Alternative titles; symbols
SNOMEDCT: 82236004; ICD10CM: E83.31; ORPHA: 89936; DO: 0050445;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp22.11 | Hypophosphatemic rickets, X-linked dominant | 307800 | X-linked dominant | 3 | PHEX | 300550 |
A number sign (#) is used with this entry because X-linked dominant hypophosphatemic rickets (XLHRD) is caused by mutation in the phosphate-regulating endopeptidase gene (PHEX; 300550) on chromosome Xp22.
For a general phenotypic description and a discussion of genetic heterogeneity of hypophosphatemic rickets, see 193100.
X-linked dominant hypophosphatemic rickets (XLHRD), although variable in its expressivity, is characterized by rickets with bone deformities, short stature, dental anomalies, and at the biologic level, hypophosphatemia with low renal phosphate reabsorption, normal serum calcium level with hypocalciuria, normal or low serum level of vitamin D (1,25(OH)2D3, or calcitriol), normal serum level of PTH, and increased activity of serum alkaline phosphatases (summary by Gaucher et al., 2009).
Winters et al. (1958) observed hypophosphatemia in a large North Carolina family of English-Scottish extraction. The degree of depression of serum phosphate was the same in males and females, although the severity of bone disease was much less severe in females. There were no instances of male-to-male transmission of either bone disease or hypophosphatemia, and all daughters of hypophosphatemic males were themselves hypophosphatemic, suggesting X-linked dominant inheritance. Affected persons, both males and females, showed a reduction in renal phosphate reabsorption per glomerular filtration rate (TmP/GFR) to about 50% of normal.
In a study of patients with hypophosphatemia, Stickler (1969) concluded that hypophosphatemia was already present in the neonatal period, that alkaline phosphatase was elevated at 1 month of age, and that early treatment with high doses of vitamin D did not prevent growth failure. Patients with the X-linked disorder do not show muscle weakness, tetany, or hypocalcemia.
Adults, especially males, with XLH may develop progressive ankylosis of the spine and major joints, simulating ankylosing spondylitis (106300). Highman et al. (1970) reported compression of the spinal cord or 'spinal stenosis,' and noted that treatment with vitamin D may be responsible. Moser and Fessel (1974) commented on the misdiagnosis of ankylosing spondylitis in adults. Adams and Davies (1986) described 4 XLH patients with spinal cord compression; 3 had successful treatment with decompressive laminectomy. At surgery, new bone formation in the ligamentum flavum and thickening of laminae were found to be responsible for the canal stenosis and cord compression. Computed tomography was useful in evaluating the site and extent of intraspinal new bone formation.
Polisson et al. (1985) studied the calcification and ossification of entheses (tendons, ligaments, and joint capsules) in 26 patients from 11 kindreds with XLH. They found entheses involvement in 69% of patients, with the most commonly affected sites being the hand and sacroiliac joints. Histologic examination of 1 case showed intratendinous lamellar bone without inflammatory cells. Polisson et al. (1985) concluded that calcification of entheses is an integral part of XLH, which can be differentiated from degenerative disorders and seronegative spondyloarthropathies. Hardy et al. (1989) analyzed the skeletal radiographic features in 38 'essentially untreated' adults with XLH. Osteoarthritis was common in the ankles, wrists, knees, feet, and sacroiliac joints. All of the older patients had enthesopathy, often accompanied by extra ossicles. Curvatures of the lower-extremity long bones were common in all age groups. Other findings included flaring of the iliac wings, trapezoidal distal femoral condyles, shortening of the talar neck, and flattening of the talar dome. The findings were more severe in men.
Shields et al. (1990) used the index they call PRATIO (ratio of pulp area to tooth area) to study patients with X-linked hypophosphatemia. They found high values in affected males and intermediate values in heterozygous females, suggesting primary expression of the causative gene in the teeth, as well as in the kidney.
