X-Linked Hypophosphataemic Rickets and Hereditary Hypophosphataemic Rickets

X-linked hypophosphataemia (XLH, PHEX) and related hereditary forms: autosomal dominant (FGF23), autosomal recessive (DMP1, ENPP1, FAM20C) and hereditary hypophosphataemic rickets with hypercalciuria (SLC34A3).

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

X-linked hypophosphataemic rickets is the most common hereditary form of rickets due to renal phosphate wasting and accounts for approximately 80% of genetically determined hypophosphataemic rickets [8, 11]. The historical designation “vitamin D-resistant rickets” summarises the clinical observation that distinguished it from nutritional rickets: the child has rachitic deformities, but the doses of vitamin D that cure the nutritional form do not correct the disease [1]. Current understanding, however, shifts the focus of the disease from vitamin D metabolism to a bone–kidney endocrine axis, in which the osteocyte produces an excess of a phosphaturic hormone, FGF23. This conceptual change explains the biochemistry, guides the differential diagnosis and underpins targeted therapy.

Clinical and radiological descriptions now recognised as XLH emerged from 1937 onwards, with reports of progressive lower-limb bowing, tibial torsion and short stature, and the subsequent identification of X-linked transmission [6]. In 1958, Winters, Graham, Williams, McFalls and Burnett published the genetic study of families with familial hypophosphataemia and vitamin D-resistant rickets, accompanied by a literature review, which became the reference for the mode of transmission [13]. The molecular basis was identified in 1995 by the HYP Consortium, which used positional cloning at Xp22.1 to isolate a gene with homology to endopeptidases, then named PEX, and demonstrated intragenic deletions and splicing and frameshift variants in patients [14].

The following decade added the pieces linking the gene to physiology. In 1997, Econs and McEnery characterised an extended family with autosomal dominant hypophosphataemic rickets, with delayed-onset penetrance and loss of the defect in some individuals after puberty [15]. In 2000, the ADHR Consortium identified missense variants in the FGF23 gene in this dominant form [16], and in 2001 Shimada and colleagues cloned FGF23 from a tumour causing oncogenic osteomalacia, showed that its continuous production reproduced the phenotype and proposed that variants in the RXXR cleavage motif prevent proteolytic inactivation [17]. In 2003, circulating FGF23 measurements revealed raised concentrations in patients with XLH and oncogenic osteomalacia [18]. The recessive forms were subsequently associated with DMP1 in 2006, ENPP1 in 2010 and FAM20C in 2013, and the form with hypercalciuria with SLC34A3 in 2006 [19–24].

For decades, treatment consisted of oral phosphate salts in several daily doses, combined with an active vitamin D analogue, a regimen that improves rickets and growth but does not normalise fasting serum phosphate, further stimulates FGF23 and exposes the patient to hyperparathyroidism and nephrocalcinosis [5]. Burosumab, an antibody directed against FGF23, received conditional authorisation in the European Union on 19 February 2018 and approval in the United States on 17 April 2018 [10, 25]. The 2025 European update and 2025 international paediatric guideline position it as first-line treatment in children, whereas the European recommendations reserve it for defined situations in adults [5, 6]. This article addresses XLH as the principal entity and describes the other hereditary forms of hypophosphataemic rickets in dedicated subsections, because their shared or divergent mechanism in relation to FGF23 determines opposing management approaches.

2. Molecular Genetics and Pathophysiology

2.1. Phosphate regulation and the FGF23–Klotho axis

Filtered phosphate is reabsorbed in the proximal tubule by the sodium–phosphate cotransporters NaPi-IIa (encoded by SLC34A1) and NaPi-IIc (encoded by SLC34A3). FGF23, produced mainly by osteocytes and osteoblasts, binds to the FGFR1c receptor with α-Klotho as a coreceptor and causes internalisation of these transporters, with phosphaturia; it simultaneously reduces renal 1α-hydroxylase and increases 24-hydroxylase, reducing the synthesis and accelerating the degradation of 1,25-dihydroxyvitamin D [1, 5]. Under normal conditions, hypophosphataemia suppresses FGF23 synthesis and release, so normal or raised FGF23 in the presence of low phosphate indicates inappropriate secretion [5]. The mature protein is cleaved by proprotein convertases between amino acids 179 and 180, producing inactive fragments; “intact” assays measure the whole molecule, and “C-terminal” assays measure the whole molecule and the fragment [11].

2.2. PHEX and X-linked hypophosphataemia

PHEX is located at Xp22.11 and encodes a membrane-bound neutral endopeptidase expressed predominantly in osteoblasts, osteocytes and odontoblasts; the physiological substrate responsible for the disease has not been identified [1]. Pathogenic variants cause loss of function and lead to increased circulating FGF23 through an as yet unexplained mechanism, with no demonstrated direct link between PHEX and FGF23 [1]. The dual disturbance — renal phosphate wasting and relative calcitriol deficiency — impairs mineralisation of the growth plate (rickets) and osteoid (osteomalacia) [1]. The table in the atlas of skeletal dysplasias summarises the mechanism as loss of function of a circulating factor regulating renal phosphate transport and vitamin D synthesis, with relatively low calcitriol [7].

A second component is independent of serum phosphate. ASARM peptides (acidic serine- and aspartate-rich motif) derived from SIBLING family proteins, such as MEPE, DMP1 and osteopontin, inhibit mineralisation; osteopontin is degraded by PHEX and contributes to XLH osteomalacia independently of hypophosphataemia [1]. In dentine, these peptides accumulate in unmineralised spaces, contributing to dental fragility [11]. Enthesopathy may represent a biomechanical adaptation to osteomalacia, and impaired 1,25-dihydroxyvitamin D signalling at the enthesis may be sufficient to trigger it [1]. The European update emphasises that excess FGF23 explains many, but not all, complications [5].

2.3. Variant spectrum, testing and genotype–phenotype correlation

According to HGMD data cited by GeneReviews, about 85% of pathogenic PHEX variants are detectable by sequencing and about 15% are deletions or duplications of one or more exons, requiring targeted copy-number analysis [1]. These proportions describe the type of published variant and are not equivalent to the clinical sensitivity of the test. In 118 French pedigrees, PHEX variants were found in 87% of familial cases and 72% of sporadic cases [26], and the 2019 European recommendation reports confirmation or exclusion in about 70–90% of cases [8]. The 2018 French PNDS (French National Diagnosis and Care Protocol), focused on hereditary hypophosphataemias with raised FGF23, estimates that about 80% of these patients carry a PHEX variant and that about 10% remain without a variant identified in the known genes; in some de novo cases the variant is postzygotic and present in mosaic form [12]. Deep intronic variants may require RNA analysis, for example of cells obtained from urine, and somatic mosaicism may escape blood analysis and be detected in saliva or skin by next-generation sequencing [1].

