Disorder of Phosphate Metabolism

8/8/2019 Disorder of Phosphate Metabolism

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Chapter 10. PRIMARY DISORDERS OF PHOSPHATEMETABOLISM

Thomas O Carpenter, M.D.Professor of Pediatrics, Yale University School of Medicine, New Haven, CT

Marc K Drezner, M.D.Professor of Medicine, University of Wisconsin, Madison, WI

Updated: September 30, 2007

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Phosphorus plays an important role in growth, development, bone formation,

acid-base regulation, and cellular metabolism. Inorganic phosphorus existsprimarily as the critical structural ion, phosphate (PO 4), which serves as aconstituent of hydroxyapatite, the mineral basis of the vertebrate skeleton,and at the molecular level, providing the molecular backbone of DNA. Itschemical properties allow its use as a biological energy store as adenosinetriphosphate. Additionally, phosphorus influences a variety of enzymaticreactions (e.g. glycolysis) and protein functions (e.g. the oxygen-carryingcapacity of hemoglobin by regulation of 2,3-diphosphoglycerate synthesis).Finally, phosphorus is an important signaling moiety, as phosphorylation anddephosphorylation of protein structures serves as an activation signal.Indeed, phosphorus is one of the most abundant components of all tissues,and disturbances in its homeostasis can affect almost any organ system. Most

phosphorus within the body is in bone (600-700 g), while the remainder islargely distributed in soft tissue (100-200 g). The plasma contains 11-12mg/dL of total phosphorus (in both organic and inorganic states) in adults.Inorganic phosphorus (Pi) primarily exists as phosphate (PO 4), and is thecommonly measured fraction, found in plasma at concentrations averaging 4mg/dl in older children and adults. Plasma Pi concentrations values in childrenare higher, often up to 8 mg/dl in infants, and gradually declining throughoutchildhood to adult values. The organic phosphorus component is primarilyfound in phospholipids and is not routinely assessed, and comprisesapproximately two-thirds of the total plasma phosphorus (1). Thus the termplasma phosphorus generally is used when referring to plasma Piconcentrations, and because plasma Pi is nearly all in the form of the PO 4ion,the terms phosphorus and phosphate are often interchangeably used in theclinical chemistry laboratory.

The critical role that phosphorus plays in cell physiology has resulted in thedevelopment of elaborate mechanisms designed to maintain phosphatebalance. These adaptive changes are manifest by a constellation ofmeasurable responses, the severity of which is modified by the differencebetween metabolic Pi need and exogenous Pi supply. Such regulationmaintains the plasma and extracellular fluid phosphorus within a relativelynarrow range and depends primarily upon gastrointestinal absorption andrenal excretion as mechanisms to effect homeostasis. Although investigators

have recognized a variety of hormones which influence these variousprocesses, in concert with associated changes in other metabolic pathways,

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the sensory system, the messenger and the mechanisms underlyingdiscriminant regulation of Pi balance remain incompletely understood.

While long-term changes in Pi balance depend on these variables, short-termchanges in Pi concentrations can occur due to redistribution between the

extracellular fluid and either bone or cell constituents. Such redistributionresults secondary to various mechanisms including: elevated levels of insulinand/or glucose; increased concentrations of circulating catecholamines;respiratory alkalosis; enhanced cell production or anabolism; and rapid boneremineralization.

REGULATION OF PHOSPHORUS HOMEOSTASIS

The majority of ingested phosphorus is absorbed in the small intestine;hormonal regulation of this process plays only a minor role in normal Pihomeostasis. In contrast, the predominant site of regulation of Pi balance, isat the kidney level, where renal tubular reclamation of filtered Pi occurs in

response to complex regulatory mechanisms. Thus the fate of Pi is generallyrenal elimination, incorporation into organic forms in proliferating cells, ordeposition into the mineral phase of bone as hydroxyapatite. During times ofsevere phosphorus deprivation, the phosphate contained in bone mineralprovides a source of phosphorus for the metabolic needs of the organism. Thespecific roles that the intestine and kidney play in this complex process arediscussed below.

GASTROINTESTINAL ABSORPTION OF PHOSPHORUS

The small intestine is an important site for Pi absorption with transport

greatest in the jejunum and ileum and less in the duodenum. In normaladults net Pi absorption is a linear function of dietary Pi intake. For a dietaryPi range of 4 to 30 mg/kg/day, the net Pi absorption averages 60 to 65% ofthe intake (2). Intestinal Pi absorption occurs via two routes (Figure 1), acellularly mediated active transport mechanism and diffusional flux, largelythrough a paracellular shunt pathway (3). In this regard, several vitamin Dresponsive Na +-dependent phosphate cotransporters have been identified inintestinal brush border membranes, which have a high affinity for Pi binding(4-8). Energy for this electrochemical uphill process is provided by the sodiumgradient, which is maintained by sodium-potassium ATPase. The phosphateincorporated into intestinal cells by this mechanism is ferried from the apicalpole to the basolateral pole likely through restricted channels such as themicrotubules. Exit of Pi from the enterocyte across the basolateral membrane

and into the circulation is down electrical and perhaps concentrationgradients. Although such active transport systems are responsive to 25(OH)Dand 1,25(OH)2D (2,9), these hormones and systems play a relatively minorrole in normal Pi homeostasis. Indeed, during vitamin D deficiency thepercentage of phosphorus absorbed from the diet is reduced by only 15%.

Figure 1. Model of inorganic phosphate (HPO 4=) transport in theintestine. At the luminal surface of the enterocyte the brush bordermembrane harbors a 1,25(OH)2D responsive 2Na +/ HPO 4=transporter, which has high affinity for HPO 4=. Energy for this

sodium dependent phosphate transport is provided by an inwarddownhill sodium gradient, maintained by transport of Na +from the

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cell via a Na +/K +ATPase cotransporter at the basolateral membrane.The HPO 4=incorporated into the enterocytes by this mechanism isincorporated into microtubules and ferried across the cell, wheretransfer to the circulation occurs down electrical and concentrationgradients. The vast majority of HPO 4=absorption occurs via theprocess of diffusional aborption across the intercellular spaces in theintestine.

The vast majority of Pi absorption occurs via the process of diffusionalabsorption. This results as a consequence of the relatively low Km of theactive transport process (2 mM) and the luminal Pi content during feeding,which generally exceeds 5 mM throughout the intestine even during fasting

(10-12). The diffusion is mediated through the paracellular space and,therefore, is primarily a function of Pi intake. Because most diets contain anabundance of Pi, the quantity absorbed always exceeds the need. Factorswhich may adversely influence the diffusional process are the formation ofnonabsorbable calcium, aluminum or magnesium phosphate salts in theintestine and age, which reduces Pi absorption by as much as 50%.

