Clinical characteristics.

The phenotypic spectrum of X-linked hypophosphatemia (XLH) ranges from isolated hypophosphatemia to severe lower-extremity bowing. XLH frequently manifests in the first two years of life when lower-extremity bowing becomes evident with the onset of weight bearing; however, it sometimes is not manifest until adulthood, as previously unevaluated short stature. In adults, enthesopathy (calcification of the tendons, ligaments, and joint capsules) associated with joint pain and impaired mobility may be the initial presenting complaint. Persons with XLH are prone to spontaneous dental abscesses; sensorineural hearing loss has also been reported.

Diagnosis/testing.

Low serum phosphate concentration and reduced tubular resorption of phosphate corrected for glomerular filtration rate (TmP/GFR) are characteristic. Additionally, the normal physiologic response to hypophosphatemia of an elevation of 1,25 (OH)₂ vitamin D is absent. Serum calcium and 25-hydroxy vitamin D are within the normal range; parathyroid hormone is normal to slightly elevated. Alkaline phosphatase is characteristically elevated in children, especially during periods of rapid growth, and usually returns to normal in adulthood with or without treatment. Identification of a hemizygous (in males) or heterozygous (in females) pathogenic variant in PHEX by molecular genetic testing confirms the diagnosis.

Management.

Treatment of manifestations: Pain and lower-extremity bowing improve with frequent oral administration of phosphate and high-dose calcitriol. Children are generally treated from the time of diagnosis until long bone growth is complete. The role of pharmacologic treatment in adults is less clear; such 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. Persistent lower-limb bowing and/or torsion resulting in misalignment of the lower extremity may require surgery.

Prevention of primary manifestations: Frequent oral administration of phosphate and high-dose calcitriol to minimize bowing of long bones during growth. Good oral hygiene with flossing, regular dental care, and active strategies to prevent dental abscesses.

Surveillance: For individuals on calcitriol and phosphate therapy:

• Quarterly monitoring of serum concentrations of phosphate, calcium, creatinine, alkaline phosphatase, intact parathyroid hormone; and urinary calcium, phosphate, and creatinine for evidence of hyperparathyroidism and increased renal phosphate or calcium excretion
• Annual lower-extremity x-rays to assess skeletal response to treatment
• Periodic renal ultrasound examination to assess for nephrocalcinosis
• Dental follow up twice a year

Agents/circumstances to avoid: Treatment with phosphate without calcitriol because of the increased risk for hyperparathyroidism.

Evaluation of relatives at risk: Molecular genetic testing (if the PHEX pathogenic variant has been identified in the family) or biochemical testing of infants at risk to ensure early treatment for optimal outcome.

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.

Genetic counseling.

X-linked hypophosphatemia is inherited in an X-linked manner. An affected male passes the pathogenic variant to all his daughters and none of his sons; an affected female passes the pathogenic variant to 50% of her offspring. Offspring who inherit the pathogenic variant will be affected, but because of the great intrafamilial variation, severity cannot be predicted. Prenatal testing for a pregnancy at increased risk is possible if the PHEX pathogenic variant in the family has been identified.

Suggestive Findings

X-linked hypophosphatemia (XLH) should be suspected in an individual with the following clinical findings, radiographic findings, and results of biochemical testing. It should be noted that this is a dominant X-linked disorder in which males and females are similarly affected.

Biochemical

The two main laboratory findings characteristic of XLH are low-serum phosphate concentration and reduced tubular resorption of phosphate corrected for glomerular filtration rate.

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 Intervals

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Age	mg/dL	mmol/L
0-5 days	4.8-8.2	1.55-2.65
1-3 yrs	3.8-6.5	1.25-2.10
4-11 yrs	3.7-5.6	1.20-1.80
12-15 yrs	2.9-5.4	0.95-1.75
>15 yrs	2.7-4.7	0.90-1.50

Lockitch 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 & Bijvoet [1975] (see Figure 1).

Figure 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: 1 (more...)

