rickets is a common condition in children that occurs due to a defect in bone mineralization which leads to abnormalities of growth plate cartilage that are predominantly observed in long bones . it may occur due to deficiency of calcium , phosphorous , or vitamin d. the equivalent in adults is a generalized softening of the skeleton due to defective mineralization , known as osteomalacia . it prevents apoptosis in the hypertrophic cells in the growth plate . in the absence of apoptosis , the hypertrophic cells accumulate in the growth plate and form the rachitic bone . in calcipenic rickets , phosphaturia leading to hypophosphatemia occurs due to secondary hyperparathyroidism . in phosphopenic rickets ( hypophosphatemic rickets ) , phosphate deficiency is the primary defect that results most commonly from increased renal excretion of phosphate . classification of rickets ( adhr : autosomal dominant hypophosphatemic rickets , arhr : autosomal recessive hypophosphatemic rickets , ens : epidermal nevus syndrome , fgf23 : fibroblast growth factor 23 , fs : fanconi syndrome , hhrh : hypophosphatemic rickets with hypercalciuria , npt2a : sodium phosphate cotransporter 2a , nherf1 : sodium hydrogen exchange regulator factor 1 , ogd : osteoglophonic dysplasia , pth : parathyroid hormone , tio : tumor - induced osteomalacia , vit d : vitamin d , xlh : x - linked hypophosphatemic rickets ) differences between calcipenic and phosphopenic rickets hypophosphatemic rickets is the most common type of nonazotemic , refractory rickets in indian children . most of the hypophosphatemic disorders are inherited , though they may rarely be acquired [ tumor - induced osteomalacia ( tio ) , drug - induced fanconi syndrome ] . they may exist as isolated defects or associated with generalized proximal tubular dysfunction ( fanconi syndrome ) . the tubular maximum reabsorption of phosphate per glomerular filtration rate ( tmp / gfr ) ( calculated by nomogram ) provides the best estimate of renal phosphate loss . in the absence of secondary hyperparathyroidism , decreased tmp / gfr indicates renal phosphate loss as the primary defect . although most patients have normal 25-oh vitamin d levels , low levels do not rule out hypophosphatemic rickets , especially in those from indian ancestry . after renal phosphate wasting is documented by tmp / gfr measurement , the next important step is to determine whether the phosphate loss is isolated or accompanied by other tubular losses . knowledge regarding the pathophysiology of phosphate homeostasis is essential for better understanding of hypophosphatemic rickets . fibroblast growth factor 23 ( fgf23 ) , pth , and calcitriol play a major role in the phosphate homeostasis and their interaction is summarized in figure 2 . fgf23 , a phosphatonin , is the most important player that is implicated in the pathogenesis of most of the disorders with hypophosphatemic rickets / osteomalacia . interaction of klotho with the fgfr1c converts it into a receptor specific for fgf23 function . decrease in the serum phosphorus level decreases fgf23 and pth levels , while 1,25(oh)2d level is increased . x - linked hypophosphatemic ( xlh ) rickets is an x - linked dominant disorder first described by albright in 1939 . it is the most common cause of heritable rickets , with an incidence of 1:20,000 live births . phosphate regulating gene with homologies to endopeptidase on x chromosome ( phex ) mutations are also described in familial hypophosphatemic rickets patients of indian origin . xlh rickets occurs due to inactivating mutations in phex which encodes a metalloprotease that cleaves small peptide hormones . it is expressed in bone , teeth , and parathyroid glands , but not in kidney . it does not seem to cleave fgf23 directly , but the severity of the disease and specific clinical manifestations are variable even among members of the same family . in a recent study , patients with clearly deleterious ( that resulted in premature stop codons , which included nonsense mutations , insertion or deletion and splice site mutations ) phex mutations had lower tubular reabsorption of phosphate and 1,25(oh)2d levels than those with plausible causative mutations ( which included missense mutations and an in - frame three - nucleotide deletion ) . in addition to the mineralization defect induced by hypophosphatemia , an intrinsic osteoblast defect also contributes to the bone disease and does not appear to respond to conventional treatment . pathophysiology of fgf23-mediated hypophosphatemic rickets ( xlh : x - linked hypophosphatemic rickets , adhr : autosomal dominant hypophosphatemic rickets , tio : tumor - induced osteomalacia , fgf23 : fibroblast growth factor 23 ) unlike vitamin d deficiency , craniotabes and rachitic rosary are not seen , and the first usual finding is frontal bossing which may appear as early as 6 months of age . as the child starts walking , lower limbs are more affected leading to coxa vara , genu valgum , and genu varum . these abnormalities include abscessed noncarious teeth , enamel defects , enlarged pulp chambers , and taurodontium . biochemical evaluation would reveal low serum phosphorus , normal calcium , normal or slightly elevated pth , and decreased tmp / gfr ( calculated by nomogram ) . current standard of care is phosphate replacement in the form of phosphate mixture and with 1,25(oh)2d3 or 1-ohd3 . some patients can have marked improvement in bony deformity with treatment , hence corrective osteotomy should be considered only after adequate duration of medical therapy . as the child progresses to adulthood , the phosphate requirements decrease due to closure of epiphyses and decreased bone turnover . hence , only those adults who are symptomatic in the form of bone pains , muscle weakness , or pseudofractures require therapy . phosphate is generally administered at 2040 mg / kg / day in three to five divided doses ( up to a maximum of 23 g / day ) . therapy should be targeted to maintain serum phosphorus in the low normal range , normalize alkaline phosphatase , and prevent secondary hyperparathyroidism , hypercalcemia , or hypercalciuria . serum calcium , phosphorus , creatinine , and spot urinary calcium / creatinine should be monitored every 34 months . phosphate and calcitriol