with a negative blood result is followed by lesional tissue testing (angiofibroma, ungual fibroma, angiomyolipoma) and, for variants potentially affecting splicing, RNA analysis [1, 15, 63].

The report should state the gene, reference transcript with version — NM_000368.5 for TSC1 and NM_000548.5 for TSC2, MANE Select transcripts confirmed at NCBI —, the variant in normalised HGVS nomenclature at DNA and protein levels, zygosity (heterozygosity or mosaicism, with allele fraction), ACMG/AMP classification and limitations [1, 7]. The consulted ClinGen specification registry has no expert panel specification for TSC1 or TSC2, so the general ACMG/AMP rules apply alongside the restrictive definition of a pathogenic variant in the 2021 criteria (clear inactivation, absence of protein synthesis or demonstrated functional effect) [15, 64]. Older literature numbered variants using earlier transcript versions and sometimes single-letter protein notation; citations of these variants should state the normalised form and, when different, the original form. A variant of uncertain significance does not become pathogenic through clinical response to an mTOR inhibitor, because this class acts on the pathway and does not confirm the aetiology, or through partial segregation in a small family; functional assays of mTORC1 activity, such as those used in the Brazilian series to reclassify seven TSC2 variants, are the appropriate route, presented as research until formal reclassification [61].

5.7 Diagnosis of lymphangioleiomyomatosis and relationship with TSC

The French LAM PNDS (French National Diagnosis and Care Protocol) adopts the criteria of the ATS/JRS guidelines: characteristic high-resolution chest CT (more than 10 round, thin-walled cysts with walls less than 3 mm thick, diffusely distributed in normal parenchyma) or compatible CT (more than 2 and up to 10 cysts), together with at least one additional criterion: renal angiomyolipoma, retroperitoneal or pelvic lymphangioleiomyoma, serum VEGF-D ≥ 800 pg/mL, chylous pleural effusion or ascites, a TSC context or histological confirmation by an experienced pathologist [28, 29]. In a patient with known TSC, a characteristic CT is sufficient for diagnosis [14]. VEGF-D ≥ 800 pg/mL has a sensitivity of 73% and a specificity of 100% in the presence of a suggestive radiological picture, but it is normal in 20–30% of patients, and the assay is available only in specialised laboratories [29]. Biopsy is needed only in a minority, when the diagnosis is uncertain and there is a therapeutic indication: video-assisted thoracoscopic lung biopsy is the reference technique, often at the same time as pleurodesis; transbronchial biopsy has a yield of approximately 50%; cryobiopsy is not validated; and biopsy of a lymphangioma is discouraged if imaging is diagnostic; immunohistochemistry shows smooth muscle actin, desmin, HMB-45, Melan-A and PNL2, with oestrogen or progesterone receptors in approximately half of cases [29]. These criteria apply only to women; in men with TSC, LAM is possible but rarely has clinical expression [29].

Every patient with LAM should be assessed for TSC: a focused personal and family history (epilepsy, cognitive or behavioural disorders, skin lesions treated with laser, rhabdomyoma in childhood, renal tumour or haemorrhage, retinal lesions), dermatological examination and fundoscopy by specialists experienced in TSC, review of CT scans in bone window looking for sclerotic lesions and, if there is suspicion, neurological symptoms or bilateral angiomyolipomas, brain MRI with a FLAIR sequence [29]. The two PNDS documents diverge on molecular testing in apparently sporadic LAM: the TSC PNDS considers it legitimate, whereas the LAM PNDS considers it unnecessary as routine, except on the advice of a geneticist, because the somatic TSC2 variant is confined to LAM cells and is not detectable in blood; both recommend it when TSC is suspected, in which case the variant is identified in 85–90% of cases [14, 29]. The nature of the variant does not modulate individual prognosis or LAM treatment, but it is of interest to the family [29]. The baseline LAM assessment also includes baseline arterial blood gases, a 6-minute walk test, plethysmography (volumes are underestimated by helium dilution in cystic diseases), echocardiography in severe disease or before transplantation, renal function with albuminuria, liver function and bone densitometry; outside TSC, brain MRI is justified only for symptoms of meningioma, the risk of which increases with high-dose progestogens (nomegestrol acetate, chlormadinone acetate) [29].

6. Differential Diagnosis

Differential diagnosis is chiefly undertaken manifestation by manifestation, because many TSC findings are non-specific in isolation [1].

Distinguishing TSC from isolated somatic lesions has decisive counselling implications: women with LAM and renal angiomyolipomas without other manifestations do not transmit TSC or LAM to their children, and a variant restricted to a tumour or dysplastic cortex does not constitute TSC [1, 4].

7. Treatments and Risk Management Strategies

7.1 General principles and organisation of care

TSC treatment rests on three pillars: scheduled surveillance by organ system to detect complications while treatable; mechanism-directed treatment with mTOR inhibitors; and multidisciplinary supportive care focused on quality of life [1, 15]. SGRT described treatment as symptomatic and multidisciplinary [11]; this approach remains the foundation but has been complemented by targeted therapy, termed as such by GeneReviews because mTOR inhibitors replace, within the cell, the function normally performed by the hamartin–tuberin complex [1]. Ideally, patients are followed at centres experienced in TSC, with coordination between neurology, nephrology, respiratory medicine, cardiology, dermatology, ophthalmology, psychiatry and genetics [15]. In France, the TSC PNDS (French National Diagnosis and Care Protocol) organises the care pathway around the reference and competence centres for rare epilepsies (CRéER, DéfiScience health network), with multidisciplinary team meetings (RCP) for decisions on mTOR inhibitors and complex cases, designated TSC referring physicians in some centres and coordination by the family doctor, the paediatrician or the most involved specialist; LAM is directed to the reference centre for rare lung diseases (OrphaLung) and its network of competence centres, within the RespiFIL network, which organises a monthly national RCP by videoconference [14, 29]. Transition to adult care is presented as a moment for a complete review of lesions and needs, with multidisciplinary neurocognitive assessment when necessary, social support for educational and vocational guidance and discussion of contraception, sexuality and pregnancy; it may take the form of a detailed letter to the family doctor and adult specialists, a transition RCP, joint consultations between the paediatric referring physician and the adult specialists or dedicated therapeutic education sessions [14]. In a survey cited by the PNDS, patients' concerns centred on mental and physical health, participation, self-management, family planning and adverse drug effects, and adults asked for a designated referring physician [14]. The LAM PNDS proposes therapeutic education to all patients, without imposing it, with individual interviews and group workshops on the disease, inhaled treatments and oxygen, action plans for exacerbations, smoking cessation, physical activity and travel [29].

7.2 Recommended surveillance by organ system

Adapted from Northrup et al. 2021 (Table 3) and GeneReviews (Table 7) [1, 15].

Smoking and oestrogen use should be avoided in adolescent and adult women (both associated with LAM risk or worsening), as should nephrectomy [1, 9]. The Oxford Desk Reference also advises caution with air travel in oxygen-dependent patients or those with pneumothorax in the preceding month [9].

7.3 Epilepsy

Infantile spasms. Infantile spasms are a neurological emergency in an infant with TSC, and vigabatrin is first-line treatment; if spasms do not cease within 2 weeks, ACTH or prednisolone is added as second-line treatment [1, 15]. Vigabatrin is an irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase. In the US, vigabatrin (Sabril®) is approved as monotherapy for infantile spasms from 1 month to 2 years when benefit outweighs the risk of visual loss, and as adjunctive therapy for refractory complex focal seizures from age 2 years, without being indicated as a first-line drug for the latter [26]. In the European Union, besides national Sabril® authorisations, the paediatric formulation Kigabeq® is centrally authorised for children from 1 month to younger than 7 years, as monotherapy for infantile spasms and in combination for resistant focal epilepsies [65]. The FDA-labelled dose for infantile spasms is 50 mg/kg/day (25 mg/kg twice daily), increased by 25 to 50 mg/kg/day every 3 days to a maximum of 150 mg/kg/day (75 mg/kg twice daily), with adjustment in renal impairment and gradual tapering on discontinuation [26]. The European SmPC for Kigabeq® specifies the same starting dose (50 mg/kg/day) and the same maximum (150 mg/kg/day), but with increments of 25 mg/kg/day every 3 days [65]. The principal adverse effect is permanent concentric visual field constriction (boxed warning), requiring visual assessment within 4 weeks of initiation, every 3 months during treatment and 3–6 months after discontinuation [1, 26]; use should be restricted to the lowest dose and shortest duration compatible with clinical goals [26].

