Version May 2024
INTRODUCTION — Hereditary hypophosphatemic rickets refers to several inherited disorders characterized by renal phosphate wasting, the most common of which is X-linked hypophosphatemia (XLH). An acquired disorder, tumor-induced osteomalacia (TIO), has similar clinical manifestations to the inherited disorders.
The etiology and treatment of hereditary hypophosphatemic rickets and TIO will be reviewed here. The clinical manifestations and evaluation of rickets and osteomalacia are discussed separately. (See "Overview of rickets in children" and "Epidemiology and etiology of osteomalacia".)
OVERVIEW OF MECHANISMS — X-linked hypophosphatemia (XLH), other inherited forms of fibroblast growth factor 23 (FGF23)-mediated hypophosphatemic rickets, and tumor-induced osteomalacia (TIO) are all characterized by hypophosphatemia, normal serum levels of calcium, and either normal or modestly elevated levels of parathyroid hormone (PTH). These disorders have high or inappropriately normal circulating levels of FGF23, a circulating hormone that causes renal phosphate wasting and is a common final pathway (figure 1). The elevated FGF23 activity is the basis for treatment with the anti-FGF23 monoclonal antibody burosumab. (See 'X-linked hypophosphatemia' below.)
By contrast, FGF23 activity does not mediate the renal phosphate wasting in hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and Dent disease (see 'Hypophosphatemia with hypercalciuria' below) or in Fanconi syndrome (primary impairment of proximal tubular function). (See "Hypophosphatemia: Causes of hypophosphatemia", section on 'Fanconi syndrome'.)
In the past, the term vitamin D-resistant rickets (VDRR) originally was used to describe these hereditary syndromes because they had certain features typical of vitamin D deficiency but did not respond to vitamin D replacement or pharmacologic doses of vitamin D. This disorder is now called hereditary hypophosphatemic rickets because the primary problem is now recognized as phosphate wasting rather than primary vitamin D resistance.
By contrast, primary vitamin D resistance, characterized by hypocalcemia as well as hypophosphatemia, does occur and results from inherited defects in either the vitamin D metabolic pathway or the calcitriol receptor. (See "Etiology and treatment of calcipenic rickets in children", section on 'Hereditary resistance to vitamin D' and "Etiology and treatment of calcipenic rickets in children", section on '1-alpha-hydroxylase deficiency'.)
X-LINKED HYPOPHOSPHATEMIA — X-linked hypophosphatemia (XLH; MIM #307800) is a dominant disorder with a prevalence of approximately 1 case per 20,000 live births [1]. It is by far the most common cause of hereditary hypophosphatemic rickets. Most cases are familial, but a significant minority appear to arise sporadically. XLH is completely penetrant, but the severity varies widely, even among members of the same family. Whether males are more severely affected than females is unclear. However, in the largest reported series of XLH patients, no sex difference in disease severity was detected [2]. To best study this phenomenon, however, a within-family comparison would be ideal, as anecdotal reports of milder disease in females with certain variants have been published [3,4].
Pathogenesis — The pathogenesis of XLH is not fully understood. A number of studies indicate that the functional renal tubular abnormality in patients with XLH, and in the corresponding mouse model (Hyp mouse), is caused by one or more circulating factors rather than by a defect in the kidney [5,6]. Because these circulating factors promote phosphate excretion and impair bone mineralization, they have been termed "phosphatonins" or "minhibins" [7].
The gene responsible for XLH was identified on chromosome Xp22.1 and named PHEX (phosphate-regulating protein with homology to endopeptidases on the X chromosome), which is expressed predominantly in bone and teeth [8-10]. This gene encodes a cell surface-bound protein-cleaving enzyme (endopeptidase). A large number of inactivating variants in PHEX can cause XLH, and there is no obvious correlation between genotype and phenotype [11]. In a study of 118 families with at least one case of hypophosphatemic rickets, pathogenic PHEX gene variants were found in 87 percent of familial cases and in 72 percent of apparently sporadic cases [11]. Interestingly, those with a sporadic variant pass the disease to their children in an X-linked dominant inheritance pattern [12]. In addition, in some cases of familial and sporadic disease in which typical exonic PHEX variants are not apparent, intronic PHEX variants have been detected that result in messenger RNA (mRNA) splicing abnormalities [13]. Further, some of the apparently sporadic cases (11.5 percent) are due to a single-base change in the 3'-UTR (untranslated region) of PHEX (c.*231A>G) [3]; however, more recent analyses have identified that patients with this variant also have a duplication in the coding sequence of exons 13 to 15. Thus, it is not clear whether the UTR base change or the duplication is causing the disease.
Inactivating variants in the PHEX gene (in bone tissue) cause XLH by increasing production, through an unknown mechanism, of fibroblast growth factor 23 (FGF23), a phosphatonin [14]. FGF23, in turn, acts as a counterregulatory hormone to inhibit phosphate reabsorption by sodium/phosphate cotransporters in the kidney, acting through specific FGF receptors with the important cofactor, klotho protein [15]. Elevated levels of FGF23 also appear to be an important common pathway for other (but not all) forms of hereditary hypophosphatemic rickets, as well as tumor-induced osteomalacia (TIO), although mechanisms for the increased FGF23 vary among these disorders (figure 1).
Treatment of XLH with phosphate and vitamin D supplementation leads to increased FGF23 levels. Mouse models of XLH (the Hyp mouse and the PhexK496X mouse) suggest that the phosphate set point for FGF23 production is altered by variants damaging to PHEX [16]. An altered phosphate set point would explain why FGF23 levels increase when patients with XLH are treated with phosphate.
Thus, FGF23 appears to mediate the renal abnormalities of XLH, primarily phosphate wasting; the resultant hypophosphatemia contributes to, but may not be fully responsible for, the bone demineralization and rickets, suggesting that FGF23 may not mediate all elements of the XLH phenotype. Experimental evidence in transgenic animals suggests that the mineralization defect, in part, may involve mechanisms other than FGF23-mediated phosphate wasting [17,18]. Some of the other clinical manifestations of XLH (such as enthesopathy and dental abnormalities) also may be mediated by mechanisms other than FGF23.
Clinical features — Skeletal abnormalities, including rickets, osteomalacia, and growth failure, are the major clinical findings in children with XLH. Adults with XLH may develop significant functional impairment and multiple complications, emphasizing that the disorder is truly lifelong and not simply a disorder of the growth plate that resolves with the cessation of growth.
●Musculoskeletal abnormalities – Hypophosphatemia, slow growth, and rickets and osteomalacia are the major clinical findings in children with XLH. Low serum phosphate is often present soon after birth. However, it is only at the time of weightbearing that leg deformities (eg, bowing) and progressive departure from normal growth rate become sufficiently striking to attract medical attention. By that time, most children have radiographic evidence of rickets, particularly at the growth plates around the knee, which can cause severe bone pain. The axial skeleton often has a dense appearance. Iliac bone biopsies (not necessary for diagnosis in uncomplicated cases) show osteomalacia and hypomineralized periosteocytic lesions that are typical for this disorder [19]. The defects in bone mineralization consistently respond well to treatment with phosphate and calcitriol, but the effects of this treatment on skeletal growth are highly variable. One study suggests that the severity of the growth defect in affected children and the response to phosphate and calcitriol therapy may be predicted by the presenting height [20]. Another study found an association of both presenting height and growth response to this therapy with the Hap1(-) genotype of the vitamin D receptor promoter [21] in an XLH cohort in France [20]. In children with severe short stature, recombinant growth hormone has been suggested as an adjuvant treatment [22], although reports of efficacy are not consistent. (See 'Adjuvant therapy' below.)
