Review of Childhood Genetic Nephrolithiasis and Nephrocalcinosis

Overview

Journal Front Genet

Date 2024 Apr 12

PMID 38606357

Authors

Ashley M Gefen

Joshua J Zaritsky

Affiliations

Soon will be listed here.

Abstract

Nephrolithiasis (NL) is a common condition worldwide. The incidence of NL and nephrocalcinosis (NC) has been increasing, along with their associated morbidity and economic burden. The etiology of NL and NC is multifactorial and includes both environmental components and genetic components, with multiple studies showing high heritability. Causative gene variants have been detected in up to 32% of children with NL and NC. Children with NL and NC are genotypically heterogenous, but often phenotypically relatively homogenous, and there are subsequently little data on the predictors of genetic childhood NL and NC. Most genetic diseases associated with NL and NC are secondary to hypercalciuria, including those secondary to hypercalcemia, renal phosphate wasting, renal magnesium wasting, distal renal tubular acidosis (RTA), proximal tubulopathies, mixed or variable tubulopathies, Bartter syndrome, hyperaldosteronism and pseudohyperaldosteronism, and hyperparathyroidism and hypoparathyroidism. The remaining minority of genetic diseases associated with NL and NC are secondary to hyperoxaluria, cystinuria, hyperuricosuria, xanthinuria, other metabolic disorders, and multifactorial etiologies. Genome-wide association studies (GWAS) in adults have identified multiple polygenic traits associated with NL and NC, often involving genes that are involved in calcium, phosphorus, magnesium, and vitamin D homeostasis. Compared to adults, there is a relative paucity of studies in children with NL and NC. This review aims to focus on the genetic component of NL and NC in children.

Citing Articles

Opportunities in Primary and Enteric Hyperoxaluria at the Cross-Roads Between the Clinic and Laboratory.

Cellini B, Baum M, Frishberg Y, Groothoff J, Harris P, Hulton S Kidney Int Rep. 2024; 9(11):3083-3096.

PMID: 39534212 PMC: 11551133. DOI: 10.1016/j.ekir.2024.08.031.

References

Hayes W, Sas D, Magen D, Shasha-Lavsky H, Michael M, Sellier-Leclerc A . Efficacy and safety of lumasiran for infants and young children with primary hyperoxaluria type 1: 12-month analysis of the phase 3 ILLUMINATE-B trial. Pediatr Nephrol. 2022; 38(4):1075-1086. PMC: 9925547. DOI: 10.1007/s00467-022-05684-1. View

Knoll T, Zollner A, Wendt-Nordahl G, Michel M, Alken P . Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and follow-up. Pediatr Nephrol. 2004; 20(1):19-24. DOI: 10.1007/s00467-004-1663-1. View

Mabillard H, Sayer J . The Molecular Genetics of Gordon Syndrome. Genes (Basel). 2019; 10(12). PMC: 6947027. DOI: 10.3390/genes10120986. View

Rhodes H, Yarram-Smith L, Rice S, Tabaksert A, Edwards N, Hartley A . Clinical and genetic analysis of patients with cystinuria in the United Kingdom. Clin J Am Soc Nephrol. 2015; 10(7):1235-45. PMC: 4491297. DOI: 10.2215/CJN.10981114. View

Jayasinghe K, Stark Z, Kerr P, Gaff C, Martyn M, Whitlam J . Clinical impact of genomic testing in patients with suspected monogenic kidney disease. Genet Med. 2020; 23(1):183-191. PMC: 7790755. DOI: 10.1038/s41436-020-00963-4. View

Mittal K, Anandpara K, Dey A, Sharma R, Thakkar H, Hira P . An Association of Chronic Hyperaldosteronism with Medullary Nephrocalcinosis. Pol J Radiol. 2015; 80:417-24. PMC: 4564071. DOI: 10.12659/PJR.894674. View

Karim Z, Gerard B, Bakouh N, Alili R, Leroy C, Beck L . NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med. 2008; 359(11):1128-35. DOI: 10.1056/NEJMoa0802836. View

Zikanova M, Wahezi D, Hay A, Stiburkova B, Pitts 3rd C, Musalkova D . Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females. Rheumatology (Oxford). 2018; 57(7):1180-1185. PMC: 6232955. DOI: 10.1093/rheumatology/key041. View

De Vries A, Kochwa S, LAZEBNIK J, Frank M, Djaldetti M . Glycinuria, a hereditary disorder associated with nephrolithiasis. Am J Med. 1957; 23(3):408-15. DOI: 10.1016/0002-9343(57)90320-0. View

10.

Monico C, Rossetti S, Belostotsky R, Cogal A, Herges R, Seide B . Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clin J Am Soc Nephrol. 2011; 6(9):2289-95. PMC: 3358997. DOI: 10.2215/CJN.02760311. View

11.

Gee H, Jun I, Braun D, Lawson J, Halbritter J, Shril S . Mutations in SLC26A1 Cause Nephrolithiasis. Am J Hum Genet. 2016; 98(6):1228-1234. PMC: 4908148. DOI: 10.1016/j.ajhg.2016.03.026. View

12.

Maxit C, Denzler I, Marchione D, Agosta G, Koster J, Wanders R . Novel PEX3 Gene Mutations Resulting in a Moderate Zellweger Spectrum Disorder. JIMD Rep. 2016; 34:71-75. PMC: 5509555. DOI: 10.1007/8904_2016_10. View

13.

Pitt J, Willis F, Tzanakos N, Belostotsky R, Frishberg Y . 4-hydroxyglutamate is a biomarker for primary hyperoxaluria type 3. JIMD Rep. 2014; 15:1-6. PMC: 4270872. DOI: 10.1007/8904_2013_291. View

14.

Johannes L, Fu C, Schwarz G . Molybdenum Cofactor Deficiency in Humans. Molecules. 2022; 27(20). PMC: 9607355. DOI: 10.3390/molecules27206896. View

15.

AlAzami A, Al-Qattan S, Faqeih E, Alhashem A, Alshammari M, Alzahrani F . Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue. Hum Genet. 2016; 135(5):525-540. DOI: 10.1007/s00439-016-1660-z. View

16.

Kaiyrzhanov R, Rocca C, Suri M, Gulieva S, Zaki M, Henig N . Biallelic loss of EMC10 leads to mild to severe intellectual disability. Ann Clin Transl Neurol. 2022; 9(7):1080-1089. PMC: 9268894. DOI: 10.1002/acn3.51602. View

17.

Nitschke Y, Baujat G, Botschen U, Wittkampf T, du Moulin M, Stella J . Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet. 2012; 90(1):25-39. PMC: 3257960. DOI: 10.1016/j.ajhg.2011.11.020. View

18.

Urabe Y, Tanikawa C, Takahashi A, Okada Y, Morizono T, Tsunoda T . A genome-wide association study of nephrolithiasis in the Japanese population identifies novel susceptible Loci at 5q35.3, 7p14.3, and 13q14.1. PLoS Genet. 2012; 8(3):e1002541. PMC: 3291538. DOI: 10.1371/journal.pgen.1002541. View

19.

Prie D, Huart V, Bakouh N, Planelles G, Dellis O, Gerard B . Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med. 2002; 347(13):983-91. DOI: 10.1056/NEJMoa020028. View

20.

AlAzami A, Patel N, Shamseldin H, Anazi S, Al-Dosari M, Alzahrani F . Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 2015; 10(2):148-61. DOI: 10.1016/j.celrep.2014.12.015. View