The French PNDS (French National Diagnosis and Care Protocol) sets the recommended vigabatrin dose for spasms in TSC at 100–150 mg/kg/day orally before 2 years of age (maximum 150 mg/kg/day), noting that the risk of relapse is lower above 100 mg/kg/day and that the response is faster (on average 3 days) and more frequent than with hydrocortisone or ACTH [14]. As the guideline dose, it is the reference; the FDA and Kigabeq® labels reach the same range by titration from 50 mg/kg/day, with the same maximum of 150 mg/kg/day [14, 26, 65]. As second line, the PNDS reserves oral corticosteroids or ACTH for vigabatrin failure with hypsarrhythmia and accepts topiramate when there are only focal or multifocal abnormalities without hypsarrhythmia; mTOR inhibitors below 2 years of age are outside the marketing authorisation in France, although preliminary data suggest efficacy and tolerability comparable to those in older children [14]. The visual monitoring under vigabatrin proposed by the PNDS is less frequent than that in the label: a baseline examination before or within 4 weeks of initiation and then annually during treatment, always with age-appropriate visual field testing; electroretinography (with a 30–50% reduction in photopic b-wave or 30 Hz flicker amplitude considered significant) is not recommended routinely, because it is poorly available and difficult to perform after 2 years of age, and OCT of the nerve fibre layer has no validated threshold; in a North American registry, visual assessment was inconclusive in 35% of adults and 40% of children, and in the presence of toxicity the decision to stop is made case by case, because the benefit often outweighs the risk [14].

EEG-guided preventive treatment. Because epileptiform EEG activity frequently precedes seizures, the 2021 consensus introduced serial EEG surveillance in asymptomatic infants and recommends considering vigabatrin when sharp waves or polyspikes appear on EEG, to prevent spasms and delay focal seizures [1, 15]. EPISTOP showed that preventive treatment prolonged time to the first seizure and reduced the risk of clinical seizures, drug-resistant epilepsy and infantile spasms at 24 months [59]; the randomised, double-blind PREVeNT trial demonstrated neither improved development at 24 months nor a reduction in focal or drug-resistant epilepsy, although early vigabatrin reduced and delayed spasms [66]; at the 36-month assessment, published in 2025, there were also no differences in development or in the frequency of autism spectrum disorder (31% of the 58 participants assessed) between treatment groups [67]. Accordingly, GeneReviews emphasises that preventive treatment may prevent spasms and delay seizure onset but has not demonstrated better developmental outcomes than early recognition and control of clinical seizures [1]. This is an off-label use of vigabatrin.

The French PNDS, published before the PREVeNT results, adopts a tighter EEG schedule in the first months than the international consensus (standard video-EEG every 4 weeks before 6 months, every 6 weeks from 6 to 12 months and every 3 months from 12 to 24 months), defines epileptiform abnormalities as focal paroxysmal activity in more than 10% of the recording or multifocal or diffuse activity, with or without hypsarrhythmia, and recommends vigabatrin for seizures or subclinical discharges and, on the basis of EPISTOP, also for these abnormalities, stopping treatment at 2 years if there are no seizures [14]. To facilitate EEG in poorly cooperative children, it proposes premedication with oral melatonin, 3 mg from 1 to 4 years and 6 mg from 5 to 16 years, 15 minutes before electrode placement [14]. After 2 years of age, without known epilepsy, routine EEG is not recommended and is performed when seizures are suspected or there are marked neurodevelopmental disorders [14].

Focal seizures and drug-resistant epilepsy. Outside infantile spasms, seizure treatment follows that for other focal epilepsies [1]. Everolimus and a specific cannabidiol formulation demonstrated efficacy in randomised trials, but comparative data do not support preference for either drug or any other antiseizure medication [1]. Up to two-thirds of epilepsies resist polytherapy with antiseizure medications and mTOR inhibitors, and epilepsy surgery (resection of the epileptogenic tuber) should be considered in refractory patients, alongside a ketogenic diet [1, 15].

The French PNDS adds that most European experts prefer vigabatrin for focal epilepsies beginning before 1 year of age, also to prevent spasms, and that at other ages the choice follows seizure type and comorbidities, particularly psychiatric ones; in adults whose first seizure leads to the diagnosis, it recommends treating immediately, because of the high risk of recurrence, and avoiding vigabatrin as first line [14]. In a series of 160 patients, only 35% were seizure-free, and the risk of recurrence after withdrawal in controlled patients ranges from 9% to 27% across studies, up to 10 years later [14]. Drug resistance (50–60% compared with approximately 30% across all epilepsies) should prompt early presurgical evaluation, beginning with prolonged video-EEG to record seizures; invasive exploration with intracerebral electrodes, which allows focal thermocoagulation, is indicated when anatomo-electro-clinical correlations are unclear, when functional areas are nearby or after failure of a first operation, and multifocality, spasms or multiple seizure types do not contraindicate exploration [14]. The meta-analyses cited report 69–75% good outcomes after surgery (Engel class I in 56–57% and class II in 13–18%); vagus nerve stimulation, when curative surgery is not possible, achieves a ≥ 50% seizure reduction in 70–80% of patients but, according to the PNDS, complicates brain MRI and contraindicates thoracoabdominal MRI, which interferes with renal surveillance; the ketogenic diet has no particularities in TSC and is impractical in adults [14].

Everolimus tablets for oral suspension (Afinitor Disperz® in the US; Votubia® dispersible tablets in the EU) are approved as adjunctive therapy for TSC-associated focal seizures from age 2 years (FDA, 10 April 2018; in the EU, for refractory focal seizures with or without secondary generalisation) [18, 19, 68]. In EXIST-3 (366 patients with refractory focal seizures despite ≥ 2 antiseizure regimens), median reduction in seizure frequency during maintenance was 29.3% at a target trough concentration of 3–7 ng/mL, 39.6% at 9–15 ng/mL and 14.9% with placebo, and response rates (reduction ≥ 50%) were 28.2%, 40% and 15.1%, respectively [18, 69]. During the post-extension phase, 50.7% of patients had a persistent response, and the response rate rose to 63.9% at the end of the extension phase [70]. The FDA-labelled starting dose is 5 mg/m² once daily [18]. The EU summary of product characteristics (SmPC) specifies 6 mg/m² below age 6 years and 5 mg/m² from age 6 years, or 9 and 8 mg/m², respectively, with CYP3A4/P-glycoprotein inducers [19]. Both labels require dose titration by whole-blood trough concentration, targeting 5–15 ng/mL, with no fixed maximum dose defined in the source (section 7.4) [18, 19].

Cannabidiol (Epidiolex® in the US; Epidyolex® in the EU), whose antiseizure mechanism is unclear and does not depend on cannabinoid receptors, is FDA-approved for TSC-associated seizures from age 1 year (31 July 2020) and, in the EU, as adjunctive therapy for TSC-associated seizures from age 2 years [20, 21, 68]. In GWPCARE6 (224 patients aged 1 to 65 years, baseline median 57 seizures per 28 days, 33% receiving vigabatrin), TSC-associated seizures decreased by 48.6% with 25 mg/kg/day versus 26.5% with placebo (relative reduction 30.1%; 95% CI 13.9–43.3%), and 50 mg/kg/day provided no additional efficacy and caused more adverse effects [21, 71]. The FDA-labelled TSC dose is 2.5 mg/kg twice daily, increased weekly by 2.5 mg/kg twice daily to the recommended maintenance dose of 12.5 mg/kg twice daily (25 mg/kg/day), from age 1 year; efficacy of lower doses has not been studied in TSC [20]. The European SmPC specifies 2.5 mg/kg twice daily for one week, 5 mg/kg twice daily during the second week with response assessment and, according to response and tolerance, weekly increments of 2.5 mg/kg twice daily to a maximum of 12.5 mg/kg twice daily (25 mg/kg/day) [21]. Transaminases and total bilirubin should be measured before initiation [20]. In the TSC trial, the most frequent adverse effects with 25 mg/kg/day were diarrhoea (31% versus 25% with placebo), transaminase elevation (25% versus 0%), decreased appetite (20%), fever (19%), vomiting (17%) and somnolence (13%); discontinuation for adverse effects occurred in 11% (mainly rash) versus 3% with placebo [20]. Cannabidiol increases everolimus concentrations, so everolimus should be measured 2 weeks after starting or stopping cannabidiol [18].