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_phosphate

The age-related reference ranges for the TmP/GFR are shown in Table 2 [Payne 1998].

Table 2.

Age-Based Normal TmP/GFR Reference Intervals

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Age	Sex	Range (mg/dL)	Range (mmol/L)
Birth	Both	3.6-8.6	1.43-3.43
3 mos	Both	3.7-8.25	1.48-3.30
6 mos	Both	2.9-6.5	1.15-2.60
2-15 yrs	Both	2.9-6.5	1.15-2.44
25-35 yrs	Male	2.5-3.4	1.00-1.35
25-35 yrs	Female	2.4-3.6	0.96-1.44
45-55 yrs	Male	2.2-3.4	0.90-1.35
45-55 yrs	Female	2.2-3.6	0.88-1.42
65-75 yrs	Both	2.0-3.4	0.80-1.35

Payne [1998]

Note: For the calculation of the TRP the urine should be collected as an untimed urine after an overnight fast.

Other suggestive laboratory findings include:

• Normal serum calcium and 25-hydroxyvitamin D [25(OH)D]. Note: If the serum 25(OH)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 hypophosphatemia
• Normal parathyroid hormone level; however, it may be minimally elevated in some individuals.
• Absence of glycosuria, bicarbonaturia, proteinuria, or amino aciduria

Establishing the Diagnosis

The diagnosis of XLH is established in a proband with low serum phosphate concentration (see Table 1), a reduced TmP/GFR based on normative values for age (see Table 2), an inappropriate level of calcitriol for the level of hypophosphatemia, and/or by identification on molecular genetic testing of:

• A hemizygous PHEX pathogenic (or likely pathogenic) variant in a male proband; or
• A heterozygous PHEX pathogenic (or likely pathogenic) variant in a female proband.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of PHEX is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
• A multigene panel that includes PHEX and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

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.

Genotype-Phenotype Correlations

Several studies have evaluated genotype-phenotype correlations in XLH.

• The largest study, involving 59 persons, correlated dental and hearing defects with pathogenic variants in exons near the 5' (or beginning) of the gene and increased head length with pathogenic variants in exons near the end of the gene [Popowska et al 2001].
• Two studies suggested a correlation between more severe bone disease (defined by the severity of bowing and a history of osteotomies) and truncating variants [Holm et al 2001] or pathogenic variants in the C-terminal portion of PHEX [Song et al 2007].
• A study by Morey et al [2011] showed that clearly deleterious PHEX pathogenic variants (nonsense variants, insertions or deletions, and splice site variants leading to premature stop codons) had lower tubular resorption of phosphate and lower calcitriol levels than did plausibly deleterious variants (missense changes or in-frame deletions).

Penetrance

Despite a wide degree of clinical variability in XLH, penetrance is often said to be 100% by age one year [Sabbagh et al 2014]. There is no known difference between penetrance in males and females.

One instance of discordance for XLH in monozygotic twin girls was reported by Owen et al [2009]: at age 19 months the girls were diagnosed with XLH based on biochemical findings and family history; no PHEX pathogenic variant was identified in either twin. One twin was significantly shorter than the other (length z scores: -1.3 vs -0.4). The shorter twin had marked bilateral genu varum; the other twin had mild genu valgum. The authors proposed that non-penetrance resulted from discordant X-chromosome inactivation with non-random lack of PHEX expression in critical tissues.

Nomenclature

X-linked hypophosphatemia (or its common abbreviation, XLH) is the current and preferable term. Other terms that have been used:

• X-linked hypophosphatemic rickets (XLH)
• Hypophosphatemic rickets
• X-linked dominant hypophosphatemic rickets (XLHR)
• X-linked rickets (XLR)
• Vitamin D-resistant rickets
• X-linked vitamin D-resistant rickets (VDRR)
• Hypophosphatemic vitamin D-resistant rickets (HPDR)
• Phosphate diabetes
• Familial hypophosphatemic rickets

Prevalence

The incidence of XLH is 3.9-5 per 100,000 live births [Davies & Stanbury 1981, Beck-Nielsen et al 2009].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with X-linked hypophosphatemia (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
• Craniofacial examination for signs of craniosynostosis
• Dental examination
• Hearing evaluation

Adults

• X-ray of skeletal sites with reported pain to assess for possible enthesopathy or stress fractures
• Dental examination
• Hearing evaluation

Individuals of any age

• Evaluation of those with headache and vertigo for Chiari malformation
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Pharmacologic 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. Two different regimens have been used, but have not been compared:

• Low dose. 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].
• High dose. 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 [Sabbagh et al 2014].

