DiagnosisClinical Diagnosis The diagnosis of X-linked hypophosphatemia (XLH) is based on clinical findings, radiographic findings, biochemical testing, and family history. Clinical findings of rickets that often prompt consideration of XLH are: In children. Progressive lower extremity bowing with a decrease in height velocity after the child starts ambulating and the characteristic clinical signs of rickets: rachitic rosary, craniotabes, Harrison’s groove, and epiphyseal swellingIn adults. Musculoskeletal complaints, stress-fractures, dental abscesses, and/or the diagnosis of XLH in an offspring Radiographic findings. In children: the metaphyses may be widened, frayed, or cupped; sometimes rachitic rosary or beading of the ribs results from poor skeletal mineralization leading to overgrowth of the costochondral joint cartilage. Although involvement of the metaphyses of the lower limbs is typical, any metaphysis can be involved.TestingThe two main laboratory findings characteristic of XLH are:Low serum phosphate concentration. Normal phosphate concentrations vary with age with higher values observed in infants; therefore, it is important to use the age-related values. One widely used data set is reviewed in Table 1. Several studies have reported the normative data for age-related serum phosphate values [reviewed by Meites 1989]. Table 1. Age-Based Normal Serum Phosphate Reference IntervalsView in own windowAgemg/dLmmol/L0-5 days4.8-8.21.55-2.651-3 yrs3.8-6.51.25-2.104-11 yrs3.7-5.61.20-1.8012-15 yrs2.9-5.40.95-1.75>15 yrs2.7-4.70.90-1.50Lockitch et al [1988]Reduced tubular resorption of phosphate corrected for glomerular filtration rate (TmP/GFR). Historically, the calculation of TmP/GFR has relied on the nomogram-based method described by Walton and Bijvoet [1975] (Figure 1). In order to use the nomogram, the tubular resorption of phosphate (TRP) must first be calculated as follows:
TRP= 1- [(urine_phosphate/ plasma_phosphate)/(urine_creatinine/plasma_creatinine)]
When the TRP is less than 0.86, the TmP/GFR can be calculated directly as follows:
TmP/GFR= TRP x Plasma_{phosphateThe age-related reference ranges for the TmP/GFR are shown in Table 2 [Payne 1998].FigureFigure 1. Nomogram from Walton & Bijvoet [1975] for calculation of the tubular resorption of phosphate corrected for glomerular filtration rate (TmP/GFR) utilizing the plasma phosphate concentration and the calculated tubular resorption of phosphate: (more...)Table 2. Age-Based Normal TmP/GFR Reference IntervalsView in own windowAgeSexRange (mg/dL)Range (mmol/L)BirthBoth3.6-8.61.43-3.433 mosBoth3.7-8.251.48-3.306 mosBoth2.9-6.51.15-2.602-15 yrsBoth2.9-6.51.15-2.4425-35 yrsMale2.5- 3.41.00-1.3525-35 yrsFemale2.4- 3.60.96-1.4445-55 yrsMale2.2- 3.40.90-1.3545-55 yrsFemale2.2- 3.60.88-1.4265-75 yrsBoth2.0- 3.40.80-1.35Payne [1998]Note: For the calculation of the TRP the urine should be collected as an untimed urine after an overnight fast.Other laboratory findings include: Normal serum calcium and 25 OH vitamin D. Note: If the serum 25 OH vitamin D concentration is low, vitamin D levels need to be replete before the diagnosis of XLH can be confirmed by laboratory testing. Inappropriately normal serum calcitriol concentration in the presence of hypophosphatemiaNormal parathyroid hormone level; however, it may be minimally elevated in some individuals. Absence of glycosuria, bicarbonaturia, proteinuria, or amino aciduriaMolecular Genetic Testing Gene. PHEX (phosphate regulating endopeptidase homolog, X-linked) is the only gene in which mutations are known to cause XLH.Clinical testingSequence analysis of the 22 exon coding region and intronic borders of PHEX detected mutations in 57%-78% of individuals with the clinical and biochemical diagnosis of XLH [Holm et al 1997, Dixon et al 1998, Ichikawa et al 2008, Gaucher et al 2009, Ruppe et al 2011]. Some of the reports suggest a lower rate of mutation detection in simplex cases (i.e., a single occurrence in a family); however, this has not been clearly documented. Deletion/duplication analysis. Two studies utilized multiplex ligation-dependent probe amplification (MLPA) to detect deletions and duplications [Clausmeyer et al 2009, Morey et al 2011]. Of note, using both exon sequencing and MLPA analysis, Morey et al [2011] detected mutations in 100% of their cohort of 36 unrelated families. In contrast, the Clausmeyer study (which also utilized both techniques) failed to find a mutation in a subset of individuals tested. Table 3. Summary of Molecular Genetic Testing Used in X-Linked HypophosphatemiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityPHEXSequence analysisSequence variants 2Near 100% 3, 4ClinicalDeletion / duplication analysis 5Deletion / duplication of one or more exons or the whole