7.4 mTOR inhibitors: everolimus

Everolimus is a rapamycin derivative (rapalogue) that inhibits mTORC1 by blocking binding of the accessory protein raptor to mTOR [1]. In the US, it has three TSC indications: renal angiomyolipoma in adults not requiring immediate surgery (Afinitor®, 26 April 2012); SEGA requiring therapeutic intervention but not curatively resectable, in adults and children from age 1 year (Afinitor®, accelerated approval on 29 October 2010, and Afinitor Disperz®, 29 August 2012); and focal seizures (section 7.3) [18, 68]. In the EU, Votubia® was authorised on 2 September 2011 and is indicated for renal angiomyolipoma in adults at risk of complications (due to size, aneurysm, or multiple or bilateral tumours) who do not require immediate surgery, SEGA requiring intervention but unsuitable for surgery, and refractory focal seizures from age 2 years [19].

Sources: FDA label for Afinitor®/Afinitor Disperz® (2026) and Votubia® SmPC [18, 19].

Dose adjustment uses a simple proportion (new dose = current dose × target concentration/current concentration), with increments no greater than 5 mg per titration (FDA label) or increments of 1 to 4 mg (European SmPC) [18, 19]. Measurement is repeated 1–2 weeks after initiation, dose adjustment or formulation change, 2 weeks after introducing or stopping moderate inhibitors or strong inducers of CYP3A4/P-glycoprotein or cannabidiol, and every 3–6 months if body surface area changes [18]. Afinitor® and Afinitor Disperz® should not be combined to achieve the daily dose, and strong CYP3A4 inhibitors should be avoided [18]. In severe hepatic impairment (Child–Pugh C), the starting dose for SEGA and seizures, in children and adults, is 2.5 mg/m² once daily, adjusted by trough concentration, with no fixed maximum dose defined in the source [18].

For the paediatric indications (SEGA and epilepsy), the French TSC PNDS (French National Diagnosis and Care Protocol) proposes a fixed starting dose by body surface area band (2.5 mg/day up to 1.2 m², 5 mg/day between 1.3 and 2.1 m² and 7.5 mg/day from 2.2 m²), with a target trough concentration of 5–15 ng/mL measured on day 15, pretreatment assessment with full blood count, liver and renal function, blood glucose and lipid profile, and follow-up MRI at 3 and 6 months for SEGA [14]. In adults with angiomyolipoma or LAM, it starts at 5 mg/day and increases according to trough concentration and imaging up to a maximum of 10 mg/day, with baseline lipid profile, creatinine and albuminuria and routine monitoring of proteinuria, because this class can cause focal segmental glomerulosclerosis [14]; the LAM PNDS specifies, in adult women, 5–10 mg/day as a single morning dose, mentions frequent initiation at 2.5 or 5 mg/day and a usual target trough concentration of 5–15 ng/mL [29]. The fixed PNDS bands do not coincide with the current posology of the European SmPC for Votubia®, which is the reference because it is based on pharmacokinetics and the EXIST trials: in SEGA, 4.5 mg/m²/day (7 mg/m²/day between 1 and less than 3 years), with trough concentration measured at least 1 week after initiation or each change and titration in 2.5 mg increments to 5–15 ng/mL, and reassessment of volume at 3 months; in seizures, the doses per m² in section 7.3; in angiomyolipoma, a fixed 10 mg/day, the EXIST-2 dose [18, 19]. In a child with a body surface area of 1.2 m², for example, the SmPC starting dose is approximately 5 mg/day, twice that of the PNDS band, and in a small child the difference is greater; the 2021 French regimen (paediatric bands and a 5 mg/day start in adults) stands as a dated national position, subsequently adjusted by trough concentration, and the enzyme inducers used in epilepsy may require higher doses to reach the target [14, 18, 19]. Before elective surgery, the PNDS requires everolimus to be stopped at least 7 days before and 7 days after the procedure, whereas the FDA label specifies at least 1 week before [14, 18]. In the double-blind phase of EXIST-2 (79 patients on everolimus and 39 on placebo; median duration 48 weeks), the most frequent adverse effects were stomatitis (48% versus 8%), nasopharyngitis (24% versus 31%) and acneiform lesions (22% versus 5%) [72]. The FDA label, which groups stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis and glossodynia, records 78% versus 23% (grade 3 in 6%), and 52% of treated patients required dose interruption or reduction for adverse reactions, mainly stomatitis [18]. In the 4-year update (112 patients, median exposure 46.9 months), the most frequent adverse effects suspected to be related to everolimus were stomatitis (42%), hypercholesterolaemia (30.4%), acne (25.9%), aphthous stomatitis and nasopharyngitis (21.4% each), with peak onset in the first year; approximately 80% of patients required at least one dose interruption or reduction, 8.9% discontinued the study because of adverse effects and infections led to interruptions or adjustments in 36.6% [73]. The French PNDS, summarising these data, gives stomatitis in 46% and attributes the 36.6% to all dose reductions or interruptions [14].

Efficacy. In EXIST-1 (117 patients with SEGA, median age 9.5 years), the response rate (≥ 50% volume reduction) was 35% with everolimus versus 0% with placebo, with no progression in the active arm and progression in 15.4% of the placebo arm [18, 74]; GeneReviews reports > 30% volume reduction in 65–79% of patients, maintained for up to 3 years [1]. In EXIST-2 (118 patients with angiomyolipoma ≥ 3 cm, 113 with TSC), the response rate was 41.8% versus 0%, with significantly longer time to progression (HR 0.08) and skin lesion response in 26% versus 0%; during 3.9 years of follow-up, no patient required nephrectomy for progression [18, 72].

Adverse effects and management. Stomatitis (oral ulcers and mucositis) occurs in 44–78% of patients, particularly during the first 8 weeks; an alcohol-free dexamethasone oral solution mouth rinse, started with the drug, reduces incidence and severity, and mouthwashes containing alcohol, hydrogen peroxide, iodine or thyme should be avoided [18]. Non-infectious pneumonitis, a class effect, occurs in up to 19%, with grade 3–4 forms in up to 4%; in symptomatic grade 2–4 cases, treatment is withheld or permanently discontinued and corticosteroids may be used with Pneumocystis jirovecii prophylaxis [18]. The drug is immunosuppressive, with bacterial, fungal and viral infections that are more severe below age 6 years; live vaccines should be avoided and childhood vaccination completed before initiation [18]. Hyperglycaemia, hypercholesterolaemia and hypertriglyceridaemia occur in up to 75%, 86% and 73%, respectively, requiring glucose and lipid monitoring before and periodically during treatment [18]. Other effects include myelosuppression, renal impairment and proteinuria (renal function before treatment and annually), angioedema (particularly with angiotensin-converting enzyme inhibitors), delayed wound healing (withhold at least 1 week before elective surgery), amenorrhoea and menstrual irregularities, and embryo-fetal toxicity, requiring effective contraception [18]. Dose reductions follow severity: for grade 2 stomatitis, withhold until grade 0–1 and resume the same dose; for grade 3, resume at 50% of the dose [18].

