Familial tuberous sclerosis (ORPHA:805) due to a previously undescribed mutation of the TSC2 gene (literature data and clinical observation

BACKGROUND. Tuberous sclerosis is an orphan systemic disease with an autosomal dominant inheritance characterized by the formation of tumor–like benign nodular hamartomas with lesions of the skin, nervous system, retina, kidneys, heart, and lungs. In 50–70 % of children and adolescents with tuberous sclerosis, the renal phenotype is more often diagnosed in the form of angiomyelitis and kidney parenchymal cysts. The presence of kidney damage complicates the course and prognosis of tuberous sclerosis due to the risk of acute kidney injury and the progression of chronic kidney disease.
OBJECTIVE: To describe familial tuberous sclerosis (ORPHA:805) due to a pathogenic mutation of the TSC2 gene with an autosomal dominant type of inheritance.
PATIENTS AND METHODS. The features of the clinical phenotype and genotype of tuberous sclerosis in a 16–year-old proband girl and her 45-year-old male father are described. Genealogical, clinical, imaging, functional, and molecular genetic research methods have been applied. The molecular genetic research method was performed in the laboratory of molecular pathology of the medical and genetic center of Genomed.
RESULTS. A 16-year–old patient was diagnosed with tuberous sclerosis at an early age in the presence of 2 major criteria (1. rhabdomyoma of the heart prenatally and at birth, 2. cortical tubers of the frontal and parietal regions, foci of calcification in the cerebellum, decreased hypocampus manifested by delayed speech development and epilepsy with atonic and generalized tonic-clonic seizures in infancy and early age). Manifestations of the renal phenotype (increased kidney volume and parenchymal cysts) They were detected at the age of 6 years, liver angiomyolipomas were noted at the age of 8, and kidneys at the age of 16. A molecular genetic study identified a pathogenic mutation of the TSC2 gene in the proband (c.1052AG, p.Lys351Arg). The renal function in proband at the age of 16 years corresponds to stage 2 of chronic kidney disease (GFR 84ml/min/1.73 m2). A similar mutation was detected in Proband's father, who has a normal glomerular filtration rate (134ml/min/1.73 m2), a single kidney cyst, tuberous sclerosis was diagnosed at the age of 45 according to 2 major criteria (3 periarticular fibroids and 3 hypopigmented spots over 5 mm on the skin).
СONCLUSION. The features of the clinical phenotype of familial orphan tuberous sclerosis due to a previously undescribed mutation of the TSC2 gene in a proband girl and father are described.

1. Caliment A, Van Reeth O, Hougardy Ch et al. A step – by – step, multidisciplinary strategy to maximize the yield of genetic testing in pediatric patients with chronic kidney diseases. Pediatr Nephrol 2024;39(9):2733–2740. doi: 10.1007/s00467-024-06299-4

2. Ziegler WH, Lüdiger S, Hassan F et al. Primary URECs: a source to better understand the pathology of renal tubular epithelia in pediatric hereditary cystic kidney diseases [Электронный ресурс] Orphanet J Rare Dis 2022;17(1):122. Режим доступа: https://pubmed.ncbi.nlm.nih.gov/35264234/

3. The portal for rare diseases and orphan drugs [Электронный ресурс]. Режим доступа: https://www.orpha.net

4. Международная классификация болезней 10-го пересмотра [Электронный ресурс]. Режим доступа: http:// mkb– 10.com/index.php?pid=16627

5. Dorofeeva MU, Belousova ED, Pivovarova A, and others. The first results of the functioning of the Registry of patients with tuberous sclerosis. Russian Bulletin of Perinatology and Pediatrics 2015;60(5):113–120 (In Russ.)

6. Torres VE, Harris PC. Cystic diseases of the kidney. In: BM Brenner (Ed.). The kidney (10 th ed.). Philadelphia: WB Saunders, 2016. [Электронный ресурс]. Режим доступа: https://abdominalkey.com/cystic-diseases-of-the-kidneys/

7. Hereditary kidney diseases in children. Guidelines for Doctors, ed. N. D. Savenkova. Levsha, Saint Petersburg, 2020, 440 с. (In Russ.)

8. Morozov SL, Piruzieva OR, Dorofeeva MU and others. Kidney angiomyolipomas in children with tuberous sclerosis – the current state of the problem. Practical medicine 2022;20(2):45–49 (In Russ.)] doi: 10.32000/2072-1757-2022-2-45-49

9. Andreeva EF, Savenkova ND. Kidney cysts in tuberous sclerosis in infants. Russian Bulletin of Perinatology and Pediatrics 2018;63(1):100–105 (In Russ.)] doi:10.21508/1027-4065-2018-63-1-100-105

10. Jóźwiak S, Sadowski K, Borkowska J et al. Liver angiomyolipomas in tuberous sclerosis complex-their incidence and course. Pediatr Neurol 2018;78:20–26. doi: 10.1016/j.pediatrneurol.2017.09.012

11. Ritter DM, Fessler BK, Ebrahimi-Fakhari D. et al. Prevalence of thoracoabdominal imaging findings in tuberous sclerosis complex. Orphanet J Rare Dis 2022;17(1):124. doi: 10.1186/s13023-022-02277-x

12. The national сenter for biotechnology information (NCBI) [Электронный ресурс] режим доступа: https://www.ncbi.nlm.nih.gov

13. The genome aggregation database (gnomAD) [Электронный ресурс] режим доступа: http://gnomad-sg.org

14. DTreePred: an online viewer based on machine learning for pathogenicity prediction of genomic variants [Электронный ресурс] режим доступа: https://bioinfo.imd.ufrn.br/dtreepred/

15. Dabora SL, Roberts P, Nieto A et al. Association between a high-expressing interferon-gamma allele and a lower frequency of kidney angiomyolipomas in TSC2 patients. Am J Hum Genet 2002;71(4):750–758. doi: 10.1086/342718

16. Limavady A, Marlais M. Nutritional status as a predictive factor for paediatric tuberous sclerosis complex-associated kidney angiomyolipomas: a retrospective analysis. Eur J Pediatr 2024;183(6):2563–2570. doi: 10.1007/s00431-024-05520-8