Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation

Abstract

Phosphorous is essential for multiple cellular functions and constitutes an important mineral in bone. Hypophosphatemia in children leads to rickets resulting in abnormal growth and often skeletal deformities. Among various causes of low serum phosphorous are inherited disorders associated with increased urinary excretion of phosphate, including autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemia (XLH), autosomal recessive hypophosphatemia (ARHP), and hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Recent genetic analyses and subsequent biochemical and animal studies have revealed several novel molecules that appear to play key roles in the regulation of renal phosphate handling. These include a protein with abundant expression in bone, fibroblast growth factor 23 (FGF23), which has proven to be a circulating hormone that inhibits tubular reabsorption of phosphate in the kidney. Two other bone-specific proteins, PHEX and dentin matrix protein 1 (DMP1), appear to be necessary for limiting the expression of fibroblast growth factor 23, thereby allowing sufficient renal conservation of phosphate. This review focuses on the clinical, biochemical, and genetic features of inherited hypophosphatemic disorders, and presents the current understanding of hormonal and molecular mechanisms that govern phosphorous homeostasis.

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

“…7,8 XLHR, ADHR, ARHR1 and ARHR2 share identical biochemical characteristics of excessive renal phosphate wasting and low-serum phosphate associated with elevated levels of serum FGF23 and accompanied by inappropriately low serum 1,25-dihydroxyvitamin D (1,25(OH) 2 D). 8,9 Two types of HR differ biochemically from the four described types, as they are characterised by hypercalciuria: Hereditary HR with hypercalciuria (HHRH; MIM 241530), where the hypercalciuria is due to increased serum 1,25(OH) 2 D. The inheritance is autosomal recessive and the disease is caused by a mutation in the sodium-cotransporter gene (SLC34A3; MIM 609826), identified in 2006. 10,11 The second type is X-linked recessive HR (MIM 300554), characterised by proximal renal tubulopathy and Fanconi syndrome caused by a mutation in the gene coding for the chloride channel 5 (CLCN5; MIM 300008).…”

“…[15][16][17] In the HR types characterised by hypercalciuria, treatment is oral phosphate supplementation alone. 9 The aim of this study was to identify the underlying genetic mutation in patients with HR by use of the traditional methods of genetic analysis and in addition the recently introduced MLPA method. The finding of a genetic diagnosis enables genetic counselling and early diagnosis ensures early treatment of affected offspring.…”

Common Genetic Variants Associate with Serum Phosphorus Concentration

“…Rare phosphorus wasting disorders, such as hypophosphatemic rickets, are caused by specific mutations in genes within phosphorus metabolic pathways. 9,10 Genetic disruption of hormones that regulate phosphorus alters circulating phosphorus concentrations in animal models. 11,12 Moreover, dietary phosphorus intake is only weakly associated with the serum phosphorus concentration in humans.…”

Monogenic Phosphate Balance Disorders

“…The gene is expressed in a wide variety of tissues including the kidney with a higher expression in mature osteoblasts and odontoblasts. The substrate for the gene product is not known, but the pathogenesis seems to involve phosphate regulating humoral factors, phosphatonins, where the fibroblast growth factor-23 (FGFR-23) is central (Jonsson, Zahradnik et al 2003;Juppner 2007;Bastepe and Juppner 2008).…”

“…The most common clinical manifestations include genu varus, radiological rickets, short stature, bone pain, dental abscesses and calcification of tendons, ligaments and joint capsules with boys being more severely affected than girls and a wide variation between families (Econs, Samsa et al 1994;Carpenter 1997;Bastepe and Juppner 2008). Some patients may even have craniosynosteosis and spinal stenosis.…”