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

Abstract

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)D levels, which sets this fibroblast growth factor 23 (FGF23)-independent disorder apart from the more common X-linked hypophosphatemia. The elevated 1,25(OH)D 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)D 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.

Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations

“…It is expressed almost exclusively in the apical membrane of the proximal renal tubule where it is responsible for the regulated reabsorption of filtered phosphate. This function is shared with at least two other sodium dependent phosphate transporters, NaPi-IIc (SLC34A3) and Pit2 (SLC20A2) [4,96]. It has been estimated based on a Slc34a1 KO mouse model that NaPi-IIa mediates about 70 % of the reabsorption of phosphate from the ultrafiltrate [2].…”

“…Mutations in both SLC34A1 and SLC34A3 result in renal phosphate wasting and nephrocalcinosis and -lithiasis, but the clinical pictures differ in that rickets is a major manifestation of SLC34A3 but not SLC34A1 mutations [4].…”

Hypophosphatemic Rickets with Hypercalciuria: A Novel Homozygous Mutation in SLC34A3 and Literature Review

“…The clinical manifestations in bone are highly variable; some patients have no obvious bone abnormality, while others have rickets that can range from mild to severe. It is uncertain what underlies this variation in phenotype (5).…”

Role of sodium‐dependent Pi transporter/Npt2c on Pi homeostasis in klotho knockout mice different properties between juvenile and adult stages

“…The phenotypic differences resulting from NPT2A and NPT2C gene mutations may be due to differential dominance of the transporters involved in Pi homeostasis. In humans, NPT2C mutations cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a primary renal Pi wasting disorder that results in increased serum 1,25-dihydroxy vitamin D3 [1,25(OH) 2 D 3 ] concentrations with associated intestinal Ca 2+ hyperabsorption, hypercalciuria, and rickets/osteomalacia (Bergwitz & Miyamoto, 2019;Bergwitz et al, 2006;Lorenz-Depiereux et al, 2006;Yamamoto et al, 2007). In mice, disruption of Npt2c (Npt2 designate a mouse NaPi-2) causes hypercalciuria and increased serum 1,25(OH) 2 D 3 concentrations, but not hypophosphatemia, rickets, or nephrocalcinosis (Segawa, Onitsuka, Kuwahata, et al, 2009).…”