7.5 SEGA

mTOR inhibitor treatment is recommended for growing or large SEGA with mild to moderate symptoms (including asymptomatic ventriculomegaly) in patients who are not surgical candidates or prefer medical treatment [1, 15]. Neurosurgical resection is indicated when SEGA size causes potentially fatal neurological symptoms; acute hydrocephalus is a surgical emergency and may require temporary or permanent cerebrospinal fluid diversion, and minimally invasive techniques in experienced teams may reduce morbidity [1, 9]. Outcomes are better with early detection and treatment [1]. The French PNDS considers that a growing SEGA larger than 1 cm should be treated, with or without symptoms, and places surgery as the first option whenever an experienced neurosurgeon is available, because surgical morbidity and mortality depend mainly on experience; in practice, a single, unilateral, completely resectable SEGA without comorbidities favours surgery, while multiple, bilateral, infiltrating or difficult-to-access SEGA, or comorbidities that would also benefit from the drug (angiomyolipomas, LAM, epilepsy), favour everolimus, in a shared decision that weighs adverse effects, cost and duration of treatment [14]. Symptomatic hydrocephalus increases surgical risk; after excision, external ventricular drainage for 48 hours prevents acute intracranial hypertension, responsible for most of the deaths described, and transient neurological deficits and electrolyte disturbances, seizures and, in the youngest children, subdural effusions may occur; postoperative CT and MRI at 3 months are performed [14]. There is no recurrence after total excision, but other SEGA may grow, so removal of all accessible lesions at the same operation is advised; everolimus can treat progressive postoperative remnants, and on everolimus MRI is performed at 3 months and then every 6 months [14]. This preference for surgery distinguishes the PNDS from the international consensus, which accepts surgery or an mTOR inhibitor for asymptomatic growing SEGA [14, 15].

7.6 Renal angiomyolipoma and renal disease

An mTOR inhibitor is first-line treatment for an asymptomatic growing angiomyolipoma larger than 4 cm, or a rapidly growing lesion larger than 3 cm [1]. Smith's states that lesions above 3.5–4 cm should be considered for prophylactic arterial embolisation or nephron-sparing surgery [2]. Second-line options include selective embolisation followed by corticosteroids, parenchyma-sparing resection or ablation of exophytic lesions; acute haemorrhage is treated by embolisation followed by corticosteroids [1]. Selective arterial embolisation is minimally invasive, prevents rupture and preserves adjacent parenchyma [11]. Nephrectomy should be avoided because of high complication rates and the risk of future renal failure [1]. Hypertension should be treated; renin–angiotensin system inhibitors are usually preferred, bearing in mind the risk of angioedema with everolimus [15, 18]. Renal cysts are managed by nephrology and surgery; in TSC2/PKD1 syndrome, management includes that of ADPKD, with strict blood pressure control and renal function surveillance [1, 41]. The French PNDS documents detail the options. In rupture with acute haemorrhage, selective arterial embolisation is the treatment of choice, with haemostatic surgery, which often ends in nephrectomy, reserved for failure or impossibility of embolisation with a threat to life [14, 29]. Preventive treatment is proposed by most teams for angiomyolipomas at high haemorrhagic risk (larger than 4 cm or aneurysms larger than 5 mm), decided at a meeting with a urologist, interventional radiologist and nephrologist, choosing between surgery, embolisation, percutaneous ablation and mTOR inhibitors; the first three options are radical and the last only suspensive [14]. Embolisation combines alcohol, microparticles and coils, is followed by a post-embolisation inflammatory syndrome that is prevented with corticosteroids, and revascularisation from other pedicles occurs in almost half of cases, which may require a further session; it remains the treatment of choice when aneurysms are present, whereas radiofrequency and above all cryoablation permanently devascularise angiomyolipomas without aneurysms [14]. Angiomyolipomas larger than 3 cm are eligible for an mTOR inhibitor, proposed particularly when they are bilateral, numerous, large and inaccessible to radical treatments; the LAM PNDS indicates everolimus as first line for asymptomatic growing angiomyolipomas larger than 3 cm, particularly when they cannot be embolised [14, 29]. A lesion without visible fat may be an angiomyolipoma with microscopic fat, an epithelioid angiomyolipoma or a carcinoma, and should be biopsied if it is large or grows quickly (more than 0.5 cm per year); conservative surgery is reserved for suspected malignancy [14, 29]. For hypertension or pathological microalbuminuria, the PNDS prefers an angiotensin-converting enzyme inhibitor, in the absence of renal failure [14]. The annual nephrology consultation assesses renal function, blood pressure and albuminuria, with more frequent consultations on everolimus, in associated polycystic kidney disease and in renal failure [14].

7.7 Cardiac rhabdomyomas

Most rhabdomyomas regress without treatment. In severe outflow tract obstruction, an mTOR inhibitor may be considered, with open cardiac surgery as the alternative [1]. mTOR inhibitors have also been used successfully for rhabdomyoma-associated arrhythmias [1]. Prenatal sirolimus use (administered to the mother) has been described in off-label case reports, with variable results and safety concerns (section 10) [62]. According to the French PNDS, only large, obstructive rhabdomyomas with life-threatening haemodynamic effects justify resection; in severe neonatal obstruction, prostaglandin E2 infusion keeps the ductus arteriosus open and stabilises the newborn until surgery, and mTOR inhibitors may have a role when resection is expected to be avoided [14]. Arrhythmias are treated as in other contexts, with reported efficacy of beta-blockers, digoxin and amiodarone [14].

7.8 Lymphangioleiomyomatosis

Oral sirolimus has been FDA-approved for LAM treatment since 28 May 2015 [24, 68]. In MILES (89 patients), the slope of forced expiratory volume in one second (FEV1) was −12 ± 2 mL/month with placebo and 1 ± 2 mL/month with sirolimus (mean difference 153 mL over 12 months, approximately 11% of baseline FEV1), with a fall in serum VEGF-D; functional decline resumed after discontinuation [24, 75]. The labelled starting dose in adults with LAM is 2 mg/day, with trough measurement 10–20 days later and a target of 5–15 ng/mL; no fixed maximum dose is defined in the source [24]. In the EU, Rapamune® is authorised only for sporadic LAM with moderate pulmonary disease or declining pulmonary function, so its use in TSC-associated LAM is off-label in the EU [25]. The 2016 ATS/JRS guideline recommends sirolimus in patients with abnormal or declining pulmonary function [28], and the complementary 2017 guideline recommends high-resolution CT for diagnosis and pleurodesis after the first pneumothorax [76]; avoidance of smoking and oestrogens remains applicable to all patients [1]. Everolimus (EXIST-2) also reduced angiomyolipomas in patients with sporadic LAM [72].