Patients with XLH have normal or low serum levels of 1,25-dihydroxyvitamin D3 (also known as calcitriol, the active form of vitamin D), despite having hypophosphatemia, which is a known stimulus of 25-hydroxyvitamin D-1-alpha-hydroxylase activity (CYP27B1; 609506). Administration of parathyroid hormone (PTH; 168450) results in blunted stimulation of serum calcitriol levels in both humans and the murine model of XLH, the 'Hyp' mouse. However, Econs et al. (1992) found that calcitriol concentrations increased in XLH patients in response to calcitonin (114130), as had been observed in the mouse. The findings indicated that patients with XLH have an incomplete defect in the regulation of 25-hydroxyvitamin D-1-alpha-hydroxylase activity: no response to PTH, but normal response to calcitonin.
Deafness has been rarely reported in humans with X-linked hypophosphatemia (Davies et al., 1984; O'Malley et al., 1985). However, Fishman et al. (2004) concluded that hearing impairment is not a feature of XLH in childhood. They found that 15 of 15 children under the age of 18 years showed no deficits attributable to XLH; 1 had hearing loss due to other causes. Three of 10 parents with XLH did show sensorineural hearing loss, suggesting that hearing loss in adults is due to XLH, particularly in cases with severe bone involvement.
Glorieux et al. (1972) found growth restoration in patients with XLH when inorganic phosphate and vitamin D2 were administered, consistent with the theory that the defect was primarily due to loss of phosphate at the level of the renal tubule. They also showed a direct correlation between the level of serum inorganic phosphate and whole blood oxygen pressure at 50% oxygen saturation, and speculated that low Pi may inhibit synthesis of 2,3-diphosphoglycerate in red cells with resulting inhibition of release of oxygen to tissues. Glorieux et al. (1972) suggested that this might be the mechanism of growth retardation.
On the basis of a follow-up study, McNair and Stickler (1969) questioned whether vitamin D therapy had any beneficial effect on growth in familial hypophosphatemic rickets. Stickler and Morgenstern (1989) analyzed heights and symptoms of 52 patients, aged at least 18 years, with hypophosphatemic rickets. They found no evidence that any form of treatment had any effect on adult height, symptoms, or alkaline phosphatase levels. There was a negative relation between adult height and the number of osteotomies undergone. Stickler and Morgenstern (1989) concluded that complications of treatment with vitamin D, such as renal failure, which appeared secondary to vitamin D intoxication in 3 patients in their twenties, outweighed any possible benefits.
Both vitamin D and phosphate supplementation are necessary for the treatment of X-linked hypophosphatemia, whereas calcitriol alone and phosphate alone appear to suffice in the autosomal dominant (193100) and autosomal recessive (241520) disorders, respectively. Harrell et al. (1985) found that complete healing of the bone lesions in X-linked hypophosphatemic patients could be induced with supraphysiologic doses of calcitriol, 1,25(OH)2-vitamin D, in combination with oral phosphorus. Although calcitriol dose reduction was necessary once healing was achieved, bone was maintained normally for up to a year on lower doses of 1,25(OH)-vitamin D and continued phosphorus supplementation. However, therapy only partially corrected skeletal lesions and was often complicated by hyperparathyroidism.
Because of the disputed value of phosphate and vitamin D therapy and the recognized complication of nephrocalcinosis, Verge et al. (1991), in Sydney, Australia, studied therapy in 9 boys and 15 girls and compared the results with those reported in 1971 in 16 untreated Australian patients. The 19 patients treated for at least 2 years before the onset of puberty had a mean height standard-deviation score of -1.08, as compared with -2.05 in the untreated historical controls. Nineteen of the 24 patients had nephrocalcinosis detected on renal ultrasonography. The grade of nephrocalcinosis was significantly correlated with the mean phosphate dose, but not with the dose of vitamin D or the duration of therapy. However, all patients had normal serum creatinine concentrations. Glorieux (1991) suggested that the reason Verge et al. (1991) failed to find a correlation with the dose of vitamin D was due to their use of a narrow range of dosages in their patients. Glorieux (1991) commented that combined treatment had brought about a dramatic decrease in the need for corrective osteotomies in this disorder and that the question of whether treatment should be continued after growth has ceased remained an open question. He also referred to the informative patient described by Harrison et al. (1966): a girl with dwarfism and X-linked hypophosphatemic rickets had severe vitamin D intoxication at the age of 3 years, which permanently reduced her glomerular filtration rate by 50%. As a consequence of the renal dysfunction, her serum phosphate concentration thereafter became normal and her growth rate accelerated so that her height reached the 50th percentile by the time she became an adult.
