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Background <p>Limited research exists regarding the genetic profile, clinical characteristics, and outcomes of refractory rickets in children from India.</p> Methods <p>Patients with refractory rickets aged ≤ 18&#xa0;years were enrolled. Data regarding clinical features, etiology, genotype–phenotype correlation, and estimated glomerular filtration rate (eGFR) were recorded.</p> Results <p>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 <i>SLC4A1</i> (<i>n</i> = 14), <i>CTNS</i> (<i>n</i> = 9), <i>PHEX</i> (<i>n</i> = 8), <i>WDR72</i> (<i>n</i> = 5), <i>OCRL</i> (<i>n</i> = 2), <i>SLC2A2</i> (<i>n</i> = 3), <i>ATP6V0A4</i> (<i>n</i> = 4), <i>VDR</i> (<i>n</i> = 3), <i>CLDN16</i> (<i>n</i> = 2), <i>ATP6V1B1</i> (<i>n</i> = 1), <i>SLC12A1</i> (<i>n</i> = 1)<i>, CLCN5</i> (<i>n</i> = 1), <i>SLC34A3</i> (<i>n</i> = 1), <i>ATP7B</i> (<i>n</i> = 1), and <i>KCNJ1</i> (<i>n</i> = 1). Fifteen novel P/LP variants and five novel variants-of-uncertain-significance (VUS) were identified. c.2573C &gt; A in exon 19 among <i>SLC4A1</i>-dRTA (<i>n</i> = 14) was a recurrent mutation. Five patients with cystinosis, two patients with <i>SLC4A1</i>-dRTA, two with <i>WDR72</i>-dRTA, and two with Bartter syndrome showed progression to CKD stage 2 or greater during follow-up.</p> Conclusions <p>dRTA, X-linked hypophosphatemic rickets, and cystinosis were common causes of refractory rickets. The c.2573C &gt; A variant in exon 19 was a recurrent mutation in <i>SLC4A1</i>-dRTA.</p> Graphical Abstract <p></p>

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Etiology, clinical characteristics, genetic profile, and outcomes of children with refractory rickets at a referral center in India: a cohort study

  • 期刊论文

  • 发表日期：

    2025年1月25日

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  • Varna Mathew,
  • Bobbity Deepthi,
  • Sudarsan Krishnasamy,
  • Prabhaker Yadav,
  • Madhileti Sravani,
  • Gopalan Suresh Ramprabhu,
  • Girish Chandra Bhatt,
  • Kausik Mandal,
  • Sriram Krishnamurthy

摘要

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.

Graphical Abstract