Genotype–phenotype correlation is inconsistent. Individual studies have associated truncating or C-terminal region variants with more severe bone disease, but others have not confirmed this association; in one series, variants producing premature termination codons were associated with lower tubular phosphate reabsorption and calcitriol than missense variants or in-frame deletions [1]. A complex allele merits specific mention: NM_000444.6:c.*231A>G, in the 3′ untranslated region, in cis with an out-of-frame duplication of exons 13–15, is common in individuals from North America [1, 2]. In a five-generation North American family with 22 untreated individuals carrying this allele, most had normal stature, 50% were normophosphataemic and 13 had received another diagnosis, mainly ankylosing spondylitis [27]. The exon duplication designation does not follow current HGVS nomenclature, as noted by GeneReviews itself; it is retained here as described in the literature, without manual conversion [1].

2.4. Related hereditary forms

ADHR (FGF23). Variants affect arginine residues in the cleavage motif (Arg176 and Arg179), stabilising the intact active form [1, 11, 17]. A validated example is NM_020638.3:c.527G>A, p.(Arg176Gln), classified as pathogenic in ClinVar [2, 33]. Expression is iron-sensitive: iron deficiency increases FGF23 transcription, and because the mutant protein is not efficiently cleaved, intact FGF23 rises [11]. In a 12-month prospective open-label trial involving six adults carrying p.Arg176Gln, five completed the protocol; intact FGF23 normalised in all five at month 12, and the three hypophosphataemic patients normalised their serum phosphate and discontinued calcitriol and phosphate [28]. The family described by Econs and McEnery included 23 affected individuals, with one subgroup presenting in adolescence or adulthood with bone pain, weakness and insufficiency fractures without deformity, and another with childhood rickets, in whom some lost the phosphate-wasting defect after puberty [15].

ARHR1 (DMP1). DMP1 is a matrix protein expressed in osteoblasts and osteocytes; its absence impairs osteocyte maturation and increases FGF23 expression, with isolated renal phosphate wasting and normocalciuria [19, 20]. In a review of 30 cases (25 from the literature and 5 Chinese), variants affecting the C-terminal fragment were associated with shorter stature (z-score −3.4 ± 1.6 versus −1.0 ± 1.6) and lower serum phosphate than those affecting only the N-terminal fragment; radiology showed coexisting osteomalacia and osteosclerosis, with relatively high axial areal bone mineral density and altered peripheral microarchitecture [34]. Severe enthesopathy with fibrosis and soft-tissue calcification is prominent [35].

ARHR2 (ENPP1). ENPP1 hydrolyses extracellular ATP into AMP and inorganic pyrophosphate, the principal inhibitor of hydroxyapatite deposition; its deficiency causes arterial calcification and, in survivors, FGF23-mediated hypophosphataemic rickets [29, 36]. GACI and ARHR2 constitute a phenotypic spectrum; the mean age at onset of hypophosphataemia is 1.6 years, and among 16 survivors with a mean age of 11.7 years, 11 (69%) already had rickets, with a Kaplan–Meier estimate that almost all would develop it by 14 years [29]. In the analysis of 84 individuals with ENPP1 deficiency, 51 had a diagnosis of GACI, 11 of ARHR2 and 22 of both, with infant mortality of 44% in the GACI group [37]. Of the 11 initially diagnosed with ARHR2, seven had cardiovascular manifestations, mainly hypertension or valvular involvement [29]. Intact FGF23 is raised or at the upper limit of normal [29]. A consanguineous family illustrates the variability: father and son were homozygous for the same variant, the father with hypophosphataemic rickets and aortic root dissection at 28 years, and the son with GACI and hypophosphataemia [29].

Associated with FAM20C. Biallelic variants cause Raine dysplasia, initially described as a lethal neonatal osteosclerotic dysplasia; patients with a mild phenotype may survive to adulthood without bone sclerosis, with craniosynostosis and dental anomalies including amelogenesis imperfecta [38]. Exome sequencing in two Norwegian siblings with hypophosphataemia and severe dental demineralisation disease identified compound heterozygous FAM20C variants, with dysregulated FGF23, hyperphosphaturia, intracerebral calcifications and osteosclerosis of the long bones without rickets [22]. FAM20C phosphorylates FGF23 and promotes its processing; its loss prevents FGF23 degradation [11].

HHRH (SLC34A3). Described in a consanguineous Bedouin family, with a homozygous single-nucleotide deletion truncating NaPi-IIc in the first transmembrane domain, and confirmed in other families with biallelic variants [23, 24]. Primary transporter loss causes hypophosphataemia, FGF23 suppression, an appropriate rise in 1,25-dihydroxyvitamin D, increased intestinal calcium absorption and hypercalciuria [24, 39]. In a pooled analysis of 304 individuals from 145 families, biallelic carriers had penetrance above 90% for renal and skeletal phenotypes; heterozygotes had an intermediate biochemical profile, with idiopathic hypercalciuria in 38% and a skeletal phenotype in 23% [30]. A family with apparently dominant inheritance had digenic heterozygous variants in SLC34A3 and SLC34A1, with a gene dosage effect [40].

Others. A de novo balanced t(9;13) translocation with a breakpoint adjacent to KL increased α-Klotho and FGF23, with hypophosphataemic rickets and hyperparathyroidism [31]. Conversely, deficiency of GALNT3, which normally O-glycosylates FGF23 and prevents its inactivation, causes familial hyperphosphataemic tumoral calcinosis or hyperphosphataemic hyperostosis syndrome, the biochemical mirror image of the forms described here [41].

3. Clinical Spectrum and Manifestations by System

3.1. Presentation and natural history

The clinical spectrum of XLH ranges from isolated hypophosphataemia to severe lower-limb bowing and craniosynostosis; the usual presentation is in the first two years, when the onset of walking makes the bowing evident, but the disease may only be recognised in adulthood in the setting of uninvestigated short stature [1]. Rachitic deformities usually become visible at around 6 months and, during the second year, the child shows delayed walking, waddling gait, varus or valgus deformity with a torsional component, metaphyseal widening of the wrists and ankles, thickening of the costochondral junctions and reduced growth velocity [8]. The French PNDS (French National Diagnosis and Care Protocol) describes genu varum in about two thirds and genu valgum in about one third of children, usually of the same type on both sides but sometimes with opposite deformities, and adds bone pain predominantly in the knees and lower limbs and reduced walking distance [12]. In the newborn, serum phosphate and ALP are often normal for age, but by 3 months most infants already show hypophosphataemia and rising ALP [6]. The bone dysplasia atlas records the typical presentation of hereditary rickets with bowed legs at 2–3 years, the possibility of late presentation, even in adulthood, and the absence of muscle weakness as a feature of XLH, in contrast with vitamin D-dependent forms [7].

GeneReviews summarises the frequency of manifestations in children and adults, emphasising that values depend on age, treatment, population and the definition used [1].

All heterozygous women are affected, and clinical and biochemical features are the same in both sexes; severity may differ within the same family without males necessarily being more affected, although several studies have described somewhat more pronounced growth impairment and skeletal dysmorphism in hemizygous males [1]. In the North American family with the c.*231A>G allele, more men than women had gait abnormalities (42.9% versus 13.3%), lower-limb deformity (71.4% versus 26.7%) and enthesopathy (85.7% versus 40%) [27].