Approximately 25 to 40 percent of children who are managed with phosphate and calcitriol require orthopedic surgical intervention [23]. Surgeries typically consist of either osteotomy to correct bowing or tibial torsion or hemi-epiphysiodesis (asymmetric growth plate clamping), a guided growth approach to straighten low extremities mechanically that is feasible only in growing children.
Among adult patients who were treated with phosphate and calcitriol during childhood, most have defects in stature due to limitations in growth during childhood. Osteoarthritis is nearly universal in the adult population, with onset decades earlier than observed in a typical adult population. Enthesopathy (calcification of tendons, ligaments, and joint capsules) and/or development of osteophytes are also nearly universally encountered, usually beginning in the late second or third decade of life [24]. Spinal stenosis is a rare and severe late complication (in some cases, related to ossification of the longitudinal spinal ligaments) and can be extremely painful and debilitating.
Many adult patients who have discontinued phosphate and calcitriol therapy have subclinical chronic symptoms of weakness, fatigue, bone pain, and gait abnormalities. They may not recognize these symptoms but may come to medical attention when they bring their affected children to a bone specialist for therapy; they tend to report clear improvement after initiation of therapy. The muscle weakness is more often reported by adults with XLH compared with children.
●Laboratory abnormalities – In addition to hypophosphatemia and a decreased tubular reabsorptive threshold for phosphate, untreated patients with XLH have normal serum levels of calcium, normal-to-high parathyroid hormone (PTH) levels, elevated (or sometimes normal) alkaline phosphatase activity, normal plasma 25-hydroxyvitamin D concentrations, and normal or slightly reduced plasma 1,25-dihydroxyvitamin D concentrations. The last finding suggests that regulation of 1,25-dihydroxyvitamin D synthesis is abnormal in XLH because the expected physiologic response to hypophosphatemia is an increase in 1,25-dihydroxyvitamin D levels. This defect appears to result from both increased catabolism of 1,25-dihydroxyvitamin D (due to increased expression of the CYP24A1 gene, which encodes 1,25-dihydroxyvitamin D-24-hydroxylase), as well as decreased formation of 1,25 dihydroxyvitamin D from its precursor, 25-hydroxyvitamin D (due to decreased expression of the CYP27B1 gene, which encodes 25-hydroxyvitamin D-1-alpha-hydroxylase) [25]. (See "Overview of vitamin D", section on 'Metabolism'.)
●Hyperparathyroidism – Despite chronic hypophosphatemia, which typically inhibits PTH secretion, patients with XLH exhibit hypersecretion of PTH, a phenomenon that is poorly understood. We have observed elevated circulating PTH levels in numerous patients prior to the onset of any therapy. Furthermore, PTH hypersecretion is exacerbated after initiation of phosphate therapy, despite only modest increases in the serum phosphate level. With careful medical management and avoidance of extremely high phosphate doses, hyperparathyroidism requiring medical intervention can usually be avoided. (See 'Hyperparathyroidism' below.)
●Renal disease – Nephrocalcinosis, usually of a low grade, is present in most children who are treated with the phosphate and calcitriol regimen, and the likelihood of this complication is positively correlated with the dose of phosphate. Progression of nephrocalcinosis has been associated with transient elevations in serum creatinine, which resolve with interruption of therapy [26]. Observational studies have shown that long-term (evident for approximately 20 years) low-grade nephrocalcinosis is not likely to have significant clinical consequences [27]. (See 'Nephrocalcinosis' below.)
Historically, patients managed with older therapies (which chronically employed high doses of vitamin D) sometimes developed progressive loss of renal function. This complication is typically not encountered with the treatment regimen of calcitriol and phosphate if adequate monitoring of biochemical status is performed.
●Other – Other clinical features may include:
•Mild to moderate hearing loss in adulthood and, infrequently, tinnitus and Meniere disease may occur, presumably due to protracted osteomalacia of the otic capsule.
•Defects in the mineralization of dentin occasionally occur and may contribute to the development of dental abscesses and early loss of dentition in young adults. Periodontal osteomalacia and reduced cementum have also been described. (See "Developmental defects of the teeth".)
•Hypertension has been identified in many of these patients, although it is not clear if this is due to the disease itself or to the treatment [28,29]. In particular, there is an association between hypertension and hyperparathyroidism, which frequently develops as a consequence of treatment regimens that include oral phosphate supplementation [28]. (See 'Hyperparathyroidism' below.)
•Craniosynostosis, Chiari I malformation, and other craniofacial anomalies develop in some patients, with no clear relationship to therapy [30].
Diagnosis
●Familial cases – Younger siblings of affected patients should be screened to diagnose the disorder before rickets or other complications develop. We generally screen infants in affected families at two to three months of age, when biochemical abnormalities are usually evident.
Screening can be accomplished by measuring fasting serum phosphate and alkaline phosphatase and, if necessary, renal phosphate excretion. For a child whose family history and pedigree are consistent with X-linked disease, the finding of low serum phosphate with increased alkaline phosphatase activity is sufficient to confirm the diagnosis and initiate treatment. Molecular testing for a pathogenic PHEX gene variant is not generally necessary for diagnosis, but it may be useful to confirm the diagnosis and mode of heritability or for genetic counseling.
●Others – Children without a family history of XLH typically come to medical attention when they present with signs and symptoms of rickets, such as bowing of the legs when the child begins to bear weight. During the evaluation for rickets, the possibility of XLH should be raised by the finding of low serum phosphate and normal or mildly elevated PTH. These findings distinguish XLH and other forms of "phosphopenic" rickets from nutritional rickets due to vitamin D deficiency. (See "Overview of rickets in children", section on 'Initial classification'.)
To investigate a child with suspected XLH and no known affected family members, we generally rely on the following tests to secure a diagnosis:
•Serum calcium, phosphate, and alkaline phosphatase
•PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D
•Urinary calcium excretion
•Indices of renal tubular phosphate handling – Maximal tubular reabsorption of phosphate per glomerular filtration rate (TmP/GFR) and tubular reabsorption of phosphate (see "Overview of the causes and treatment of hyperphosphatemia", section on 'Increased tubular reabsorption of phosphate')
For these nonfamilial cases, we reserve testing for PHEX gene variants for patients with atypical presentations or for those who desire genetic counseling.
Genetic testing also may be helpful in the setting of disease presenting at older ages, when TIO is a clinical consideration (see 'Tumor-induced osteomalacia' below). In rare cases where it is unclear as to whether the expected consequences of elevated FGF23 exposure are present, it may also be helpful to obtain a circulating FGF23 level.
Treatment
Treatment with burosumab — The goal of therapy in children with XLH is to decrease the severity of the bone abnormalities (rickets and osteomalacia), improve growth and physical activity, and reduce the associated bone/joint pain. While treatment with phosphate and calcitriol meets some of these objectives, such treatment often leads to significant untoward side effects that often limit long-term adherence to the therapy. In 2018, the US Food and Drug Administration (FDA) and European Medicines Agency approved burosumab, a human anti-FGF23 monoclonal antibody that appears to be effective for treatment of XLH in children one year and older [31,32]; FDA approval has been extended to children as young as six months of age and older. Burosumab offers a more effective therapeutic strategy with limited side effects. Burosumab is also FDA approved for treatment of XLH in adults and for treatment of TIO.
Children
●Indications – Burosumab is generally the treatment of choice for untreated children with XLH and also for those who have received phosphate and calcitriol therapy with limited benefits, difficulty with adherence to therapy, and/or harsh side effects.