The French TSC and LAM PNDS documents (French National Diagnosis and Care Protocol) indicate sirolimus in patients with FEV1 below 70% predicted or with accelerated decline, usually defined as more than 90 mL/year (approximately three times the physiological decline, a threshold not validated in a trial), and possibly with a marked and unexplained reduction in carbon monoxide diffusing capacity; the indication is decided at an RCP by a respiratory physician from a reference or competence centre, and menopausal status is weighed, because the disease progresses less after menopause [14, 29]. In MILES, the benefit also extended to forced vital capacity and quality of life, without improvement in the walk test or diffusing capacity, with no difference between sporadic and TSC-associated LAM (8 of the 89 patients), and it was greater in patients with raised VEGF-D [14, 29]. The LAM PNDS dates the authorisation of sirolimus for this indication to 2018; the European SmPC restricts it to sporadic LAM [25, 29]. The LAM PNDS regimen is 2 mg/day as a single fasting morning dose, with trough concentration measured 3 weeks after initiation or each dose change and then every 3 months, and a target of 5–12 ng/mL, preferring the lowest possible value (5–10 ng/mL) [29]. As the guideline dose, it is the reference; the FDA label starts at the same dose, but measures the concentration at 10–20 days and accepts 5–15 ng/mL [24, 29]. Before initiation, full blood count, creatinine, liver function, fasting blood glucose, lipid profile and plasma β-hCG are assessed, vaccinations are updated and effective contraception is ensured; the same tests, the trough concentration and CD4 lymphocytes are repeated at 3 weeks and then at least every 3 months, with Pneumocystis prophylaxis if CD4 counts are below 200/mm³ [29]. Contraindications are pregnancy, breastfeeding, inadequate contraception, transaminases above 3 times normal, haematocrit below 30%, platelets below 80 G/L, neutrophils below 1 G/L or leucocytes below 3 G/L, uncontrolled hyperlipidaemia, inability to undergo monitoring, creatinine clearance below 60 mL/min, cancer in the previous 2 years (except basal cell or squamous cell skin carcinoma), coronary or cerebrovascular atherosclerotic disease and hypersensitivity [29]. Treatment is not started with active infection, pneumothorax in the previous 2 months or surgery with sutures less than 2 months earlier, and it is suspended for infection, pneumothorax, surgery and listing for transplantation [29]. The most frequent adverse effects, according to the PNDS, include hypercholesterolaemia and hypertriglyceridaemia (45%), diarrhoea (32%), acne (31%), abdominal pain (29%), anaemia (27%), arthralgia (25%), urinary tract infection (23%) and peripheral oedema (16%), as well as interstitial pneumonitis; for aphthous ulcers it proposes brushing and chlorhexidine mouthwash after meals, for no more than one week at a time, and avoidance of aphthogenic foods [29]. Everolimus, evaluated in an open-label phase 2 trial (24 patients, mean FEV1 increase of 114 mL at 26 weeks), has no approved indication in LAM, but is considered an alternative in case of sirolimus intolerance or when there is a concomitant renal or neurological indication in TSC [14, 29].

Symptomatic treatment of LAM, according to the PNDS documents, includes inhaled bronchodilators if there is an objective response or perceived benefit (approximately a quarter of patients respond, and these reportedly have a faster decline), without inhaled corticosteroids; vaccination against influenza, pneumococcus and SARS-CoV-2, particularly on an mTOR inhibitor; pulmonary rehabilitation preceded by cardiopulmonary exercise testing; nutritional and psychological support; treatment of osteoporosis in patients with severe lung disease and osteopenia; and long-term oxygen therapy according to the usual criteria (PaO2 ≤ 55 mmHg, or 56–60 mmHg with polycythaemia, pulmonary hypertension, right heart failure or nocturnal desaturation) or ambulatory oxygen if exertional saturation falls below 80% [29]. Progestogens are no longer used as treatment [29]. For pneumothorax, emergency aspiration or drainage may be needed, but ipsilateral pleurodesis is recommended from the first episode, preferably by mechanical abrasion and by a surgical team linked to a transplant centre, with talc and pleurectomy reserved for refractory recurrences, because they increase the haemorrhagic risk of a future transplant without contraindicating it; pleurodesis reduces recurrence from more than 70% to 20–30% [14, 29]. In symptomatic and persistent chylothorax, sirolimus is the indicated treatment and also makes chylous ascites regress; a fat-free diet with medium-chain triglycerides, lymphatic interventional radiology and thoracic duct ligation are exceptional resources [29]. Lung transplantation (1.1% of indications; survival of 94%, 73% and 56% at 1, 5 and 10 years) is discussed for NYHA class III–IV dyspnoea with FEV1 below 30%, resting hypoxaemia, rapid decline or pulmonary hypertension; double-lung transplantation is preferred in young women, and in TSC the assessment includes neurological, cognitive and renal comorbidities, interactions between antiseizure medications and immunosuppressants and prior treatment of angiomyolipomas with haemorrhagic risk, which continue to be monitored after transplantation [14, 29]. Air travel increases the risk of pneumothorax only slightly (approximately threefold) and should not be discouraged in patients with preserved function; it is contraindicated with untreated pneumothorax or pneumothorax treated in the last month, and the need for in-flight oxygen is assessed in advanced disease [29]. Orphanet publishes a LAM emergency card intended for emergency departments [29].

7.9 Facial angiofibromas and other skin lesions

Topical sirolimus 0.2% gel (Hyftor®; 2 mg sirolimus per gram) has been FDA-approved since 22 March 2022 for TSC-associated facial angiofibromas in adults and children from age 6 years, and approved by the European Commission since 15 May 2023 for the same indication and age group [22, 23, 68]. It is applied to facial skin affected by angiofibromas twice daily (morning and bedtime), without an occlusive dressing; the European SmPC specifies 125 mg gel (0.5 cm, 0.25 mg sirolimus) per 50 cm² of lesion, with a maximum daily dose of 600 mg gel (approximately 2 cm; 1.2 mg sirolimus) from ages 6 to 11 years and 800 mg (approximately 2.5 cm; 1.6 mg sirolimus) from age 12 years, divided between the two applications [22, 23]. If there is no improvement within 12 weeks, continuation should be reassessed, and age-appropriate vaccinations should be completed before initiation [22]. In the Japanese phase 3 trial (62 patients), the proportion classified as “improved” or “markedly improved” at 12 weeks on a composite measure of size and erythema was 23% versus 6% with vehicle according to the investigator's in-person assessment presented in the label, whereas publication of the same trial, using photographic assessment by an independent committee, reported improvement in 60% versus 0% [22, 77]; the difference reflects the endpoint definition and assessment method, rather than separate trials. TREATMENT, using compounded topical rapamycin, confirmed the benefit of this class [78]. The most frequent adverse effects are dry skin, application-site irritation, pruritus, acne, acneiform dermatitis, ocular hyperaemia and cutaneous bleeding [22]. Oral mTOR inhibitors prescribed for other indications also reduce angiofibromas, and the two routes may be combined [1, 72]. Physical treatments (laser, surgical excision) retain a role in fibrotic lesions and symptomatic ungual fibromas [15]. The French TSC PNDS (French National Diagnosis and Care Protocol), which predates the European authorisation of Hyftor®, recommended a compounded 0.1% sirolimus preparation (rapamycin 0.03 g, Transcutol® 1.5 g and Excipial® cream to 30 g), already used in several centres; this concentration is half that of the authorised gel (0.2%), and the preparation is not the approved medicine [14, 22, 23]. The same PNDS justifies treating angiofibromas even without serious manifestations, because they bleed on contact, are traumatised by stereotypies and become more prominent with sun exposure; it recommends photoprotection (clothing and sunscreen) taught from diagnosis in children, because loss of heterozygosity in angiofibromas appears to be favoured by ultraviolet radiation, with vitamin D supplementation if photoprotection causes deficiency, and does not dismiss corrective camouflage make-up; vascular laser and surgery are used for large or bleeding lesions, at the cost of pain, prolonged healing and recurrence [14].

7.10 TAND

The 2023 consensus recommendations rest on the principle “screen, act and repeat”: screening at least annually using the TAND Checklist, assessment and intervention according to the identified cluster with evidence-based biological, psychological and social approaches, and periodic reassessment [27]. Referral to developmental paediatrics or psychiatry according to presentation, applied behaviour analysis for ASD and consideration of pharmacological therapy for ADHD are recommended [1]. Core intervention plan components include recognising the impact of physical health problems and the role of caregivers and family [1]. Evidence suggests that everolimus reduces some ASD manifestations in addition to SEGA volume and seizures, although this has not been demonstrated in randomised trials [1]. The French PNDS considers the evidence insufficient to use mTOR inhibitors for any aspect of TAND and recommends interventions with solid evidence for ASD, ADHD and anxiety, screening at every consultation, at least annually, with the French version of the TAND Checklist, formal assessments when there is doubt and, in adults, according to medico-social, educational or vocational guidance needs, training of parents to recognise emerging manifestations, and psychological and social support for families to prevent caregiver burnout [14].

