Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/NaPi-IIc can be masked by vitamin D deficiency and can be associated with renal calcifications

Abstract

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by mutations in SLC34A3, the gene encoding the renal sodium-phosphate co-transporter NaPi-IIc. Despite increased urinary calcium excretion, HHRH is typically not associated with kidney stones prior to treatment. However, here we describe two sisters, who displayed nephrolithiasis or nephrocalcinosis upon presentation. The index patient, II-4, presented with short stature, bone pain, and knee X-rays suggestive of mild rickets at age 8.5 years. Laboratory evaluation showed hypophosphatemia, elevated 1,25(OH) (2) vitamin D levels, and hypercalciuria, later also developing vitamin D deficiency. Her sister, II-6, had a low normal serum phosphorous level, biochemically vitamin D deficiency and no evidence for osteomalacia, but had undergone left nephro-ureterectomy at age 17 because of ureteral stricture secondary to renal calculi. Nucleotide sequence analysis of DNA from II-4 and II-6 revealed a homozygous missense mutation c.586G>A (p.G196R) in SLC34A3/NaPi-IIc. Ultrasonographic examinations prior to treatment showed grade I nephrocalcinosis for II-4, while II-6 had grade I-II nephrocalcinosis in her remaining kidney. Four siblings and the mother were heterozygous carriers of the mutation, but showed no biochemical abnormalities. With oral phosphate supplements, hypophosphatemia and hypercalciuria improved in both homozygous individuals. Renal calcifications that are presumably due to increased urinary calcium excretion can be the presenting finding in homozygous carriers of G196R in SLC34A3/NaPi-IIc, and some or all laboratory features of HHRH may be masked by vitamin D deficiency.

Fig. 1

Haplotype analysis of the kindred. A: Pedigree: Solid circles or squares indicate individuals, who developed rickets during childhood along with renal phosphate-wasting, hypophosphatemia, and hypercalciuria. Open symbols indicate individuals who were healthy. Samples from individuals with dashed lines were unavailable for genotyping. B: Haplotypes for chromosomal region 9q34 between markers D9S1826 and D9S1838. Alleles for microsatellite markers are designated as bp or coded; the haplotype associated with HHRH is depicted by numbers on gray background. The father’s haplotype is deduced (numbers in italic), no genotyping data are available for II-10; the mutation c.586G>A(p.G196R) was identified by nucleotide sequencing analysis and confirmed on at least two independent PCR products. Clinical and biochemical parameters of the available family members are prior to therapy. Age-related reference ranges in brackets. n.d. = not done.

Fig. 2

Ultrasound of the left kidney and X-rays of individual II-4 homozygous for the G196R mutation. Panels a to e show the renal ultrasound (a: age 8; 10 years, b: age 9; 8 years, c: age 10; 9 years, d: age 11; 5 years, e: age 12; 2 years). Panel a was taken before initiation of therapy and demonstrates slight nephrocalcinosis corresponding to grade I, nephrocalcinosis worsens slightly in due course to grade IIa (panels b to e). Panel f demonstrates the X-ray of the hand before therapy (age 8; 5 years) with a bone age of 6; 6 years (Greulich and Pyle) and shows slight flaring and mild osteopenia apart from brachymesophalangia. Panel g shows the X-ray of the right knee (age 11; 5 years) with epiphyseal flaring, numerous transverse striations in the metaphysis and Erlenmeyer flask deformities in the metaphysic.

Fig. 3

Ultrasound and X-ray of individual II-6. Panel a shows the X-ray of the left hand at age 25 years with cortical thickening and ulnar deviation in the interphalangeal joints Dig II and III. Panel b depicts the ultrasound of the remaining right kidney at age 25 years before initiation of therapy, showing slight medullary nephrocalcinosis. Panel c demonstrates the ultrasound of the right kidney after 2 months of therapy with phosphorus continuing to show medullary nephrocalcinosis.