gene 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. In a male, lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons; confirmation may require additional testing by deletion/duplication analysis. In a heterozygous female, sequence analysis of genomic DNA cannot detect deletion of one or more exons or an entire X-linked gene.4. Morey et al [2011]5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandLaboratory testing reveals low serum phosphate concentration with a reduced TmP/GFR based on normative values for age. Single gene testing. PHEX molecular genetic testing (sequence analysis followed by deletion/duplication analysis as needed) can be used to confirm the diagnosis, but is not required to establish the diagnosis in the presence of the characteristic biochemical findings. Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having hypophosphatemic rickets is use of a multi-gene panel. See Differential Diagnosis. This strategy of testing is useful when PHEX testing is negative. As with PHEX testing, it can be used to confirm a diagnosis but is not required to establish the diagnosis in the presence of diagnostic laboratory data. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in PHEX.}}

Natural History The clinical presentation of X-linked hypophosphatemia (XLH) ranges from isolated hypophosphatemia to severe lower extremity bowing. The diagnosis is frequently made in the first two years of life when lower extremity bowing becomes evident with the onset of weight bearing; however, because of the extremely variable presentation, the diagnosis is sometimes not made until adulthood.Skeletal abnormalities. Individuals with XLH commonly present with short stature and lower extremity bowing (valgus or varus deformities). Adults with XLH have a significantly reduced final height with a standard deviation score (SDS) of -1.9 in comparison to reference standards. The patients appear disproportionate, with leg length scores (-2.7) being significantly lower than those for sitting height (-1.1) [Beck-Nielsen et al 2010]. In a longitudinal study that assessed growth in children prior to and during treatment, Zivicnjak et al [2011a] found that untreated children had disproportionate total height (-2.48 SDS) to sitting height (-0.99 SDS); lower leg length was -2.90 SDS. During treatment there was an uncoupling of growth between the trunk and the legs: the difference between SDS sitting and lower leg length became more pronounced as the subjects grew.Jehan et al [2008] described changes in growth that are associated with different vitamin D receptor promoter haplotypes, providing a possible explanation for some of the clinical variability observed in XLH.In adults, calcification of the tendons, ligaments, and joint capsules, known as enthesopathy, can cause joint pain and impair mobility [Polisson et al 1985]. Increased osteophyte formation with spinal hyperostosis and arthritis or fusion of the sacroiliac joints can also lead to pain and compromised mobility. Enthesopathy of vertebral ligaments has been reported as well [Beck-Nielsen et al 2010], including a case report of spinal cord compression and paraplegia following calcification of the ligamenta flava [Vera et al 1997]. A radiologic survey of 38 untreated adults revealed flaring of the iliac wings, trapezoidal distal femoral condyles, shortening of the talar neck and flattening of the talar dome [Hardy et al 1989]. Looser’s zone or pseudofractures that may be symptomatic or asymptomatic were seen commonly and have been reported to occur at any age.Cranial structures. Cranial abnormalities include frontal bossing, craniosynostosis, and Chiari malformations. A detailed cephalometric study revealed an increased head length, a decreased occipital breadth, and a low mean cephalic index (the ratio of the maximum width of the head multiplied by 100 divided by its maximum length) [Pronicka et al 2004]. The incidence of Chiari malformations, which may cause headache and vertigo, has not been determined. Dental abnormalities. Persons with XLH are prone to spontaneous dental abscesses, which have been attributed to changes in the dentin component of teeth: irregular spaces with defective mineralization in the tooth dentin have been described [Boukpessi et al 2006]; panoramic imaging reveals enlarged pulp chambers with prominent pulp horns leading to susceptibility for abscess formation [Baroncelli et al 2006].Hearing loss. Sensorineural hearing loss has been reported; the actual prevalence of hearing loss is not known. Radiographic evaluation of a small number of persons with XLH and hearing loss showed generalized osteosclerosis and thickening of the petrous bone [O'Malley et al 1988], a finding that has not been evaluated in other cohorts.