7.11 Other manifestations

Retinal hamartomas are managed by ophthalmology, with surveillance for rapid growth or visual compromise [1]. Extrarenal angiomyolipomas may benefit from an mTOR inhibitor if they grow rapidly or compress structures, avoiding surgery [1]. Non-functioning pancreatic neuroendocrine tumours follow standard surveillance and treatment [1]. Oral health requires meticulous hygiene and six-monthly visits [15]. The French PNDS proposes an oral examination every 6 to 12 months, as in the general population, oral hygiene education adapted to intellectual disability (using oral health networks for people with disabilities), restoration of enamel pits if caries risk is high, excision of oral fibromas that are symptomatic or hinder hygiene, with possible recurrence, and panoramic radiography for mandibular bone lesions (asymmetry, swelling, abnormal eruption), treated by excision or curettage if symptomatic [14]. Retinal hamartomas complicated by haemorrhage or exudation are first observed, because they often resolve spontaneously; if they persist and threaten vision, argon laser photocoagulation, photodynamic therapy, transpupillary thermotherapy, intravitreal anti-VEGF or corticosteroids and surgery are discussed, and mTOR inhibitors prescribed for other indications make aggressive hamartomas regress; in patients with visual impairment, correction of refractive errors, amblyopia treatment and visual stimulation form part of the plan [14].

7.12 Pregnancy

In women with epilepsy, antiseizure medication use during pregnancy reduces maternal risk, although some drugs may increase fetal risk according to the drug, dose and stage of pregnancy; discussion should occur before conception, with possible transition to lower-risk drugs [1]. Everolimus has embryo-fetal toxicity and requires effective contraception during treatment [18]. In women with LAM, the decision to become pregnant should be discussed with respiratory medicine because pulmonary disease may worsen and pneumothorax may occur during pregnancy [28]. The French PNDS documents (French National Diagnosis and Care Protocol) add that combined oestrogen–progestogen contraception and pregnancy favour the growth and spontaneous rupture of angiomyolipomas and that, in women with angiomyolipomas or LAM, oestrogens by any route (oral, transdermal or vaginal ring) should be avoided, including menopausal hormone therapy and phytoestrogens; progestogen-only contraception (oral, implant, injectable), intrauterine devices (progestogen or copper), barrier methods and tubal ligation are acceptable, and local oestrogens are discussed only case by case in refractory genitourinary syndrome [14, 29]. High-dose progestogens, no longer used as LAM treatment, require MRI surveillance for meningioma risk when prescribed for other indications [29]. Before conception, they recommend a genetics consultation, respiratory assessment with pulmonary function tests and recent renal imaging to exclude aneurysms larger than 5 mm, which, if present, should be embolised preventively, because haemorrhagic risk increases during pregnancy and mTOR inhibitors are contraindicated; antiseizure medications, mTOR inhibitors and angiotensin-converting enzyme inhibitors require review of the benefit–risk balance, with all the physicians involved informed of the plan [14, 29]. Pregnancy may be discouraged, case by case, in advanced or progressive forms of LAM; it should be followed by a respiratory physician and an obstetrician, with the mode of delivery discussed according to the risk of pneumothorax, and hormonal stimulation for medically assisted reproduction may also worsen the disease; very large kidneys may prevent the normal progression of pregnancy [14, 29].

7.13 Evidence hierarchy, regulatory status and access

The evidence is classified into peer-reviewed publications, preliminary results (sponsor announcements and results published only in the trial registry), regulatory opinions (CHMP) and authorisation decisions (European Commission, FDA). Authorisation does not guarantee marketing, reimbursement or access in each country, and indications differ between jurisdictions, formulations and ages.

The distinction between evidence extrapolation and off-label use has several applications in TSC. Maternal sirolimus for fetal rhabdomyomas (section 10.1), preventive vigabatrin, everolimus for obstructive rhabdomyomas and topical sirolimus below age 6 years are off-label uses supported by case series or trials whose endpoint differs from the clinical objective; using adult angiomyolipoma data to justify treating small angiomyolipomas in children is extrapolation because EXIST-2 enrolled patients with lesions measuring at least 3 cm [72]. In Portugal, centrally authorised medicines become legally authorised through the European Commission decision, but hospital access and reimbursement depend on INFARMED assessment; no public data on the funding status of these drugs for TSC in Portugal were identified in the consulted sources.

7.14 Pivotal trials and comparison limitations

These trials do not allow drugs to be ranked against one another. Endpoints differ (volumetric response rate, median seizure reduction, functional slope, photographic scale), populations differ in age, severity and concomitant treatment (TrustTSC admitted patients already receiving mTOR inhibitors and cannabidiol, which was not equally the case in earlier trials), and individual median seizure reduction is not equivalent to the population mean reduction or proportion of seizure-free patients. Relative reductions should be interpreted alongside the remaining absolute burden: in GWPCARE6, the 30% relative reduction versus placebo corresponds to patients who continue, on average, to have approximately half their baseline seizures. Topical sirolimus illustrates how the same trial may produce a 23% or 60% response depending on the assessor and endpoint definition. Prevention trials illustrate the importance of the precise endpoint: EPISTOP showed delayed seizures (primary endpoint), while PREVeNT, focused on cognitive development, was negative; neither demonstrated developmental benefit. Negative or terminated trials (TrustTSC, PREVeNT for its primary endpoint, the cannabidiol study below age 2 years) should be considered alongside positive trials.

Therapies in development. In October 2026, ongoing studies included STOP2B (sirolimus for epilepsy prevention in infants, phase 2, NCT05104983), the Astroscape study of radiprodil (an antagonist of the NMDA receptor GluN2B subunit) for seizures associated with TSC and focal cortical dysplasia (phase 1b/2, NCT06392009), and a phase 2 AV078 trial not yet recruiting; the phase 2 basimglurant trial (an mGluR5 receptor modulator) concluded in April 2025, without results published in the consulted indexed literature [82]. No TSC authorisation application was identified for any of these drugs.

7.15 French PNDS documents (HAS, 2021): divergences from the other sources

The date of the two PNDS documents (October 2021) explains some of the divergences: they predate the publication of PREVeNT, the European authorisation of Hyftor® and the 2023 TAND consensus [23, 27, 66, 67]. For doses, the rule followed in this article is the guideline as reference and the label as comparison; the TSC PNDS already records the 2021 European extension of cannabidiol to TSC, with the 25 and 50 mg/kg/day doses tested in GWPCARE6 and better tolerability with 25 mg/kg/day, which is the maximum labelled dose, consistent with section 7.3 [14].

8. Reproductive Options and Family Counselling

8.1 Mode of inheritance and risk to relatives

TSC is inherited in an autosomal dominant manner [1]. Approximately one-third of patients have an affected parent and two-thirds result from a de novo variant (60% according to the Oxford Desk Reference); de novo germline variants are less frequent in TSC1 than in TSC2 [1, 2, 9]. Penetrance is virtually complete in adulthood, and molecular studies have explained rare cases of apparent non-penetrance through two different variants in the family or gonadal mosaicism [1, 9].

SGRT states that in isolated cases due to a new variant, sibling recurrence risk is negligible [11]; current gonadal mosaicism data nevertheless indicate a residual 1–2% risk, which should be communicated and justifies offering testing to siblings and prenatal diagnosis in future pregnancies even when the variant is not detected in the parents [1, 9, 10].

The French PNDS (French National Diagnosis and Care Protocol) estimates the recurrence risk for the couple after a de novo variant at 2%, because of the frequency of parental germline mosaicism, and mosaicism in the proband at 5–10% of patients, with a transmission risk that is difficult to estimate (between 0 and 50%); in a mosaic male proband, quantitative testing of sperm may be offered, which does not eliminate the risk [14]. It also distinguishes paucisymptomatic forms that may be mosaics with germline involvement from purely somatic mosaic forms without transmission risk, such as sporadic LAM, isolated SEGA and probably some isolated rhabdomyomas, angiofibromas or ungual fibromas; in sporadic LAM, genetic counselling is unnecessary [14, 29].

8.2 Assessment of parents and siblings

Parents of an apparently isolated proband should undergo molecular testing if the proband's variant is known; otherwise, assessment should include a detailed Wood's lamp skin examination, fundus examination by an experienced ophthalmologist, brain imaging (CT or MRI) and renal imaging [1, 9]. This assessment frequently reveals a mildly affected parent who escaped diagnosis [1, 2]. Because somatic mosaicism for large rearrangements may affect 5% of patients with normal sequencing results, careful parental assessment is recommended before counselling [2]. An apparently negative family history can only be confirmed after parental clinical or molecular assessment [1]. When the familial variant is known, molecular testing replaces detailed clinical assessment of apparently unaffected relatives and should be offered to siblings even when the variant is de novo [9].