RENAL EXCRETION OF PHOSPHORUS

The kidney is immediately responsive to changes in serum Pi levels or todietary Pi intake. The balance between the rates of glomerular filtration andtubular reabsorption (13) determines net renal handling of Pi. Piconcentration in the glomerular ultrafiltrate is approximately 90% of that inplasma, as not all of the plasma Pi is ultrafilterable (14). Since the product of

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the serum Pi concentration and the glomerular filtration rate (GFR)approximates the filtered load of Pi, a change in the GFR may influence Pihomeostasis if uncompensated by commensurate changes in tubularreabsorption.

The major site of phosphate reabsorption is the proximal convoluted tubule,at which 60% to 70% of reabsorption occurs (Figure 2). Along the proximalconvoluted tubule the transport is heterogeneous, with greatest activity in theS1 segment. Further, increasing, but not conclusive, data supports theexistence of a Pi reabsorptive mechanism in the distal tubule. Currently,however, conclusive proof for tubular secretion of Pi in humans is lacking(15).

Figure 2. Distribution of Pi reabsorption and hormone-dependentadenylate cyclase activity throughout the renal tubule. The renaltubule consist of a proximal convoluted tubule (PCT), composed of anS1, S2 and S3 segment, a proximal straight tubule (PST), also known

as the S3 segment, the loop of Henle, the medullary ascending limb(MAL), the cortical ascending limb (CAL), the distal convoluted tubule(DCT) and three segments of the collecting tubule: the corticalcollecting tubule (CCT); the outer medullary collecting tubule (OMCT);and the inner medullary collecting tubule (IMCT). Pi reabsorptionoccurs primarily in the PCT but is present is the PST and DCT, sites atwhich parathyroid hormone (PTH) dependent adenylate cyclase islocalized. In contrast, calcitonin alters Pi transport at sites devoid ofcalcitonin dependent adenylate cyclase, suggesting that Pireabsorption in response to this stimulus occurs by a distinctlydifferent mechanism.

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At all three sites of Pi reabsorption, the proximal convoluted tubule, proximalstraight tubule and distal tubule, several investigators have mapped PTH-sensitive adenylate cyclase (Figure 2) (15,16). Not surprisingly, there is clearevidence that PTH decreases Pi reabsorption at these loci by a cAMP-dependent process, as well as a cAMP independent signaling mechanism. Incontrast, calcitonin-sensitive adenylate cyclase maps to the medullary andcortical thick ascending limbs and the distal tubule (Figure 2) (17).Nevertheless, calcitonin inhibits Pi reabsorption in the proximal convoluted

and proximal straight tubule by a cAMP-independent mechanism that may bemediated by a rise in intracellular calcium (18).

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Mechanism of Phosphate Transport

Investigations of the cellular events involved in Pi movement from the renaltubule luminal fluid to the peritubular capillary blood indicate that Pireabsorption occurs principally by a unidirectional process that proceeds

transcellularly. Entry of Pi into the tubular cell across the luminal membraneproceeds by way of a saturable active transport system that is sodium-dependent (analogous to the sodium-dependent co-transport in the intestine)(Figure 3). The rate of Pi transport is dependent on the magnitude of the Na+gradient maintained across the luminal membrane, which depends on the Na+/ATPase or sodium pump on the basolateral membrane. Further, the ratelimiting step in transcellular transport is likely the Na +-dependent entry of Piacross the luminal membrane, a process with a low Km for luminal phosphate(~0.43M) which permits highly efficient transport.

Figure 3. Model of inorganic phosphate transcellular transport in theproximal tubule. At the brush border a Na +/H +exchanger and Na+/HPO 4-co-transporters operate. The NaPi2a transporter is mostabundant and is an electrogenic transporter with a 3:1 (Na: PO 4)stoichiometry. The less abundant NaPi2c transporter is electroneutralwith a 2:1 (Na: PO 4) stoichiometry. The HPO 4-that enters the cellacross the luminal surface mixes with the intracellular pool of Pi andis transported across the basolateral membrane via an anionexchange mechanism. On the basolateral membrane there are Na+/HPO 4-cotransporters and a Na +/K +ATPase. The ATPase pumps Na+out of the cell maintaining the inward downhill Na gradient, whichserves as the driving force for luminal entry of Na +.

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The phosphate that enters the tubule cell plays a major role in governingvarious aspects of cell metabolism and function and is in rapid exchange withintracellular phosphate. Under these conditions the relatively stable free Pconcentration in the cytosol implies that Pi entry into the cell across the brushborder membrane must be tightly coupled with its exit across the basolateralmembrane (Figure 3). The transport of phosphate across the basolateralmembrane is apparently a passive process driven by an electrical gradientsecondary to an anion exchange mechanism. However, several P transportpathways have been postulated, including Na +-Pi cotransport and anunspecific P leak, as well as anion exchange. In any case, the basolateral Pitransport serves at least two functions: 1) complete transcellular Pireabsorption when luminal Pi entry exceeds the cellular Pi requirments; and2) guaranteed basolateral Pi influx if apical Pi entry is insufficient to satisfycellular requirements (19). Regulation of basolateral Pi transport however, isnot well understood.

Pi entry into epithelium is believed to be performed by three classes of Na-Pi

cotransporters (20-24) (type I, type II and type III Na-Pi cotransporters). Thethree families of Na-Pi cotransporters share no significant homology in theirprimary amino acid sequence and exhibit substantial variability in substrateaffinity, pH dependence and tissue expression. The tissue expression, therelative renal abundance and overall transport characteristics of type I, II andIII Na-Pi cotransporters suggest that the type IIa transporter plays a key rolein brush-border membrane Pi flux. Indeed, changes in expression of the typeIIa Na-Pi cotransporter protein parallel alterations in proximal tubular Pihandling, documenting its physiological importance (25,26). In addition,molecular and/or genetic suppression of the type IIa Na-Pi cotransportersupports its role in mediating brush-border membrane Na-Pi cotransport.Thus, intravenous injection of specific antisense oligonucleotides reduces

brush-border membrane Na-Pi cotransport activity in accord with a decreasein type IIa cotransporter protein (27). In addition, disruption of the type IIaNa-Pi cotransporter gene (Npt2) in mice leads to a 70% reduction in brush-border Na-Pi cotransport rate and complete loss of the protein (28,29).Nevertheless, the recent finding of impaired renal tubular reabsorption of Pi inthe setting of loss of function mutations in the the type IIc Na-Picotransporter (30) suggests a role for this transporter in maintenance ofnormal Pi homeostasis as well as the type IIa transporters.

