Late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH) due to mutation of SLC34A3/NPT2c

Abstract

Objective To identify a genetic basis for markedly reduced bone density and multiple fractures in an adult patient with hypophosphatemia and hypercalciuria. Subjects A 54-year-old Vietnamese man, his unaffected two daughters and wife. Methods We performed biochemical studies and sequenced the SLC34A3 gene using genomic DNA from peripheral blood mononuclear cells. Results Biochemical evaluation of the proband revealed hypophosphatemia with increased renal phosphate wasting, hypercalciuria, low serum parathyroid hormone (PTH) and an elevated serum 1,25(OH)2D level. Mutation analysis of SLC34A3 gene revealed that the patient was a compound heterozygote for two nonsynonymous nucleotide substitutions: a novel c.571G>A (p.G191S) damaging mutation and the previously reported c.200G>A (p.R67H) polymorphism, consistent with the clinical diagnosis of late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH). His wife and older daughter both carried the p.R67H polymorphism, while his younger daughter was compound heterozygous for p.R67H and p.G191S. Conclusions HHRH is an uncommon autosomal recessive disease that generally manifests in childhood as rickets or nephrolithiasis, but an adult onset phenotype may occur in heterozygous carriers of SLC34A3 mutations. The severe presentation of this proband in adulthood with marked nephrolithiasis, multiple fractures and low bone density emphasizes the importance of measuring the serum phosphorus level in patients with suspected but unexplained osteoporosis and/or recurrent renal stones. The recognition of late-onset HHRH facilitates timely institution of appropriate therapy.

Rare, genetically conditioned forms of rickets: Differential diagnosis and advances in diagnostics and treatment

“…The group of hypophosphatemic rickets related to a primary kidney pathology includes hereditary hypophosphatemic rickets with hypercalciuria (HHRH, OMIM #241530), related to a mutation with loss of function of the solute carrier family 34 member 3 (SLC34A3) gene (locus 9q34), encoding a protein of the renal NaPi-IIc co-transporter. Clinical symptoms include nephrocalcinosis and nephrolithiasis 27. A mutation of another gene for the sodium-phosphate transporter-solute carrier family 34 member 1 (SLC34A1) (locus 5q35)-in turn follows the autosomal dominant inheritance pattern and is responsible for the occurrence of NPHLOP1(OMIM #612286) syndrome that is characterised by coexistence of nephrolithiasis, osteoporosis and hypophosphatemic rickets.…”

Personalized Intervention in Monogenic Stone Formers

“…Despite the “rickets” designation, late adult onset of HHRH with osteomalacia and recurrent stones was recently reported. 27 A likely heterozygous individual was successfully treated with phosphate, and the authors surmised that heterozygous HHRH may be an overlooked cause of idiopathic low bone density and hypercalciuria.…”

“…27,28 Phosphate supplementation is also effective in treating IIH due to SLC34A1 . While further study is needed to determine if forme frustes of HHRH and IIH are prevalent in the general population of stone formers, a trial of phosphate therapy might be considered for those observed to have a mutation and increased 1,25(OH)2D.…”

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

“…As a result, they contribute to diminished phosphate reabsorption in patients with HHRH. 7,26,27 The inheritance pattern of this disorder is autosomal recessive and biallelic mutation is essential for clinical manifestation. However, familial studies revealed that single mutations could also cause some clinical symptoms of HHRH.…”

“…27 Hypercalciuria, which is present in these patients, increases the risk of nephrolithiasis. 24,26 It is interesting to note that Napi-2a cannot compensate for Napi-2c, while both cotransporters act as a modulator of phosphate reabsorption. The reason for this discrepancy is the transient expression of these 2 factors during development.…”