Tuberous sclerosis complex (TSC) : expert recommendations for provision of coordinated care

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem genetic disorder characterized by benign tumors in multiple organs, including the skin, brain, kidneys, and lungs and occasional malignant tumors. Hamartomas in the brain, retina, and sometimes other organs also occur (1–3). The estimated prevalence is 1:600–1:10,000 live births in the general population (4–6). Patients present at different ages with different manifestations, and varying degrees of organ involvement (Figure 1). CNS manifestations of TSC mainly present in childhood, affect around 85% of patients (8), frequently resulting in epilepsy refractory to treatment, intellectual impairment, autistic spectrum disorder, attention deficit hyperactivity disorder, and behavioral problems (1–3). Renal angiomyolipomas (AMLs) occur in ~80% of patients (9); kidney disease is the leading cause of death in adults with TSC (10). TSC is complex and highly varied (Figure 1) necessitating careful coordination of care, which is lacking for most patients in the UK. Some TSC manifestations are rarer; e.g., subependymal giant cell astrocytoma (SEGA) occurs in around 20–24% of patients (11, 12) (Figure 2). The major unsolved problem in TSC is refractory epilepsy and TSC-associated neuropsychiatric disorders (TAND); of which preliminary evidence suggests refractory epilepsy is a major cause (13–15). TSC, like other complex rare diseases, is a major burden to patients, families and healthcare systems. Optimizing care will alleviate some of this while waiting for medical research to deliver a cure. Classically, a clinical diagnosis of TSC is made by identifying major and minor features (Table 1) (1, 16). With wider availability of genetic testing, identification of pathogenic mutations in TSC1 or TSC2 is now sufficient to establish a diagnosis, regardless of the presence of clinical features (1, 16), and is particularly useful in confirming a suspected diagnosis, as many clinical TSC manifestations are infrequent in young patients (1, 16). The approval of the mTORC1 inhibitor—everolimus—for the treatment of AMLs, SEGA, and refractory epilepsy represents a significant advance in the potential management of the disease (17–19). Whilst not licensed in Europe, the Federal Drugs Agency (FDA) have also approved sirolimus for use in pulmonary lymphangioleiomyomatosis (LAM) (18). Refractory seizures adversely affect early development (20). Furthermore, appropriate early treatment of infantile spasms with vigabatrin has been shown to reduce the long-term impact of the neurological and neuropsychiatric aspects of TSC on patients (13, 14). A retrospective UK cohort study linking Clinical Practice Research Datalink (CPRD) to Hospital Episode Statistics (HES) data identified 334 patients with TSC revealed a much lower frequency of complications than would be expected from previous research; the disparity possibly reflecting under-recognition, and hence suggestive of inadequate medical care (7). It is clear from these findings, and the observation that many new patients referred to TSC clinics have never had holistic systematic monitoring, that many patients receive inadequate care. In the UK, about 1000 TSC families are known to the UK Tuberous Sclerosis Association, known as the TSA (Patient organization), and a similar number (usually the same families) attend UK specialist TSC clinics. Therefore, in most other cases, the quality of care delivered is unknown. Given the range of organ systems affected by TSC, its treatment requires coordination across a number of medical specialties over a patient's lifetime (Table 2). Currently in the UK, 16 centers host specialist TSC clinics—but most UK TSC patients are not currently managed within them. These specialist clinics have often been founded by enthusiastic clinicians but are frequently inadequately funded. The transition from pediatric to adult services can be particularly challenging in the absence of a systematic service. In Wales, a specialist TSC clinic that has been established through a partnership, between a pharmaceutical company and the NHS, awaits the development of a fully sustainable commissioning model. In Northern Ireland, a TSC clinic has been running since 1995, and directly reviews the majority of TSC patients in the region. In the UK, specialized service specifications are in place for adults and children with genetic disorders such as cystic fibrosis and inherited metabolic disorders. These are funded by NHS England, the Department of Health, Social Services and Public Safety in Northern Ireland, and Welsh Health Specialized Services Committee in Wales. However, no similar service or service specification is yet available for TSC patients. We propose a comprehensive, holistic model of care—to manage patients that present with a range of manifestations, requiring specialist management from a wide range of specialties (Figures 1, 2).