Rickets is a common condition in children due to defective mineralization of growing bone caused by a deficiency or impaired metabolism of vitamin D, phosphorus, or calcium leading to bony deformities and stunted growth in children. While assessment of serum calcium, inorganic phosphorus, alkaline phosphatase, parathyroid hormone, 1,25-dihydroxy vitamin D [1,25(OH)2D], and urinary excretion of calcium and phosphate helps in classifying and managing rickets, genetic evaluation is often needed in a subset of patients for appropriate management. Underlying genetic etiology can be either pure monogenic rickets or secondary to renal tubular dysfunction due to inherited metabolic conditions such as hereditary tyrosinemia 1 or Fanconi-Bickel syndrome. Monogenic or genetic rickets could be vitamin D-dependent rickets (VDDR) or hypophosphatemic rickets (HR), the latter being either FGF23-dependent or FGF23-independent. Depending upon the type of inheritance, genetic rickets occurs due to mono or biallelic variants in either of 20 genes (such as PHEX, FGF23, DMP1, ENPP1, SLC34A3, SLC34A1, SLC9A3R1, CLCN5, OCRL1, FGFR1, FAM20C for hypophosphatemic rickets and CYP27B1, CYP2R1, CYP3A4, VDR for vitamin D-dependent rickets). In this issue of the journal, Jacob et al. have studied 10 families with monogenic rickets at different ages with varying phenotypic severity across various genetic etiologies [1].

Beck-Nielsen et al., reported the contribution of genetic causes of rickets to be about 13% in the pre-genomic era [2]. However, the contribution of genetic causes has increased over a period with the discovery of novel genes by next-generation sequencing. One such example includes SGK3, a novel renal phosphate transport regulator associated with autosomal dominant hypophosphatemic rickets [3]. Another newly described condition includes autosomal dominant renal Fanconi syndrome and kidney failure due to partial glycine amidinotransferase (GATM) deficiency, a disorder of creatine metabolism without any neurological involvement [4]. Interestingly, digenic inheritance has also been reported in a family that harbored monoallelic SLC34A3 and SLC34A1 variants associated with hereditary hypophosphatemic rickets with hypercalciuria [5]. Although inactivating biallelic variants found in the DNA binding domain (DBD) implicate a severe phenotype in autosomal recessive vitamin D-dependent rickets type 2A (VDDR2A) [6], the genotype-phenotype correlation is not elusive for genetic rickets. Jacob et al. found a homozygous Arg391Cys variant in the C-terminal ligand-binding domain (LBD) yet with a severe phenotype due to poor vitamin D responsive element (VDRE) binding in vivo and reduced transactivation [1].

As nutritional and genetic rickets are clinically indistinguishable, the presence of consanguinity, a positive family history, and other systemic features should be actively looked for. Poor response to vitamin D therapy is another important clue. The presence of these clues in a patient with rickets warrants genetic testing using exome sequencing for early diagnosis, initiation of specific therapy, and genetic counseling.