3.2. Appendicular skeleton and growth

In a longitudinal study, untreated children had total height 2.48 standard deviations below the mean, sitting height 0.99 below and leg length 2.90 below; during treatment, trunk–leg disproportion increased [1]. Adults attain a final height 1.9 standard deviations below the mean, with leg length 2.7 below and sitting height 1.1 below [1]. In a multicentre series of 228 children treated with phosphate and active vitamin D, the median height z-score fell from approximately 0 at 3 months to approximately −1.6 at 2 years [5]. Genu varum or valgum may be associated with femoral and tibial torsion, and measurement of intercondylar and intermalleolar distances is used for monitoring [1]. Some deformities persist despite apparently adequate therapy and require surgical correction [1].

3.3. Osteomalacia, pseudofractures, enthesopathy and osteoarthritis in adults

Looser zones, or pseudofractures, may be symptomatic or asymptomatic and occur at any age, particularly in weight-bearing bones [1, 5]. In the phase 3 adult trial, 52% of the 134 participants had active fractures (12%) or active pseudofractures (47%) at baseline [10]. Calcification of tendons, ligaments and joint capsules — non-inflammatory enthesopathy — causes pain and stiffness; in a retrospective analysis of 26 patients from 11 families, aged 1 to 62 years, 69% had generalised entheseal calcification, with prevalence and extent increasing with age, unrelated to sex, and intratendinous lamellar bone without inflammatory cells on histology [42]. At a French referral centre, 67% of 114 adults had spinal or pelvic enthesopathies, associated with age and severe dental disease, without correlation with the type of PHEX variant [43]. In the phase 3 trial, 99.3% of adults had radiologically confirmed enthesopathy at baseline [5].

Calcification of spinal ligaments may cause canal stenosis, spinal cord compression, dysphagia and, rarely, paraplegia; ossification of the posterior longitudinal ligament may lead to myelopathy [1, 7]. Osteophyte formation, vertebral hyperostosis and sacroiliac fusion may mimic ankylosing spondylitis [1]. Early, disabling osteoarthritis of the large lower-limb joints has been described in more than 50% of patients by 30 years and in up to 85% with ageing [5]. Lower-limb muscle strength and functional capacity are reduced, but severe muscle weakness, particularly of the upper limbs, should suggest another cause, such as oncogenic osteomalacia or Fanconi syndrome [1].

3.4. Skull and nervous system

Craniosynostosis usually affects the sagittal suture, with dolichocephaly or scaphocephaly and a low cephalic index, and manifests somewhat later than congenital craniosynostosis [1, 8]. In a retrospective computed tomography study of 44 French children, 59% had complete or partial fusion of the sagittal suture, 25% cerebellar tonsillar protrusion, only two patients had neurological symptoms and four (9%) required neurosurgery [44]. In the multinational prospective XLH-DMP study, with the clinical history of 287 children, craniosynostosis was reported in 19%, Chiari type 1 malformation in 2.4%, syringomyelia in 1% and severe headache in 6.3% [6]. The difference between these proportions reflects the method: studies with systematic imaging detect more cases than registries based on clinical history. Chiari type 1 malformation is often asymptomatic, but compression of the brainstem and upper cervical cord may cause occipital pain aggravated by the Valsalva manoeuvre, motor or sensory deficits, central apnoeas and cranial nerve dysfunction [8]. The French PNDS (French National Diagnosis and Care Protocol) adds that secondary craniosynostosis, mainly sagittal and rarely coronal, may appear so late that skull shape changes little and only imaging reveals it, and that craniocerebral disproportion may cause chronic intracranial hypertension with papilloedema, cerebellar tonsillar descent and cervical, sometimes lumbar or holocord, syringomyelia [12].

3.5. Teeth and periodontium

Dentine is the most affected tissue: unmineralised interglobular spaces, enlarged pulp chambers and prominent pulp horns extending to the dentino-enamel junction allow bacterial invasion through microcracks in the enamel, which is apparently normal but thinner [6, 11]. The result is pulp necrosis and "spontaneous" abscesses in teeth without caries or trauma, which may progress to maxillofacial cellulitis; periodontitis is more frequent and severe in adults, with loss of teeth and implants [5, 8]. XLH does not increase susceptibility to caries [8]. The European update illustrates these findings with a 5-year-old child with a spontaneous abscess of a primary incisor, cellulitis at 7 years and a panoramic radiograph at 8 years showing enlarged pulp chambers, and with a 49-year-old woman with generalised horizontal alveolar bone loss (Figure 2 of the article) [5]. On radiography (panoramic, bitewing or periapical), the French PNDS (French National Diagnosis and Care Protocol) describes enlarged pulp chambers with prominent horns, dentine hypomineralisation visible beneath the dentino-enamel junction and extensive periapical lesions without apparent dental cause; in adults, the presence of several devitalised teeth, especially in the mandibular incisor–canine block, moderate to severe periodontitis, multiple asymptomatic periapical lesions and generalised alveolar bone loss is typical [12].

3.6. Hearing, kidney and comorbidities

Sensorineural hearing loss and tinnitus occur in children and adults; the true prevalence is unknown, and generalised osteosclerosis and thickening of the petrous bone have been described in patients with hearing loss [1]. The international paediatric guideline reports hearing loss in up to 8% of children, more often asymmetric and sensorineural [6]. The French PNDS (French National Diagnosis and Care Protocol) distinguishes conductive hearing loss, due to ossicular involvement, from sensorineural loss due to inner-ear damage, also describes vestibular deficits, usually compensated but aggravated by lower-limb abnormalities, and points out that the absence of involvement in childhood does not exclude a late deficit, including sudden hearing loss in adults [12]. Nephrocalcinosis and nephrolithiasis are mainly complications of treatment with phosphate and active vitamin D, with nephrocalcinosis described in 25–60% and nephrolithiasis in about 10% [1]. Secondary hyperparathyroidism was present in 25% of one cohort, and tertiary, hypercalcaemic hyperparathyroidism in about 10% or fewer [1]. Arterial hypertension, overweight with insulin resistance and metabolic syndrome appear more frequent than in the general population, partly as an effect of phosphate therapy; data on left ventricular hypertrophy are conflicting [1]. In the UK primary care database, mortality was higher than in controls (hazard ratio 2.93; 95% CI 1.24–6.91), with deaths among cases at a median age of 64 years [45].

3.7. Particular features of the other forms

In ADHR, onset may be late and, rarely, phosphate wasting regresses [1]. In ARHR1, adults have hyperostotic osteomalacia, extensive enthesopathy with fibrosis and soft-tissue calcification, dental abscesses and hearing deficits [34, 35]. In ENPP1 deficiency, the infantile phase is dominated by arterial calcification with hypertension, heart failure and high mortality; survivors develop rickets, painful enthesopathy, hearing loss and joint involvement, and remain at cardiovascular risk [29, 37]. The FAM20C-associated form combines hypophosphataemia, osteosclerosis, dental anomalies and intracranial calcifications [7, 22]. In HHRH, hypercalciuria leads to stones or nephrocalcinosis, and some carriers have only a renal phenotype [30].

