A New Kindred with Hereditary Hypophosphatemic Rickets with Hypercalciuria: Implications for Correct Diagnosis and Treatment

Abstract

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a new autosomal form of hypophosphatemic rickets, recently described. This disease is characterized, and differs from other forms of hereditary hypophosphatemic rickets and/or osteomalacia by increased serum levels of 1,25-dihydroxyvitamin D, hypercalciuria and complete remission of the disease on phosphate therapy alone. However, only another probable Israeli kindred, and seemingly a few sporadic cases from Europe, North America and Japan have been reported in the literature. We describe here a new kindred of Jewish Yemenite origin (unrelated to other Israeli families) with typical HHRH. Two additional members of this family suffer from a milder asymptomatic form of the disease, which presents as absorptive hypercalciuria without signs or symptoms of bone disease. It seems to us that HHRH is underdiagnosed, due to its similarity to other hypophosphatemic syndromes in clinical, radiological and most biochemical parameters. Therefore, it is recommended that urinary calcium excretion and serum 1,25-di-hydroxyvitamin D concentrations be measured in every patient with hypophosphatemic rickets/and or osteomalacia before the initiation of any therapy. The correct diagnosis of HHRN is of immense therapeutic implications. Phosphate therapy alone could cause a complete remission in HHRH, while the addition of active vitamin D metabolites, as is recommended in hypophosphatemic vitamin D resistant rickets, could cause deterioration in the patient’s condition.

Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities

“…Mice homozygous for the disrupted Npt2 gene have the biochemical features of patients with HHRH (43)(44)(45)(46)(47), yet the bone phenotype is markedly different in the human and mouse disorders. Children with HHRH present with radiological features of rickets, and adult patients with histomorphometric findings that are consistent with osteomalacia, such as irregular mineralization fronts, markedly elevated osteoid surface and seam width, increased number of osteoid lamellae, and prolonged mineralization time (48).…”

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

“…Adults also had weakness, bone pain, fractures, and osteomalacia but they were not short in stature and they did not have any deformity in their lower extremity. 24 Deletion in the exon 9 and 7 have also been reported in SLC34A3. Other types of mutations include silent and donor splice site mutations, and most of the mutations were associated with loss of function in SLC34A3 protein.…”

“…In comparison with other types of rickets, patients affected by HHRH exhibit an increase in serum 1,25(OH)2D. 23,24 Therefore, this biochemical feature can be used as a differential diagnosis of HHRH from other types of hypophosphatemia. Moreover, elevated levels of 1,25OH 2 D 3 are accompanied by hypercalciuria and suppression of PTH secretion.…”

“…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.…”

Hypophosphatemic rickets and osteomalacia

“…The hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive disease characterized by hypophosphatemia, hyperphosphaturia, normal PTH serum levels and increased plasma levels of 1,25(OH) 2 Vitamin D 3 , that is responsible for hypercalciuria (2,18). The increased plasma levels of 1,25(OH) 2 VitaminD 3 and the hypercalciuria distinguish the HHRH from the other causes of hypophosphatemic rickets.…”