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] (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 variant in a male proband; or
• A heterozygous PHEX pathogenic variant in a female proband.

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 at the most reasonable cost 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 comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing 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: -1.3 vs -0.4 SD). 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].