4. Clinical Recognition and Warning Signs

Recognition begins with rickets unresponsive to usual vitamin D doses. In infants and children, warning signs are progressive lower-limb bowing after walking onset, growth deceleration, epiphyseal swelling, rachitic rosary, Harrison sulcus, craniotabes or craniosynostosis, and dental abscesses [1]. The Brazilian textbook of genetic syndromes also lists delayed fontanelle closure, widening of the wrists, distal radial and ulnar bowing, scoliosis, genu valgum or varum, osteopenia and bone pain [4]. The Oxford handbook includes hypophosphataemic rickets among the causes of long-bone bowing when assessing skeletal dysplasia and notes that metaphyseal dysplasias are difficult to distinguish radiologically from metabolic diseases such as rickets [46].

In adults, suspicion should arise with disproportionate short stature and short lower limbs, residual deformities, joint pain, enthesopathy and stiffness of the hips, spine and shoulders, insufficiency fractures, dental abscesses, fatigue, chronic pain, weakness, sleep disturbances, sensorineural hearing loss or Chiari malformation [1]. A previous diagnosis of ankylosing spondylitis, early osteoarthritis or Forestier disease should be reviewed when hypophosphataemia and enthesopathy coexist; an adult erroneously diagnosed with achondroplasia has also been described [11, 27].

In families with XLH, screening at-risk relatives allows diagnosis before deformities develop. The absence of a family history does not exclude the diagnosis: approximately one third of published patients had no family history, and the ESCEO consensus estimates 20–30% sporadic disease [8, 11]. The consensus recommends testing newborns from affected families and, while awaiting the genetic result, measuring plasma creatinine, ALP, PTH, 25-hydroxyvitamin D and phosphate, and urinary phosphate and creatinine, at 7 days and, if normal, at one month of life [11]. GeneReviews recommends reassessment every 2–3 months until at least 1 year in infants with initially normal results [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no formal scored clinical criteria; the guidelines define the diagnosis by the combination of clinical, radiological and biochemical findings and by genetic confirmation. The 2025 European update recommends considering XLH in a child with clinical, biochemical or radiological signs of rickets, reduced growth velocity and phosphate below the age-specific reference interval, with isolated renal phosphate wasting and without vitamin D or calcium deficiency, especially with a positive family history (grade B, moderate recommendation) [5]. In adults or adolescents with closed growth plates, suspicion rests on lower-limb deformity and signs of osteomalacia — pseudofractures, early osteoarthritis, spinal degeneration and stenosis, dental abscesses and enthesopathies — with hypophosphataemia due to isolated renal wasting (grade B) [5]. The international paediatric guideline proposes that the diagnosis can be made in the presence of chronic hypophosphataemia without another cause of renal phosphate wasting, reinforced by an X-linked inheritance pattern [6]. GeneReviews establishes the diagnosis by identification of a hemizygous pathogenic or likely pathogenic variant in males or a heterozygous one in females, in a proband with suggestive findings; a variant of uncertain significance neither establishes nor excludes the diagnosis [1]. The French PNDS (French National Diagnosis and Care Protocol) confirms the diagnosis in children by the combination of hypophosphataemia with selective renal phosphate wasting (phosphaturia inappropriate to the phosphataemia without glycosuria or proteinuria and/or tubular phosphate reabsorption below 85% of the filtered load), raised ALP, normal or upper-normal PTH, normal or lower-normal calcium and low calciuria, with raised or inappropriately high-normal intact FGF23; in adults it requires the same findings, with normal or raised PTH and without requiring raised ALP, which is less frequent at this age [12].

5.2. Biochemical assessment

GeneReviews reproduces Payne's age-specific TmP/GFR intervals: at birth 1.43–3.43 mmol/L; at 3 months 1.48–3.30 mmol/L; at 6 months 1.15–2.60 mmol/L; from 2 to 15 years 1.15–2.44 mmol/L; from 25 to 35 years 1.00–1.35 mmol/L in men and 0.96–1.44 mmol/L in women; from 45 to 55 years 0.90–1.35 and 0.88–1.42 mmol/L; and from 65 to 75 years 0.80–1.35 mmol/L, recommending a spot urine sample after overnight fasting [1]. The Walton and Bijvoet nomogram may overestimate values in children [1]. The European update states that non-fasting phosphate values, interpreted using continuous paediatric intervals, appear appropriate in children, that the Brodehl formula is reliable in both fasting and non-fasting conditions, and that an online z-score calculator is available [5]. The international paediatric guideline prefers morning samples after at least 2–3 hours of fasting, with blood and urine collected simultaneously or less than 2 hours apart; it considers a urinary calcium/creatinine ratio < 0.2 mg/mg (< 1.4 mmol/mmol in some laboratories) and 24-hour urinary calcium < 4 mg/kg/day normal [6]. The European update gives upper calcium/creatinine ratio limits (mol/mol) of 2.2 below 1 year, 1.4 between 1 and 3 years, 1.1 between 3 and 5 years, 0.8 between 5 and 7 years, 0.7 between 7 and 18 years and 0.57 above 18 years [5]. The ESCEO consensus notes the circadian rhythm of phosphate, with a nadir around 11 o'clock, and the possibility of pseudohypophosphataemia due to monoclonal immunoglobulin, drugs or hyperbilirubinaemia [11]. The Brazilian textbook presents the same reasoning using the tubular phosphate reabsorption rate, (1 − fractional phosphorus excretion) × 100 [4].

Regarding FGF23, in a study of 149 patients with FGF23-dependent or -independent hypophosphataemia, an intact FGF23 threshold of 27 pg/mL was 100% sensitive and 100% specific in distinguishing the two categories; a 90 RU/mL threshold for the C-terminal assay specifically separated oncogenic osteomalacia from independent forms, and using the laboratory upper limit for the C-terminal assay (180 RU/mL) would have led to misdiagnosis in more than half of patients with FGF23-mediated hypophosphataemia [47]. These values derive from a single assay (Immutopics) in a National Institutes of Health reference cohort; in Japanese patients, a threshold of 30 pg/mL has been described with another assay [5]. FGF23 should be sampled 1 to 2 weeks after stopping phosphate and calcitriol, and burosumab interferes with the assays [5, 11]. The French PNDS (French National Diagnosis and Care Protocol) describes three assays used in France: the C-terminal assay (upper reference limit 120 RU/mL), the Immutopics intact assay (below 50 pg/mL) and, since 2016, the Liaison intact assay (23–93 pg/mL), considered the most reliable; only measurement of the intact form allows inappropriate FGF23 secretion to be asserted, because other diseases raise the C-terminal fragment alone. The indication for the assay and for genetic testing lies with the reference centre, and in 2018 FGF23 was not reimbursed by French health insurance [12].

