Etiology, Clinical Characteristics, Genetic Profile, and Outcomes of Children with Refractory Rickets at a Referral Center in India: a Cohort Study

Overview

Journal Pediatr Nephrol

Date 2025 Jan 25

PMID 39862309

Authors

Varna Mathew

Bobbity Deepthi

Sudarsan Krishnasamy

Prabhaker Yadav

Madhileti Sravani

Gopalan Suresh Ramprabhu

Girish Chandra Bhatt

Kausik Mandal

Sriram Krishnamurthy

Affiliations

Soon will be listed here.

Abstract

Background: Limited research exists regarding the genetic profile, clinical characteristics, and outcomes of refractory rickets in children from India.

Methods: Patients with refractory rickets aged ≤ 18 years were enrolled. Data regarding clinical features, etiology, genotype-phenotype correlation, and estimated glomerular filtration rate (eGFR) were recorded.

Results: Seventy-two patients with refractory rickets (non-nutritional, with normal kidney function at presentation) from 65 families attending the pediatric nephrology clinic from 2005-2024 were included. Median (IQR) age at first presentation was 2 (1, 4) years. Clinical features included failure-to-thrive (49 [68.1%]), polyuria (37 [51.4%]), nephrocalcinosis (33 [45.8%]), fractures (10 [13.9%]), and hypokalemic paralysis (4 [5.6%]). Major etiologies included distal renal tubular acidosis (dRTA) [34(47.2%)], hereditary hypophosphatemic rickets (11 [15.3%]), cystinosis (9 [12.5%]), Lowe syndrome (3 [4.2%]), vitamin D-dependent rickets (4 [5.5%]), and Fanconi-Bickel syndrome (3 [4.2%]). Next-generation sequencing identified 61 variants among 71 children tested (85.9%), of which 56 variants (among 55 children) were pathogenic (P)/likely-pathogenic (LP) (77.5% diagnostic-yield). P/LP variants included SLC4A1 (n = 14), CTNS (n = 9), PHEX (n = 8), WDR72 (n = 5), OCRL (n = 2), SLC2A2 (n = 3), ATP6V0A4 (n = 4), VDR (n = 3), CLDN16 (n = 2), ATP6V1B1 (n = 1), SLC12A1 (n = 1), CLCN5 (n = 1), SLC34A3 (n = 1), ATP7B (n = 1), and KCNJ1 (n = 1). Fifteen novel P/LP variants and five novel variants-of-uncertain-significance (VUS) were identified. c.2573C > A in exon 19 among SLC4A1-dRTA (n = 14) was a recurrent mutation. Five patients with cystinosis, two patients with SLC4A1-dRTA, two with WDR72-dRTA, and two with Bartter syndrome showed progression to CKD stage 2 or greater during follow-up.

Conclusions: dRTA, X-linked hypophosphatemic rickets, and cystinosis were common causes of refractory rickets. The c.2573C > A variant in exon 19 was a recurrent mutation in SLC4A1-dRTA.

References

Lambert A, Linglart A . Hypocalcaemic and hypophosphatemic rickets. Best Pract Res Clin Endocrinol Metab. 2018; 32(4):455-476. DOI: 10.1016/j.beem.2018.05.009. View

Sabbagh Y, Carpenter T, Demay M . Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc Natl Acad Sci U S A. 2005; 102(27):9637-42. PMC: 1172249. DOI: 10.1073/pnas.0502249102. View

Roizen J, Li D, OLear L, Javaid M, Shaw N, Ebeling P . CYP3A4 mutation causes vitamin D-dependent rickets type 3. J Clin Invest. 2018; 128(5):1913-1918. PMC: 5919884. DOI: 10.1172/JCI98680. View

Haffner D, Leifheit-Nestler M, Grund A, Schnabel D . Rickets guidance: part I-diagnostic workup. Pediatr Nephrol. 2021; 37(9):2013-2036. PMC: 9307538. DOI: 10.1007/s00467-021-05328-w. View

Tavana N, Thilakavathy K, Kennerson M, Ting T . Genetic basis of hereditary hypophosphataemic rickets and phenotype presentation in children and adults. Endokrynol Pol. 2021; 72(4):366-394. DOI: 10.5603/EP.a2021.0062. View