Several hormones and metabolic pertubations are able to modulatephosphate reabsorption by the kidney. Among these PTH, PTHrP, calcitonin,

TGFb, glucocorticoids and phosphate loading inhibit renal phosphatereclamation. In contrast, IGF-1, insulin, thyroid hormone, 1,25(OH)2D, EGFand phosphate deprivation (depletion) stimulate renal phosphatereabsorption. More recently the study of disorders of renal phosphate wastinghas revealed important functions of FGF23, a novel member of the fibroblastgrowth factor family, with respect to renal Pi homeostasis. The commontarget for this hormonal regulation is the renal proximal tubular cell.

Investigations of classical PTH effects on proximal tubule phosphate transportindicate that both the cAMP-protein kinase A and the phospholipase C-proteinkinase C signal transduction pathways modulate this process. The PTHmediated inhibition of phosphate reabsorption operates through the protein

kinase C system at low hormone concentrations (10-8 to 10-10 M) and viaprotein kinase A at higher concentrations. More recently the mechanism by

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which these second messenger systems alter phosphate transport hasbecome apparent. PTH, after interaction with its receptor effects a rapid andirreversible endocytosis of Pi transporters to the lysosomal compartment,where subsequent proteolytic degradation of the transporters occur. Recoveryof Na-Pi cotransport activity following PTH inhibition requires proteinsynthesis, consistent with this observation. In concert with these findings,recent studies indicate that expression of the Npt2 protein at renal tubularsites is increased in parathyroidectomized rats and decreased after PTHtreatment. In addition, Northern blot analysis of total RNA shows that theabundance of Npt2-specific mRNA is not changed by parathyroidectomy but isminimally decreased in response to administration of parathyroid hormone.These data indicate that parathyroid hormone regulation of renal Na-Picotransport is determined by changes in the abundance of Npt2 protein in therenal brush border membrane (31). Certain aspects of Pi homeostasis at therenal level, however, are not explained by actions of PTH. For instance, evenin the setting where parathyroid glands have been removed, regulation ofrenal P transport by dietary P content still exists, implying that other

mediators of this process are at work.

Although PTH has been the most well-documented physiologic regulator ofrenal Pi excretion, the recently described actions of FGF23, a novel memberof the fibroblast growth factor family, suggest an important role for thishormone as an important regulator of Pi homeostasis. Although there aremany gaps in our understanding of this new pathway, several points havebeen established:

1. Mice overexpressing FGF23 demonstrate increased renal Pi clearanceand concomitant hypophosphatemia (32).

2. FGF23KO mice retain P at the kidney and are hyperphosphatemic(33) .

3. Administration to mice of an FGF23 neutralizing antibody increasesserum Pi (34).

4. The presumed pathway for FGF23 action involves interaction withFGFRs on the basolateral surface of the renal tubular cell (35).

5. The FGF23/FGFR interaction is facilitated by yet another novel protein,klotho, which forms a ternary complex with FGF23 and FGFR allowingfor signal transduction. It appears that klotho is necessary for thisinteraction to result in a biological response of FGF23, and is mediatedthrough ERK signaling (36).

6. FGF23 levels are regulated in part by dietary Pi status, so that

circulating levels increase during Pi loading and decrease during Pideprivation (37).

The actions of FGF23 and other related proteins as mediators of disease arediscussed in detail in the section on Pathophysiology of XLH (see below).Other potential regulators of renal Pi handling have been suggested. Theseinclude fragments of matrix extracellular glycoprotein (MEPE), secretedfrizzled related protein-4 (sFRP4), stanniocalcin, and other FGFs, includingFGF7 (38-41).

Indeed, repeated observations have confirmed that the balance betweenurinary excretion and dietary input of Pi is maintained not only in normal

humans but in patients with hyper- and hypoparathyroidism. In fact, therenal tubule has an intrinsic ability to adjust Pi reabsorption rate according to

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dietary Pi intake and the bodys Pi supply and demand. Thus Pi reabsorptionis increased under conditions of greater need, such as rapid growth,pregnancy, lactation and dietary restriction. Conversely, in times of surfeit,such as slow growth, chronic renal failure or dietary excess, renal Pireabsorption is curtailed. Such changes in response to chronic changes in Piavailability are characterized by parallel changes in Na-phosphate cotransportactivity, the Npt2 mRNA level and Npt2 protein abundance. In contrast, theacute adaptation to altered dietary Pi is marked by parallel changes in Na-phosphate cotransporter activity and Npt2 protein abundance in the absenceof a change in Npt2 mRNA. Thus, in response to chronic conditions proteinsynthesis is requisite in the adaptive response, while under acute conditionsthe number of Npt2 cotransporters is rapidly changed by mechanismsindependent of de novo protein synthesis, such as insertion of existingtransporters in the apical membrane or internalization of existingtransporters.

CLINICAL DISORDERS OF PHOSPHATE METABOLISM

A variety of genetic diseases and disorders due to therapeutic agents andphysiological adaptations affect phosphate homeostasis. Not surprisingly,since the kidney is the primary regulatory site for phosphate homeostasis,aberrant phosphate metabolism results most commonly from altered renal Pihandling. Moreover, the vast majority of the primary diseases are phosphatelosing disorders in which renal Pi wasting and hypophosphatemia predominateand osteomalacia and rickets are characteristic presenting symptoms.Osteomalacia and rickets are disorders of calcification characterized bydefects of bone mineralization in adults and bone and cartilage mineralizationin youths. In osteomalacia, there is a failure to normally mineralize the newly

formed organic matrix (osteoid) of bone. In rickets, a disease of children,there is not only abnormal mineralization of bone but defective cartilagegrowth plate calcification at the epiphyses as well. Apoptosis of chondrocytesin the hypertrophic zone is reduced, typically resulting in an expandedhypertrophic zone, delayed mineralization and vascularization of thecalcification front, with an overall appearance of a widened and disorganizedgrowth plate (42).

The remainder of this chapter reviews the pathophysiology ofhypophosphatemic rachitic and osteomalacic disorders, and provides asystematic approach to the diagnosis and management of these diseases. Thediscussion will focus on disorders in which primary disturbances in phosphate

homeostasis occur, emphasizing X-linked hypophosphatemicrickets/osteomalacia (XLH). We will also discuss other disorders includinghereditary hypophosphatemic rickets with hypercalciuria (HHRH); autosomaldominant and autosomal recessive hypophosphatemic rickets (ADHR andARHR); Dent's disease; and tumor induced osteomalacia (TIO).