Sampling conditions determine interpretation. Less than 1% of body phosphate is extracellular, and increased glycolysis (acute hyperventilation, glucose or fructose intake) lowers phosphataemia by about 0.1 mmol/L in non-depleted individuals and much more in depleted ones. In adults, phosphataemia rises after 11 a.m. to an evening value about 0.3 mmol/L higher than the morning value, has a further nocturnal peak at around 2–3 a.m. and reaches its minimum between 8 and 10 a.m.; children have a similar rhythm, and reference intervals were defined in fasting morning samples. It is measured in serum or heparinised plasma (plasma gives values 0.06–0.10 mmol/L lower than serum), avoiding EDTA and citrate, which interfere with the phosphomolybdate complex. High-dose mannitol causes pseudohypophosphataemia; monoclonal immunoglobulins (myeloma, Waldenström macroglobulinaemia), hyperbilirubinaemia, hyperlipidaemia, high-dose liposomal amphotericin B and contamination by tissue plasminogen activator or heparin may falsely raise phosphate and mask true hypophosphataemia [12]. The ESCEO consensus places the circadian nadir at around 11 a.m. and lists monoclonal immunoglobulin among the causes of pseudohypophosphataemia [11], whereas the PNDS places the minimum between 8 and 10 a.m. and describes monoclonal interference mainly as a false elevation; in both cases, the practical rule is to sample in the morning, fasting and without interfering substances.

The PNDS reproduces age-specific reference intervals that help avoid overlooking hypophosphataemia or raised ALP [12].

The ALP intervals were adapted by the PNDS from a Canadian paediatric reference cohort (Colantonio and colleagues, 2012) and depend on the laboratory method. The PNDS calcium/creatinine ratio limits differ from those of the 2025 European update: they are more permissive from 4 to 10 years (1.16 mmol/mmol, against 0.8 from 5 to 7 years and 0.7 from 7 to 18 years) and more restrictive in adults (0.40, against 0.57), so the laboratory and guideline used should be explicit when classifying hypercalciuria [5, 12]. The 15–40 ng/mL interval for 25-hydroxyvitamin D in appendix 4 also does not match the PNDS's own therapeutic target of 20–80 ng/mL or the 20 ng/mL (50 nmol/L) threshold of the European update, so a value between 15 and 20 ng/mL, "normal" in that table, warrants correction with colecalciferol [5, 12].

5.3. Imaging

Radiographs of the wrists, knees and ankles are usually sufficient to diagnose rickets; in XLH the cortex appears thickened and signs of bone resorption are absent, in contrast with nutritional rickets [8]. The atlas describes metaphyseal changes with fraying, cupping and widening, coarse trabeculae, bowing of the long bones, pseudofractures, ectopic ossification at tendon insertions and in the paravertebral ligament and, at a late stage, diffuse osteosclerosis, mainly axial [7]. The atlas figures illustrate a girl aged 3 years and 8 months with dolichocephaly due to secondary craniosynostosis, coxa vara with a femoral neck pseudofracture, genu valgum and widened metaphyses, and an 11-year-old boy with bowed long bones and fibular pseudofractures (Figures 15.3.1–15.3.3) [7]. The table in the Brazilian textbook includes widening of the epiphyses, loss of definition of the epiphyseal–metaphyseal zone, cupping and disorganisation of the growth plate, reduced trabecular pattern, osteopenia and Looser pseudofractures [4]. The recommended initial assessment includes weight-bearing lower-limb alignment radiography with a low-dose technique, renal ultrasonography, orthopantomography or cone-beam computed tomography from 6 years according to clinical findings, and brain and spinal MRI when skull shape suggests craniosynostosis or there are signs of intracranial hypertension [5]. Densitometry and bone scintigraphy are not routinely recommended, because density is typically high and does not guide decisions [1, 5]. Bone biopsy is not necessary for diagnosis; it may show unmineralised periosteocytic lesions [1]. The French PNDS (French National Diagnosis and Care Protocol) stresses that densitometry does not contribute to the diagnosis of osteomalacia and recommends low-radiation systems, such as EOS®, for weight-bearing lower-limb radiographs [12].

5.4. Genetic testing and reporting

The European update recommends confirming the diagnosis by genetic analysis in children and adults, when available (grade B), and, if the result is negative for PHEX, considering DMP1, ENPP1, FGF23 and acquired forms (grade B); in the absence of genetic testing, X-linked inheritance and non-suppressed intact FGF23 with hypophosphataemia support the diagnosis (grade C) [5]. The international paediatric guideline suggests a panel including PHEX, FGF23, DMP1, ENPP1, FAM20C, KL, FGFR1, INPPL1, RAS genes, GNAS, SLC34A1, SLC34A3, CLCN5, CTNS and NHERF1, among others [6]. The ESCEO consensus justifies genetic confirmation by the fact that burosumab is approved only for XLH and oncogenic osteomalacia [11]. In France, the PNDS (French National Diagnosis and Care Protocol) considers next-generation sequencing of a panel with all genes involved in FGF23 production and signalling to be the most relevant approach [12].

The report should specify the gene, transcript with version (for PHEX, NM_000444.6, MANE Select), HGVS variant nomenclature, zygosity (hemizygous in males, heterozygous in females), classification according to ACMG/AMP criteria and technical limitations, particularly coverage of deletions and duplications, intronic regions and mosaicism [1, 2]. The international paediatric guideline notes that, if genetic testing first suggested XLH, diagnosis requires a compatible clinical and biochemical profile and may require reassessment with age [6].

5.5. Algorithm

The European guideline algorithm begins with a child or adult with rickets or osteomalacia and hypophosphataemia. First, metabolic acidosis, renal diseases with non-selective tubular wasting and calcipenic diseases with secondary hyperparathyroidism are excluded. Next, urinary calcium and 1,25-dihydroxyvitamin D distinguish FGF23-mediated diseases from primary tubular losses due to NaPi-IIa and NaPi-IIc defects, which feature raised 1,25-dihydroxyvitamin D, hypercalciuria, suppressed FGF23 and low PTH; finally, X-linked inheritance with complete penetrance in females strongly supports XLH, to be genetically confirmed [5, 8]. With unsuppressed FGF23, the differential diagnosis is restricted to a few entities, XLH being the most common [5]. The algorithm reproduced in the Brazilian textbook follows the same initial division: raised PTH points towards hypocalcaemic rickets (nutritional, malabsorption, vitamin D-dependent types I and II), and normal PTH with low phosphate towards hypophosphataemic forms [4].

5.6. Initial assessment of disease extent

Once the diagnosis is confirmed, the French PNDS (French National Diagnosis and Care Protocol) defines a different initial assessment before and after 5 years of age and in adults [12].

The inclusion of densitometry in the initial adult assessment distinguishes the PNDS from the 2025 European update, which does not recommend it routinely; the PNDS, for its part, specifies that densitometry does not diagnose osteomalacia [5, 12].

6. Differential Diagnosis

6.1. Calcipenic rickets

Nutritional rickets and XLH may coexist; if phosphate does not normalise after correction of vitamin D and calcium, XLH should be considered [8]. The differential table in the Brazilian textbook emphasises that nutritional rickets features a high tubular phosphate reabsorption rate, hypocalcaemia and vitamin D deficiency, whereas Fanconi syndrome is associated with metabolic acidosis, fluid and electrolyte disturbances, proteinuria and aminoaciduria [4].

