Objective: To explore the clinical manifestation of a case of hereditary hypophosphataemic rickets with hypercalcuria (HHRH), describe a potentially novel mutation and identify key learning points in the diagnosis and management.
Background: Inherited forms of hypophosphoatameic rickets such as XLH have phosphaturia, often mediated by elevated FGF-23 levels and low or inappropriately normal 1,25 OHD levels. Conversely, in HHRH, loss of function mutations in the SLC34A3 gene, which encode the proximal renal tubule sodium phosphate co-transporter, prevent proximal tubule phosphate re-absorption; the FGF-23 levels are low and the 1,25 Vitamin D levels are elevated, resulting in hypercalciuria. Treatment is with oral phosphate only as active vitamin D is contraindicated due to the risk of nephrocalcinosis.
Case report: A female infant presented at 12 months old with rickets. There was no family history of metabolic bone disease. The co-existing Vitamin D deficiency was corrected. Initial investigations also showed a low phosphate 0.47nmol/l (1.42-1.99mmol/l), normal calcium 2.33mmol/l (2.20-2.60mmol/l), elevated ALP 1140IU/l (142-336iu/l), inappropriately normal PTH 1.9pmol/l (1.5-7.6pmol/l) and an elevated 1,25 OHD 187pmol/l (20-120pmol/l). Further investigations demonstrated phosphate loss (TmP/GFR 0.9mmol/l) (1.15 - 2.44), with an initially reported high FGF-23 1073RU/ml (<100). The urine calcium:creatinine ratio could not be calculated due to a low urine creatinine (urine calcium 1.08, urine creatinine <1). Due to delays in genetic test results, she was presumed to have FGF-23 mediated hypophosphataemic rickets and commenced on oral phosphate and low doses of activated Vitamin D. Subsequently the genetics report demonstrated a homozygous mutation on SLC34A3 gene (NM_080877.2: c.1211G>C p.(Gly404Ala) Location: GRCH37(hg19) Chr:9:140129059) with confirmed biparental inheritance. This has been classed as a variant of uncertain significance until functional mRNA analysis is undertaken. Based on these genetic results alfacalcidol was discontinued. The FGF-23 result was re-visited, which identified, the C-terminal fragment had been measured (which has a longer half-life), rather than the biologically active molecule ‘intact’ FGF-23.
Conclusion: Clues to the diagnosis of HHRH include an elevated urine calcium:creatinine ratio, elevated 1,25 Vitamin D and a normal FGF23. The learning points here include measuring ‘intact’ FGF-23 and not to overlook a urine calcium in the presence of an undetectable urine creatinine. Genetic testing is crucial in the diagnosis of hypophosphataemic rickets to ensure appropriate therapy. This potentially novel mutation is undergoing functional analysis in an effort to further understand the genotype phenotype relationship.
15 Sep 2022 - 17 Sep 2022