Incidence of tuberous sclerosis and age at first diagnosis: new data and emerging trends from a national, prospective surveillance study

Abstract

Background: Tuberous Sclerosis Complex (TSC) is a rare multisystem disorder. In 2012 diagnostic criteria for TSC were revised. However, data on the incidence of TSC are limited.

Methods: Prospective, national surveillance study in Germany over a 2-year-period (03/2015-02/2017) using current revised criteria for TSC. Patients up to the age of 18 years with a new diagnosis of definite or possible TSC (clinical and/or genetic) were included. The aims of this study were 1) to generate up-to-date data on the incidence of definite or possible TSC, 2) to assess age at first diagnosis, and 3) to compare these data with previous epidemiologic data.

Results: In total, 86 patients met inclusion criteria (definite or possible TSC) with a median age at diagnosis of 6 months (range: 5 months before birth - 197 months of age). Among patients identified with features of TSC, 73.3% met criteria for definite diagnosis (median age: 7 months) and 26.7% met criteria for a possible diagnosis (median age: 3 months). 55.8% of patients were male. When excluding prenatally diagnosed patients, median age at diagnosis was 11 months with a range of 0 to 197 months. The 3 most common clinical features at diagnosis of TSC were central nervous system involvement in 73.3% patients (of these 95.2% experienced seizures), cutaneous involvement in 58.1% patients (with the most common lesion being hypomelanotic macules in 92%) and cardiac rhabdomyoma in half of the patients. Cardiac rhabdomyoma were detected by prenatal ultrasonography in 22.1% of patients. The presence of cardiac rhabdomyoma was associated with cardiac arrhythmias in 25.6% (about 13% of all diagnosed patients) in our cohort. The overall prevalence of seizure disorders was 69.8%. The annual incidence rate of TSC is estimated at a minimum of 1:17.785 live births. However correcting for underreporting, the estimated incidence rate of definite or possible TSC is approximately 1:6.760-1:13.520 live births in Germany.

Conclusions: This is the first study that assessed prospectively the incidence rate of TSC in children and adolescents using the updated diagnostic criteria of 2012. This prospective surveillance study demonstrates a low age at first diagnosis (median: 6 months), likely due to antenatal detection of cardiac rhabdomyoma. Early diagnosis bears the potential for implementing effective therapies at an earlier stage.

Keywords: Epidemiology; Everolimus; Incidence; Infantile spasms; Neurologic manifestations; Prenatal rhabdomyoma, hamartomas; Seizures; Tuberous sclerosis; mTOR.

Fig. 1

Cumulative age distribution at first diagnosis

Fig. 2

Clinical features leading to first diagnosis. * Including seizures, developmental delay, neuropsychiatric disorders (e.g. autistic characteristics); multiple entries possible. Abbreviations: CNS (central nervous system); (n: number of patients)

Fig. 3

Clinical features after comprehensive diagnostic work-up. The majority of patients presented with CNS involvement (cortical dysplasias 51.5% (44/86); subependymal nodules (SEN) 47.7% (41/86) and subependymal giant cell astrocytoma (SEGA) 5,8% (5/86). Followed by cardiac rhabydomyoma in 59.3% (51/86) and hypomelanotic macules in 53.5% (46/86). The other clinical symptoms were heterogeneous. (n: number of patients)

Fig. 4

Tests used to establish the diagnosis. The most common diagnostic study performed was echocardiography in 90.7% (78/86), followed by ultrasound (cerebral or abdominal) in 89.5% (77/86). An electroencephalogram (EEG) was performed in 84.9% (73/86). Cranial magnetic resonance imaging (cMRI) was obtained in 74.4% (64/86) as well as cranial CT imaging in 3 patients (3.4%). Formal skin examination was only performed in 33.7% (29/86), while cutaneous involvement was noted in 58.1% of all patients. (n: number of patients)