Differential DiagnosisHypophosphatemic rickets multi-gene panels may include testing for a number of the genes associated with disorders discussed in this section. X-linked hypophosphatemia (XLH) shares clinical findings, radiographic findings, and biochemical profile with other genetic and acquired disorders of renal phosphate wasting.Table 4. Disorders of Renal Phosphate Wasting without HypercalciuriaView in own windowDisorderDefectPhenotype OMIM NumberGene/Locus OMIM NumberXLHPHEX mutation307800300550ADHRFGF23 mutation193100605380ARHR1DMP1 mutation241520600980ARHR2 ENPP1 mutation613312173335TIOMesenchymal tumor XLH = X-linked hypophosphatemiaADHR = autosomal dominant hypophosphatemic ricketsARHR1 = autosomal recessive hypophosphatemic rickets 1ARHR2 = autosomal recessive hypophosphatemic rickets 2TIO = tumor-induced osteomalaciaAutosomal dominant hypophosphatemic rickets (ADHR). Clinical and biochemical features are similar to those of XLH. The incidence of ADHR is unknown. It is much rarer than XLH: the number of reported kindreds is in the 100s. In some instances onset of ADHR is delayed and, rarely, the phosphate wasting resolves later in life [Econs & McEnery 1997]. Mutations in FGF23 are causative (Table 4). ADHR results in the stabilization of the full-length active form of the protein leading to prolonged or enhanced FGF23 action. Autosomal recessive hypophosphatemic rickets (ARHR) is an extremely rare form of hypophosphatemic rickets caused by mutations in DMP1 (ARHR1) [Feng et al 2006, Lorenz-Depiereux et al 2006] or ENPP1 (ARHR2) [Lorenz-Depiereux et al 2010, Levy-Litan et al 2010] (Table 4). To date only a few kindreds have been identified.Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia (OOM), is a paraneoplastic syndrome in which secretion of FGF23 by slow-growing mesenchymal tumors known as ‘phosphaturic mesenchymal tumors, mixed connective tissue type’ results in biochemical features like those of XLH [Folpe et al 2004]. Although the majority of individuals with TIO are adults, TIO can occur at any age. Over 300 affected individuals have been reported [Chong et al 2011]. Adults frequently have progressive muscle and bone pain; children have the skeletal deformities and growth retardation observed in XLH. Treatment relies on localization and resection of the tumor.Other disorders that have similar biochemical profiles to XLH and have distinguishing clinical features include:McCune Albright syndrome, characterized by fibrous dysplasia of the bone, precocious puberty, and café au lait lesions. The hypophosphatemic rickets observed in McCune Albright syndrome are associated with overproduction of FGF23 by the fibrous dysplastic bone resulting in renal phosphate wasting [Riminucci et al 2003].Linear nevus sebaceous syndrome (or epidermal nevus syndrome), characterized by multiple cutaneous nevi with radiologic evidence of fibrous dysplasia. The hypophosphatemia that is frequent in this disorder is biochemically indistinguishable from that seen in XLH. FGF23 is also implicated as the cause of the phosphate wasting in this disorder [Hoffman et al 2005].Hypophosphatemic disorders associated with increased 1,25(OH)₂ vitamin D and hypercalciuria (rather than the inappropriately normal 1,25(OH)₂ vitamin D that is seen in XLH) include:Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), caused by mutations in SLC34A3 (OMIM 241530)Hypophosphatemic nephrolithiasis/osteoporosis 1 and 2 (NPHLOP1, OMIM 612286 and NPHLOP2, OMIM 612287) caused by mutations in SLC34A1 (OMIM 182309) and SLC9A3R1 (OMIM 604990), respectivelyHypophosphatemic rickets, X-linked recessive (OMIM 300554) caused by mutations in CLCN5 (OMIM 300008)Renal phosphate loss can also be seen in Fanconi syndrome, in which the proximal renal tubule transport of many different substances can be impaired. Fanconi syndrome is differentiated from XLH by the presence of glycosuria, bicarbonaturia, and/or amino aciduria.The rachitic skeletal changes of nutritional and hereditary forms of rickets are indistinguishable. These types of rickets can be distinguished by biochemical testing: in hypophosphatemic rickets, serum concentrations of 25 OH vitamin D and calcium are normal, whereas in vitamin D-deficient rickets the 25 OH vitamin D serum concentration is low and the calcium concentration may be low or normal. The different forms of hypophosphatemic rickets are distinguished by the presence of hypercalciuria or elevated 1,25(OH)2D. Mode of inheritance and molecular genetic testing help distinguish the different forms of hereditary hypophosphatemic rickets without hypercalciuria (of which XLH is the most common).Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with X-linked hyposphatemia (XLH), the following evaluations are recommended:Children A lower extremity x-ray (teleoroentgenogram), and x-ray of the wrists to assess the extent of skeletal disease Bone age measurement to evaluate growth potential Dental examination Hearing evaluation Craniofacial examinationAdultsX-ray of skeletal sites with reported pain to assess for possible enthesopathy or stress fracturesDental examinationHearing evaluationIndividuals of any age. Evaluation of those with headache and vertigo for Chiari malformationTreatment of ManifestationsPharmacologic treatment focuses on improving pain and correcting bone deformation In children, treatment generally begins at the time of diagnosis and continues until long bone growth is complete. Treatment for most children consists of oral phosphate administered three to five times daily and high-dose calcitriol, the active form of vitamin D. Treatment is generally started at a low dose to avoid the gastrointestinal side effects of diarrhea and gastrointestinal upset. The doses are then titrated to a weight-based dose of calcitriol at 20 to 30 ng/kg/day administered in two to three divided doses and phosphate at 20 to 40 mg/kg/day administered in three to five divided doses [Carpenter et al 2011]. Some clinicians favor a high dose phase of treatment for up to a year. The high dose phase consists of calcitriol at 50-70 ng/kg/day (up to a maximum dose of 3.0 µg daily) along with the phosphate [Auricchio et al 2008]. The two different regimens have not been compared. The doses are adjusted based on (1) evidence of therapeutic success, including reduction in serum alkaline phosphatase activity, changes in musculoskeletal examination, improvement in radiographic rachitic changes, and, when possible, improved growth velocity; and (2) evidence of therapeutic complications, including hyperparathyroidism, hypercalciuria, and nephrocalcinosis (see Prevention of Secondary Complications). Note: Normalization of the serum phosphate concentration is not a therapeutic goal as normal serum phosphate concentration frequently indicates overtreatment and increases the risk for treatment-related complications.After growth is complete, lower doses of the medications can be used to reach the treatment goals. In adults, the role of treatment has not been well studied; treatment is generally reserved for individuals with symptoms, such as skeletal pain, upcoming orthopedic surgery, biochemical evidence of osteomalacia with an elevated alkaline phosphatase, or recurrent pseudofractures or stress fractures [Carpenter et al 2011]. The calcitriol doses that are frequently employed in adults are in the range of 0.50 to 0.75 µg daily; the phosphate is given as 750 to 1000 mg/day in three to four divided doses. As with children, the phosphate dose is slowly titrated to avoid gastrointestinal side effects: starting dose is 250 mg/day and titrated up by 250 mg/day each week until the final dose is reached. Orthopedic treatment. Despite what appears to be adequate pharmacologic therapy (see following Note:), some individuals have persistent lower limb bowing and torsion, which may lead to misalignment of the lower extremity. In these individuals, surgical treatment is frequently pursued. No control trials of the different surgical techniques have been undertaken; the literature consists of case series. Note: Poor compliance with pharmacologic therapy during childhood and the teen years may be one factor for persistent lower limb deformities. In prepubertal children who have not yet reached their peak growth velocity (generally before age 10 years), stapling or toggle plate insertion can be considered as a minimally invasive method of reversible hemi-epiphysiodesis [Novais & Stevens 2006]. Note: The risk with this procedure is prematurely stopping growth. In older children and adults, surgical techniques reported include distraction osteogenesis by external fixation, acute correction by external fixation with intramedullary nailing, internal fixation with intramedullary nailing, and acute correction intramedullary nailing [Song et al 2006, Petje et al 2008]. Additionally, total hip and knee arthroplasty