MINERALIZATION OF BONE AND CARTILAGE

Mineralization of bone is a complex process in which a calcium-phosphatemineral phase is deposited in a highly ordered fashion within the organicmatrix (43). Apart from the availability of calcium and phosphorus,

requirements for normal mineralization include: 1) adequate metabolic andtransport function of chondrocytes and osteoblasts to regulate the

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concentration of calcium, phosphorus and other ions at the calcification sites;2) the presence of collagen with unique type, number and distribution ofcross-links, distinct patterns of hydroxylation and glycosylation and abundantphosphate content, which collectively facilitate deposition of mineral at gaps(or "hole zones") between the distal ends of collagen molecules; 3) a lowconcentration of mineralization inhibitors (such as pyrophosphates andproteoglycans) in bone matrix; and 4) maintenance of an appropriate pH ofapproximately 7.6 for deposition of calcium-phosphate complexes.

The abnormal mineralization in the hypophosphatemic disorders, is due mostlikely to phosphopenia at calcification sites and, in some cases, paracrineinhibitory factors, which result in accumulation of unmineralized osteoid, asine qua non for the diagnosis of osteomalacia. Since the resultant abundantosteoid is not unique, however, establishing the diagnosis of osteomalaciahistopathologically requires demonstration that abnormal mineralization, andnot increased production, underlies the pathologic abnormality (44, 45).Concordance of these events is manifest by an increase in the bone forming

surface covered by incompletely mineralized osteoid, an increase in osteoidvolume and thickness and a decrease in the mineralization front (thepercentage of osteoid-covered bone-forming surface undergoing calcification)or the mineral apposition rate.

Inadequate growth plate cartilage mineralization in rickets is primarilyobserved in the hypertrophic zone of chondrocytes. Irregular alignment andmore extensive disorganization of the growth plate may be evident withincreasing severity of disease. Calcification in the interstitial regions of thishypertrophic zone is defective. Grossly, these changes result in increasedthickness of the epiphyseal plate, and an increase in transverse diameter thatoften extends beyond the ends of the bone and causes characteristic cuppingor flaring.

CLINICAL DISORDERS

X-LINKED HYPOPHOSPHATEMIC RICKETS/OSTEOMALACIA

X-linked hypophosphatemic rickets/osteomalacia is the most common"vitamin D resistant" disease in man. The syndrome occurs as an X-linkeddominant manifest by renal phosphate wasting and consequenthypophosphatemia (Table 1). Additional characteristic features of the diseaseinclude growth retardation, osteomalacia and rickets in growing children. Theclinical expression of the disease is widely variable, ranging from a mildabnormality, the apparent isolated occurrence of hypophosphatemia, tosevere bone disease. Evidence of a gene dose effect has been controversial,although most would agree that phenotypic differences between males (witha mutated gene on their only X chromosome) and females (who areheterozygous for the defective X-linked gene) are not striking. Generally,evidence of disease may be detected at or shortly after birth. However,features of the disease may not become apparent until age 6 to 12 months orolder (46). The most common clinically evident manifestations of XLH are

short stature and limb deformities. Growth abnormalities and limb deformities

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Additional signs of the disease may include delayed dentition and dentalabscesses (48, 49), which are thought to arise from the limited mineralizationof the dentine compartment of the tooth. An enlarged pulp chamber isevident on dental radiographs. Osteophytes, enthesopathy (50) andcraniosynostosis are not uncommon. Strikingly absent are common featuresobserved in vitamin D deficiency rickets, such as muscle weakness, tetanyand convulsions.

Adults with XLH may be asymptomatic or present with severe bone pain. Onclinical examination they often display evidence of post-rachitic deformities,such as bowed legs or short stature. However, radiographic or biochemicalabnormalities typical of active bone disease are usually absent. In contrast,some adult patients present with "active" osteomalacia, characterizedradiographically by pseudofractures, coarsened trabeculation, rarified areasand/or non-union fractures, and biochemically by elevated serum alkalinephosphatase activity. Symptoms at presentation may reflect the end-result ofchronic changes, and may not correlate with apparent current activity of thedisease. Many adults demonstrate progressive enthesopathy and boneovergrowth. Fusion of the sacroiliac joint(s) and severe symptomatic spinalstenosis are not uncommon (51).

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In spite of marked variability in the clinical presentation of the disease, bonebiopsy in affected children and adults universally reveals low turnoverosteomalacia without osteopenia (Figure 5). Histomorphometry of biopsysamples invariably demonstrates a reduced rate of formation, diffuse patchyhypomineralization, a decrease in mineralizing surfaces and characteristicareas of hypomineralization of the periosteocytic lacunae (52).

Figure 5. Section from an undecalcified bone biopsy in an untreatedpatient with X-linked hypophosphatemia. The Goldner stain revealsmineralized bone (blue/green) and an abundance of unmineralizedosteoid (red) covering a substantial portion of the surfaces. Thewidth of the osteoid seams is substantially increased.

Clinical Biochemistry

As previously noted, the primary biochemical abnormality of XLH ishypophosphatemia due to increased urinary phosphate excretion. Moreover,mild gastrointestinal phosphate malabsorption is present in the majority ofpatients, which may contribute to the evolution of the hypophosphatemia(Table 1) (53, 54).

In contrast, the serum calcium concentration in affected subjects is normaldespite gastrointestinal malabsorption of calcium. However, as a consequence

of this defect, urinary calcium is often decreased. Circulating PTH levels maybe normal to modestly elevated in nave patients, but treatment withphosphate salts may aggravate this tendency such that persistent secondaryhyperparathyroidism may occur. Prior to the initiation of therapy, serum25(OH)D levels are normal, and serum 1,25(OH)2D levels are in the lownormal range (55, 56). The paradoxical occurrence of hypophosphatemia and

normal serum calcitriol levels in affected subjects is consistent with aberrantregulation of synthesis of this metabolite (due to decreased 25(OH)D-1a-

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hydroxylase activity) and its clearance (due to increased 25(OH)D-24-hydroxylase activity), findings that have been demonstrated in the Hypmouse, the murine homologue of the human disease (57, 58).

