A Clinical and Molecular Genetic Study of Hypophosphatemic Rickets in Children

Abstract

X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets, hereditary hypophosphatemic rickets with hypercalciuria, and tumor-induced osteomalacia share clinical and biochemical features, and are collectively referred to as hypophosphatemic rickets (HR). Recently, the molecular bases of HR were elucidated. A review of medical records and mutational analyses of the PHEX and FGF23 genes were performed on 17 unrelated Korean children with HR. The male-to-female ratio was 3:14, and 5 patients were familial. Initial laboratory tests revealed typical features of HR. Seven different PHEX mutations were detected in 8 patients: 2 missense mutations, 2 nonsense mutations, and 3 short deletions. No functional FGF23 mutation was detected in any patient. Patients with the PHEX mutation tended to have more severe skeletal disease than those without. Of the patients with this mutation, no genotype-phenotype correlation and no gene dosage effect were noted. Treatment with vitamin D and phosphate resulted in only a partial growth improvement in most cases, and was frequently complicated by hypercalciuria, hypercalcemia, nephrocalcinosis, or hyperparathyroidism. Renal glycosuria was detected in six cases and was associated with more severe skeletal disease. We conclude that current HR treatment is not fully safe or effective, and that close monitoring of treatment effectiveness and for complications should be performed during long-term treatment.No genotype-phenotype correlation in XLH was detected in this study, but a large-scaled study on this topic is warranted. The large proportion of patients with a normal genetic study suggests the possibility of other causative gene(s HR is defined as a group of rachitic bone diseases associated with chronic hypophosphatemia, which results from defects in the renal tubular reabsorption of filtered phosphate (1-8). Clinically, XLH, ADHR, HHRH, and TIO can be categorized as HR (1-8).XLH is the most common form of hereditary HR (2-6) and is caused by loss-of-function mutations in the PHEX gene (phosphate regulating gene with homologies to endopeptidases on the X chromosome). On the other hand, ADHR is far less common than XLH (2-6), and is associated with a gain-offunction mutation in the FGF23 gene encoding FGF23. The mutant FGF23 molecule is resistant inactivation by proteolytic cleavage (2,(5)(6)(7)(8)(9)(10)(11)(12). Moreover, TIO is an acquired form of HR, which is caused by a variety of benign primitive mesenchymal tumors that secrete FGF23 (2,7,13). HHRH is a rare hereditary disease and its underlying pathogenesis remains to be elucidated.Several studies of the molecular defects in XLH, ADHR, and TIO support a model of a common pathogenetic mechanism in these three diseases (2,6,14). In this model, FGF23 has been suggested to be the main circulating phosphaturic factor (2,6,14), and the circulating level of FGF23 is determined in part by the rate of its proteolytic cleavage by PHEX protease (9,13,15). The common abnormality shared by loss-of-function mutation...

Comparative study of children with calciopaenic and phosphopaenic rickets seen at Chris Hani Baragwanath Hospital

“…These findings are similar to studies from the Republic of Korea and north India, 5,12 which found a greater number of female patients (82% and 70.5% respectively) than male patients with hypophosphataemic rickets. In these studies, a positive family history was noted in 29% and 35.3% respectively.…”

Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets

“…The overall median detection rate of gene mutations reported in previous studies comprising 15 or more HR probands was 66% (range 43-100%), 20,[27][28][29][30][31][32][37][38][39][40][41] in familial probands 66% (44-100%), and in sporadic probands the detection rate was 50% (29-100%). 20,[27][28][29][30]32,37,38 In our study, the MLPA analysis added three PHEX mutations not identified by PCR, dHPLC or sequencing, thus increasing our overall detection rate from 78 to 88%, in familial probands from 67 to 83% and in sporadic probands from 83 to 92%. Our high detection rate of gene mutations, especially among the sporadic patients, may also be due to the robust inclusion/ exclusion criteria of this study.…”

Hypophosphatemic rickets and osteomalacia

“…In XHR, hyperphosphaturia derives from mutations in the PHEX gene (Phosphate regulating gene with homologies to Endopeptidases on the X-chromossome) (1)(2)(3)(13)(14)(15)(16). This gene, whose locus is Xp22.1, encodes a membrane endopeptidase (Znmetaloprotease), called Phex, mainly expressed in bone and teeth.…”

“…HR comprises a set of disorders, inherited and acquired, that shares a common pathophysiology: diminished phosphate reabsorption in renal tubules (3,(13)(14)(15). This process, established by an impaired phosphorus renal handling, leads to chronic hyperphosphaturia and hypophosphatemia, which are associated to unsuitable normal or low levels of 1,25(OH) 2 VitaminD 3.…”

“…Although these diseases have different etiopathogenies, biochemical and molecular evidences point to a common pathophysiological basis: increased activity of a phosphaturic factor (2,(13)(14)(15). There are some other bone diseases associated with phosphaturic imbalance, such as hereditary hypophosphatemic rickets with hipercalcemia (HHRH) and McCune Albright Syndrome (3).…”