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.

Jehan et al [2008] described differences in growth during treatment that are associated with different vitamin D receptor promoter haplotypes, providing a possible explanation for some of the clinical variability observed in XLH.

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 at 250 mg/day and titrating 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 by 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. Treatment in adults has not been shown to influence enthesopathy [Connor et al 2015].

Craniofacial treatment. Although hypophosphatemic rickets is a rare condition, a recent review from three neurosurgical centers reported on ten patients treated over 20 years and recommended prompt referral to a craniofacial specialist when head shape abnormalities are seen in patients with this disorder [Vega et al 2016].

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. A recent study has suggested that treatment of adults with phosphate and calcitriol can improve the severity of dental disease [Connor et al 2015].

Sensorineural hearing loss has been reported in persons with XLH; individuals with this complication are treated in a standard manner. See Hereditary Hearing Loss and Deafness Overview, Management.

Prevention of Primary Manifestations

See Treatment of Manifestations, Pharmacologic treatment.

Prevention of Secondary Complications

Hyperparathyroidism 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. The clinical trial (comprising 8 individuals ages 6-19) involved in-patient monitoring of phosphate, iPTH, and Tmp/GFR after a single dose of cinacalcet; results showed a decrease in iPTH and an increase in phosphate and TmP/GFR.

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 [Carpenter et al 2011, Sabbagh et al 2014].

Surveillance

Periodic 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 complications
• Intermittent monitoring of lower-extremity x-rays (teleoroentgenograms) to assess skeletal response to treatment. The frequency has not been well established; although annual imaging can be considered, the decision for imaging should be based on symptoms and physical examination findings.
• Renal ultrasound examination to assess for nephrocalcinosis. The frequency has not been well established.
• Dental follow up twice a year (as for children and teenagers at high risk for caries)

Agents/Circumstances to Avoid

It is recommended that treatment with unopposed phosphate (without 1,25(OH)₂ vitamin D) be avoided as this is felt to increase the risk for hyperparathyroidism.

Although 1,25(OH)₂ vitamin D has been used as a single agent, this use is felt to increase the risk for hypercalcemia, hypercalciuria, and nephrocalcinosis.

Evaluation of Relatives at Risk

Testing of at-risk infants and children is warranted to ensure early diagnosis and early treatment for optimal outcome.

Evaluation can be accomplished by:

• Molecular genetic testing if the PHEX pathogenic variant has been identified in an affected family member;
• Biochemical testing consisting of serum phosphorus, creatinine, calcium, alkaline phosphatase, intact parathyroid hormone, 25-hydroxy vitamin D [25(OH)D], and 1,25(OH)₂ vitamin D concentrations and urine phosphorus and creatinine concentrations. Infants with initially normal test results require reevaluation every two to three months until at least age one year.

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 on the use of phosphate and calcitriol in pregnant women with XLH are available. 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. Those individuals who are not on therapy at the time of conception are generally not started on treatment during pregnancy.

Therapies Under Investigation

Currently, a novel therapeutic agent KRN23 is under investigation for XLH. This is a recombinant human monoclonal antibody targeting FGF23 (see Molecular Genetics). A randomized trial of a single dose of KRN23 has shown an increase in the renal tubular threshold for phosphate reabsorption (TmP/GFR) and an increase in serum Pi and 1,25(OH)₂D compared with placebo [Carpenter et al 2014]. A second study in adults looking at monthly dosing of KRN23 for 16 months demonstrated increases in serum phosphate, TmP/GFR, and 1,25 (OH)2D3 [Imel et al 2015]. Analysis from quality of life testing during the first four months of the trial showed improvements in physical functioning and stiffness [Ruppe et al 2016]. Phase II studies in adults and children with XLH are ongoing.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

X-linked hypophosphatemia (XLH) is inherited in an X-linked dominant manner.

