CLINICAL CHARACTERISTICS, GENETIC PROFILE AND OUTCOMES OF CHILDREN WITH NON-AZOTEMIC REFRACTORY RICKETS: A COHORT STUDY

Introduction:

Refractory rickets is a form of rickets encompassing varied genetic etiologies, broadly classified as phosphopenic or calcipenic. There is paucity of information on diseases causing non-azotemic refractory rickets from India, as well as their genetic profile and outcomes.  

Methods:

Children aged less than 18 years, diagnosed with non-azotemic refractory rickets and attending the pediatric nephrology clinic were enrolled and data on clinical features, consanguinity, underlying etiology, genetic profile, and follow-up data including estimated glomerular filtration rate (eGFR) were noted. Genotype-phenotype correlation was attempted. 

Results:

This cohort study included 72 patients with non-azotemic refractory rickets from 66 families. The median (IQR) age at first presentation was 2 (1, 4) years. Symptoms 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 %)]. 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 [3 (4.2%)], Fanconi-Bickel syndrome [3 (4.2%)], Bartter syndrome [2 (2.8%)], Dent disease [2 (2.8%)], familial hypomagnesemia with hypercalciuria and nephrocalcinosis [2 (2.8%)], tyrosinemia type 1 [1 (1.4%)] and Fanconi renotubular syndrome type 2 [1 (1.4%). Next generation sequencing identified 61 variants among 71 children tested (85.9%), out of which 56 variants (among 55 children) were pathogenic/ likely pathogenic (77.5% diagnostic yield). Pathogenic/likely pathogenic variants were noted in 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) (Figure 1). A total of 15 novel pathogenic/ likely pathogenic variants; and 5 novel variants of uncertain significance were identified. The c.2573C>A variant in exon 19 of SLC4A1 gene was a mutational hotspot in dRTA with south East Asian ovalocytosis. The cohort was followed up for a median (IQR) duration of 2 (1.5, 5) years and a total of 11 (15.3%) children progressed to CKD stage 2 or greater by the last follow-up.  

Conclusions:

dRTA, X-linked hypophosphatemic rickets and cystinosis were the commonest causes of non-azotemic refractory rickets. A significant number of children with non-azotemic refractory rickets (15.3%) experienced decline in eGFR on follow-up

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.