•Untreated (newly presenting) children – For untreated children who present with moderate or severe rickets, burosumab is the treatment of choice, based on the enhanced benefit of this drug compared with therapy with phosphate and calcitriol (as evidenced in the randomized clinical trial described below). For untreated children who present with mild rickets, there are no data comparing the relative benefit of burosumab and therapy with phosphate and calcitriol. Nevertheless, burosumab should be considered the treatment of choice because of its demonstrated efficacy in the management of XLH, the importance of treating children effectively early in the course of their disease, and the potential adverse effects and treatment burden of phosphate and calcitriol therapy, which include poor palatability and the need for frequent biochemical monitoring. Moreover, repetitive phosphate dosing has limited efficacy for sustaining the serum phosphate at a level that will optimally benefit the skeleton. That being said, use of therapy with phosphate and calcitriol in mildly affected patients may be considered due to the substantially higher cost of burosumab and the absence of studies documenting the long-term safety of this drug (current data on burosumab describes treatment for up to three years). Should treatment with phosphate and calcitriol be initiated, assessment of the effects of such therapy should initially occur after 8 to 12 weeks and continued therapy frequently monitored, as described below.
•Children previously treated with phosphate and calcitriol – For children who have responded inadequately to phosphate and calcitriol (as indicated by poor healing of existent rickets), burosumab should be considered the treatment of choice, based on the enhanced benefit of this drug (as evidenced in the randomized clinical trial described below). For children who appear to have responded well to phosphate and calcitriol (by increased growth and/or healing of the rickets), the decision to switch to burosumab includes other considerations. Possible reasons to switch to burosumab include the favorable efficacy of burosumab compared with that of phosphate and calcitriol (as demonstrated in the randomized clinical trial described below and previously reported short-term studies) and the potential adverse effects and treatment burden of phosphate and calcitriol therapy noted above. Burosumab therapy is far more convenient and facilitates compliance with the treatment regimen since it is administered only every two weeks by subcutaneous injection and requires minimal monitoring after the initial dose titration. However, the treatment decision between therapy with phosphate and calcitriol and burosumab may be influenced by the substantially higher cost of burosumab compared with phosphate and calcitriol therapy and the absence of long-term safety and efficacy data. The full implications of switching to burosumab require studies with longer-term outcomes.
●Administration – For children with XLH, burosumab is dosed starting at 0.8 mg/kg (or 1 mg/kg for those weighing <10 kg), given subcutaneously every two weeks, then escalated as needed to achieve normal serum phosphate (maximum dose approximately 2 mg/kg or 90 mg) [33]. Burosumab should never be given in combination with oral phosphate and activated vitamin D metabolites (eg, calcitriol [1,25-dihydroxyvitamin D], paricalcitol, doxercalciferol, calcifediol, or alfacalcidol) or to patients with severe renal impairment.
●Efficacy and safety – The efficacy and safety of burosumab were shown in a randomized, multicenter, open-label clinical trial in 61 children 1 to 12 years of age with XLH who had hypophosphatemia and radiographic evidence of moderate to severe rickets despite treatment with phosphate and calcitriol [34]. After 64 weeks of treatment, subjects treated with burosumab were more likely to achieve substantial healing of rickets compared with phosphate and calcitriol therapy (87 versus 19 percent; odds ratio 34, 95% CI 6-206), as determined by a radiographic global impression of change score. Subjects treated with burosumab also had significantly greater decreases in serum alkaline phosphatase activity, improvements in renal phosphate wasting and lower limb deformity, and slightly greater increases in linear growth velocity and functional mobility. These findings are similar to those from two phase 2 clinical trials of burosumab in children [35,36]. Because the randomized trial only included children with moderate to severe rickets, its results do not apply to children with minimal radiographic evidence of disease.
Patient-reported outcomes also improved in children treated with burosumab compared with conventional therapy, particularly for pain interference (ie, the extent to which pain interferes with various activities) [37]. In a smaller cohort of children, the benefits of therapy with burosumab on rickets severity and fasting serum phosphorus were maintained for 160 weeks [38].
Most treatment-related side effects of burosumab were injection site reactions, which were mild and resolved within a few days, and none of the subjects discontinued burosumab or had dose-limiting toxic effects. Of note, only limited data are available regarding the effects of burosumab therapy on the concurrent osteomalacia in children with XLH. While the available information indicates improvement in osteomalacia, it remains unknown if burosumab will induce complete healing of the abnormal mineralization underlying the osteomalacia.
Dental abscesses and caries developed in 28 percent of patients treated with burosumab, compared with 9 percent of those treated with phosphate and calcitriol therapy, perhaps because dental complications of XLH may be independent of FGF23 and are therefore not targeted by burosumab [34]. In a post hoc analysis of this study, dental abscesses were not seen in children younger than five years old [39].
Adults — The benefit of burosumab therapy in adults with XLH is more difficult to quantify as they do not manifest active rickets and their height is already established. However, there may be significant benefit to treatment because the hypophosphatemia may contribute to bone and joint pain, failure to heal fractures, and other symptoms such as muscle weakness and poor stamina.
In a 24-week randomized trial in symptomatic adults with XLH, treatment with burosumab improved stiffness compared with placebo, as determined by a standardized measure of osteoarthritis symptoms [40]. Burosumab treatment was also associated with significantly higher rates of fracture healing during 24 weeks of treatment (43 percent) compared with placebo (8 percent). Interestingly, these fractures tend to be asymptomatic, so they may be recognized only if the patient is evaluated with routine screening radiographs. Subsequent reports on the open-label extension of this study indicated continued fracture healing through the 24- to 48-week period of treatment (approximately 70 percent) [41] and improvements in patient-related outcomes (six-minute walk tests were durable through 96 weeks) [42], indicating that sustained therapy increases the likelihood of restoring a functional skeleton and improving symptoms in affected adults. A long-term study in adults found that burosumab effectively maintained normal serum phosphate and biomarkers of bone metabolism in at least 85 percent of participants, with no significant adverse effects, for up to 3.5 years follow-up [43].
In spite of these observations, it remains unclear if all adults with XLH should receive burosumab therapy for several reasons, including: (1) the occurrence of bone or joint pain is variable in affected subjects; (2) untreated hypophosphatemia may have limited consequences in adults; (3) while treatment results in higher rates of fracture healing, there are no data indicating that burosumab therapy prevents the occurrence of fractures; and (4) the potential high cost of burosumab therapy. On the other hand, clinical trials in adults with limited symptomatology indicate that treatment with burosumab results in increased activity levels and sense of well-being and very few of these patients choose to stop treatment.
Until further data are available, our practice is to offer burosumab therapy to any adult patient who has the above noted symptoms or those with asymptomatic fractures. To detect asymptomatic fractures that would benefit from therapy, we routinely perform radiographs of the lower extremities, including the feet. The optimal duration of therapy has not been established, and longer-term observation and studies are warranted to establish long-term strategies. Finally, for any patient scheduled for an elective orthopedic surgical procedure, we recommend a course of therapy (either burosumab or phosphate and calcitriol) for six months prior to the procedure to ensure optimal healing of the bone and secure placement of hardware.
For adults with XLH, burosumab is dosed starting at approximately 1 mg/kg given every four weeks, with titration if necessary to a maximum dose of 90 mg every four weeks, targeting normal serum phosphate. However, we have observed that some patients, particularly those with mild disease, have developed back pain on these doses and have responded to reductions in dose to the 0.5 to 0.6 mg/kg/month range, with no apparent reduction in efficacy. Burosumab should not be given in combination with oral phosphate and activated vitamin D metabolites (eg, calcitriol [1,25-dihydroxyvitamin D], paricalcitol, doxercalciferol, calcifediol, or alfacalcidol) or to patients with severe renal impairment.