8.3 Predictive testing in minors

Predictive testing of asymptomatic at-risk relatives, including children, is recommended because it guides surveillance and early treatment (for example, EEG surveillance in an infant) [1]. It should be preceded by formal counselling, with a plan for communicating results to parents and children, discussion of socioeconomic consequences and the need for long-term follow-up [1]. In France, presymptomatic testing of relatives is carried out at a genetics clinic with psychological support, within a multidisciplinary presymptomatic diagnosis team declared to the Agence de la biomédecine; without an identified variant, a complete clinical assessment (skin, fundus, brain and renal imaging) may be falsely reassuring in a child who has not yet developed signs, who should continue to be monitored [14].

8.4 Reproductive options

The ideal time to assess risk and discuss options is before pregnancy, and counselling should be offered to affected or at-risk young adults [1]. When the familial variant is known, options include prenatal diagnosis by chorionic villus sampling or amniocentesis, preimplantation genetic diagnosis and, according to availability and family structure, non-invasive prenatal testing [1, 9]. Without an identified variant, high-resolution fetal ultrasound and fetal MRI may be used in pregnancies at 50% risk, with unknown sensitivity and a timing limitation (rhabdomyomas usually detectable only in the third trimester) [1]. In low-risk pregnancies with a fetal rhabdomyoma, TSC risk is high (section 5.4) [1]. The decision about prenatal diagnosis is personal, and perspectives may differ between professionals and within families [1]. DNA banking should be considered for probands without a molecular diagnosis [1]. In France, molecular prenatal diagnosis requires a genetics consultation and discussion at the CPDPN; non-invasive prenatal diagnosis on maternal blood may be offered in certain situations, and preimplantation diagnosis is available when the parental variant is known; the preconception consultation also addresses the risk of progression of renal and pulmonary lesions in the affected woman and adoption as an alternative [14].

8.5 Counselling considerations

Variable expression is central to counselling: a parent with minimal manifestations may have a child with infantile spasms and severe intellectual disability, and vice versa [9, 31]. Female heterozygotes tend to have milder neurological manifestations [1]. Genotype (TSC1 versus TSC2, missense variants associated with mild disease, contiguous deletion involving PKD1) allows some prognostic refinement but should not be used to reduce surveillance [1, 15]. Women with TSC should be informed of LAM risk and the need to avoid oestrogen-containing contraception and smoking [1, 9]. Patient organisations such as the Tuberous Sclerosis Association (UK), TSC Alliance (US) and LAM Foundation provide support [1, 9]; the Tuberous Sclerosis Complex International federation lists Associação de Esclerose Tuberosa em Portugal and Associação Brasileira de Esclerose Tuberosa (ABET) as national associations [30]. In Europe, referral to specialist centres primarily occurs through ERN EpiCARE, with ERKNet and ERN-LUNG for renal disease and LAM. In France, the PNDS (French National Diagnosis and Care Protocol) recommends that every patient be in contact with a reference or competence centre for rare epilepsies (CRéER; coordinated in Lille and at Necker-Enfants malades Hospital, with centres at Pitié-Salpêtrière, Robert-Debré and Nancy), whose map is published by the DéfiScience network, and, for LAM, with the reference centre for rare lung diseases (coordinated in Lyon) and the competence centres of the RespiFIL network [14, 29]. The PNDS serves as the basis for the care protocol established by the attending physician with the Assurance maladie medical adviser to apply for exemption from patient co-payment as a condition not on the official list (affection hors liste); disability compensation needs are addressed to the Maison départementale des personnes handicapées (MDPH) [14]. The diagnosis should be communicated at a dedicated consultation, after specialist advice, adapted to the family history (anxiety in de novo forms, guilt in familial forms), with information on warning signs, assessment of the psychological impact and an offer of support [14]. The French associations are the Association Sclérose Tubéreuse de Bourneville (ASTB, founded in 1991, with approximately 500 members, active in France, Switzerland and among French-speaking patients, with a dedicated health record booklet and participation in the TOSCA registry and in the translation of the TAND Checklist) and France Lymphangioléiomyomatose (FLAM, founded in 2001, a member of the Alliance Maladies Rares and of EURORDIS) [14, 29].

9. Special Considerations: Population Diversity and Epidemiology

TSC occurs in all populations, without a known founder effect or noteworthy population-specific recurrent variants, consistent with the high proportion of de novo variants and large size of TSC2 [1, 38]. Frequency estimates depend on study design: birth incidence studies correcting for underreporting approach 1:6,000–1:10,000, whereas registries and point prevalence studies yield lower values, explained by mortality, underrecognition of mild and mosaic forms, and differences in diagnostic access [1, 3].

No population-based incidence or prevalence studies were found for Portugal, Brazil or most countries in sub-Saharan Africa and Latin America; available Brazilian data derive from tertiary-centre cohorts and cannot estimate population frequency [61, 90]. SGRT states that the Black population might be less affected and that there is a slight male predominance [11]; these observations should be interpreted in light of underrecognition, as TSC is poorly described in patients from sub-Saharan Africa or of African ancestry, where presentation may be late and diagnosis depends primarily on cutaneous signs [60, 91]. In a series of 12 patients in Guinea, epileptic seizures revealed the disease in a setting of limited resources [91]. In dark skin, hypomelanotic macules are easier to see with the naked eye, whereas in very fair skin a Wood's lamp is frequently indispensable [9]. In East Asia, population-based studies show high survival, with survival rates of 98.6% at age 20 years and 79.5% at age 50 years in Hong Kong and a standardised mortality ratio of 4.99 in Taiwan [88, 89]. Unequal access to mTOR inhibitors, MRI surveillance and TAND assessment is probably the main determinant of differences in outcomes between regions, but systematic comparative data are lacking.

10. Illustrative Clinical Case

10.1 Prenatal diagnosis following cardiac rhabdomyoma (published case)

A 28-year-old pregnant woman without a relevant family history underwent routine ultrasound at 28.1 weeks, identifying a large right ventricular mass consistent with a rhabdomyoma [62]. Fetal brain MRI demonstrated cortico-subcortical tubers and subependymal nodules, allowing a clinical TSC diagnosis (three major criteria: cardiac rhabdomyoma, cortical tubers and subependymal nodules) [15, 62]. At 30.4 weeks, because of significant pericardial effusion, maternal oral sirolimus (3 mg/day) was started off-label; the effusion persisted and required pericardiocentesis at 33.6 weeks, and the dose was increased to 6 mg/day at 35.6 weeks, with a concentration of 3.76 ng/mL and no improvement. For comparison, the starting dose of oral sirolimus in adult LAM is 2 mg/day in the FDA label, and the European SmPC for Rapamune® states that it should not be used in pregnancy unless clearly necessary, with effective contraception during treatment and for 12 weeks afterwards; no label provides for maternal administration for fetal treatment, so both doses in this case are outside the labelled conditions [24, 25]. The mother had no adverse effects. Genetic testing confirmed the pathogenic TSC2 variant c.1372C>T, corresponding to p.(Arg458Ter) in the MANE transcript NM_000548.5, classified as pathogenic in ClinVar by multiple submitters without conflicts (VCV000049153) [92]. After birth, the newborn received a single sirolimus dose and developed necrotising enterocolitis [62]. In the original open-access article (https://pmc.ncbi.nlm.nih.gov/articles/PMC12293696/), Figure 1 shows the ultrasound image of the rhabdomyoma with pericardial effusion, and Figure 2 shows fetal cardiac and brain MRI.

