1. Briefly description of TSC and its characteristics
Tuberous sclerosis complex is an autosomal dominant hereditary disease. Clinically, it is characterized by cutaneous sebaceous adenoma, epilepsy, and mental retardation. It can also affect multiple systems such as the kidney, heart, lungs, and eyes, manifesting as multiple hamartomas throughout the body[5, 6]. Tuberous sclerosis is primarily caused by mutations in the TSC1 or TSC2 genes. The TSC1 gene encodes the hamartin protein and the TSC2 gene encodes the tuberin protein. These two proteins form a complex that inhibits the mTOR pathway, regulates cell growth and metabolism, and inhibits abnormal cell proliferation, tumor cell formation and metastasis[7-9]. When the TSC1 or TSC2 gene is mutated, activation of the mTOR pathway leads to abnormal cell proliferation, causing tumor-like lesions.
Until the 1980s, scholars diagnosed TSC based on severe and typical clinical manifestations. In 1992, the International Tuberous Sclerosis Association (NTSA) formulated the diagnostic criteria for tuberous sclerosis. In 1998, the diagnostic criteria for TSC were based on the clinical and mutational characteristics of tuberous sclerosis. Revisited in 2012, the International Tuberous Sclerosis Alliance further improved this standard, adding genetic testing to the diagnostic criteria.
Detection of pathogenic TSC1 or TSC2 gene mutations in genetic diagnosis can be used as a separate diagnostic criterion. Clinical diagnostic criteria include 11 major diagnoses and 6 minor diagnoses ; the main criteria include ① Hypomelanotic macules (≥3, at least 5mm diameter), ② Angiofibromas (≥3) fibrous cephalic plaque, ③ Ungual fibromas(≥2), ④ Shagreen patch, ⑤ Multiple retinal hamartoma, ⑥ Cerebral cortical dysplasia, ⑦ Subependymal nodules, ⑧ Subependymal giant cell astrocytoma, ⑨ Cardiac rhabdomyoma, ⑩ Pulmonary lymphangioleiomyoma and angiomyolipomas(≥2). Minor criteria include: ① “Confetti” skin lesions, ② Dental enamel pits (≥3), ③ Intraoral fibroma (≥2), ④ Retinal achromic patch, ⑤ multiple renal cysts, and ⑥ non-renal hamartoma. The disease can also be diagnosed when two major criteria or one major criterion and two minor criteria are met.
2. The diagnosis and treatment process in this case
In this case, the onset occurred in infancy, with cardiac damage as the first symptom, and cardiac color Doppler ultrasound mainly manifested as apical hypertrophic cardiomyopathy. During the follow-up process, no clinical manifestation of other systems has appeared, and the diagnosis was "hypertrophic cardiomyopathy", which had been treated with beta-blockers orally. More than 10 days before admission, paroxysmal syncope appeared. Because of her "heart disease history", she was admitted to the hospital and the possibility of "cardiogenic syncope" was first considered. The electrocardiogram on admission showed sinus arrhythmia, myocardial damage and delay of intraventricular conduction. In order to further clarify the diagnosis and eliminate syncope caused by intermittent arrhythmia, dynamic electrocardiogram was performed in this patient. The result showed that atrial premature beats, some of which were triad, with occasional ventricular premature beats，and delay of intraventricular conduction，myocardial damage and abnormal Q wave. Color Doppler ultrasound indicated obtuse left ventricular apex, local ventricular aneurysm formation, abnormal motion of the segmental ventricular wall and papillary muscle echo enhancement. Cardiac biomarkers were almost normal including AST (26U/L), CK (152U/L), LDH (279U/L), and cTnI<1.9pg/mL. However NT-proBNP was increased （401.9pg / mL）. Although cardiac syncope was highly suspected, epilepsy needed to be further excluded given the history of febrile convulsion. Thus EEG and brain MRI were required to further clarify the diagnosis. On the second day of admission, during rounds, "syncope" occurred suddenly, manifested as head tilting to one side, unresponsiveness without twitches and soft bilateral limbs. The seizure lasted for approximately 30 seconds and then resolved spontaneously without incontinence. Checking her medical history with her parents confirmed that similar seizures had occurred in the past and were called "syncope". Therefore, clinical considerations were corrected to "epilepsy" rather than "syncope". Subsequent examination results were reported successively : an abnormal children's EEG was reported, with slightly more sharp waves in the left anterior temporal region. Brain MRI diagnosis indicated bilateral frontal parietal occipital cortex and subcortical abnormal signal focus, with bilateral lateral ventricle marginal nodules considered to be caused by tuberous sclerosis (TS), which is consistent with the diagnosis of tuberous sclerosis. Further genetic testing detected the TSC2 gene mutation, which is consistent with the diagnosis of tuberous sclerosis.