6.2. Phosphopenic rickets and tubular losses

In fibrous dysplasia and McCune–Albright syndrome, renal phosphate wasting, with or without rickets or osteomalacia, occurs in approximately 50% of patients and is attributed to FGF23 production by dysplastic tissue; the aetiology is a somatic activating GNAS variant [48, 49]. The atlas illustrates a 12-year-old boy with “ground-glass” fibrous dysplasia and a femoral pseudofracture (Figure 15.3.5) [7]. In linear sebaceous naevus syndrome, vitamin D-resistant rickets is a variant of tumour-induced osteomalacia, reversible after removal of the skin lesions, and the aetiology is a somatic HRAS or KRAS variant [50]. Oncogenic osteomalacia shares the biochemistry of XLH, but dental complications, enthesopathy and osteoarthritis are less common and bone mineral density is typically low [11]. Intravenous iron-induced hypophosphataemia has been summarised as “6H syndrome”: high FGF23, hyperphosphaturia, hypophosphataemia, hypovitaminosis D, hypocalcaemia and secondary hyperparathyroidism [5]. Tenofovir and adefovir also cause hypophosphataemic osteomalacia, usually with Fanconi syndrome [1].

The French PNDS (French National Diagnosis and Care Protocol) excludes from its scope renal phosphate losses due to primary tubulopathy or drug toxicity and nutritional deficiencies, and organises chronic acquired hypophosphataemias by phosphaturia. With low phosphaturia, the causes are insufficient intake (inadequate parenteral nutrition, deficiencies), intestinal malabsorption (vitamin D deficiency, pseudo-deficiency rickets, prolonged antacids, malabsorption, chronic liver disease, alcoholism) and redistribution (erythropoietin in cirrhotic patients; in acute forms, refeeding, hungry bone syndrome after parathyroidectomy, respiratory alkalosis, diabetic ketoacidosis, lymphoma, acute leukaemia and bone marrow transplantation), as well as severe sepsis, extensive burns, inadequate dialysis, hypothermia and paracetamol or salicylate poisoning. With high phosphaturia (24-hour phosphaturia above 20 mmol and TRP below 85%), the causes are proximal tubulopathies (Fanconi syndrome; tenofovir, acetazolamide, platinum salts, ifosfamide, diuretics, glucocorticoids), primary or secondary hyperparathyroidism, FGF23-dependent losses (hypophosphataemic rickets, oncogenic osteomalacia, fibrous dysplasia, McCune-Albright syndrome) and FGF23-independent losses (idiopathic phosphate diabetes and NaPi-IIa or NaPi-IIc transporter disorders with hypercalciuria) [12]. In oncogenic osteomalacia, the hypophosphataemia is acquired and profound, the mesenchymal tumour is usually benign and small, and the 2018 PNDS indicated indium-111-labelled octreotide scintigraphy to locate it [12].

Dent disease, which is X-linked recessive, is characterised by low-molecular-weight proteinuria, hypercalciuria and at least one further finding among nephrocalcinosis, nephrolithiasis, haematuria, hypophosphataemia or chronic kidney disease; it may be accompanied by rickets or osteomalacia, and 30–80% of affected males reach end-stage kidney disease between 30 and 50 years [32]. The atlas classifies the CLCN5-related form as “X-linked recessive hypophosphataemic rickets”, a variant of Dent disease, with hypercalciuria, nephrocalcinosis and renal failure [7]. In cystinosis and other hereditary forms of Fanconi syndrome, hypophosphataemia occurs in the context of generalised proximal tubular dysfunction, with normal or raised FGF23 depending only on the stage of chronic kidney disease [8].

6.3. Skeletal dysplasias and other conditions

Schmid metaphyseal chondrodysplasia has normal bone structure and coxa magna; the biochemical abnormalities of hypophosphataemic rickets establish the diagnosis, and vitamin D, given after a mistaken diagnosis of rickets, is contraindicated in metaphyseal chondrodysplasias [7, 51]. In hypophosphatasia, serum ALP is low, urinary phosphoethanolamine is raised and tongue-like metaphyseal ossification defects differ from the metaphyseal fraying of rickets [7, 51]. Jansen metaphyseal dysplasia (PTH1R) features more pronounced short stature, hypophosphataemia, hypercalciuria, raised 1,25-dihydroxyvitamin D and nephrocalcinosis [1]. Hypochondroplasia is distinguished by shortening of the lumbar vertebral pedicles and absence of coxa vara [51]. In children with fractures, the differential diagnosis of abuse includes nutritional rickets [46]. Ankylosing spondylitis is the principal misdiagnosis in adults, as shown by the family with the c.*231A>G allele [27].

7. Treatments and Risk Management Strategies

7.1. Goals and organisation of care

Treatment aims to heal or prevent rickets and osteomalacia, relieve pain, promote healing of fractures and pseudofractures and, in children, stimulate growth and correct or prevent deformities, while avoiding complications of therapy itself [1]. Guidelines recommend multidisciplinary care organised by a metabolic bone disease specialist, in referral centres and with attention to transition to adult care [1, 5]. The 2025 European update stopped using the term “conventional treatment” for phosphate with active vitamin D because most European children with XLH are now treated with burosumab [5]; in this article the term is used solely for clarity, as in GeneReviews and the ESCEO consensus.

In France, the 2018 PNDS (French National Diagnosis and Care Protocol) organises the care pathway around the reference centre for rare diseases of calcium and phosphate metabolism and the competence centres, integrated into the OSCAR rare disease health network. The diagnosis is communicated in a dedicated consultation by an expert from the centre, in the presence of the parents when the patient is a minor, with the contact details of the RVRH-XLH association, which since 2011 has brought together patients with hereditary hypophosphataemia with raised FGF23. The team includes the attending physician, paediatrician, endocrinologist, rheumatologist, nephrologist, orthopaedic surgeon, neurosurgeon, ENT specialist, ophthalmologist, dentist and orthodontist, biologist, radiologist, geneticist, physiotherapist or adapted physical activity, dietitian, podiatrist, psychologist, nurse and social worker. The care protocol for exemption from patient co-payment as ALD 17 (off-list long-term condition) is requested by the centre expert below 16 years of age and by the attending physician above 16 years, mentioning ENT, dental care and orthodontics; multiple daily dosing at school is covered by an individualised reception plan (PAI), and the MDPH (departmental centre for disabled people) intervenes in compensation for disability [12].

7.2. Burosumab (Crysvita®)

Mechanism and pharmacology. Burosumab is a fully human IgG1 monoclonal antibody that binds to FGF23 and inhibits its activity, restoring tubular phosphate reabsorption and increasing 1,25-dihydroxyvitamin D [8, 9]. It has linear kinetics between 0.1 and 1 mg/kg, a Tmax of 8 to 11 days and a half-life of approximately 19 days [9]. In children, TmP/GFR and phosphate rise within the first week; ALP improves within 6 months and normalises within 12 months in most patients [5]. It is supplied in single-dose vials of 10, 20 and 30 mg/mL; prefilled syringes of 10, 20 and 30 mg are also available in the EU [9, 10].

Regulatory status.