Treatment with phosphate and calcitriol — For more than 30 years, treatment of XLH has consisted of the oral administration of phosphate and calcitriol [44]. For children with XLH, use of phosphate and calcitriol should likely be confined to those circumstances where burosumab is not available or is contraindicated, because of a serious allergic complication, or in children with a sufficiently mild phenotype for whom burosumab would seem unlikely to offer greater benefit at lower risk than phosphate and calcitriol.
When XLH is treated with phosphate, the resultant increase in plasma phosphate concentration with each dose transiently lowers the ionized calcium concentration. Phosphate therapy causes secondary hyperparathyroidism because of both hypocalcemia and the inherent defect in maintaining circulating calcitriol levels, which normally inhibits PTH secretion. The elevated PTH levels increase urinary phosphate excretion and can aggravate the bone disease, thereby defeating the aim of oral therapy. The administration of calcitriol increases the intestinal absorption of calcium, and, together with a direct calcitriol effect, this aids in the suppression of PTH levels. Calcitriol also enhances intestinal phosphate absorption. (See 'Hyperparathyroidism' below.)
The approach to phosphate and calcitriol therapy differs for children compared with adults:
Children
●Goals – When phosphate and calcitriol are used to treat XLH in children, the goal is to correct or minimize rickets/osteomalacia, as assessed by resolution of radiographic and skeletal abnormalities. Important measures of successful treatment include enhanced height velocity, improvement in lower extremity bowing and associated abnormalities, and radiographic evidence of epiphyseal healing. Unlike with burosumab treatment, normalization of the serum phosphate concentration is not a goal of treatment with phosphate and calcitriol. This is because of potential long-term adverse effects of high doses of phosphate and/or calcitriol, such as nephrocalcinosis and secondary hyperparathyroidism.
●Drugs and dosing – For children (prior to epiphyseal closure), dosing is:
•Calcitriol (1,25-dihydroxyvitamin D) – 10 to 20 ng/kg per dose, twice daily (20 to 40 ng/kg/day).
•Phosphate – Administered in four to five doses per day, spaced at similar intervals through the waking hours; the starting dose is 40 mg of elemental phosphorus/kg per day. Some catch-up growth should be noticeable within the first year of therapy. If this does not occur despite good compliance, the daily phosphorus dose should be increased in steps of 250 mg to 500 mg up to a maximum of 2000 mg/day.
Addition of a calcimimetic (cinacalcet) to phosphate and calcitriol has been advocated to prevent secondary hyperparathyroidism [45,46]. The rationale for this strategy is that reduction of PTH levels should limit the renal phosphate wasting caused by elevated FGF23, allow the use of lower doses of phosphate and calcitriol, and reduce the risk of nephrocalcinosis. Calcimimetics have been used effectively to reduce PTH in chronic kidney disease and in TIO [47]. However, long-term studies in children with XLH are necessary before calcimimetics can be generally recommended. (See 'Hyperparathyroidism' below.)
Various forms of phosphate salts are available (eg, sodium phosphate and potassium phosphate) with no obvious advantage of one preparation over another. Tablets usually contain 250 mg elemental phosphorus per pill. Children who cannot take pills can receive phosphate supplementation in the form of Joulie's solution (155 g of dibasic anhydrous sodium phosphate and 64 g of phosphoric acid 85 percent per liter solution, corresponding to 50 mg/mL of elemental phosphorus). The amount of phosphate supplementation is usually limited by the occurrence of diarrhea. If diarrhea is a problem, the dose of phosphorus should be decreased by 250 to 500 mg and then gradually re-increased in steps of 125 mg. The aim should be to administer the minimum amount of phosphate that is sufficient for normal growth. Slow growth and persistently elevated alkaline phosphatase activity indicate inadequate dose of phosphate or compliance with therapy.
●Monitoring – Children should be seen every three months to monitor height; serum concentrations of calcium, phosphate, alkaline phosphatase, and creatinine; and random spot urinary calcium:creatinine ratio. In patients who are treated with phosphate and calcitriol, renal ultrasonography should initially be performed annually to evaluate nephrocalcinosis (see 'Nephrocalcinosis' below). However, at the doses used above, we have rarely seen progression and have decreased the frequency of these tests to every three to five years if the level of nephrocalcinosis is stable. A radiograph of the distal femoral and proximal tibial sites is assessed every two years to exclude the reappearance of rickets and to determine bone age. This monitoring represents a significant burden of treatment but is essential because most patients need frequent dose adjustments for optimal efficacy and to minimize side effects.
Measures of therapeutic efficacy should include enhanced height velocity, improvement in lower extremity bowing and associated abnormalities, and radiographic evidence of epiphyseal healing. A failure to obtain these endpoints should trigger a review of adherence to treatment and dose adjustment, if necessary and practical. With the exception of a small percentage of affected patients who are innately resistant to therapy, maintenance of acceptable height velocity and improvement in skeletal deformities generally indicate adequate dosing. Since the aim of treatment is to achieve normal growth, therapy is maintained at least as long as the growth plates are open (usually until the age of 15 years in females and 18 years in males).
Periodic evaluation by orthopedics and trained physical therapists is useful to identify early changes in tibial torsion or to initiate epiphysiodesis (growth plate clamping) in a timely manner. This technique employs "staples" or a commercially available system (brand name eight-Plate) to mechanically straighten the lower extremities during growth by clamping endochondral bone formation at the lateral or medial physes, as appropriate, diminishing the need for osteotomy [48,49]. Scoliosis may also complicate the course of childhood XLH, albeit infrequently.
●Outcomes – In the majority of prepubertal children who are treated with phosphate and calcitriol, radiologic signs of rickets disappear, growth improves [50,51], and deformities of the lower limbs are prevented or corrected [44]. However, despite this treatment, many children also require orthopedic surgery; most adults have short stature, and many have bony deformities or functional impairment (see 'Clinical features' above). Other effects of therapy include transient elevations (but not normalization) in the serum phosphate concentration, increase in urinary calcium excretion, improvement in bone or joint pain, and a significant decrease in osteoid thickness and mean osteoid volume [26]. The characteristic hypomineralized periosteocytic lesions persist on biopsy even though the histologic appearance of osteomalacia improves [19].
Adults
●Goals – In contrast with therapy for children, once a patient reaches adult height and the epiphyses have fused, the conventional goal for adults has been to simply manage generalized bone pain, enhance limited mobility (if either occurs), and cure any nonunion fractures. Histologic evidence of osteomalacia persists regardless of treatment with phosphate and calcitriol [19], and the consequences of the persistent osteomalacia may well play a role in the later development of enthesopathy, arthritis, and musculoskeletal pain. However, as conventional therapy with phosphate and calcitriol requires significant monitoring and may result in complications, a standard approach has often not been employed.
If burosumab therapy is not available, we suggest offering phosphate and calcitriol therapy to symptomatic adult patients, provided that they are willing to adhere closely to clinician's instructions for dosing and monitoring. In addition, adult patients may benefit from treatment during the three to six months prior to an orthopedic procedure because this may reduce recovery time and the risk of prosthetic loosening in patients undergoing joint replacement.
●Drugs and dosing – For adults managed with phosphate and calcitriol, appropriate doses are:
•Calcitriol – 0.5 to 1 mcg/day, in two divided doses
•Phosphate – 1 to 2 g of elemental phosphorus/day, in three to four divided doses
Adults treated with phosphate and calcitriol should be monitored at least every six months for serum phosphate, calcium, creatinine, and PTH. Regular monitoring is important because patients who have been stable on safe and effective doses of phosphate and calcitriol for months or years may suddenly develop toxicity, manifest by hypercalcemia and hyperphosphatemia. These events probably are triggered by sufficient healing of the skeleton to minimize the rate of mineral uptake in the skeleton, thus forcing elevations in circulating and urinary concentrations of calcium and phosphate. (See 'Complications of phosphate-calcitriol therapy' below.)
