A rare case of tuberous sclerosis complex-associated renal cell carcinoma

SA Journal of Radiology ISSN: (Online) 2078-6778, (Print) 1027-202X Page 1 of 5 Case Report A rare case of tuberous sclerosis complex-associated renal cell carcinoma Authors: Humphrey Mapuranga1 Bianca Douglas-Jones2 Danelo du Plessis3 Camilla E. le Roux1 Christel du Buisson4 Shahida Moosa2 Affiliations: 1 Department of RadioDiagnosis, Faculty of Medical Imaging and Clinical Oncology, Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa Department of Medical Genetics, Division of Molecular Biology and Human Genetics, Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa Renal cell carcinoma is rarely described in paediatric patients with tuberous sclerosis complex. This report describes a case of an 11-year-old male with tuberous sclerosis-associated renal cell carcinoma. Keywords: tuberous sclerosis complex; renal cell carcinoma; paediatric; neuro-cutaneous; hamartomas. Introduction Tuberous sclerosis complex (TSC) is one of a large heterogeneous group of neurocutaneous syndromes with characteristic involvement of structures derived from embryologic neuroectoderm, and a prevalence of 1 in 6000–10 000 persons. The disease is characterised by slowgrowing hamartomas with multisystem involvement being typical. 2 Department of Surgery, Division of Urology, Faculty of Medicine and Health Sciences, Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa 3 Department of Paediatrics and Child Health, Paediatric Nephrology, Faculty of Medicine and Health Sciences, Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa 4 Project Research Registration: Project Number: 23549 Corresponding author: Camilla le Roux, Dates: Received: 23 Jan. 2022 Accepted: 23 Mar. 2022 Published: 20 May 2022 Read online: Scan this QR code with your smart phone or mobile device to read online. Tuberous sclerosis complex is an autosomal-dominant disorder, caused by heterozygous variants in one of the two genes: TSC1, which encodes for hamartin (located on chromosome 9q34), or TSC2, which encodes for tuberin (located on chromosome 16p13.3). Hamartin and tuberin act together as tumour suppressors and are components of the mammalian target of rapamycin (mTOR) signalling pathway.1,2 A clinical diagnosis of TSC is established if the individual has (1) two major clinical criteria, (2) one major and two or more minor criteria, or (3) the identification of a pathogenic variant in either TSC1 or TSC2 on genetic testing. Major criteria include multiple angiofibroma (≥ 3), cardiac rhabdomyoma, cortical dysplasias including tubers and white matter migration lines, hypomelanotic macules (≥ 3 mm of > 5 mm in diameter), lymphangioleiomyomatosis, retinal nodular hamartomas, shagreen patches, subependymal giant cell astrocytomas, subependymal nodules and ungual fibromas. Minor features include ‘confetti’ lesions on the skin, dental enamel pits, intraoral fibromas, multiple renal cysts, non-renal hamartomas and retinal achromic patches. Angiomyolipomas (AMLs) are the most common renal lesions associated with TSC and are present in 75% – 80% of patients. Renal cell carcinomas (RCCs) are very rare in patients with TSC (1% – 4%) (2). Moreover, the average age of diagnosis of RCC in patients with TSC is 30 years, with the youngest TSC-associated RCC reported in a 6-month-old girl.3 The clear cell, papillary and chromophobe RCC subtypes have been described in association with TSC.1,4 Renal cysts and oncocytomas may also occur.1,4 This report describes a unique case of an 11-year-old boy with confirmed TSC-associated RCC and highlight his management. Patient presentation An 11-year-old boy was referred to paediatric nephrology at Tygerberg Hospital with a clinical concern of hypertension following a seizure at his local hospital. He had a history of generalized tonic-clonic seizures from the age of three years. The seizure episodes were managed and controlled with sodium valproate. At presentation, he was fully awake and alert but persistently hypertensive with a blood pressure higher than the 95th percentile for his height, age and gender. How to cite this article: Mapuranga H, Douglas-Jones B, Du Plessis D, Le Roux CE, Du Buisson C, Moosa S. A rare case of tuberous sclerosis complex-associated renal cell carcinoma. S Afr J Rad. 2022;26(1), a2406. https://doi.org/10.4102/sajr.v26i1.2406 Copyright: © 2022. The Authors. Licensee: AOSIS. This work is licensed under the Creative Commons Attribution License. http://www.sajr.org.za Open Access Page 2 of 5 The patient was examined by a medical geneticist, and the clinical diagnosis of TSC was made, based on fulfillment of two major criteria: (1) > 3 hypomelanotic macules of > 5 mm in diameter, and (2) facial angiofibromas, in addition to further TSC-related features, like multiple ‘confetti’ skin lesions on his neck and chest and the clinical suspicion of multiple renal cysts. Based on the cystic kidneys, a contiguous gene deletion involving both TSC2 and PKD1 on chromosome 16p13.3 was considered as part of the differential molecular diagnosis, in addition to variants in TSC1 or TSC2. Initial imaging evaluation at our institution included renal ultrasound, which demonstrated multiple bilateral mild to markedly hypoechoic cortical masses (Figure 1a and b). Magnetic resonance imaging (MRI) of the brain and abdomen was subsequently performed. Brain imaging demonstrated T2-weighted hypointense subependymal nodules (Figure 2a and b) with a subependymal giant cell astrocytoma (Figure 2a to d). Fluidattenuated inversion recovery (FLAIR) demonstrated a Case Report multiple hyperintense cortical tubers (Figure 2c) and hyperintense white matter radial bands (Figure 2e). No retinal hamartomas were identified. Abdominal MRI demonstrated numerous bilateral renal cortical T2-weighted hypo to hyperintense (Figures 3a and b), T1-weighted hypointense mass lesions (Figure 4a). Fat suppression failed to demonstrate fat content (not shown). Post-contrast enhancement of bilateral renal mass lesions was seen. (Figure 4b and c). Time of flight MRI imaging of the abdominal aorta and renal arteries excluded renal artery stenosis (not shown). A radiological guided biopsy of the left midpole lesion was performed and confirmed tuberous sclerosis-associated RCC of the left kidney. No concrete evidence of cardiac abnormalities, specifically rhabdomyomas, was found on echocardiogram. Testing, management and outcome Genetic testing was performed in a stepwise manner. First, a chromosomal microarray was done and excluded the presence of a contiguous gene deletion on chromosome 16p13.3. The next step in testing was a TSC gene panel (Invitae, United States [US]), which included sequencing and deletion/duplication analysis of TSC1 and TSC2. This showed a pathogenic variant in TSC2 (c.5238_5255del; p.His1746_Arg1751del), which is a known pathogenic variant and definitively confirms the diagnosis. The patient was started on sirolimus (a ora (...truncated)