Petersen et al. (1992) reviewed the growth patterns of 20 children with XLH. Their findings suggested that calcitriol has a direct effect on the renal tubule to improve reclamation of inorganic phosphate in this disorder. Heterozygous girls appeared to respond to therapy better than did hemizygous boys, an observation that provided evidence for a gene dosage effect in the expression of this disorder.
Firth et al. (1985) reported 2 patients with hypophosphatemic rickets in whom long-term (over 10 years) therapy with phosphate and vitamin D resulted in hypercalcemic hyperparathyroidism with surgically proven adenomatous hyperplasia, consistent with tertiary hyperparathyroidism. Rivkees et al. (1992) reported the development of tertiary hyperparathyroidism in 3 girls with hypophosphatemic rickets treated with high doses of phosphate and vitamin D. Even in the presence of very high parathyroid hormone, oral phosphate lowered serum calcium and stimulated further PTH secretion. Surgical resection in all 3 cases showed profound multiglandular parathyroid hyperplasia. Carpenter et al. (1994) demonstrated exaggerated nocturnal rises in PTH in patients with XLH. They suggested that hyperparathyroidism in untreated XLH is a secondary event that compensates for impaired skeletal calcium mobilization. Hyperparathyroidism may contribute to the pathogenesis of nephrocalcinosis and precede the development of tertiary hyperparathyroidism. Although 2 of their patients with previous elevations of PTH showed normalization after medication adjustments, continued therapy appeared to aggravate the hyperparathyroidism. Tertiary hyperparathyroidism is thus a complication of treatment that exacerbates the primary disease process of renal tubular phosphate wasting, often prompting an increase in supplementary phosphate, which further stimulates the parathyroid gland. Savio et al. (2004) reported 6 unrelated patients with XLH who developed tertiary hyperparathyroidism after long-term therapy with phosphate and vitamin D. After parathyroidectomy, the patients developed severe hypocalcemia necessitating intravenous calcium infusion. Long-term, all patients achieved normocalcemia.
In a placebo-controlled trial of 24,25(OH)2D3 supplementation in 15 HYP patients, Carpenter et al. (1996) found that supplementation with 24,25(OH)2D3 normalized PTH values in 9 subjects (peak PTH was 46.5 +/- 6.6 pmol/L at entry, 42.3 +/- 5.9 pmol/L after placebo, and 23.3 +/- 5.4 pmol/L after 24,25(OH)2D3). Nephrogenous cAMP decreased at night, coincident with the decrease in PTH, and serum phosphorus was slightly greater with 24,25(OH)2D3 treatment. Radiographic features of rickets improved during 24,25(OH)2D3 supplementation in children, and osteoid surface decreased in bone biopsies of adults.
Despite oral phosphate and 1,25-dihydroxyvitamin D3 treatment, many patients with X-linked hypophosphatemic rickets have suboptimal growth and bone healing. In a study of 19 well-controlled HYP patients, Makitie et al. (2003) found that the 8 patients who had treatment before age 1.0 years had higher median height z-scores than the 11 patients with treatment onset after age 1.0 years. Scores were higher in the early treatment group at treatment onset (-0.4 SD vs -1.7 SD), at the end of the first treatment year (-0.7 SD vs -1.8 SD), throughout childhood, and until predicted adult height. The degree of hypophosphatemia was similar in both groups, but serum alkaline phosphatase remained higher in the second group throughout childhood. Radiographic signs of rickets were more marked in the second group, but even patients with early treatment developed significant skeletal changes of rickets. The authors concluded that treatment commenced in early infancy results in improved outcome in patients with XLH, but does not completely normalize skeletal development.