In our experience, measurement of bone-specific alkaline phosphatase appears to be superior to total serum alkaline phosphatase in the adult population for monitoring XLH, and we have incorporated this measure into the routine monitoring of adult patients.
●Follow-up – It is controversial whether phosphate and calcitriol therapy should be continued on a routine basis for adults. The goal of therapy in this age group is to resolve the precipitating factor leading to initiation of therapy. In the case of bone pain, treatment can be discontinued if the pain resolves or improves. However, in some patients, the pain recurs, sometimes requiring chronic treatment with relatively low doses of phosphate and calcitriol. In some cases, the use of calcitriol alone, or together with small doses of phosphate, may be warranted. One observational study of 52 adults with XLH reported that treatment was also associated with a reduced frequency of dental abscesses but was not associated with improvement in radiographically determined enthesopathy [52].
●Pregnancy – It is unclear whether therapy should be prescribed in pregnant women with XLH. If a woman is being treated with phosphate and calcitriol at the time of conception, the therapy is typically continued but with close monitoring of the urinary calcium:creatinine ratio for early detection of hypercalciuria [53]. Although the plasma phosphate concentration of the fetus is determined by diffusion across the placenta, it seems reasonable to maintain a higher level of phosphate in the pregnant mother than that in the untreated state. Nonetheless, women who are not on therapy at the time of conception are generally not started on treatment during pregnancy. Studies are necessary to determine if hypophosphatemia during pregnancy affects bone mineralization or development in the fetus.
Complications of phosphate-calcitriol therapy — The two important complications of the treatment of XLH using phosphate and calcitriol are nephrocalcinosis and hyperparathyroidism.
Nephrocalcinosis — Nephrocalcinosis can be demonstrated on renal ultrasonography in up to 80 percent of patients with XLH treated with phosphate and calcitriol and is associated with renal tubular acidosis [26,54]. The renal calcifications are located primarily in the tubules and are composed exclusively of calcium phosphate [55]. The degree of calcium phosphate deposition correlates with the mean phosphate dose but not with the dose of calcitriol or the duration of therapy [26,55].
Although most patients have a normal plasma creatinine concentration, the long-term effect of nephrocalcinosis on renal function is not known. However, normal kidney function has been maintained in XLH despite long-standing medullary nephrocalcinosis. Isolated cases of renal insufficiency have also been reported [55] and, in the authors' experience, occurs in the presence of hypertension.
It has also been speculated that the development of nephrocalcinosis results from intermittent episodes of hypercalcemia and hypercalciuria. These can result from an excessive calcitriol dose or from noncompliance with oral phosphate supplementation [56]. Thus, careful monitoring and control of serum and urine calcium are necessary to minimize nephrocalcinosis. The dose of calcitriol should be reduced when hypercalcemia or hypercalciuria occur. Alternatively, administration of thiazide diuretics with or without amiloride may arrest the progression of nephrocalcinosis [57] (see 'Adjuvant therapy' below), though the combination of a thiazide and calcitriol obligates the monitoring of serum calcium to avoid hypercalcemia. The importance of strict adherence to the burdensome phosphate supplementation schedule must be repeatedly emphasized to the patients and their caretakers.
Studies in Hyp mice suggest that nonhypercalcemic analogues of calcitriol, such as 22-oxacalcitriol, may provide a similar increase in plasma phosphate without producing hypercalcemia or hypercalciuria [7]. These analogues have not been evaluated in humans.
Hyperparathyroidism — Hyperparathyroidism occurs with some frequency in XLH. Mild elevations in PTH may occur prior to institution of treatment; however, this can be exacerbated by therapy with phosphate and calcitriol [58]. It is thought that complexing of calcium with phosphate supplements results in intermittent hypocalcemia and persistent stimulation of PTH release despite the administration of calcitriol. When this secondary hyperparathyroidism is not adequately controlled, autonomous (tertiary) hyperparathyroidism can occur, necessitating surgical intervention [59,60].
This complication can often be managed with decreases in the dose of phosphate or cessation altogether if necessary. If the serum or urinary calcium excretion allows, upward adjustments in calcitriol can also be effective in attenuating the elevated PTH levels. Other approaches have included the use of paricalcitol (a vitamin D analog) [61] or cinacalcet (a calcimimetic) [62]. In a double-blinded study, paricalcitol suppressed PTH levels when added to the ongoing calcitriol and phosphate regimen or simply added alone if the patient is not otherwise treated [61]. Surgical removal of the parathyroid glands may be indicated in severe disease. The typical finding is multigland parathyroid hyperplasia, and, if this is borne out by imaging studies, removal of three and one-half of the four parathyroid glands is usually performed.
Adjuvant therapy — Several forms of adjuvant therapy have been tested to improve the efficacy and/or diminish side effects of phosphate and calcitriol in XLH. Such adjuvant treatment is likely not necessary in conjunction with burosumab.
●Hydrochlorothiazide, with or without amiloride – Observational studies of children with XLH show that the addition of hydrochlorothiazide, or hydrochlorothiazide and amiloride, decreases urinary calcium excretion and prevents progression of nephrocalcinosis [57,63]. This approach may be useful in the management of hypophosphatemic rickets if the results are confirmed in larger studies.
●Growth hormone (GH) – The administration of recombinant human GH (rhGH) can improve short-term growth in children with XLH [64]. This may translate into an increased final height, as shown in a long-term study of six patients [22]. Nevertheless, other studies have not confirmed significant changes in attained versus predicted adult height and it is possible that treatment with GH aggravates the preexistent disproportionate stature of such children (ie, increased ratio of trunk to leg length) [65]. As an example, a three-year study in rhGH-treated children showed improvement in predicted adult height but failure to normalize the body disproportion [66]. These data suggest a highly variable outcome to this approach and do not support the recommendation of GH therapy outside of a research setting.
●24,25-dihydroxyvitamin D – A placebo-controlled trial on 15 patients with XLH tested the value of 24,25-dihydroxyvitamin D as a supplement to standard treatment [67]. The main effect was improved control of hyperparathyroidism. Unfortunately, 24,25-dihydroxyvitamin D is not available as a pharmaceutical agent. (See "Overview of vitamin D", section on 'Metabolism'.)
AUTOSOMAL DOMINANT HYPOPHOSPHATEMIA — Autosomal dominant hypophosphatemic rickets (ADHR; MIM #193100) is a rare syndrome of renal phosphate wasting with rickets or osteomalacia that is transmitted as an autosomal dominant trait [68].
Pathogenesis — ADHR results from missense variants in the gene encoding fibroblast growth factor 23 (FGF23) that prevent its proteolytic cleavage and thereby increase circulating FGF23 levels. Several variants in the FGF23 gene causing ADHR (including R176Q, R176W, R179Q, R179W) have been reported, each resulting in an amino acid change at 176RXXR179/S180, a subtilisin-like protein convertase consensus cleavage site [14,69-73].
However, serum FGF23 concentrations are not consistently elevated in individuals with ADHR and the severity of renal phosphate wasting may wax and wane; FGF23 concentrations are normal during quiescent periods when serum phosphate levels are normal, and they are elevated during active, hypophosphatemic phases of the disease [68].