Genetics

With the recognition that hypophosphatemia is the definitive marker for XLH,Winters et al (59) and Burnett et al (60) discovered that this disease istransmitted as an X-linked dominant disorder. Analysis of data from 13multigenerational pedigrees identified PHEX (for phosphate regulating genewith homologies to endopeptidases located on the X chromosome) as thegene mutated in XLH (61). PHEX is located on chromosome Xp22.1, andencodes a 749-amino acid protein with three putative domains: 1) a smallaminoterminal intracellular tail; 2) a single, short transmembrane domain;and 3) a large carboxyterminal extracellular domain, containing tenconserved cysteine residues and a HEXXH pentapeptide motif, whichcharacterizes many zinc metalloproteases. Further studies have revealed that

PHEX is homologous to the M13 family of membrane-bound metalloproteases,or neutral endopeptidases. M13 family members, including neutralendopeptidase 24.11 (NEP), endothelin-converting enzymes 1 and 2 (ECE-1and ECE-2), the Kell blood group antigen (KELL), neprilysin-like peptide(NL1), and endothelin converting enzyme-like 1 (ECEL1), degrade or activatea variety of peptide hormones. In addition, like other neutral endopeptidases,immunofluorescent studies have revealed a cell-surface location for PHEX inan orientation consistent with a type II integral membrane glycoprotein (62).It has been demonstrated that certain missense mutations in PHEX thatsubstitute a highly conserved cysteine residue will interfere with normaltrafficking of the molecule to the plasma membrane (63). Thus it appearsthat one mechanism associated with the pathophysiology of XLH is to preventPHEX from locating to the cell membrane.

Phex is predominantly expressed in bones (in osteoblasts/osteocytes) andteeth (in odontoblasts/ameloblasts) (64-67); mRNA, protein or both have alsobeen found in lung, brain, muscle, gonads, skin and parathyroid glands.Subcellular locations appear to be the plasma membrane, endoplasmicreticulum and Golgi organelle. Immunohistochemistry studies suggest thatPhex is most abundant on the cell surface of the osteocyte. In sum, theontogeny of Phex expression suggests a possible role in mineralization invivo.

The work of several groups has documented PHEX mutations in >160 patients(68-76). Mutations are scattered throughout the 749-amino acid extracellulardomain, encoded by exons 2-22, and are diverse, consisting of deletions,insertions and duplications, as well as splice site, nonsense and missensemutations.

The location of Phex expression in bone cells have led to the hypothesis thatdiminished PHEX/Phex expression in bone initiates the cascade of eventsresponsible for the pathogenesis of XLH. In order to confirm this possibility,several investigators have used targeted over-expression of Phex in attemptsto normalize osteoblast mineralization, in vitro, and rescue the Hypphenotype in vivo (77-79). Results from these studies fail to support thewidely held opinion that abnormal PHEX/Phex function in mature osteoblaststriggers the hypophosphatemia. However, partial rescue of the mineralization

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defect in Hyp mice occurs, suggesting that local effects of the PHEX mutationmay play some role in the mineralization process, but cannot completelyrestore the skeleton to normality. In sum, it seems that the temporal anddevelopmental expression of either the osteocalcin or type I collagenpromoter-driven Phex expression may not mimic endogenous Phexregulation. Thus, limitation of Phex expression to the mature osteoblastappears insufficient to completely rescue the phenotype

Pathophysiology

The primary inborn error in XLH results in an expressed abnormality of therenal proximal tubule that impairs Pi reabsorption. The immediate cause ofthis abnormality is the decreased abundance of the NPT2a mRNA andimmunoreactive protein in the proximal convoluted tubule cells (80, 81). Theidentification of a hypophosphatemic factor, FGF23, isolated from tumorscausing a similar hypophosphatemic syndrome, tumor-induced osteomalacia,raised the possibility that this factor could also mediate the

hypophosphatemia of XLH. Indeed mean circulating FGF23 concentrations aregreater in XLH patients than in control samples, further providing evidence tothis effect. Animal studies of renal cross-transplantation between Hyp andnormal mice resulted in neither transfer of the mutant phenotype withintroduction of Hyp kidney to a normal host, nor its correction withintroduction of a normal kidney to a Hyp host. These findings are mostconsistent with humoral mediation of the Pi wasting in the disease (82).Moreover classical parabiosis experiments suggested that a cross-circulatingfactor could mediate renal phosphate wasting (83).

One natural hypothesis derived from this new information would be that PHEX(a member of the M13 family of zinc-dependent type II cell surfacemembrane metalloproteinases) could serve as a processor of a phosphaturichormone such as FGF23. However, it does not appear that FGF23 is asubstrate for PHEX, and the nature of the role PHEX plays in this pathway isnot clear. Exploration of diseases related to XLH have resulted in identificationof factors that may be important elements of the pathway that relates PHEXto reduced renal tubular reabsorption of Pi. Autosomal DominantHypophosphatemic Rickets (ADHR) results from mutations in FGF23 thatresult in an apparent gain of function of the protein (84). These mutationsdisrupt an RXXR protease recognition site, and thereby protect FGF23 fromproteolysis, resulting in reduced clearance and elevating circulating levels,which likely leads to Pi wasting. FGF23 has been identified as a product of

tumors causing Tumor-Induced Osteomalacia (TIO)(85). Transgenic micewhich overexpress FGF23, exhibit retarded growth, hypophosphatemia,decreased serum 1,25(OH)2D levels and rickets/osteomalacia, all features ofXLH. The recent description of Autosomal Recessive HypophosphatemicRickets (86), due to homozygous loss of function mutations in DMP1 haveintroduced further complexities. DMP1 is a matrix protein of the SIBLING(small integrin binding ligand N-glycated) family, and, like PHEX and FGF23has been primarily identified in osteocytes. Furthermore, FGF23 levels areelevated in patients with ARHR, and in mice with biallelic disruption of DMP1.

In sum, a variety of recent findings suggest that enhanced FGF23 activity iscommon to several of the phosphate-wasting disorders. In particular, those

disorders that share the combined defects of inappropriate circulating levelsof 1,25(OH)2D and renal tubular Pi wasting seem to be mediated by

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increased FGF23 levels. This coincidence of findings holds for XLH, ADHR,ARHR, and TIO, and are consistent with the notion that FGF23 is a directregulator of Pi homeostasis at the renal level, and also has the effect ofdown-regulating metabolism of vitamin D to its active form. The teleologicalappeal to this argument stems from the provision of 2 major Pi regulatinghormones in the body: firstly, PTH (primarily responsive to serum Ca levels),which also serves to increase Ca levels via an increase in circulating1,25(OH)2D, and secondly, FGF23 (primarily responsive to Pi), whichcounters PTHs calcemic effect by reducing 1,25(OH)2D levels (Figure 6).