Nehgme et al. (1997) evaluated cardiovascular status in 13 XLH patients. While their serum calcium and creatinine clearances were normal, they all had mild to moderate nephrocalcinosis. Left ventricular hypertrophy was diagnosed by electrocardiogram in 3 and by ultrasonography in 7. Although baseline blood pressures (BP) were normal, the patients showed an abnormal increase in diastolic BP at all levels of workload; their peak/(mean +/- SD) exercise diastolic BP was 91 +/- 12 versus 72 +/- 6 mm Hg in controls (p less than 0.0001). The authors suggested that patients with XLH should be monitored closely for the development of hypertension and left ventricular hypertrophy.
Seikaly et al. (1997) studied the effects of recombinant growth hormone (GH; 139250) therapy on height, mineral metabolism, parathyroid function, serum 1,25-(OH)2 vitamin D, osteocalcin, growth hormone, urinary calcium, phosphate, nephrocalcinosis, renal function, and bone density in 5 children with XLH. The growth velocity standard deviation score was -1.90 +/- 0.40 during 12 months of placebo administration and 4.04 +/- 1.50 during 12 months of recombinant GH therapy. An increase in serum phosphate from 0.88 +/- 0.07 to 1.17 +/- 0.14 mmol/L, and in the tubular maximum for phosphate reabsorption from 2.12 +/- 0.15 to 3.41 +/- 0.25 mg/dL, was observed after 3 months of recombinant GH therapy. However, both serum phosphate and tubular maximum for phosphate reabsorption were unchanged from baseline after 6, 9, and 12 months of recombinant GH therapy. Seikaly et al. (1997) concluded that patients with XLH have an improvement in linear growth and a transient increase in serum phosphate attributable to a transient decrease in urinary phosphate excretion when treated with recombinant GH.
Liu et al. (2011) measured the serum levels of FGF23 (605380) and indices of mineral metabolism over 24 hours in 7 untreated patients with X-linked hypophosphatemia and in 6 controls after a single subcutaneous injection of 200 IU of salmon calcitonin. The patients had a significant drop in serum FGF23 level from baseline 4 hours after injection, and levels remained below baseline for 16 hours. The controls showed no significant change in FGF23 levels. Liu et al. (2011) suggested that their study raised the possibility that calcitonin is a therapeutic option for patients with X-linked hypophosphatemia.
Carpenter et al. (2018) performed an open-label, phase 2 clinical trial randomly assigning 52 children between 5 and 12 years of age with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab, a monoclonal antibody that targets FGF23, either every 2 weeks or every 4 weeks. The primary endpoint was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score. In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Treatment with burosumab improved the severity of rickets, linear growth, renal tubular phosphate reabsorption, and serum phosphorus levels. Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity. Carpenter et al. (2018) concluded that burosumab at a dose of approximately 1.0 mg/kg administered every 2 weeks is an appropriate regimen for improving renal tubular phosphate reabsorption and clinical outcomes in children with X-linked hypophosphatemia.
By an oral phosphate tolerance test, Condon et al. (1970) demonstrated defective intestinal absorption of phosphate in familial hypophosphatemia. Short et al. (1973) demonstrated a defect in transport of inorganic phosphate by intestinal mucosa in familial hypophosphatemia. Earp et al. (1970) and Cohanim et al. (1972) found that treatment with 25-hydroxycholecalciferol was ineffective in patients with familial hypophosphatemic rickets, suggesting that the basic defect was not in the conversion of vitamin D to the active form. Glorieux and Scriver (1972) postulated a defect in the parathyroid hormone-sensitive component of phosphate transport in kidney cells. Since calcium promotes phosphate reabsorption, the authors suggested that any beneficial effect of vitamin D therapy was secondary to the effects on calcium metabolism. Short et al. (1974) proposed that the renal tubule in XLH is hyperresponsive to the phosphaturic effect of parathyroid hormone.
Quarles and Drezner (2001) reviewed the pathophysiology of X-linked hypophosphatemia.
From a study of the comparative mapping of the human and mouse X chromosomes and the location of mouse Hpdr (also symbolized Hyp), Buckle et al. (1985) predicted that the human HPDR locus may be either between GLA (300644) and HPRT (308000) or in the distal part of Xp.