Commentary. The case brings together several points from this article. Third-trimester rhabdomyoma detection is now a frequent route to diagnosis, with a very high probability of TSC when associated cerebral lesions are present [1, 9]. The pathogenic TSC2 variant c.1372C>T alone satisfies the genetic criterion [15, 62]. Most rhabdomyomas regress spontaneously, and treatment is justified only in haemodynamic compromise, using an mTOR inhibitor or surgery [1]. The efficacy of prenatal sirolimus for pericardial effusion remains uncertain, and the observed necrotising enterocolitis reinforces the need to weigh risks and benefits of fetal mTOR inhibitor therapy, which has no approved indication [62]. The postnatal plan should include parental education to recognise spasms, EEG every 6 weeks until 12 months and every 3 months until 24 months, echocardiography and electrocardiography, brain and abdominal MRI, and ophthalmological and TAND assessment [1, 15]. Parental testing, even without a family history, is indispensable for estimating recurrence risk (50% if one parent is a carrier; 1–2% if the variant is de novo) [1].

10.2 Late familial diagnosis following an affected child (unpublished composite illustrative case)

An 8-month-old girl presents with clusters of spasms on awakening for 5 days and cessation of skill acquisition. Wood's lamp examination reveals five hypomelanotic macules measuring 1–3 cm on the trunk; EEG shows hypsarrhythmia and brain MRI demonstrates multiple cortical tubers and calcified subependymal nodules. A definite clinical diagnosis (three major criteria) is established, and vigabatrin is initiated that day according to the labelled regimen, with baseline ophthalmological assessment [15, 26]. Genetic testing identifies a pathogenic TSC2 variant. Her 32-year-old mother, without a known epilepsy history, has three periungual fibromas on her feet and subtle angiofibromas interpreted as acne since adolescence; targeted testing confirms the same variant. Maternal abdominal MRI shows bilateral angiomyolipomas, the largest measuring 4.5 cm with documented growth, and high-resolution chest CT reveals scattered thin-walled cysts with normal respiratory function.

Commentary. This scenario, constructed from recommendations and experience described in the literature, illustrates intrafamilial variability and frequent late diagnosis in familial cases [2, 31, 93]. In the child, spasms are an emergency and vigabatrin is first-line, with ACTH or prednisolone if they do not cease within 2 weeks [1]. In the mother, an asymptomatic growing angiomyolipoma larger than 4 cm indicates an mTOR inhibitor (everolimus 10 mg/day according to the label), with dexamethasone mouth rinse to prevent stomatitis, lipid and glucose monitoring, and embolisation as second-line treatment [1, 18]. Pulmonary cysts with normal function require individualised surveillance, avoidance of oestrogens and smoking, and discussion of future pregnancies with respiratory medicine [1, 28]. The risk to each future child is 50%, and prenatal or preimplantation diagnosis is available [1]. Maternal angiomyolipoma and LAM alone would not satisfy the criteria for a definite diagnosis; the ungual fibromas, angiofibromas and, above all, pathogenic variant established it [15].

11. Prognosis and Long-Term Follow-Up

Prognosis depends on manifestation severity and is characterised by variability [2, 11]. Patients are at risk of premature death from epilepsy (including sudden unexpected death in epilepsy, SUDEP), cardiac arrhythmias, renal disease, SEGA complications or pulmonary LAM [9, 16]. In a British cohort, 16 patients died from TSC complications: eight from renal disease, four from SUDEP, two from LAM, one from SEGA and one from pancreatic neoplasia; median age at death was 33 years, and mortality was significantly higher in patients with learning difficulties (9% versus 2%) [16]. Renal disease accounts for approximately half of early deaths [1, 16], and SGRT identifies angiomyolipoma renal complications as the second cause of death, with a 25–50% bleeding risk in patients with angiomyolipomas [11]. An unknown percentage died before age 20 years from status epilepticus, general debility, pneumonia or tumour in historical series biased towards severe forms [2]. In recent East Asian population studies, most patients reach adulthood, with a median age at death of 36.6 years in Hong Kong and a standardised mortality ratio approaching 5 in Taiwan; diagnosis after age 18 years was associated with greater mortality [88, 89].

Neurocognitive prognosis is determined primarily by early epilepsy: seizure onset before age 2 years, spasm duration and drug resistance are associated with intellectual disability, ASD and TAND, whereas seizure onset after age 5 years is rarely accompanied by learning difficulties [1, 9]. Mental deterioration is unusual outside very frequent seizures or status epilepticus [2]. Skin lesions do not cause serious medical problems, but angiofibromas have cosmetic and psychosocial effects [1, 2]. Undetected SEGAs may cause significant morbidity and mortality through hydrocephalus [2]. LAM has a guarded prognosis with extensive pulmonary involvement, although only 5–10% of patients with TSC-associated LAM progress to respiratory failure [1, 9]. Rhabdomyomas regress in number and size with age [9].

Long-term follow-up rests on the 2021 consensus surveillance schedule (section 7.2), with multidisciplinary coordination and particular attention to three transitions: infancy, when EEG surveillance and prompt response to spasms influence cognitive prognosis; adolescence, with transition to adult care, emergence of angiomyolipomas and the need to continue brain MRI until age 25 years; and adult womanhood, when LAM, non-oestrogen contraception and reproductive planning become priorities [1, 15, 27]. Even patients diagnosed late may benefit from mTOR inhibitors, with reduced seizures and angiofibromas [93]. Clinical actionability of the diagnosis, classified by ClinGen as strong in childhood and moderate in adulthood, supports early identification of at-risk relatives [17].

The following schedule brings together the surveillance examinations with the sources for each interval; the international consensus values coincide with those in section 7.2, and the alternatives in the French PNDS (French National Diagnosis and Care Protocol) correspond to the divergences in section 7.15.

12. Summary and Final Considerations

Tuberous sclerosis complex is an autosomal dominant disorder, with an incidence of 1:6,000 to 1:10,000 live births, caused by loss-of-function variants in TSC1 (approximately one-quarter of cases with an identified variant) or TSC2 (approximately three-quarters), which inactivate the hamartin–tuberin complex and constitutively activate mTORC1. Lesions result from a two-hit mechanism, and approximately two-thirds of cases are de novo, with a residual recurrence risk of 1–2% from gonadal mosaicism. TSC2 is associated with a more severe phenotype than TSC1, and a contiguous TSC2/PKD1 deletion adds severe early-onset polycystic kidney disease.

Diagnosis follows the 2021 international criteria: identification of a pathogenic variant is sufficient; clinically, two major criteria or one major and two or more minor criteria are required, while the isolated combination of LAM and angiomyolipomas is insufficient. A negative blood test does not exclude diagnosis because of somatic mosaicism. Presentation depends on age, from fetal rhabdomyomas and infantile spasms through to adult angiomyolipomas and LAM.

Modern management combines scheduled surveillance by system — serial infant EEG, brain MRI until age 25 years, abdominal MRI every 1–3 years, annual TAND screening, chest CT in women — with targeted therapy. Vigabatrin is first-line for infantile spasms, and EEG-guided preventive treatment delays and reduces spasms without demonstrated developmental benefit. Everolimus is approved for SEGA (4.5 mg/m²/day), renal angiomyolipoma (10 mg/day) and refractory focal seizures (5 mg/m²/day in the US), with titration to trough concentrations of 5–15 ng/mL; cannabidiol is approved for TSC-associated seizures at up to 25 mg/kg/day; oral sirolimus for LAM and topical sirolimus 0.2% for facial angiofibromas. Renal disease is the principal cause of mortality, and neurological manifestations and TAND are the principal causes of morbidity, making lifelong renal surveillance and systematic TAND assessment the two measures with the greatest anticipated effect on prognosis. Relevant gaps persist in epidemiological data for Portugal, Brazil and much of Africa and Latin America, and in equitable access to targeted therapies.

The 2021 French PNDS documents (French National Diagnosis and Care Protocol) for TSC and LAM agree in essence with the international consensus, but diverge on operational points, such as EEG every 4 weeks before 6 months, vigabatrin at 100–150 mg/kg/day, the preference for surgery in SEGA, the sirolimus target of 5–12 ng/mL and less frequent ophthalmological and thoracic surveillance (section 7.15) [14, 29].

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