Figure 6. Scheme for the speculated pathophysiology of XLH, ARHR,TIO, and ADHR. Upper panel, osteocytes, comprising a network ofconnected cells embedded in mineralized bone are the cellular sourceof PHEX (which is mutated in XLH), DMP1 (which is mutated inARHR), and FGF23 (which is found in high concentrations in all fourof these hypophosphatmic disorders). It follows that loss of PHEX orDMP1 results in increased FGF23 production/secretion by

mechanisms that are not currently understood. Circulating FGF23concentrations may also occur secondary to the increased productionassociated with various tumors. Lower panel, circulating FGF23interacts with an FGF receptor (FGFR) on the basolateral surface ofthe proximal renal tubular cell. Klotho, produced by the distal renaltubule in both membrane bound and secretory forms is necessary forthe FGF23/FGFR interaction. Signalling through this pathway resultsin a decrease in Npt2 mRNA, thereby reducing the abundance of Picotransporters on the apical membrane and the well-describedimpairment of renal tubular Pi reabsorption. Likewise 25(OH)D-1a-hydroxylase mRNA is decreased and synthesis of 1,25(OH)2D isimpaired. In XLH and ARHR, increased production of FGF23 occurs in

the skeleton; in TIO, increased production of FGF23 occurs in tumors;in ADHR, enhanced activity of FGF23 occurs as a result of the specificmutations that retard its metabolic clearance.

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Further circumstantial evidence for the central role of FGF23 in the Pi-regulating process comes from the investigation of another group of raredisorders of Pi homeostasis in which renal Pi conservation is excessive in thesetting of increased circulating Pi levels. This group of disorders, known ashyperphosphatemic tumoral calcinosis (HTC), is manifest clinically byprecipitation of amorphous calcium-phosphate crystals in soft tissues. Thisphenomenon is thought to result from an increase in the ambient Ca x

phosphate solubility product, and occurs as a direct result of enhanced renaltubular reabsorption of Pi (87). In addition, circulating 1,25(OH)2D levels arein the high-normal to high range. Thus the precise converse of primarymetabolic derangements occurs, as compared to the XLH-related of diseases.HTC has been shown to directly result from loss of function mutations ineither of 2 proteins, FGF23, or GALNT3, a glycosylating enzyme that appearsto be necessary for appropriate O-glycosylation of FGF23 (88-90). Patientswith HTC have low intact FGF23 levels in both cases. FGF23 knockout micedevelop a hyperphosphatemic, calcifying phenotype with elevated1,25(OH)2D levels (33), similar to the premature aging mouse with disruptionof the klotho gene (91, 92). Indeed the klotho protein has been shown toserve as an essential co-factor in the receptor activation of the FGF receptorFGFR1 when FGF23 serves as the activating ligand (36), and, as predicted,

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the klotho knock out mouse demonstrates hyperphosphatemia and elevated1,25(OH)2D levels (91).

The overall physiologic importance of this regulating system will requirefurther study. It is not clear how PHEX or DMP1 result in elevated FGF23

levels. The intriguing aspect of the osteocyte as a potential central cell in thispathway also bears further study. One possible interpretation of thesefindings is that the osteocyte network throughout the skeleton may be acentral sensor of skeletal mineral demand. The coordination of certain specificmatrix proteins may play a role in the local regulation of phosphate supplyand mineralization. It follows that genetic disruption of this pathway mayresult in the profound systemic disturbances observed in the diseasesdescribed above.

Treatment

A generation ago, physicians employed pharmacological doses of vitamin D as

the cornerstone for treatment of XLH. However, long-term observationsindicate that this therapy fails to cure the disease and poses the seriousproblem of recurrent vitamin D intoxication and renal damage. Indeed, suchtreatment results only in incomplete healing of the rachitic abnormality, whilehypophosphatemia and impaired growth remain. Similar unresponsivenessprevails upon use of 25(OH)D.

With the recognition that phosphate depletion is an important contributor toimpaired skeletal mineralization, physicians began to devise treatmentstrategies that employed oral phosphate supplementation to compensate forthe renal phosphate wasting and thereby increasing the available Pi to the

mineralizing skeleton. Pharmacologic amounts of vitamin D were used incombination with phosphate supplements to counter the exacerbation ofhyperparathyroidism observed in this setting. Such combination therapy wasfound to be more effective than either administering vitamin D or phosphatealone. With the recognition that circulating 1,25(OH)2D levels are notappropriately regulated in XLH, the use of this metabolite in combination withphosphate was subsequently used to treat the disease (55, 93-95). Thenewer treatment strategy directly addresses the combined calcitriol andphosphorus deficiency characteristic of the disorder. Although thiscombination therapy has become the conventional therapy for XLH, completehealing of the skeletal lesions is usually not the case, and late complicationsof the disease are persistent and often debilitating.

In children the goal of therapy is to improve growth velocity, normalize anylower extremity defects, and heal the attendant bone disease. Generally thetreatment regimen includes a period of titration to achieve a maximum doseof 1,25(OH) 2D 3(Rocaltrol or calcitriol), 20-50 ng/kg/day in two divideddoses, and phosphorus, 1-2 gms/day in 3-5 divided doses. Occasionallypatients will prove refractory to this therapy and maximally toleratedamounts of 1,25(OH) 2D 3and phosphorus are required with daily dose limitsof 3 mcg and 2.5 gms, respectively.

Use of 1,25(OH) 2D 3/phosphorus combination therapy involves a significantrisk of toxicity. Hypercalcemia, hypercalciuria, renal calcinosis, andhyperparathyroidism can be sequelae of unmonitored therapy. Detrimentaleffects on renal function were particularly common prior to the frequent

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monitoring now generally employed with this therapy. Indeed, hypercalcemia,severe nephrocalcinosis and/or diminished creatinine clearance necessitatesappropriate dose adjustment, and in some cases discontinuation of therapy.Throughout the treatment course careful attention to renal function, as wellas serum and urine calcium is extremely important. Nevertheless, in spite ofthese varied complications of therapy, treatment of XLH often proceeds withlimited interruptions. Moreover, the improved outcome of this therapeuticintervention, compared to that achieved by previous regimens, justifies theaggressive approach that constitutes this current therapy.

While such combined therapy often improves growth velocity, refractorinessto the growth-promoting effects of treatment can be encountered in childrenwho present with markedly short stature prior to 4 years of age. For thatreason the use of recombinant growth hormone as additional treatment hasbeen suggested (96). Although positive effects have been observed in youngpatients with XLH with particularly impaired stature, this approach has notbeen universally recommended.