3. Inspiration from the diagnosis and treatment of this case
In this case, a child with a recurrent respiratory infection at the age of 8 months underwent a color Doppler ultrasound examination, which was identified as "apical hypertrophic cardiomyopathy", without related clinical manifestations, so she was allowed to follow up in the clinic regularly. Apical hypertrophic cardiomyopathy is a special type of primary hypertrophic cardiomyopathy, which was first discovered and proposed by Yamaguch et al in 1976. Apical hypertrophic cardiomyopathy is charactered by bellowing the level of the left ventricular papillary muscle, and is generally not accompanied by left ventricular outflow tract stenosis and pressure gradient, which have little effect on cardiac hemodynamics. Its clinical symptoms are not obvious, and the onset is unknown. The incidence of apical hypertrophic cardiomyopathy varies in different populations in different countries. The incidence of the disease in Japan is 15%, which is about five times that of the United States, while the incidence in Asians can be as high as 40%[15, 16]. The disease is usually more common in middle-aged men, but due to the atypical clinical symptoms of the disease, the age of diagnosis is generally later than the age of onset. The clinical manifestations of the disease are atypical. Only some patients present with atypical chest pain, low exercise tolerance, syncope, etc., so they are easily misdiagnosed and missed. They are often accidentally found when performing cardiac ultrasound or electrocardiogram. Apical hypertrophic cardiomyopathy is mainly diagnosed through electrocardiographic specific changes combined with cardiac color Doppler ultrasound or cardiac magnetic resonance. The electrocardiogram shows a characteristic huge negative T wave, and the color Doppler ultrasound shows a left ventricular apical and end-diastolic apical wall thickness ≥15mm, and the ratio of the maximum apical wall thickness to the left ventricular posterior wall thickness≥1.3. Cardiac magnetic resonance(CMR) can determine myocardial hypertrophy segments more clearly than cardiac color Doppler ultrasound ; accordingly it is the gold standard for the diagnosis of apical hypertrophic cardiomyopathy. AHCM is mainly manifested as thickened apical ventricular wall in CMR, which is spades-like.
In the present case, TSC was missed in the early stage due to the absence of skin, nervous system and other involved systems, and the color Doppler ultrasound showed "apical hypertrophic cardiomyopathy" rather than "cardiac rhabdomyosarcoma". The diagnosis of TSC was not made until the patient presented with additional symptoms and was confirmed with the MRI results combined with medical history. 45% to 60% of patients with TSC present with heart symptoms and develop rhabdomyosarcoma. Cardiac rhabdomyomas (CR) are mostly found in the fetal or infant period. On the echocardiography of the heart, abnormal areas of enhanced echo in the myocardium often appear in the ventricle, ventricular septum and papillary muscle, but appearance in the apical area is rare. The severity depends on tumor size, location, and number, etc .
Therefore, identification of unusual manifestations of enhanced echo in the myocardium by cardiac color Doppler ultrasound should lead to a consideration of the possibility of cardiac tumors. The emergence of many cardiac tumors may suggest a certain genetic disease syndrome. Among them, rhabdomyosarcoma is the most common benign cardiac tumor in children. It can be the first clinical manifestation of tuberous sclerosis and an important clue in the diagnosis of tuberous sclerosis .
Although cardiac rhabdomyosarcoma is typically identified in the ventricle and ventricular septum, it may still be located in the apex, which is a point that is easily confused with apical hypertrophic cardiomyopathy. Both have been ascribed to genetic mutations. However, apical hypertrophic cardiomyopathy has its unique ECG manifestations, and lesions are mainly located in the heart, and do not involve the whole body system, in contrast to cardiac rhabdomyomas, which highlights a major difference between the two diseases. Given the possibility of insidious and atypical tuberous sclerosis, when apical hypertrophy or cardiac tumors are identified, it is recommended to broaden the systemic examination even including genetic testing to further determine the cause, in order to reduce the misdiagnosis rate of tuberous sclerosis.