Studying 11 XLH families with RFLP markers, Read et al. (1986) mapped the XLH locus distal to DXS41, which had been located at Xp22.31-p21.3 by in situ hybridization (peak lod score of 4.82 at 10% recombination). Machler et al. (1986) found closer linkage with DXS41 (peak lod of 5.084 at theta = 0.00); there was no recombination in 17 meiotic events. Both groups concluded that the location on distal Xp is consistent with the scheme that relates the mouse and human X chromosomes by 2 inverted insertions (Buckle et al., 1985). Thakker et al. (1987) established that the HPDR1 locus lies distal to DXS41 and proximal to DXS43, located 11 cM and 14 cM, respectively, from the 2 markers.
Econs et al. (1990) demonstrated linkage of the XLH gene to a polymorphic probe derived from the glycine receptor alpha-2 gene (GLRA2; 305990). Econs et al. (1991) identified closely situated flanking markers in region Xp22.2-p22.1.
In 14 of 15 families with X-linked hypophosphatemia inherited through 2 or more generations, Rowe et al. (1992) found close linkage to 3 DNA markers. The 1 exception was a family with a large number of recombinants, 4 of which were double recombinants. Rowe et al. (1992) suggested that the disease in this family (family A) mapped elsewhere on the X chromosome or on an autosome. This family had been described by Read et al. (1986) and by Thakker et al. (1987, 1990), and was later found to have autosomal dominant disease (193100) caused by mutation in the FGF23 gene (ADHR Consortium, 2000).
In 3 unrelated patients with X-linked hypophosphatemia, the HYP Consortium (1995) identified 3 different mutations in the PHEX gene (300550.0001-300550.0003).
Holm et al. (1997) identified mutations in the PHEX gene in 9 of 22 unrelated patients: 3 nonsense mutations, a 1-bp deletion leading to a frameshift, a donor-splice site mutation, and missense mutations in 4 patients (see, e.g., 300550.0004-300550.0006).
In affected members of a kindred originally reported by Frymoyer and Hodgkin (1977) as having a distinct disorder they designated as 'adult-onset vitamin D-resistant hypophosphatemic osteomalacia' (AVDRR), Econs et al. (1998) identified a missense mutation in the PHEX gene (L555P; 300550.0007). Econs et al. (1998) concluded that there is only one form of X-linked dominant phosphate wasting.
Sabbagh et al. (2000) stated that 131 HYP-causing mutations in the PHEX gene had been reported. They announced the creation of an online PHEX mutation database for the collection and distribution of information on PHEX mutations.
Cho et al. (2005) identified mutations in the PHEX gene in 8 of 17 unrelated Korean patients with hypophosphatemic rickets; the 9 patients without mutations were all female. No genotype-phenotype correlations were identified among the children with PHEX mutations. Treatment with vitamin D and phosphate was frequently complicated by hypercalciuria, hypercalcemia, nephrocalcinosis, or hyperparathyroidism.
Makras et al. (2008) described 3 members of a family in which a splice site mutation in the PHEX gene resulted in hypophosphatemic rickets with muscle dysfunction and normal growth (300550.0011).
In a mother and her son and 2 daughters with X-linked hypophosphatemic rickets, Alhamoudi et al. (2022) identified a c.1701A-C transversion (148060.0012) at the first nucleotide of exon 17 of the PHEX gene, resulting in a synonymous alteration in the protein (R567R). Using RT-PCR, the authors showed that the variant interfered with splicing of exon 16 with 17, resulting in a shorter PHEX transcript compared to controls. Sanger sequencing of the cDNA showed complete skipping of exon 17 and direct splicing of exons 16 and 18, resulting in a frameshift and premature stop codon. The authors predicted that this led to loss of 2 conserved zinc-binding sites in exons 17 and 19, with loss of normal protein function.
For a description of the 'Hyp' mouse, a model for XLH, see 300550.
Levine et al. (2009) reviewed the elucidation of the genetic cause of X-linked hypophosphatemic rickets and examined in detail the clinical and laboratory features of the original patient, 'W.M.,' described by Albright et al. (1937).
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