Role of iron deficiency — Iron deficiency is an environmental trigger that stimulates expression of bone FGF23 messenger RNA (mRNA) and protein in both normal subjects and in patients with ADHR. Hypophosphatemic flares of ADHR often coincide with the onset of menses and following pregnancy, when iron deficiency is common. In addition, high FGF23 concentrations and low serum phosphate in patients with ADHR are associated with low levels of serum iron and ferritin. In the absence of a genetic defect, iron deficiency does not result in high FGF23 levels or phosphate wasting, because increased expression of FGF23 is matched by increased FGF23 cleavage; in patients with ADHR, the ability to increase FGF23 cleavage is impaired, which results in high FGF23 levels when iron stores are low [74].
Clinical findings — The clinical course in ADHR is similar to that usually observed in the X-linked disease. However, ADHR is especially notable for its variable age of onset and incomplete penetrance [68]. Approximately one-half of individuals harboring a variant in the causal gene present clinically evident disease at one to three years of age, which includes phosphate wasting, rickets, and lower extremity deformities. In some affected children, hypophosphatemia and the phosphate-wasting defect persist into adulthood, whereas in others, these abnormalities remit after puberty [75]. The remaining patients have delayed disease onset, ranging from 14 to 45 years. Those who present after puberty and growth plate closure generally have bone pain, weakness, and fractures but no lower extremity deformities. Such delayed presentation has been observed only in women, soon after puberty or pregnancy and delivery [75].
Treatment — Limited experience is available in the treatment of ADHR. However, because the clinical, biochemical, and radiographic characteristics of ADHR are similar to those of X-linked hypophosphatemia (XLH), analogous treatment schedules for phosphate and calcitriol are used. (See 'X-linked hypophosphatemia' above.)
Because iron deficiency may contribute to the expression of hypophosphatemia (see 'Role of iron deficiency' above), patients should be evaluated for iron deficiency and treated with iron if needed, with ongoing monitoring of iron status. In several case reports of adults with ADHR, correction of iron deficiency led to improvement in metabolic parameters and successful maintenance of normal phosphate values after discontinuation of phosphate and calcitriol therapy [76,77].
AUTOSOMAL RECESSIVE HYPOPHOSPHATEMIC RICKETS — Autosomal recessive hypophosphatemic rickets (ARHR) has been described in a few kindreds [78-81]. Affected individuals generally present in late infancy, exhibiting symptoms and biochemical abnormalities similar to those found in patients with X-linked hypophosphatemia (XLH). Bone abnormalities generally include rickets and osteomalacia, but some patients develop osteosclerosis and bone overgrowth [82]. The features of ARHR may be variable and variant-specific or age-dependent and include nerve deafness, facial and dental abnormalities, learning disabilities, joint pain, contractures and immobilization of the spine, and short and deformed long bones [79,83]. Such variability is associated with the different mechanisms causing defective gene function. Circulating fibroblast growth factor 23 (FGF23) levels are generally elevated or high-normal and inappropriate for the hypophosphatemia. The disorder has been divided into three subtypes:
●ARHR1 (MIM #241520) is caused by inactivating mutations in the DMP1 gene, which encodes Dentin matrix protein 1. Missense, nonsense, and deletion mutations have been described. This form of the disease may manifest with dense vertebral bodies and has presented in middle age as a sclerosing bone dysplasia [81]. Studies in a mouse knockout of the DMP1 gene suggest a lowered set point for phosphate sensing in FGF23 release, as in XLH [84]. A single anecdotal report describes two brothers who benefited from burosumab, but this requires further study [85].
●ARHR2 (MIM #613312) is caused by an inactivating mutation in the ENPP1 gene, which encodes ectonucleotide pyrophosphatase/phosphodiesterase 1 [78], the enzyme critical for the generation of the mineralization inhibitor, pyrophosphate. Thus, loss-of-function mutations of ENPP1 result in marked reductions in pyrophosphate levels with consequent severe vascular mineralization known as generalized arterial calcification of infancy (GACI) [86,87]. It is unclear how such patients subsequently develop elevations in circulating FGF23 levels. This finding may represent a compensatory adaptation to GACI to enhance renal phosphate elimination, thus protecting the vasculature from continued exposure to elevated phosphate concentrations and calcification, at the expense of bone mineralization. Thus, it has been speculated that treatment with burosumab may be deleterious in ARHR2 [88]. Studies in a transgenic mouse model of GACI demonstrate evidence that ENPP1 regulates FGF23 in association with alterations in Wnt [89].
Patients with ARHR2 may also present with a very early onset of hearing loss [90].
●AHRH3 is associated with variants in the FAM20C gene encoding a protein kinase [91], which phosphorylates FGF23, which in turn reduces O-glycosylation, thereby promoting cleavage of the molecule. This form of ARHR also can manifest as an osteosclerotic disorder and occurs in the context of Raine syndrome, a rare skeletal dysplasia encompassing osteomalacia, sclerosis of the base of the skull, and characteristic facies [92].
Only a few case reports have assessed therapy of ARHR. The approaches include treatment with oral phosphate and calcitriol or alfacalcidol, similar to the historic regimen employed in patients with XLH. This regimen results in improvement of rickets and diminished intermittent bone pain [83]. Anecdotal evidence suggests that ARHR1 may respond to burosumab, as mentioned above.
SGK3 DEFICIENCY — SGK3 deficiency is a novel form of autosomal dominant hypophosphatemic rickets. One report identified a kindred living in Saudi Arabia, in which five members displayed hypophosphatemia and evidence of rickets. The phenotype segregates with a splice-site mutation in the SGK3 gene, which encodes a protein kinase that regulates phosphate transport in the renal tubule [93]. Unlike the activating mutations in the FGF23 gene that cause classic ADHR, FGF23 levels in the patients with SGK3 deficiency were neither uniformly elevated nor suppressed, although levels in a murine model of this disease are low. Surprisingly, circulating calcitriol levels were low or low-normal in affected patients. Although combination therapy with calcitriol and phosphate was used to treat these patients, the ideal therapy for the disorder remains unknown.
HYPOPHOSPHATEMIA WITH HYPERCALCIURIA — The following three syndromes have a constellation of abnormalities that includes hypophosphatemia and hypercalciuria:
●Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)
●Dent disease
●Idiopathic hypercalciuria
Hypophosphatemic rickets with hypercalciuria — HHRH (MIM #241530) has been described in a few kindreds and in several sporadic cases. The disorder is inherited in an autosomal recessive fashion [94].
Pathogenesis — HHRH results from genetic variants of the renal type 2c sodium-phosphate cotransporter. In two reports on six affected kindreds with HHRH, the disease was mapped to chromosome 9q34, which contains the gene SLC34A3 that encodes the renal type 2c sodium-phosphate cotransporter [95,96]. Disease-related variants in this cotransporter were detected in all examined families (figure 1). A comparable phenotype was reported in a family with digenic heterozygous loss-of-function mutations of this transporter and of the related type 2a sodium-phosphate cotransporter (encoded by SLC34A1) [97].
Clinical features — In most patients with HHRH, disease onset is in childhood and presents with rickets and/or osteomalacia that is associated with hypophosphatemia, short stature, and secondary absorptive hypercalciuria. An adult-onset form of the disease has been recognized in patients who were heterozygous carriers of SLC34A3 gene variants and presented with markedly reduced bone density, multiple fractures, hypophosphatemia, and hypercalciuria [98]. More commonly, heterozygotes manifest milder forms of HHRH, with mild hypophosphatemia, hypercalciuria, and nephrolithiasis but no signs of bone disease; however, this form may be underdiagnosed and is less well characterized [99,100].
HHRH differs from X-linked hypophosphatemia (XLH) and autosomal dominant hypophosphatemia in that the impairment is restricted to phosphate transport and serum calcitriol concentrations are normal or often appropriately elevated for the degree of hypophosphatemia [99]. Hypercalciuria probably occurs because of high calcitriol levels and secondarily increased intestinal calcium absorption.
