Volume 1 - Issue 1, 2016

Tuberous sclerosis complex: from child to adult Back


Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that can cause non-invasive hamartomatous lesions of any number and size in almost every organ, but are most commonly observed in the brain, skin, eyes, heart, kidney and lung.1 In about 85% of TSC patients, mutations are identified either in TSC1 (chromosome 9q34) encoding hamartin or, 2–10 times more commonly, in TSC2 (chromosome 16p13) encoding tuberin.2,3 Together, hamartin and tuberin inhibit the phosphatidylinositol 3-kinase (PI3K)/insulin-activated signalling pathway, involving the mammalian target of rapamycin (mTOR) and a cascade of other downstream kinases and translational factors that stimulate protein translation, cell growth and proliferation.4 Consequently, mutations to either TSC1 or TSC2 lead to overactivation of the mTOR protein complex, resulting in abnormal neuronal cell division, differentiation and migration,5 which explains why mutations to either gene cause the same disease. The manifestations can vary greatly since TSC can affect different organ systems in different ways at different times in the individual’s life.

There is a relative paucity of large epidemiological studies regarding the prevalence of TSC. Variations in prevalence rates are likely in part to be related to differences in case ascertainment. Osborne et al found a prevalence of approximately 1 in 34 000 in the Wessex region of England.6 Based on overall data, these authors suggested a birth incidence of 1 in 5800. O’Callaghan et al, using capture–recapture analysis and taking account of unascertained cases, revised the estimate from the Wessex data to a prevalence of 3.8 per 100 000.7More recently, Devlin et al carried out a retrospective epidemiological study in Northern Ireland of the prevalence of TSC and estimated a point prevalence of 1 in 24 956 in 2004.8 This study detected a mutation in 95.8% of those tested (26% TSC1 and 74% TSC2) and a new mutation rate of 64%. In a recent large population study, Hong et al found a lower overall prevalence in Taiwan, using the national insurance database.9 This gave an overall estimated prevalence of 1 in 95 136. The estimated prevalence by age in this study was 1 in 14 608 below six years of age, 1 in 18 851 below 12 years of age and 1 in 24 617 below 18 years of age, in agreement with previous reports that have suggested a higher prevalence in children.

The diagnosis is made when two major features, or one major and two or more
minor ones are present (Box 1).10 Age plays a role in the organ involvement:
• During infancy, cardiac rhabdomyoma are detected, which typically regress in adulthood
• During childhood and adolescence, subependymal giant cell astrocytomas (SEGAs) develop. It is rare for these to develop in adulthood
• During childhood, renal angiomyolipomas (AML) can cause serious issues with bleeding because of their vascular nature, and can lead to the need for dialysis and even renal transplantation
• During adulthood, pulmonary lymphangioleiomyomatosis (LAM) usually develops.

As the phenotype is usually evident in utero, or manifests in infancy or by early
childhood with seizures, intellectual disability and characteristic skin lesions, very rarely does a patient reach adolescence or adulthood without being diagnosed. However, some findings, notably renal AML and pulmonary LAM, emerge later, placing adults with undiagnosed TSC at increased risk for morbidity and mortality.

In a retrospective study of 45 women diagnosed with TSC in adulthood, 30 met clinical criteria for TSC in childhood that remained undiagnosed for a median of 21.5 years and 15 were older than 18 years before meeting the clinical criteria for TSC.11 They had minimal morbidity during childhood but were still at risk for life-threatening pulmonary and renal manifestations with similar occurrences of pneumothorax, shortness of breath, haemoptysis, nephrectomy and death.11As transition occurs from childhood and adolescence into adulthood, both the
medical concerns and the ‘medical team’ looking after the individual with TSC change. This article focuses on the differences in presentation between the paediatric and adult ‘world’. The adult neurologist may be less familiar with TSC and the different organ manifestations to be included in regular surveillance programmes.

