One week before birth, examination revealed a strong echo mass in the heart of the fetus (patient), indicating cardiac rhabdomyoma (Fig. 1A). A regular follow-up was recommended to observe changes in the cardiac rhabdomyoma. The patient’s mother had seizures since four years old. During pregnancy, she took lamotrigine and valpromide tablets but still had seizures every month. She had multiple skin lesions, including hypomelanotic macules, shagreen patches and facial angiofibromas. The patient’s uncle had seizures and died of “brain tumor” at 25 years old. The patient’s grandfather had hypomelanotic macules, shagreen patches and facial angiofibromas. When the patient was 4 months old, the mother was hospitalized. Existing family members had underwent testing for all exons and introns of TSC1 and TSC2 genes. Test results identified TSC1 mutation (c.2356C>T, p.R786*) in the patient, his mother and grandfather (Fig. 1B). The nonsense mutation has been reported in a previous study(7). Based on both clinical signs and genetic testing, our patient was definitely diagnosed with TSC.
The cutaneous nodules of the patient first appeared behind the right ear without evident cause or tenderness and gradually growth multiple nodules at 5-month old. After 2 months, he was admitted into our department. Physical examination showed multiple nodules on the scalp, eyelids, trunk and limbs of the patient which are papules or yellow and erythematous nodules without inflammation or ulceration (Figs. 1C-D). He had one hypomelanotic macule on the abdomen (Fig. 1D). Brain computed tomography (CT) showed multiple punctate, flaky and round-like high-density holes in the bilateral lateral ventricles and bilateral subependymal. A large lesion (51 mm×46 mm) located in the posterior corner of the left lateral ventricle was diagnosed as subependymal giant cell astrocytoma (SEGA) (Fig. 2A). Head magnetic resonance imaging (MRI) showed nodules in the posterior corners of bilateral ventricles on T1- and T2-weighted images (Figs. 2B–C). Chest CT showed the presence of a pulmonary subpleural nodule in the lower left lobe (Fig 2D). Cardiac ultrasound showed cardiac rhabdomyoma in the left ventricular cavity, which was approximately 15 mm×12 mm. Abdominal ultrasonography was normal. Ophthalmologic evaluation was not performed, because the patient was too young to cooperatate. Laboratory blood tests showed that the patient had normal lipid level. He had no facial angiofibromas, shagreen patches or seizures, and his development was normal.
The cutaneous nodules were different from common TSC skin lesions. We performed biopsy on the cutaneous nodules. Histopathological examination showed typical histiocytosis in the dermis with many multinucleated giant cells and inflammatory cells (Figs. 3A–B). Cluster differentiation 68 (CD68) and CD163 were positive (Figs. 3C–D) and S100, CD1a, langerin, human melanoma black 45 (HMB-45) and Melan-A were negative in immunohistochemical staining (Figs. 3E, 3F, 3G, and 3I). The Ki-67 (Fig. 3H) proliferation index was 15%. The pathological finding of cutaneous nodules was consistent with JXG. We believed that JXG and TSC simultaneously occurred in the patient.
We gave the patient sirolimus orally to treat TSC. After 3 months, the multiple nodules disappeared and hypomelanotic macule in the abdomen did not show any change (Figs. 1E-F). We were surprised that sirolimus had a significant effect on JXG. We performed whole-exome sequencing and identified TSC1 mutation (c.2356C>T, p.R786*) in both paraffin block tissue and blood samples (Fig. 1B). No other disease-causing mutations were found. We considered JXG to be a new skin lesion of TSC.
Sirolimus was well tolerated without evident adverse reactions. After 1 year of administering sirolimus, no cutaneous nodule appeared. Cardiac ultrasound showed a reduction of cardiac rhabdomyoma in the left ventricular cavity (2 mm×4 mm). Blood routine, liver functions, kidney functions and serum electrolytes were normal. The patient continued oral sirolimus and followed up regularly every 6 months.