Treatment — Patients with HHRH should be treated with phosphate supplementation alone, using the same dosing schedule as described for X-linked hypophosphatemic rickets. Endogenous calcitriol levels are elevated, and the addition of exogenous calcitriol may be harmful [100,101]. Thus, plasma calcitriol levels and urinary calcium excretion should be measured before initiating therapy. Phosphate replacement therapy appears to normalize the serum phosphate concentration within a few days and improves but does not cure the osteomalacia. (See 'X-linked hypophosphatemia' above.)
Children should be seen every three months to monitor height; serum concentrations of calcium, phosphate, alkaline phosphatase, and creatinine; and urinary calcium excretion. Renal ultrasonography should be performed once per year to evaluate nephrocalcinosis. A hand radiograph should be obtained once per year to exclude the reappearance of rickets and to determine bone age.
Dent disease — Dent disease (MIM #300009, MIM #300555) is an X-linked recessive condition in which a primary defect in the cells of the proximal renal tubule results in a phenotype of proximal tubular solute wasting, hypercalciuria, nephrocalcinosis, kidney stones, renal failure, and, in some cases, rickets. The most consistent feature is low molecular weight (LMW) proteinuria; other evidence of proximal renal tubular solute reabsorptive failure includes glycosuria, aminoaciduria, and phosphaturia, though not bicarbonaturia. When rickets occurs, it is usually evident from early childhood, but it only occurs in approximately 25 percent of patients. In a hypophosphatemic child with rickets, if other features suggest Dent disease, urinary LMW proteins (beta-2 microglobulin and retinol-binding protein) should be measured. The disease results from variants in the CLCN5 gene encoding a voltage-gated chloride transporter in approximately 60 percent of patients and in the OCRL1 gene in another 15 percent [102-104]. The pathogenesis and clinical manifestations of this disease are discussed separately. (See "Dent disease (X-linked recessive nephrolithiasis)".)
Idiopathic hypercalciuria — Idiopathic hypercalciuria, which is a risk factor for kidney stone formation, is often associated with mild hypophosphatemia and elevated levels of calcitriol and may represent a mild proximal tubular defect [101]. (See "Kidney stones in adults: Epidemiology and risk factors".)
TUMOR-INDUCED OSTEOMALACIA — Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare acquired paraneoplastic syndrome in which the biochemical and bone mineralization abnormalities closely resemble those in genetic forms of hypophosphatemic rickets [105-108]. Clinical and experimental studies have documented that tumors produce humoral factor(s) that underlie the abnormalities that occur in TIO. The tumors, typically benign, often are small, slow-growing polymorphous neoplasms, most commonly, phosphaturic mesenchymal tumors of the mixed connective tissue type [109].
Although primarily described in adults, TIO can occur in children and adolescents [110,111]. Children with TIO present with clinical features of rickets, including gait disturbances, growth retardation, and skeletal deformities. The occult nature of TIO delays its recognition, and the time from onset of symptoms to a correct diagnosis often exceeds 2.5 years [105].
Pathogenesis — The mesenchymal tumors associated with TIO ectopically express and secrete fibroblast growth factor 23 (FGF23) and other phosphaturic proteins. Most affected patients have increased circulating FGF23 levels [19,112-115]. FGF23 decreases reabsorption of phosphate and production of 1,25-dihydroxyvitamin D by the kidney, acting via FGF receptor 1 (FGFR1) signaling [116]. The resulting hypophosphatemia causes rickets, osteomalacia, bone pain, muscle weakness, and fractures.
Serum levels of FGF23 usually fall promptly to the normal range after resection of the responsible tumors. These findings are consistent with a pathogenic role for FGF23 in most patients with TIO [19,112-114,117,118]. The other secreted proteins expressed in some mesenchymal tumors associated with TIO include MEPE (matrix extracellular phosphoglycoprotein), FGF7, and sFRP4 (secreted frizzled related protein 4), but the role of these phosphaturic proteins in the disease process remains obscure. Increased serum FGF23 levels also occur in patients with X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR), as discussed above (figure 1) [19,75,114].
Clinical features — The biochemical hallmarks of TIO are low serum phosphate levels, phosphaturia, and low or inappropriately normal levels of serum calcitriol [105,106]. Radiographs reveal evidence of rickets in children, and bone histomorphometry shows severe osteomalacia in all affected subjects. Detection and localization of the culprit tumor in TIO is crucial because surgical resection is curative. However, the mesenchymal tumors that cause this syndrome are often difficult to identify because they are small and slow growing and are frequently found in a variety of obscure anatomical locations (including long bones, distal extremities, nasopharynx, sinuses, and groin). The clinical presentation of patients with TIO is often more severe than in XLH, perhaps because the decrements in the serum phosphorus and calcitriol levels are often more severe than in XLH.
Diagnosis — Once TIO is suspected based upon the biochemical and bone abnormalities of the syndrome, confirmation of the diagnosis depends on identification and localization of the underlying tumor. Until the underlying tumor is identified, other renal phosphate-wasting disorders must be considered. However, the presence of a previously normal serum phosphate level in an affected patient, particularly an adult, generally supports the diagnosis of TIO (although, in rare instances, adults with ADHR can present with new-onset hypophosphatemia (see 'Autosomal dominant hypophosphatemia' above)). If the diagnosis remains uncertain, genetic testing can be performed, testing for variants in the FGF23 gene to exclude ADHR; the PHEX gene to exclude XLH; and the DMP1, ENPP1, and FAM20C genes to exclude ARHR.
Finding the tumors can be a major diagnostic challenge since their small size and obscure locations make them difficult to localize with conventional imaging techniques. Because in vitro studies have revealed that mesenchymal tumors frequently express somatostatin receptors, 111indium-pentetreotide scintigraphy, a scanning technique that uses a radiolabeled somatostatin analog (octreotide), has been successful in localizing the tumor in some patients [119,120]. Successful tumor localization has been reported with other imaging techniques, such as whole-body magnetic resonance imaging (MRI) and (18F)FDG-PET/CT (positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro- D-glucose integrated with computed tomography). Systemic venous sampling for FGF23 has also been used to localize causative tumors, but this technique is better suited to determine if an identified mass is producing FGF23 [121]. PET/CT scanning using 68Ga-DOTATATE has been reported to be particularly sensitive in detecting causative tumors [122-125]. Further, studies indicate that a stepwise approach of 68Ga-DOTATATE-PET/CT, systemic venous sampling for FGF23 levels, and 3-Tesla (3T)-MRI can be effective for tumor diagnosis [126]. Despite these varied approaches, the small size of the tumors and their location in bone limit the ability to identify and localize the tumor; success rates in various studies reveal tumor identification in 65 to 80 percent of patients with presumed TIO.
For patients with no identifiable tumor, the differential diagnosis includes elevated FGF23 caused by ferric carboxymaltose and certain other intravenous iron products [127-129], as well as late presentations of XLH or ADHR. (See 'X-linked hypophosphatemia' above and 'Autosomal dominant hypophosphatemia' above.)
Treatment — Definitive treatment for TIO is complete tumor resection, which leads to prompt reversal of the biochemical abnormalities and healing of the bone disease over a period of 6 to 12 weeks [105-108]. However, if the tumor is not localized by the techniques outlined above, medical management is required. Although there is limited experience with medical treatment of TIO, the clinical, biochemical, and radiologic characteristics of the disease are similar to those in XLH. Therefore, analogous treatment regimens are used for TIO. Therapy is continued indefinitely if the tumor cannot be identified and removed. In a few cases, however, recurrent search for the tumor, at various intervals after medical therapy is initiated, has resulted in successful localization of the tumor and cure of the syndrome upon its removal.