Organ manifestations at different ages

At birth: heart

Cardiac involvement is typically maximal at birth or early in life, and it may be the presenting sign of TSC, particularly in early infancy. Cardiac rhabdomyomas are benign tumours often detected antenatally that produce predominantly outflow tract obstruction, interfere with valvular function, disrupt electrical conductivity or cause arrhythmias. Rhabdomyomas usually develop between weeks 22 and 26 of gestation, and usually undergo spontaneous regression in the first few years of life. In a retrospective series from a paediatric cardiology centre, they were found in 67% of antenatal cardiac detections and were multiple in the majority.12 Of 32 patients with rhabdomyomas, four had an arrhythmia and one had heart failure. A total of 65.6% of rhabdomyomas showed spontaneous regression. Sciacca et alreported the outcome for 33 children diagnosed with cardiac rhabdomyomas in a paediatric cardiology centre.13 Of these, 30% were detected antenatally and 31 were subsequently diagnosed with TSC based on accepted diagnostic clinical criteria. In four infants the presence of the mass caused clinical effects with obstruction, heart failure or cyanosis.13 One infant died shortly after birth with severe heart failure and one required cardiac surgery. In the other two infants the rhabdomyomas regressed without intervention. The majority of lesions were multiple. During follow-up, the rhabdomyomas reduced in size in 31 of the 32 surviving children. In eight cases (24%) there were atrial and/or ventricular ectopic beats, leading to Wolf-Parkinson-White syndrome in two; however, none required medical treatment. In terms of neurological involvement, 54% of infants had infantile spasms and 80% of the patients overall developed epilepsy. The outcome for cardiac involvement was favourable in the vast majority.13

In the first year: skin

The skin is affected in all individuals with TSC, but none of the skin lesions result in serious medical problems. Dermatological features of TSC in children may be both diagnostic and require dermatological management. The TSC Dermatology and Dentistry Subcommittee of ‘The 2012 International Tuberous Sclerosis Complex Clinical Consensus Conference’ has published a review of the evidence-based literature with diagnostic and management guidelines.14 Hypomelanotic macules present in the first few years of life, but may not be evident in infants. Examination in infants and children with an ultraviolet-emitting lamp (Woods lamp) in a darkened room is an important examination in any child who has clinical features that could be applicable to TSC. This may need to be repeated in infants as the lesions evolve and enlarge.

Angiofibromas often start to develop at three to four years of age and continue
to develop through childhood.14 Facial angiofibromas, which appear later in childhood and progress during adolescence, become erythematous and nodular over time, and can easily bleed. They can be the most prominent of all skin lesions. Similarly, fibromas of the skin are rarely found in children, are common in adolescence and remain throughout adulthood. Fibromas are hamartomas of connective tissue, which consists of fat, collagen, smooth muscle, vascular structures and skin, and can be found anywhere on the skin or mucosa, including gingiva, and if found in the lumbar region are called Shagreen patches. Children can develop dental pits, gingival fibromas and bone cysts in the jaw from six to seven years of age, thus regular dental examination is important. Fibromas around the nails, or ungual fibromas, can result from trauma and are found as singular lesions in golf players. At least two ungual fibromas are the criteria for TSC, seen in about 80% of older affected adults.10

During childhood: central nervous system

In children and young people, neurological features often dominate the condition, with approximately 85% of children and adolescents having clinical features related to brain involvement, including epilepsy, intellectual impairment, challenging behaviour and autism.1 Devlin et al found that 42.5% of patients were diagnosed with TSC in the first 15 months of life, of whom 93% had epilepsy.8 An additional 13.7% presented between 15 months and five years of age, of whom the majority had epilepsy. However, 25% were not diagnosed with TSC at initial presentation despite having features that could be attributable to TSC such as infantile spasms, epilepsy, learning disability or dermatological stigmata.


Epileptogenesis in TSC is caused by molecular changes of gamma-aminobutyric acid (GABA) and glutamate receptors in dysplastic neurons resulting in diminished neuronal inhibition and enhanced excitation.15 The mTOR pathway regulates multiple cellular functions that may contribute to epileptogenesis, including protein synthesis, cell growth and proliferation, and synaptic plasticity.16 Children with TSC frequently present with seizures in infancy and often with infantile spasms. A prospective study of children attending a TSC service, found that the median age of presentation with first seizures was seven months.17 Of those with epilepsy in this study, 44% had infantile spasms. Focal seizures preceded the spasms in 32%, and 30% of children with epilepsy had a history of status epilepticus.

Age at onset largely depends on functional maturation of the cortex where the tubers are located, with temporo-occipital tubers expressing earlier than frontal ones.18 The epilepsy frequently evolves over years, with multifocal seizures arising from different tubers, or features of the Lennox-Gastaut syndrome, with tonic seizures and multiple seizure types. Children with TSC2 mutations are more likely to have a history of infantile spasms. A significant association has been found for TSC2 mutations and higher tuber count, earlier onset of seizures and an increase in the seizure severity score compared to TSC1 mutations.19