treatment leads to concurrent increases in circulating fgf23 concentrations , which may diminish therapeutic effect or contribute to complications of therapy . in 2005 , a systematic analysis concluded that there is no sufficient evidence to support the use of growth hormone ( gh ) in children with xlh . a recent study has demonstrated the efficacy of gh in children with xlh where there was significant improvement in height sds without worsening of skeletal disproportion . administration of single dose of calcitonin in xlh patients causes a significant and sustained drop in the circulating levels of fgf23 and an increase in the serum levels of phosphorus . short - term treatment with cinacalcet suppresses pth , leading to increase in tmp / gfr and serum phosphate . however , long - term studies are required to verify the persistent benefits of these drugs . isolated c - terminal tail of fgf23 alleviates hypophosphatemia , while anti - fgf23 antibodies ameliorate hypophosphatemia and improve the muscle strength and movements with no effect on growth in hyp mice . however , their use in human subjects with hypophosphatemic rickets is still under evaluation . autosomal dominant hypophosphatemic rickets ( adhr ) displays incomplete penetrance and variable age of onset . fgf23 is mutated at the cleavage site , leading to impaired cleavage of intact molecule , thereby prolonging its activity and phosphaturia [ figure 3 ] . the other subgroup presents during adolescence or adulthood with bone pain , weakness , and pseudofractures , but no deformity . some patients with childhood - onset adhr may have postpubertal spontaneous remission of biochemical abnormalities . autosomal recessive hypophosphatemic rickets ( arhr ) type 1 occurs due to loss of function mutations in dentin matrix protein 1 , a noncollagenous bone matrix protein expressed in osteoblasts and osteocytes . it occurs due to loss of function mutations in ectonucleotide pyrophosphatase / phosphodiesterase 1 ( enpp1 ) . enpp1 generates inorganic pyrophosphate ( ppi ) , an essential physiologic inhibitor of calcification , and may be associated with aberrant ectopic calcification disorders ( generalized arterial calcification of infancy ) in some cases . clinical manifestations , biochemical findings , and management of patients with arhr are similar to those with xlh . the genetic defect in hereditary hypophosphatemic rickets with hypercalciuria ( hhrh ) is loss of function mutation in the gene that encodes napi2c ( slc34a3).[3133 ] a novel mutation in this gene has also been reported in an indian patient who had rickets since childhood and developed nephrolithiasis during adulthood . bone pain , muscle weakness , and pseudofractures are the common presenting complaints , while no dental abnormalities are reported . the management of patients with hhrh differs from those with xlh since the former does not require calcitriol , which may worsen hypercalciuria and increases the predisposition for nephrocalcinosis . although hypophosphatemic rickets is often an isolated renal abnormality , sometimes it may be associated with generalized proximal tubular dysfunction . this may manifest in the form of glycosuria , hypokalemia , proximal renal tubular acidosis , hyperuricosuria , and generalized aminoaciduria . this syndrome may result from various underlying conditions including cystinosis , lowe 's syndrome , drugs , fanconi bickel syndrome , etc . this is an acquired and paraneoplastic disorder caused due to humoral products known as phosphatonins produced by the tumors . the implicated tumors are generally mesenchymal tumors of long bones , distal extremity , sinuses , nasopharynx , groin , etc . they are benign , slow growing , and predominantly of phosphaturic mesenchymal tumor of mixed connective tissue ( pmtmct ) origin . they can present at any age with longstanding history of bone pains and muscular weakness . localization can be done with octreotide scintigraphy , 18f - fluorodeoxyglucose positron emission tomography ( fdg - pet ) [ figure 4 ] , whole - body magnetic resonance imaging ( mri ) , or whole - body venous sampling of fgf23 . when the tumor remains obscure , phosphate and 1,25(oh)2d3 are given in a manner similar to that of xlh . other therapies that have been reported to be of varied use are cinacalcet and octreotide . fgf23 antibodies are also being developed . in patients with unlocalized or incompletely excised tumors , treatment with phosphate and calcitriol 18-f - fdg - pet in a patient with tumor - induced osteomalacia localizing tumor in the lower end of left femur . this tumor was removed and the histopathology showed ossifying fibroma besides xlh , adhr , arhr , hhrh , and tio , there are many other disorders of renal phosphate loss . these are summarized in table 2 . etiology and biochemistry of hypophosphatemic rickets renal phosphate wasting disorders are important causes of rickets to be thought of in appropriate clinical setting . correct identification of these disorders is important for determining therapy . in the last few years this has contributed to the identification of previously unidentified regulators of renal phosphate reabsorption . yet , many more mechanisms are to be unraveled and the world of phosphate homeostasis is getting fascinating day by day .
hypophosphatemic rickets is a disorder of bone mineralization caused due to defects ( inherited / acquired ) in the renal handling of phosphorus . 
 this group includes varied conditions , x - linked hypophosphatemic rickets being the most common inheritable form of rickets . 
 the other common forms are autosomal dominant hypophosphatemic rickets and tumor - induced osteomalacia . 
 although these conditions exhibit different etiologies , increased phosphatonins form a common link among them . 
 fibroblast growth factor 23 ( fgf23 ) is the most widely studied phosphatonin . 
 genetic studies tend to show that the phosphorus homeostasis depends on a complex osteo - renal axis , whose mechanisms have been poorly understood so far . 
 newer disorders are being added as the mechanisms in this axis get discovered . 
 this review focuses on the clinical , biochemical , genetic features and management of hypophosphatemic disorders leading to defective mineralization .