Indications for combined therapy in adults with XLH are less clear. Theoccurrence of intractable bone pain and refractory non-union fractures oftenrespond to treatment with calcitriol and phosphorus (97). However, dataremain unclear regarding the effects of treatment on fracture incidence(which may not be increased in untreated patients), enthesopathy and dentalabscesses. Therefore, the decision to treat affected adults must beindividualized.

Given the limitations with even currently advised treatment for XLH, the

quest for new and better therapies for XLH continues. The recent descriptionof correction of serum P levels and improved bony growth in Hyp mice treatedwith a neutralizing antibody to FGF23 raise the possibility that measures toinhibit action of this suspected mediator of disease will have a role in thetreatment of XLH in the future (34).

AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC RICKETS(ADHR)

Several studies have documented autosomal dominant inheritance of ahypophosphatemic disorder similar to XLH (98, 99). The phenotypicmanifestations of this disorder include the expected hypophosphatemia due torenal phosphate wasting, lower extremity deformities, andrickets/osteomalacia. Affected patients also demonstrate normal serum

25(OH)D levels, while maintaining inappropriately normal serumconcentrations of 1,25(OH)2D, in the presence of hypophosphatemia, allhallmarks of XLH (Table 1). PTH levels are normal. Long-term studies indicatethat a few of the affected female patients demonstrate delayed penetrance ofclinically apparent disease and an increased tendency for bone fracture,uncommon occurrences in XLH. In addition, among patients with theexpected biochemical features documented in childhood, rare individuals losethe renal phosphate-wasting defect after puberty. As noted above, specificmutations in FGF23 in the 176-179 amino acid residue sequence have beendiscovered in patients with ADHR (84). These mutations disrupt an RXXR

furin protease recognition site, and the resultant mutant molecule is thereby

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protected from proteolysis, and resultant elevated circulating levels of FGF23are the likely cause of the renal Pi wasting.

An apparent forme fruste of ADHR (autosomal dominant) hypophosphatemicbone disease has many of the characteristics of XLH and ADHR, but recent

reports indicate that affected children display no evidence of rachitic disease.Because this syndrome is described in only a few small kindreds, andradiographically evident rickets is not universal in children with familialhypophosphatemia, these families may have ADHR. Further observations arenecessary to discriminate this possibility.

AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIC RICKETS(ARHR)

Two recent reports describe families with phosphate wasting rickets inheritedin an autosomal recessive manner (86, 100). These patients have been foundto have the same constellation of progressive rachitic deformities seen in bothXLH and ADHR. Moreover the biochemical phenotype is manifest by the samemeasures of hypophosphatemia, excess urinary Pi losses, and aberrantvitamin D metabolism (normal circulating 25-OHD and 1,25(OH)2D levels,despite ambient hypophosphatemia) as observed in both XLH and ADHR. Inaddition to the expected phenotypic features, and in contrast to XLH, spinalradiographs of patients with ARHR reveal noticeably sclerotic vertebral bodies.In addition to the enlarged pulp chamber characteristic of teeth in individualswith XLH, enamel hypoplasia can be evident in heterozygotes. Of particularinterest is the identification of elevated levels of FGF23 in the affectedindividuals.

The identification of a progressive mineralization defect associated withhypophosphatemia in DMP1 knockout mice led to the consideration ofhomozygous loss of function in this candidate gene as the cause of ARHR.Indeed this has proven to be the case. Thus the role of the osteocyte product,DMP1, appears as either part of the PHEX-FGF23 pathway, or at least canaffect circulating FGF23 levels, perhaps independently of PHEX. Theseobservations suggest that the osteocyte plays a central role in mineralhomeostasis.

Experience with long-term follow-up is not widespread in ARHR andtherapeutic response or guidelines have not been definitively established.

TUMOR-INDUCED OSTEOMALACIA

Rickets and/or osteomalacia has been associated with various types of tumors(87). In many cases, the metabolic disturbances improved or completelydisappeared upon removal of the tumor, indicating a causal role of the tumor.Affected patients generally present with bone and muscle pain, muscleweakness, rickets/osteomalacia and occasionally recurrent fractures of longbones. Biochemistries include hypophosphatemia secondary to renalphosphate wasting and normal serum levels of calcium and 25(OH)D. Serum1,25(OH)2D is often overtly low or is otherwise inappropriately normal in thesetting of hypophosphatemia (Table 1). Aminoaciduria and/or glucosuria may

be present. Radiographic abnormalities include generalized osteopenia,pseudofractures and coarsened trabeculae, as well as widened epiphyseal

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plates in children. The histologic appearance of trabecular bone in affectedsubjects most often reflects the presence of a low turnover osteomalacia. Incontrast, bone biopsies from the few patients who have tumors that secrete anonparathyroid hormone factor(s), which activates adenylate cyclase, exhibitfeatures of enhanced bone turnover, including an increase in osteoclast andosteoblast number.

The large majority of patients with this syndrome harbor tumors ofmesenchymal origin, including primitive-appearing, mixed connective tissuelesions, osteoblastomas, nonossifying fibromas and ossifying fibromas. Inaddition tumors of epidermal and endodermal derivation have beenimplicated as causal of the disease. Indeed, the observation of tumor-inducedosteomalacia concurrent with breast carcinoma, prostate carcinoma oat cellcarcinoma, small cell carcinoma, multiple myeloma and chronic lymphocyticleukemia supports this conclusion. In addition, the occurrence of osteomalaciain patients with widespread fibrous dysplasia of bone, neurofibromatosis andlinear nevus sebaceous syndrome could be related to a similar mechanism as

with the more classic mesenchymal cell tumors. Although proof of a causalrelationship in these disorders has been precluded in general by an inability tosurgically excise the multiplicity of lesions, in one case of fibrous dysplasia,removal of virtually all of the abnormal bone did result in appropriatebiochemical and radiographic improvement.

Although this syndrome is relatively rare compared to XLH, the importance inits understanding of hypophosphatemia has been very important. The studyof these tumors eventually led to the identification and isolation of FGF23 (32,101), which has become a central factor in the entire class of disorders andrepresents a novel regulatory system affecting Pi homeostasis.

Regardless of the tumor cell type, the lesions at fault for the syndrome areoften small, difficult to locate and present in obscure areas which include thenasopharynx, jaw, sinuses, the popliteal region and the suprapatellar area. Inany case, a careful and thorough examination is necessary todocument/exclude the presence of such a tumor. Indeed, CT and/or MRI scanof a clinically suspicious area should be undertaken. Recently newer imagingtechniques such as octreotide scintigraphy or PET scans have been used tosuccessfully identify tumors that remained unidentified by other means oflocalization. Others have suggested directing imaging to anatomic regionsdefined by step-ups in FGF23 concentrations from selective venous sampling.

