Additionally, we describe a novel mutation in the SLC34AC gene. HHRH is associated with a distinct biochemical profile resulting
from the loss of function of NaPi-IIc. This includes a reduction in P reabsorption in the renal tubules leading to excessive urinary P loss. A low TmP:GFR and plasma P are characteristic of this syndrome which is often associated with an elevated 1,25(OH)2D and consequent hypercalciuria. A raised FGF23 is not a distinguishing feature of this syndrome, however we found elevated FGF23 at first presentation with rickets in 2 out of 3 cases. This may be explained by a chronically low dietary Ca intake and increased 1,25(OH)2D-driven increase in FGF23 as described in the majority of Gambian Ruxolitinib nutritional rickets . Alternatively, this may have been due, in part, to the young age of these children (< 4 y) as we have previously seen that FGF23 tends to decrease throughout childhood (unpublished data). However the FGF23 Z-scores, calculated using local age-matched control children, were high at 2.5 and 1.2. It may also, however, be an indicator of poor iron status leading to an increased expression of the FGF23 gene and a subsequent increase in degradation of the intact FGF23 hormone . However, this possibility cannot be explored in greater detail as
the C-terminal assay and not the Intact FGF23 assay Doramapimod was used to measure FGF23 concentration in this study. Some studies on HHRH cohorts, have shown that heterozygous carriers of the mutation, although asymptomatic, may present with hypercalciuria which puts them at a higher risk of developing nephrocalcinosis . We have shown that all investigated family members had varying
degrees of hypercalciuria with uCa:uCr values ranging from 0.15 to 1.05 mol/mol. However, the presence or absence of nephrocalcinosis could not be determined because of the lack of the availability of renal ultrasound. Additionally, an interesting feature of both the clinically Benzatropine affected and unaffected members of the family is that they are consistently shorter and tended to be heavier than their healthy yet undernourished peers. This may well be a function of their familial environment, or perhaps an additional feature of the mutation. A limitation of this study is that we have only described in silico predictions of the protein containing the novel S168F mutation, located within a highly conserved region, leading to a loss of function of the translated NaPi-IIc protein. Additional mutational analysis is required to determine more detailed effects of this mutation on the protein function and the prevalence of the variant allele needs to be further explored in the general Gambian population. Nevertheless, we have clearly shown that the affected siblings were homozygous in the S168F mutation, whereas the unaffected family members were carriers. In summary, this study presents a novel mutation in the SLC34AC gene causing HHRH.