Ma S, Vega-Warner V, Gillies C, Sampson M, Kher V, Sethi S . Whole Exome Sequencing Reveals Novel PHEX Splice Site Mutations in Patients with Hypophosphatemic Rickets. PLoS One. 2015; 10(6):e0130729. PMC: 4479593. DOI: 10.1371/journal.pone.0130729. View

Joshi R, Patil S, Rao S . Clinical and etiological profile of refractory rickets from western India. Indian J Pediatr. 2012; 80(7):565-9. DOI: 10.1007/s12098-012-0900-z. View

Sahay M, Sahay R . Refractory rickets in the tropics. J Pediatr Endocrinol Metab. 2010; 23(6):597-601. DOI: 10.1515/jpem.2010.098. View

Bajpai A, Bardia A, Mantan M, Hari P, Bagga A . Non-azotemic refractory rickets in Indian children. Indian Pediatr. 2005; 42(1):23-30. View

10.

Marik B, Bagga A, Sinha A, Hari P, Sharma A . Genetics of Refractory Rickets: Identification of Novel Mutations in Indian Patients and a Literature Update. J Pediatr Genet. 2018; 7(2):47-59. PMC: 5916800. DOI: 10.1055/s-0038-1624577. View

11.

Dawman L, Tiewsoh K, Barman P, Pratyusha K, Chaakchhuak L, Sharawat I . Phenotype and Genotype Profile of Children with Primary Distal Renal Tubular Acidosis: A 10-Year Experience from a North Indian Teaching Institute. J Pediatr Genet. 2022; 11(3):221-226. PMC: 9385252. DOI: 10.1055/s-0041-1724114. View

12.

Dodamani M, Sehemby M, Memon S, Sarathi V, Lila A, Chapla A . Genotype and phenotypic spectrum of vitamin D dependent rickets type 1A: our experience and systematic review. J Pediatr Endocrinol Metab. 2021; 34(12):1505-1513. DOI: 10.1515/jpem-2021-0403. View

13.

Kanakamani J, Tomar N, Kaushal E, Tandon N, Goswami R . Presence of a deletion mutation (c.716delA) in the ligand binding domain of the vitamin D receptor in an Indian patient with vitamin D-dependent rickets type II. Calcif Tissue Int. 2009; 86(1):33-41. DOI: 10.1007/s00223-009-9310-2. View

14.

Kehar M, Bijarnia S, Ellard S, Houghton J, Saxena R, Verma I . Fanconi-Bickel syndrome - mutation in SLC2A2 gene. Indian J Pediatr. 2014; 81(11):1237-9. PMC: 4353876. DOI: 10.1007/s12098-014-1487-3. View

15.

Bhardwaj S, Thergaonkar R, Sinha A, Hari P, Hi C, Bagga A . Phenotype of Dent Disease in a Cohort of Indian Children. Indian Pediatr. 2016; 53(11):977-982. DOI: 10.1007/s13312-016-0971-4. View

16.

Dayal D, Sharda S, Attri S, Kumar R . Hypophosphatemic rickets caused by a novel PHEX gene mutation in an Indian girl. J Pediatr Endocrinol Metab. 2014; 27(7-8):787-9. DOI: 10.1515/jpem-2013-0270. View

17.

Marik B, Bagga A, Sinha A, Khandelwal P, Hari P, Sharma A . Genetic and clinical profile of patients with hypophosphatemic rickets. Eur J Med Genet. 2022; 65(8):104540. DOI: 10.1016/j.ejmg.2022.104540. View

18.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

19.

Letunic I, Khedkar S, Bork P . SMART: recent updates, new developments and status in 2020. Nucleic Acids Res. 2020; 49(D1):D458-D460. PMC: 7778883. DOI: 10.1093/nar/gkaa937. View

20.

Schultz J, Milpetz F, Bork P, Ponting C . SMART, a simple modular architecture research tool: identification of signaling domains. Proc Natl Acad Sci U S A. 1998; 95(11):5857-64. PMC: 34487. DOI: 10.1073/pnas.95.11.5857. View