Discussion

As mentioned earlier, TSC can affect several parts of human body and the expression of the disease varies considerably. The diagnosis of TSC can be made clinically or through genetic testing, however, in approximately 25% of genetic tests, no mutation may be detected. ^{Reference Schwartz, Fernández and Kotulska2} Therefore, a negative genetic test does not automatically rule out the diagnosis of TSC. Nevertheless, in our case, the genetic testing revealed a positive TSC2 gene mutation.

In normal cells, the mTOR signalling cascade (also known as the phosphatidylinositol 3-kinase/protein kinase B/mTOR pathway) plays an important role in cell growth, proliferation, and survival. Inhibition of the TSC1–TSC2 complex results in the over-activation of mTOR, giving rise to cell growth and proliferation. ^{Reference Franz and Capal3} In addition, mTOR forms two distinct multiprotein complexes, mTORC1 and mTORC2, which are differentiated by their interaction partners, substrate selectivity, and sensitivity to rapamycin (sirolimus) and its analogues (e.g., Everolimus). Dysregulation of the mTOR pathway plays a role in the development of many tumours or hamartomatous lesions, including TSC and other neurological disorders. ^{Reference Franz and Capal3}

Typically, TSC is caused by a mutation in the TSC1 or the TSC2 gene. Loss of one of these genes triggers constitutive activation of the mTOR signalling pathway, giving rise to abnormal cell growth/proliferation and the subsequent formation of hamartomatous lesions. ^{Reference Franz and Capal3} The discovery of the relationship between TSC1–TSC2 and mTOR has led to significant clinical advances in the use of mTOR inhibitors, especially sirolimus and its analogue Everolimus, for the treatment of several TSC manifestations. ^{Reference Franz and Capal3,Reference Sasongko, Ismail and Zabidi-Hussin4} Recent studies have shown positive results of the use of rapamycin analogue in patients with TSC accompanied by cardiac rhabdomyoma, subependymal giant cell astrocytoma, renal angiomyolipoma, and epilepsy. ^{Reference Lam, Siroky and Henske5}

The characteristic TSC central nervous system lesions include cortical tubers (also called glioneuronal hamartomas), subependymal nodules, giant cell astrocytoma, and radiologically detectable white matter abnormalities. ^{Reference Northrup and Krueger1} Cortical tubers are the distinguishing feature of TSC and result from abnormal neuronal migration during early brain development. The increase in the number of tubers is associated with weaker cognitive functions, mental retardation, and resistant seizures. The treatment of epilepsy associated with TSC continues to be a major problem and more than 60% of the patients suffer from seizures. ^{Reference Kassiri, Snyder and Bhargava6,Reference O’Callaghan, Harris and Joinson7} In our patient, multiple subependymal nodules were observed in the T1 A sections at the caudate nucleus level (Fig 2c) and in the Sagittal T2 A section at the lateral ventricular frontal horn level (Fig 2d). Our patient had seizure attacks that developed as a result of brain involvement. These attacks, however, stopped after the Levetiracetam treatment was started.

Some studies claim that overactive mTOR signals may also cause neurosensory hearing loss, and that the treatments given to reduce mTOR activity may also act as a potential strategy to prevent hearing loss. ^{Reference Fu, Sun and Zhang8} Our patient also had congenital bilateral neurosensory hearing loss, and to the best of our knowledge, this study is the first in the literature to report a child diagnosed with both tuberous sclerosis and hearing loss.

Moreover, a vast majority of the patient with TSC has characteristic skin lesions. The most common lesions are angiofibroma (formerly called adenoma sebaceum), hypopigmented macules (also known as ash-leaf spots), Shagreen patches, and a distinctive brown fibrous plaque on the forehead. Ash-leaf spots are very common in neonatal and infants ^{Reference Northrup and Krueger1} , and it maybe the earliest noticeable sign of TSC after birth. ^{Reference Davis, Filip-Dhima and Sideridis9} Our case also had hypomelanotic lesions around the eyes and umbilicus, and on lower extremities (Fig 1 a).

Cardiac rhabdomyomas, on the other hand, are benign tumours that may occur in any area of the heart, but mostly appear in the ventricle. Although the LV and the interventricular septum are the most common locations, as in our case, it may also appear in the atrial wall or the right ventricle in approximately 30% of the cases. ^{Reference Frudit, Vitturi and Navarro10} The masses are macroscopically hard, smooth-edged, unencapsulated, white–grey, and sizes may vary from millimetres to several centimetres. Cardiac rhabdomyomas occur in approximately 60% of the TSC cases, and therefore, in the presence of rhabdomyoma in echocardiography, the patient should be evaluated in terms of TSC. ^{Reference Fuller, Wolf and Buja11} Rhabdomyomas, which are generally detected in the foetal or neonatal period, tend to regress spontaneously in the first few years after birth. ^{Reference Song, Jeong and Kim12} Therefore, these masses in the heart do not require medical or surgical treatment, unless they have severe valve regurgitation, life-threatening dysrhythmia, or severe stenosis of the ventricular outflow tract in the early postnatal period.

Clinical findings in patients with rhabdomyoma largely depend on the location and mass effect of the tumour in the heart. As a result of haemodynamic instability due to the tumour’s location, the risk of sudden death increase in such patients. ^{Reference Fuller, Wolf and Buja11} Surgical intervention is recommended only in the presence of life-threatening refractory dysrhythmia or severe haemodynamic disorder. ^{Reference Padalino, Basso and Milanesi13} Therefore, in such cases, no delay must be caused in terms of medical or surgical intervention. In cases where the tumour is multifocal, infiltrative, or very large, surgical resection is quite difficult and unfortunately, the results are not very satisfactory. ^{Reference Aw, Goyer and Raboisson14} Recent case reports and clinical trials have shown that the treatment of rapamycin analogues initiated in the early period can also effectively regress cardiac rhabdomyoma. ^{Reference Weiland, Bonello and Hill15} A rapamycin analogue (Everolimus) treatment was also started for our patient who had severe stenosis in the left ventricular outflow tract due to cardiac rhabdomyoma and developed secondary left ventricular hypertrophy. With the treatment of Everolimus, the masses in the patient’s heart shrank, and the stenosis in the left ventricular outflow tract (latest 18 mmHg) and left ventricular hypertrophy also regressed. Our patient received a total of 4 months of Everolimus treatment. At the time of treatment discontinuation, the mass in the left ventricular outflow tract was 2.7 × 2.3 mm and the mass in the left atrium was 6.3 × 5.4 mm (Fig 2b). Therefore, it was found that our patient clearly benefitted from the Everolimus treatment that saved the patient from a possible surgery.