Pathophysiology

TIO is a result of Pi wasting secondary to circulating factor(s) secreted bycausal tumors. Although the leading candidate for the cause of TIO is FGF23,a variety of other factors have been considered as a potential part of thecascade that can lead to renal Pi wasting including: 1) FRP4 (frizzled relatedprotein 4) (39), a secreted protein with phosphaturic properties, 2) FGF7,which has been identified in TIO tumors and has been shown to inhibit renalPi transport (41), 3) the SIBLING protein, MEPE (matrix extracellularphosphglycoprotein), which has been reported to generate fragments (ASARMpeptide) with potential Pi wasting capacity (38), and 4) the SIBLING protein,DMP1, which has now been implicated in ARHR, and has been shown to be inparticularly high abundance in TIO tumors (32, 86, 101, 102). It is also

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possible that these or other tumor products may have direct effects on themineralization function of the skeleton.

In contrast to these observations, patients with TIO secondary tohematogenous malignancy manifest abnormalities of the syndrome due to a

distinctly different mechanism. In these subjects the nephropathy inducedwith light chain proteinuria or other immunoglobulin derivatives results in thedecreased renal tubular reabsorption of phosphate characteristic of thedisease. Thus, light-chain nephropathy must be considered a possiblemechanism for the TIO syndrome.

Treatment

The first and foremost treatment of TIO is complete resection of the tumor.However, recurrence of mesenchymal tumors, such as giant cell tumors ofbone, or inability to resect completely certain malignancies, such as prostaticcarcinoma, has resulted in development of alternative therapeutic

intervention for the syndrome. In this regard, administration of 1,25(OH)2Dalone or in combination with phosphorus supplementation has served aseffective therapy for TIO. Doses of calcitriol required range from 1.5-3.0g/d, while those of phosphorus are 2-4 g/d. Although little information isavailable regarding the long-term consequences of such treatment, the highdoses of medicine required raise the possibility that nephrolithiasis,nephrocalcinosis and hypercalcemia may frequently complicate thetherapeutic course. Indeed, hypercalcemia secondary to parathyroidhyperfunction has been documented in at least five treated subjects. All ofthese patients received phosphorus as part of a combination regimen, which

may have stimulated parathyroid hormone secretion and exacerbated thepath to parathyroid autonomy. Thus, careful assessment of parathyroidfunction, serum and urinary calcium and renal function are essential to ensuresafe and efficacious therapy.

DENT'S DISEASE (X-LINKED RECESSIVEHYPOPHOSPHATEMIA; XLRH)

The initial description of X-linked recessive hypophosphatemic ricketsinvolved a family in which males presented with rickets or osteomalacia,hypophosphatemia, and a reduced renal threshhold for phosphatereabsorption. In contrast to patients with XLH, affected subjects exhibitedhypercalciuria, elevated serum 1,25(OH)2D levels (Table 1), and proteinuriaof up to 3 g/day. Patients also developed nephrolithiasis and nephrocalcinosis

with progressive renal failure in early adulthood. Female carriers in the familywere not hypophosphatemic and lacked any biochemical abnormalities otherthan hypercalciuria. Three related syndromes have been reportedindependently: X-linked recessive nephrolithiasis with renal failure, Dent'sdisease, and low-molecular-weight proteinuria with hypercalciuria andnephrocalcinosis. These syndromes differ in degree from each other, butcommon themes include proximal tubular reabsorptive failure, nephrolithiasis,nephrocalcinosis, progressive renal insufficiency, and, in some cases, ricketsor osteomalacia. Identification of mutations in the voltage-gated chloride-channel gene CLCN5 in all four syndromes has established that they are

phenotypic variants of a single disease and are not separate entities(103,104). However, the varied manifestations that may be associated with

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mutations in this gene, particularly the presence of hypophosphatemia andrickets/osteomalacia, underscore that environmental differences, diet, and/ormodifying genetic backgrounds may influence phenotypic expression of thedisease.

HEREDITARY HYPOPHOSPHATEMIC RICKETS WITHHYPERCALCIURIA (HHRH)

This rare autosomal recessive disease is marked by hypophosphatemic ricketswith hypercalciuria (105). Initial symptoms of the disorder generally manifestbetween 6 months to 7 years of age and usually consist of bone pain and/ordeformities of the lower extremities. Such deformities may include genuvarum or genu valgum or anterior bowing of the femur and coxa vara.Additional disease features include short stature, and radiographic signs ofrickets or osteopenia. In contrast to XLH, muscle weakness is often elicited asa presenting symptom. Affected patients may exhibit these symptoms andfeatures of the disease in variable combination and in a mild or severe form.In contrast to other diseases in which renal phosphate transport is limited,patients with HHRH exhibit increased 1,25(OH)2D production. The resultantelevated serum calcitriol levels enhance the gastrointestinal calciumabsorption, which in turn increases the filtered renal calcium load and inhibitsPTH secretion. Collectively these events produce the hypercalciuria observedin affected patients (Table 1). Although initially not thought to be part of thesyndrome, kidney stones have been reported in several patients.

In general, the severity of the bone mineralization defect correlates inverselywith the prevailing serum Pi concentration. Relatives of patients with evidentHHRH may exhibit an additional mode of disease expression (106). These

subjects manifest hypercalciuria and hypophosphatemia, but theabnormalities are less marked and occur in the absence of discernible bonedisease, which would suggest a mild phenotype in the heterozygous statewith certain mutations.

After mutations in the candidate NPT2 gene encoding Na-Pi2a transporters,were excluded as causal to HHRH, the mutated gene in HHRH was identifiedas one of the lesser abundant renal tubular Na-Pi cotransporters, Na-Pi2c (30,107). As would be predicted by the isolated loss of function of a Pitransporter, reduced serum Pi and increased renal Pi losses occur. Howeverunlike the findings in XLH, Pi wasting does not coexist with limitations in1,25(OH)2D production, and the system retains its capacity to increase

1,25(OH)2D levels in response to the ambient hypophosphatemia.

Patients with HHRH have been treated successfully with high-dosephosphorus (1 to 2.5 g/day in five divided doses) alone. In response totherapy, bone pain disappears and muscular strength improves substantially.Moreover, the majority of treated subjects exhibit accelerated linear growth,and radiologic signs of rickets are completely absent within several months.Despite this favorable response, limited studies indicate that such treatmentdoes not completely heal the associated osteomalacia. Therefore, furtherstudies are necessary to determine if phosphorus alone is truly sufficient forthis disorder.

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Disorder of Phosphate Metabolism