is sometimes required because of degenerative joint disease and enthesopathy.Dental treatment. Because individuals with XLH are susceptible to recurrent dental abscesses which may result in premature loss of decidual and permanent teeth, good oral hygiene with flossing and regular dental care and fluoride treatments are the cornerstones of prevention. Pit and fissure sealants have been recommended but have not been well studied.Sensorineural hearing loss has been reported in persons with XLH. No studies have evaluated treatment options in these patients. See Hereditary Hearing Loss and Deafness Overview, Management.Other therapies. Human growth hormone has been used to stimulate growth in persons with XLH. Although HGH therapy is theoretically beneficial because of its potential to enhance renal phosphate reabsorption, early clinical trials have not shown consistent improvement in height attained. However, the two recent studies suggest that longitudinal/linear growth improves with growth hormone treatment [Makitie et al 2008, Zivicnjak et al 2011b]. Prevention of Primary ManifestationsSee Treatment of Manifestations, Pharmacologic treatment.Prevention of Secondary ComplicationsHyperparathyroidism is associated with treatment for XLH. Rarely hyperparathyroidism is present at the time of diagnosis; most often it occurs secondary to high phosphate doses and may proceed to tertiary hyperparathyroidism. In order to monitor for these complications, intact parathyroid hormone, serum calcium concentrations, and TmP/GFR should be measured quarterly (see Surveillance). If secondary hyperparathyroidism is identified, either the calcitriol dose may be increased or the phosphate dose decreased. A small clinical trial and several case reports have investigated the use of cinacalcet in adults with XLH who have secondary hyperparathyroidism [Alon et al 2008]. No long-term studies have been conducted. Only a few case reports of the use of cinacalcet in children are available. If tertiary hyperparathyroidism is identified, surgical evaluation is warranted.Hypercalcemia and hypercalciuria may also complicate long-term treatment for XLH and is associated with high calcitriol doses. Serum calcium concentrations and urine calcium/creatinine ratio should be monitored quarterly (see Surveillance). If hypercalcemia or hypercalciuria is detected, the calcitriol dose should be decreased.Nephrocalcinosis, reported in persons medically treated for XLH, may occur independent of hypercalcemia and hypercalciuria detected on laboratory evaluation. A baseline renal ultrasound examination should be performed at the start of treatment. The frequency of renal ultrasound examination to monitor for the development of nephrocalcinosis is not established; one- to five-year intervals have been recommended [Auricchio et al 2008, Carpenter et al 2011].SurveillancePeriodic clinical evaluation to assess for disease progression, treatment response, and therapeutic complications is indicated. For individuals on calcitriol and phosphate therapy the following are recommended: Quarterly monitoring of the following: serum concentrations of phosphate, calcium, and creatinine; alkaline phosphatase level; intact parathyroid hormone level; and urinary calcium, phosphate and creatinine to identify and thus prevent therapeutic complicationsIntermittent monitoring of lower extremity x-rays (teleoroentgenograms) to assess skeletal response to treatment. The frequency has not been well established. Annual renal ultrasound examination to assess for nephrocalcinosis. Note: The frequency has not been well established.Dental follow up twice a year (as for children and teenagers with a high risk for caries)Agents/Circumstances to AvoidIt is recommended that treatment with unopposed phosphate (without 1,25(OH)₂ vitamin D) be avoided as this is felt to increase the risk of hyperparathyroidism. Although 1,25(OH)₂ vitamin D has been used as a single agent, this use is felt to increase the risk of hypercalcemia, hypercalciuria, and nephrocalcinosis.Evaluation of Relatives at RiskTesting of at-risk children is warranted to ensure early diagnosis and early treatment for optimal outcome. Evaluation can be accomplished by:Molecular genetic testing if the PHEX mutation has been identified in the familyBiochemical testing. Infants with initially normal test results require reevaluation every two to three months until at least age one year. As XLH is X-linked dominant, heterozygote females may be affected to the same degree as males; thus, no role has been established for screening asymptomatic adult family members. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management No data are available on the use of phosphate and calcitriol in pregnant women who have XLH. Most women with XLH who are on active therapy at the time of conception are continued on treatment throughout the pregnancy with vigilant monitoring of urinary calcium-to-creatinine ratios to detect hypercalciuria early in order to modify treatment accordingly. Therapies Under InvestigationCurrently, a novel therapeutic agent KRN23 is under investigation for XLH. This is a recombinant human monoclonal antibody targeting FGF23. (See Molecular Genetics.)Search clinicaltrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. X-Linked Hypophosphatemia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPHEXXp22​.11Phosphate-regulating neutral endopeptidaseCatalogue of Somatic Mutations in Cancer (COSMIC)
PHEXdb Locus Database
PHEX homepage - Mendelian genesPHEXData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for X-Linked Hypophosphatemia (View All in OMIM) View in own window 300550PHOSPHATE-REGULATING ENDOPEPTIDASE HOMOLOG, X-LINKED; PHEX 307800HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT; XLHRMolecular Genetic Pathogenesis The function of the protein produced by PHEX is unknown. It is expressed predominantly in bones and teeth in osteoblasts, osteocytes, and odontoblasts. The structure of the protein suggests that it is an endopeptidase; however, the substrate for its proteolytic activity is unknown. Mutations in PHEX lead to increased serum levels of FGF23 [Jonsson et al 2003, Weber et al 2003]. The etiology of this increase is not understood as no direct link has been demonstrated between PHEX and FGF23. FGF23, which is produced by bone lineage cells, causes hypophosphatemia through internalization of the sodium-phosphate IIa and IIc cotransporters from the renal proximal tubule, leading to a decrease in phosphate reabsorption by the kidney and phosphate wasting [Segawa et al 2007, Gattineni et al 2009]. Additionally, FGF23 causes downregulation of the renal 1 α hydroxylase enzyme and upregulation of the 24 hydroxylase enzyme leading to impaired 1,25(OH)₂ vitamin D synthesis and increased degradation [Shimada et al 2004]. This dual defect in phosphate metabolism leads to poor bone mineralization and fractures. It has also been hypothesized that mutations in PHEX lead to an increase in direct inhibitors to bone mineralization, referred to as minhibins. The identification and the mechanism of action of these minhibins are unknown; it has been proposed that proteins containing protease-resistant acidic serine-aspartate-rich motif (ASARM peptide) such as those found in MEPE, DMP1, and OPN may play a role [Addison et al 2008, Martin et al 2008, David et al 2011] in the mineralization defect seen in XLH. The role of this newly described bone-kidney axis in phosphate homeostasis and bone mineralization is an area of ongoing research.Normal allelic variants. PHEX comprises 22 exons; the transcript length is 2861 bp (NM_000444.4). Pathologic allelic variants. Pathologic mutations include missense, nonsense, deletions, small intra-exonic insertions and deletions, duplications and at splice sites. Mutations have been reported in every exon, multiple different intronic splice sites, and the 5’ UTR. To date nearly 300 pathologic allelic variants have been described. The PHEX database (see Table A, Locus Specific) is dedicated to maintaining information about nucleotide variation found in PHEX. Normal gene product. PHEX codes for a 749-amino acid protein (OMIM 300550; NP_000435.3). Although there have been many possible targets for the endopeptidase activity of PHEX, its substrate has yet to be discovered. The protein is expressed primarily in cells of bone lineage, including osteoblasts, osteocytes and odontoblasts leading to its importance in phosphate regulation and mineralization of these tissues. While PHEX is expressed primarily in cells of bone and teeth lineage, the main protein effects on renal phosphate wasting and impaired vitamin D metabolism occur in the kidney.Abnormal gene product. Mutations in PHEX are considered loss of function mutations. As the function of PHEX is unknown, little is known about the function of the abnormal gene product.