The European product information adds that safety and efficacy below 4 months have not been established in clinical studies, despite the indication starting in the first month, because no patient younger than 4 months was included in study BUR-CL207; elimination appears slower below 1 year [10]. The US label defines severe renal impairment as an estimated GFR of 15–29 mL/min/1.73 m² in children and creatinine clearance of 15–29 mL/min in adults [9]. The international paediatric guideline contraindicates the drug at GFR < 30 mL/min and in acute kidney injury and advises caution between 30 and 60 mL/min [6]. The European formulation contains sorbitol and warns patients with hereditary fructose intolerance [10]. Regarding calcimimetics, GeneReviews describes coadministration as contraindicated because of the risk of hypocalcaemia, whereas the European SmPC calls for caution and close calcium monitoring because studies are lacking [1, 10].

Dose recommendations of the guidelines. The 2025 European update acknowledges the label starting dose of 0.8 mg/kg (maximum of 2.0 mg/kg and 90 mg per dose in the paediatric label) [9, 10], but accepts that 0.4 mg/kg may suffice, with titration by phosphataemia and response (grade C, moderate); it recommends phosphate sampling 7–14 days after injection, increases no more often than every 4 weeks, increments of 0.2 mg/kg below 20 kg and maintenance of the dose when there is a satisfactory response even with phosphate below the reference interval (grade C, weak) [5]. The German registry showed median doses at 12 months between 0.2 and 2.0 mg/kg, lower in adolescents (0.7 against 1.1 mg/kg), and normalisation of ALP in 80% despite persistent mild hypophosphataemia in about half of patients [5]. The international paediatric guideline proposes adjusting the dose to obtain phosphate in the low to mid-normal range at peak and slightly below normal or at the lower limit at trough, avoiding hyperphosphataemia at any point in the cycle, and not increasing the dose solely because of weight gain [6]. In adults, the European update recommends 1.0 mg/kg every 4 weeks, fasting phosphate 7–11 days after injection, an increase up to the maximum of 90 mg if the response is insufficient and effective contraception during treatment [5]. Data from an extension study suggest that 0.5–1.0 mg/kg every 4 weeks raises phosphate above 0.8 mmol/L in most adults; in the phase 3 trial, six of 68 patients (9%) required a 50% reduction for phosphate > 1.6 mmol/L [5]. Administration every 2 weeks in adults, before the change to the US label, was described only in reports and designated as off-label use [1, 5].

Adverse effects. In the phase 3 paediatric trial, the most frequent effects with burosumab, occurring more often than in controls, were fever (55% versus 19%), injection-site reactions (52% versus 0%), cough (52% versus 19%), vomiting (41% versus 25%), extremity pain (38% versus 31%), headache (34% versus 19%), dental abscess (34% versus 13%) and caries (31% versus 6%) [9]. In adults, effects occurring in > 5% and more frequently than with placebo were back pain, headache, tooth infection, restless legs syndrome, decreased vitamin D, dizziness, constipation, cramps and increased phosphorus [9]; the ESCEO consensus reports restless legs syndrome in 11.8% versus 7.6% with placebo [11]. With exposure up to 214 weeks in children and 300 weeks in adults, the European SmPC lists reactions > 10%, including, in children, fever 53%, cough 52%, injection-site reaction 48%, headache 43%, vomiting 43%, extremity pain 38% and dental abscess 36%, and, in adults, back pain 30%, injection-site reaction 29%, headache 28%, tooth infection 28% and decreased vitamin D 28% [10]. Hypercalcaemia has been reported, severe particularly in tertiary hyperparathyroidism; burosumab should not be administered with moderate-to-severe hypercalcaemia (> 3 mmol/L) until corrected [10]. Hypersensitivity reactions were mild or moderate and require discontinuation if severe [5, 9]. Antidrug antibodies may develop, associated with falling serum phosphate [1]. FGF23 measured during treatment is falsely raised or indeterminate because of analytical interference and should therefore not be used for monitoring (grade A, strong) [5, 53].

7.3. Pivotal clinical trials

Interpretation of these studies has limitations that affect practice. The only paediatric comparative trial was open-label, included children with marked radiological rickets and excluded adolescents, mild forms and secondary hyperparathyroidism; the control group continued a regimen already used for years, and the demonstrated superiority relates to radiological and biochemical outcomes at 40–64 weeks [5, 11]. The height gain was small, approximately +0.1 to +0.2 standard deviations, and improvement in deformities occurs over 2–3 years [5]. In the same trial, dental abscesses did not decrease with burosumab; a post hoc analysis found 0% versus 25% abscesses below 5 years, but 53% versus 0% between 5 and 12 years, consistent with a window during tooth formation [5]. The systematic review cited by ClinGen estimated 38% more adverse events in children with burosumab (95% CI 14 to 60) and 19% more children with dental abscesses (95% CI −1 to 37), without serious events requiring discontinuation [59]. In adults, the controlled trial lasted 24 weeks, significant improvement was limited to stiffness and an effect on enthesopathy was not demonstrated, with a mean calcaneal enthesopathy burden (sum of superior and inferior spurs) of 5.64 cm at baseline and 5.90 cm at week 24 in the burosumab group, versus 5.54 cm at baseline in the placebo group [5, 10]. There are no trials directly comparing burosumab with phosphate and active vitamin D in adults, and comparison can only be indirect [5]. Benefits depend on continuity: in a post hoc analysis, patients who stopped the drug after 96 weeks lost their laboratory, functional and patient-reported gains, which recovered on reintroduction [5].

7.4. Oral phosphate with calcitriol or alfacalcidol

Oral phosphate is given in several doses because serum phosphate returns to baseline 1–2 hours after each dose; the active vitamin D analogue is required to counteract calcitriol deficiency, prevent phosphate-induced hyperparathyroidism and increase intestinal calcium and phosphate absorption [5]. Phosphate alone is contraindicated because it exacerbates secondary hyperparathyroidism, and doses should be calculated as elemental phosphorus because the content differs between salts [1, 8]. Normalisation of fasting phosphate is not a goal of this regimen because it indicates overtreatment; adjustments are guided by ALP, radiological rickets, deformities and growth, balanced against the risks of hyperparathyroidism, hypercalciuria and nephrocalcinosis [1, 5].

The equivalent alfacalcidol dose is 1.5–2.0 times the calcitriol dose, mainly extrapolated from studies in chronic kidney disease; calcitriol can be given in 1 or 2 doses and alfacalcidol as a single dose, and a night-time dose may reduce postprandial calcium absorption [6, 8]. Sugar-containing solutions should be used cautiously because of dental fragility, and phosphate should not be taken with calcium supplements or milk, which reduce its absorption [8]. Routine calcium supplements are not recommended, but adequate dietary intake should be ensured; a pilot trial suggested that dairy products in equimolar doses may be more effective and safer than phosphate tablets [1, 8]. Active vitamin D should be reduced or stopped during immobilisation exceeding 1 week [5]. In the United States, the consulted oral calcitriol label indicates the drug for secondary hyperparathyroidism in chronic kidney disease, dialysis-associated hypocalcaemia and hypoparathyroidism; its use in XLH is therefore off-label, supported by guidelines [60].

The 2018 French PNDS (French National Diagnosis and Care Protocol), which predates the widespread use of burosumab, presents the regimen of phosphate with alfacalcidol or calcitriol as first-line treatment, started as early as possible and continued at least until the end of growth, without specific contraindications and compatible with pregnancy and breastfeeding [12]. The indicative doses, as elemental phosphorus, are adjusted every 3 months in children and every 6 or 12 months in adults [12].

