Balkan Journal of Medical Genetics

BILATERAL RENAL ANGIOMYOLIPOMAS AND SUBEPENDYMAL GIANT CELL ASTROCYTOMA ASSOCIATED WITH TUBEROUS SCLEROSIS COMPLEX: A CASE REPORT AND REVIEW OF THE LITERATURE
Rambabova Bushljetik I, Lazareska M, Barbov I, Stankov O, Filipce V, Spasovski G
*Corresponding Author: Rambabova Bushljetik I, M.D., Ph.D., University Clinic of Nephrology, Vodnjanska 17, 1000 Skopje, Republic of North Macedonia. Tel.: +389-214-7191. Mobile: +389-72- 216-581. Fax: +389-231-1188. E-mail: irambabova@yahoo.com
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INTRODUCTION

Tuberous sclerosis complex (TSC) is a rare disease, with a birth rate of 1 in 6,000 to 1 in 10,000 newborns [1]. It is a multisystemic, autosomal dominant condition that can result in formation of hamartomas in multiple organs, mainly in brain, kidney, skin and lung. The two thirds of affected patients have sporadic mutations [2]. The British dermatologist John James Pringle first observed papular facial rash in a female patient with intellectual impairment, describing it as “adenoma sebaceum” [3]. The French neurologist Désiré-Magloire Bourneville described potato-like tumors in the brain and associated them with the cutaneous manifestations and other clinical symptoms [4]. Hence, a historical text appeared as the “Bourneville-Pringle disease” [5,6]. At a molecular basis, TSC results from a mutation in one of two TSC1 and TSC2 genes (located in chromosomes 9 and 16, respectively). These two genes encode two proteins (hamartin and tuberin), form intracellular complexes and physiologically inhibit a serine-threoninekinase, known as mTOR (mammalian target of rapamycin). Their complete loss allows unregulated stimulation of cell growth and proliferation [7]. The first TSC Consensus Conference was held in 1998 and the recommendations for diagnosis and clinical management of patients with TSC were developed [8]. At the second International TSC Consensus Conference (2012), these criteria were reviewed and updated and recommendations for diagnosis, surveillance and management of TSC patients were issued [9]. The mTOR inhibitor rapamycin, and later the rapamycin derivate, everolimus, played a significant role in solid organ transplant protocols to prevent rejection, in oncology as an anticancer target therapy and for elution of vascular stents in interventional cardiology [10]. In 2010, everolimus became the first approved therapy by the US Food and Drug Administration (FDA) for treatment of TSC-associated subependymal giant cell astrocytoma (SEGA). Later, in 2012, everolimus was also approved by the FDA to treat renal angiomyolipomas (AMLs), in TSC patients [11]. Diagnosis of TSC can be confirmed with clinical diagnostic criteria and gene testing, but in 10.0-25.0% of patients there is no gene mutation confirmed. Clinical diagnostic criteria consist of 11 major and six minor features. Definitive diagnosis can be confirmed with presence of two major or one major and two minor futures [9]. About 85.0% of patients with TSC during childhood and adolescence manifest seizures, cognitive and/or behavioral problems (autism and autism spectrum disease). A subset of adult patients have normal mental status. The main brain lesions include cortical tubers, subependymal nodules and SEGA present in only 5.0-15.0% of TSC patients. Subependymal giant cell astrocytoma can lead to ventricular enlargement and hydrocephalus increasing the rate of morbidity and mortality among this group of patients [12]. Angiomyolipomas are the most common renal lesions (~80.0% of cases) in TSC patients. They are typically multiple and bilateral, composed of abnormal blood vessels, immature smooth muscle and fat cells, and progressively enlarge from the first years of life and adolescence. Spontaneous bleeding may occur due to abnormal vasculature and aneurysm development. The size of tumors (AMLs) >4 cm is risk factors for bleeding. Except AMLs, TSC patients have been diagnosed also with multiple renal cysts [13]. Lung involvement, called lymphangioleiomyomatosis (LAM), is characterized by replacement of alveolar tissue by cystic changes and proliferation of the smooth muscle cells in pulmonary parenchyma. This condition is the third most common cause of TSC morbidity, affecting almost exclusively reproductive age females with TSC [14]. Cutaneous manifestations are observed in 90.0% of patients and present the most visible features of TSC. The most common are hypopigmented macules as pathognomonic sign for early diagnosis. Facial angiofibromas are observed in 85.0-90.0% of cases [15].

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