Risk to Family Members

Parents of a proband

• Male proband
  • The father of an affected male will not have the disorder nor will he be hemizygous for the PHEX pathogenic variant; therefore, he does not require further evaluation/testing.
  • If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous for the pathogenic variant or the affected male may have a de novo pathogenic variant. Molecular genetic testing is recommended for the mother of a male proband with an apparent de novo pathogenic variant.
  • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote and may have clinical findings. Note: If the mother of a male proband has more than one affected child and no other affected relatives and if the PHEX pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• Female proband
  • A female proband may have inherited the PHEX pathogenic variant from either her mother or her father, or the pathogenic variant may be de novo. Molecular genetic testing is recommended for the parents of a female proband with an apparent de novo pathogenic variant
  • If the pathogenic variant found in a female proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Somatic and germline mosaicism has been reported in a father who transmitted the PHEX pathogenic variant to only one of his two daughters [Goji et al 2006].
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until biochemical or molecular genetic testing is done on at-risk relatives [Gaucher et al 2009].

Sibs of a proband

• The risk to sibs depends on the genetic status of the parents:
  • If the father of the proband has a PHEX pathogenic variant, he will transmit the disease to all of his daughters (who will be affected) and none of his sons.
  • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Offspring who inherit the pathogenic variant will be affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. Somatic and germline mosaicism has been reported in a father who transmitted the PHEX pathogenic variant to only one of his two daughters [Goji et al 2006].

Offspring of a male proband. Affected males transmit the PHEX pathogenic variant to:

• All of their daughters, who will be heterozygotes and will be affected;
• None of their sons.

Offspring of a female proband

• Affected females pass the PHEX pathogenic variant to 50% of their offspring.
• Male and female offspring who inherit the pathogenic variant will be affected.

Related Genetic Counseling Issues

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant occurred, information that could help determine the genetic risk status of the extended family.

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the PHEX pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for XLH are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.

Molecular 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.

Pathogenic variants 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 pathogenic variants 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 bone-kidney axis in phosphate homeostasis and bone mineralization is an area of ongoing research.

Gene structure. PHEX comprises 22 exons; the transcript length is 2861 bp (NM_000444.4). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic variants include missense and nonsense variants, deletions, small intra-exon insertions and deletions, duplications, and splice site variants. Pathogenic variants have been reported in every exon, multiple different intronic splice sites, and the 5' UTR. To date nearly 300 pathogenic variants have been described. The PHEX database (see Table A, Locus-Specific Databases) is dedicated to maintaining information about nucleotide variation found in PHEX.

Normal gene product. PHEX codes for a 749-amino acid protein (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. Pathogenic variants in PHEX are considered loss-of-function variants. As the function of PHEX is unknown, little is known about the function of the abnormal gene product.

Author Notes

Dr Mary Ruppe is an endocrinologist who specializes in the treatment of adult and pediatric patients with metabolic bone disease. She oversees the pediatric rickets clinic at the Shriners Hospital in Houston, TX and runs a metabolic bone clinic at The Methodist Hospital in Houston, TX. She is currently the local site principal investigator for several clinical trials on the treatment of XLH and conducts a large cohort study evaluating the clinical regulators of FGF23 in XLH.

Revision History

• 13 April 2017 (ha) Comprehensive update posted live
• 16 October 2014 (me) Comprehensive update posted live
• 27 September 2012 (cd) Revision: multigene panels for hypophosphatemic rickets available clinically
• 9 February 2012 (me) Review posted live
• 1 September 2011 (mr) Initial submission

Literature Cited

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