For patients whose tumor cannot be completely resected and the biochemical sequelae of the disease persist, burosumab is the preferred form of therapy. In a small open-label study in 14 adults with TIO, patients treated with burosumab had improved biomarkers of bone turnover and parameters of osteomalacia, as observed in bone biopsies following one year of monthly injections [130]. This likely reflects correction of hypophosphatemia, a benefit achieved without the potential adverse effects of phosphate and calcitriol therapy. In general, patients tolerated the medication well and had improved well-being. In another study of 13 patients with TIO, burosumab treatment for a two-year period was associated with sustained normalization of serum phosphate concentrations, improved ambulation, and reduced pain [131]. As of June 2020, burosumab was approved by the US Food and Drug Administration (FDA) for use in patients two years or older with TIO due to tumors that cannot be curatively resected, based on the small observational studies described above [33]. When burosumab is not available or is contraindicated because of a serious allergic complication, therapy with phosphate and calcitriol should be used, based on the experience using this regimen in patients with unremitting TIO before burosumab was available.
One case report proposes yet another strategy for the treatment of TIO, in which infigratinib, an FGFR tyrosine kinase inhibitor, is used to disrupt FGFR1 downstream signaling. Intermittent use of infigratinib in a patient with TIO with widely disseminated tumor resulted in reduction in tumor burden, as well as improvement in serum phosphorus levels, although significant toxicity necessitated limited courses of therapy [132]. Use of infigratinib as a possible treatment for TIO due to unresectable or nonlocalized phosphaturic mesenchymal tumors is currently under investigation.
OTHER DISORDERS WITH ELEVATED FGF23
●Cutaneous skeletal hypophosphatemia syndrome – Cutaneous skeletal hypophosphatemia syndrome is a rare form of epidermal nevus syndrome associated with epidermal or melanocytic nevi, excess FGF23 production, and a complex skeletal disease, which appears to be in part related to the accompanying hypophosphatemia [133,134]. Many of these have been shown to be mosaic postzygotic variants in the HRAS, KRAS, and NRAS genes (and thus are sometimes termed "RAS-opathies"), although the mechanism of excess FGF23 secretion has yet to be identified (see "Epidermal nevus and epidermal nevus syndrome", section on 'Epidermal nevus syndrome'). Successful treatment with burosumab [135,136] and MEK inhibitors [137] has been reported.
●McCune-Albright syndrome – The somatic mosaic disorder McCune-Albright syndrome is due to constitutive activation of GNAS, the GTPase instrumental in adenylate cyclase activation and cyclic adenosine monophosphate (cAMP) generation. The disorder typically results in fibrous dysplasia of bone and often involves elevated FGF23 levels. Hypophosphatemia due to renal tubular phosphorus losses may occur and is associated with the degree of elevation in circulating FGF23. Moreover, the level of circulating FGF23 is related to the skeletal disease burden. Although rachitic disease is usually not the dominant skeletal issue in such cases, the need for phosphate replacement should be considered and appropriately evaluated, as described in a guideline from an international consortium [138,139]. Other clinical features of McCune-Albright syndrome are café au lait macules and endocrine hyperreactivity, classically causing precocious puberty. (See "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric bone health".)
SUMMARY AND RECOMMENDATIONS
●X-linked hypophosphatemia (XLH) – This is a dominant disorder caused by a variety of loss-of-function variants in the PHEX gene and is characterized by renal phosphate wasting, mediated by excess fibroblast growth factor 23 (FGF23) activity (figure 1). XLH is characterized by hypophosphatemia, slow growth, and rickets or osteomalacia; both males and females are affected. (See 'X-linked hypophosphatemia' above.)
•Burosumab – Burosumab, a monoclonal antibody to FGF23, is an important new option for all individuals with XLH. Selection of patients for burosumab therapy depends on the patient's age, symptoms, and treatment history (see 'Treatment with burosumab' above):
-For children who have been treated with phosphate and calcitriol with limited benefits and/or harsh side effects, we suggest switching to burosumab (Grade 2B). In a randomized, multicenter, open-label clinical trial and in short-term studies in children with XLH, burosumab normalized serum phosphate concentration and improved pain, physical function, rickets, and linear growth.
-For newly diagnosed children with XLH, we suggest treatment with burosumab rather than phosphate and calcitriol (Grade 2C). Burosumab is likely to be effective for these children, whereas most children treated with phosphate and calcitriol continue to have some physical and functional impairment, as well as the burden of this type of treatment, which includes poor palatability and need for frequent phosphate dosing, monitoring, and dose adjustments.
-For children who appear to be doing well on phosphate and calcitriol, the benefit of switching to burosumab is unclear. Possible reasons to switch to burosumab include the potential adverse effects and treatment burden of phosphate and calcitriol therapy.
-For symptomatic adults with XLH and for those with fractures, we suggest treatment with burosumab, rather than phosphate and calcitriol and rather than no treatment (Grade 2B). In a randomized trial, burosumab improved stiffness and fracture healing, as well as biochemical abnormalities. For truly asymptomatic adults, it is unclear if burosumab has clinically important benefits. (See 'Adults' above.)
Burosumab should not be given in combination with oral phosphate and calcitriol or other activated vitamin D metabolites (paricalcitol, doxercalciferol, calcifediol, or alfacalcidol) or to patients with severe renal impairment.
•Phosphate and calcitriol – If burosumab is not available, patients with XLH can be treated with phosphate and calcitriol, which has been the standard treatment for XLH for decades. The phosphate is given to replace renal losses, and calcitriol is necessary to increase the intestinal absorption of phosphate and calcium and to prevent secondary hyperparathyroidism. This therapy is continued at least through adolescence; it is controversial whether adults should continue therapy on a routine basis. (See 'Treatment with phosphate and calcitriol' above.)
●Other forms of hypophosphatemic rickets
•Autosomal dominant hypophosphatemic rickets (ADHR) and autosomal recessive hypophosphatemic rickets (ARHR) have been described in several families. The clinical manifestations are similar to those in XLH but vary with the age of onset. (See 'Autosomal dominant hypophosphatemia' above.)
•Hypophosphatemia and hypercalciuria are the key features of three syndromes: hereditary hypophosphatemic rickets with hypercalciuria (HHRH), Dent disease, and idiopathic hypercalciuria. These disorders are not mediated by FGF23 excess. (See 'Hypophosphatemia with hypercalciuria' above.)
●Tumor-induced osteomalacia (TIO) – This disorder is characterized by severe hypophosphatemia and osteomalacia, with renal phosphate wasting and an inappropriately low plasma calcitriol concentration that occurs in association with a tumor. If growth plates are still open, rickets can occur. The tumors are typically benign, small, and of mesenchymal origin, and most often secrete FGF23. The metabolic pathways involved and clinical manifestations are similar to those of XLH (figure 1). Unlike most cases of XLH, the family history is negative and the disorder is acquired; in addition, the age of onset of TIO is often in adolescence or adulthood.
Treatment of TIO is by complete resection of the culprit tumor, which is curative. For patients whose tumor cannot be completely resected or cannot be localized, we suggest treatment with burosumab rather than phosphate and calcitriol (Grade 2C). In small observational studies, treatment with burosumab was associated with normalization of serum phosphate and improvements in biomarkers of bone turnover, bone histology, pain, and ambulatory function. (See 'Tumor-induced osteomalacia' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Zalman S Agus, MD, and Marc K Drezner, MD, who contributed to earlier versions of this topic review.
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