Pflügers Archiv - European Journal of Physiology

, Volume 471, Issue 1, pp 149–163 | Cite as

Hereditary hypophosphatemic rickets with hypercalciuria: pathophysiology, clinical presentation, diagnosis and therapy

  • Clemens BergwitzEmail author
  • Ken-Ichi Miyamoto
Invited Review


Hereditary hypophosphatemic rickets with hypercalciuria (HHRH; OMIM: 241530) is a rare autosomal recessive disorder with an estimated prevalence of 1:250,000 that was originally described by Tieder et al. Individuals with HHRH carry compound-heterozygous or homozygous (comp/hom) loss-of-function mutations in the sodium-phosphate co-transporter NPT2c. These mutations result in the development of urinary phosphate (Pi) wasting and hypophosphatemic rickets, bowing, and short stature, as well as appropriately elevated 1,25(OH)2D levels, which sets this fibroblast growth factor 23 (FGF23)-independent disorder apart from the more common X-linked hypophosphatemia. The elevated 1,25(OH)2D levels in turn result in hypercalciuria due to enhanced intestinal calcium absorption and reduced parathyroid hormone (PTH)-dependent calcium-reabsorption in the distal renal tubules, leading to the development of kidney stones and/or nephrocalcinosis in approximately half of the individuals with HHRH. Even heterozygous NPT2c mutations are frequently associated with isolated hypercalciuria (IH), which increases the risk of kidney stones or nephrocalcinosis threefold in affected individuals compared with the general population. Bone disease is generally absent in individuals with IH, in contrast to those with HHRH. Treatment of HHRH and IH consists of monotherapy with oral Pi supplements, while active vitamin D analogs are contraindicated, mainly because the endogenous 1,25(OH)2D levels are already elevated but also to prevent further worsening of the hypercalciuria. Long-term studies to determine whether oral Pi supplementation alone is sufficient to prevent renal calcifications and bone loss, however, are lacking. It is also unknown how therapy should be monitored, whether secondary hyperparathyroidism can develop, and whether Pi requirements decrease with age, as observed in some FGF23-dependent hypophosphatemic disorders, or whether this can lead to osteoporosis.


Rickets Hypophosphatemia HHRH NPT2c SLC34A3 Osteoporosis Nephrolithiasis Nephrocalcinosis Renal phosphate-wasting Hyperphosphaturia 



We thank Wenzhen Zhao, B.C. candidate for editorial help.

Funding information

This work was in part supported by the Yale O’Brien Center (Pilot grant to C.B., NIH P30DK079310).


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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Section Endocrinology and MetabolismYale University School of MedicineNew HavenUSA
  2. 2.Department of Molecular NutritionTokushima University Graduate School of Biomedical SciencesTokushimaJapan

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