Phosphate doses should be at least 4 hours apart (4 daily doses at initiation) and 20 minutes away from bottle feeds, milk and dairy products. The biological targets are ALP close to the upper limit of normal for age, with normal calciuria and PTH; normalisation of phosphate is not a goal of the regimen. 25-hydroxyvitamin D is given to all patients, lifelong, for concentrations between 20 and 80 ng/mL [12].

These doses differ from current guidelines. In children, the PNDS phosphate dose for 0–5 years (55–70 mg/kg/day) lies at or above the upper limit of the European range of 20–60 mg/kg/day, and alfacalcidol is given at a fixed dose (1.0–3 µg/day depending on age), whereas the European guidelines, the ESCEO consensus and the international paediatric guideline calculate it by weight (25–50 ng/kg/day) [5, 6, 8, 11]. In adults, the PNDS agrees with the ESCEO consensus on phosphorus up to 2,000 mg/day, but divides it into 2 doses and allows alfacalcidol up to 2.0 µg/day, whereas the 2025 European update indicates 200–1,600 mg/day in at least 3 doses and alfacalcidol 0.5–1.5 µg/day [5, 11]. Under the rule adopted in this article, the reference doses are those of the 2025 guidelines, and those of the PNDS are presented as 2018 French practice.

The most common adverse effects of phosphate are diarrhoea, cramps and abdominal pain, reduced by gradual increases [1]. Nephrocalcinosis has been described in 30–70% of treated patients and is associated mainly with phosphate doses [8]. Persistent hyperparathyroidism was described in 62% and 25%, and hypercalcaemic hyperparathyroidism in 17% and 10%, in two large paediatric and adult cohorts receiving long-term treatment [5]. Ectopic calcifications have been described without hypercalcaemia or hyperphosphataemia [1]. Hypercalciuria and hypercalcaemia are associated with high calcitriol doses or tertiary hyperparathyroidism and require active vitamin D reduction [1]. To prevent nephrocalcinosis, maintaining normal urinary calcium is recommended and, with hypercalciuria, regular hydration, potassium citrate and sodium restriction (grade C) [5]; the 2019 guidelines warn that urinary alkalinisation increases the risk of phosphate precipitation [8].

7.5. Whom to treat and with what: recommendations and divergences

The three sources agree on the need to treat children early: treatment started before 1 year was associated with better height and less rachitic activity in a series of 19 patients, without completely normalising the skeleton [61]. They differ on the position of burosumab in mild paediatric forms, in infants and in adults, reflecting the trial populations, the method (the international panel used GRADE; the European one, Delphi with a 70% threshold) and access [5, 6]. The international paediatric guideline stresses the variability of approval and funding between countries, by age and by severity [6]. The case in section 10 shows the clinical consequence of an interruption imposed by funding. The 2018 French PNDS (French National Diagnosis and Care Protocol) predates the published phase 3 paediatric trials and the indication extensions: it placed the conventional regimen as first line and burosumab in severe, refractory or complicated forms, stressing that the latter normalises phosphataemia and restores endogenous calcitriol synthesis, and considered its place in adults still to be defined; it therefore differs from the 2025 European update and international guideline in children. It also differs on transition, by leaving the decision to continue treatment to the transition consultation, whereas the European update recommends continuing burosumab until the mid-third decade, and in adults, by proposing to treat postmenopausal women at risk of fragility, a situation that the other sources do not single out [5, 6, 12].

7.6. Hyperparathyroidism, growth hormone and other measures

The European update recommends 25-hydroxyvitamin D > 20 ng/mL (50 nmol/L), with colecalciferol or ergocalciferol if necessary (grade B), age-appropriate calcium intake (grade B, strong) and, for hyperparathyroidism on the conventional regimen, increasing active vitamin D and/or reducing phosphate; with persistent hypercalciuria or hypercalcaemia, reducing or stopping both [5]. Cinacalcet, without an approved indication in this setting, may be considered in severe or refractory hypercalcaemic hyperparathyroidism, with caution because of hypocalcaemia and QT interval prolongation; persistent hypercalcaemic hyperparathyroidism should be treated by parathyroidectomy, with recurrence in about 10% [5, 8]. After parathyroidectomy, hungry bone syndrome with profound hypocalcaemia is frequent [1]. Paricalcitol reduced PTH in a randomised trial, at the cost of worsening hypercalciuria [1, 11]. The French PNDS (French National Diagnosis and Care Protocol) defines tertiary hyperparathyroidism as hypercalcaemia with normal or raised PTH, partly caused or aggravated by phosphate and by underdosing of active vitamin D, usually preceded by a secondary phase with raised PTH without hypercalcaemia that worsens the hypophosphataemia. With raised PTH, phosphate is reduced and/or active vitamin D increased and vitamin D deficiency corrected; in the autonomous form with hypercalcaemia, treatment is surgical, because cinacalcet has shown no benefit, after renal imaging, densitometry (lumbar spine, proximal femur and radius), sestamibi (MIBI) scintigraphy, parathyroid ultrasonography and calcitonin measurement. Surgery should be performed by an expert surgeon, because of the possibility of multiglandular disease, and, if hyperparathyroidism appears before 30 years of age, testing for MEN1, CDKN1B and CDC73 (HRPT2) variants is recommended, even without a syndromic or familial picture [12]. The position on cinacalcet differs from the 2025 European update, which accepts it in severe or refractory hypercalcaemic hyperparathyroidism before parathyroidectomy [5].

Recombinant growth hormone transiently increases phosphate and growth velocity, but does not improve rickets, and results on final height are conflicting [1]. The European update accepts it, with a weak recommendation, in children with persistent short stature, controlled ALP and PTH and bone age below 13 years in girls and 14 in boys [5]; the international paediatric guideline does not recommend its routine use, citing the randomised trial without benefit on near-final height [6]. The French PNDS (French National Diagnosis and Care Protocol) considers growth hormone, outside the marketing authorisation and after multidisciplinary discussion, in children who remain below −2 standard deviations in height despite balanced treatment and normalised ALP [12].

For musculoskeletal pain, physiotherapy, analgesics (including short courses of non-steroidal anti-inflammatory drugs), joint injections for degenerative changes, rehabilitation, physical activity and pain, orthopaedic, physical medicine or rheumatology consultation are recommended for persistent symptoms [5]. Physical activity should be supported, all sports are permitted unless individually contraindicated, and obesity prevention, smoking cessation and limiting alcohol are recommended [5]. The international paediatric guideline advises caution with high-impact and twisting activities and discourages orthoses, which tend to increase intoeing [6].

The French PNDS (French National Diagnosis and Care Protocol) recommends colecalciferol in all patients and lifelong, for 25-hydroxyvitamin D between 20 and 80 ng/mL, age-appropriate dietary calcium intake, without calcium supplements, occasional paracetamol for lower-limb pain in children and, in symptomatic adults, at least one rheumatology consultation, with step 1 to 3 analgesics, short courses of anti-inflammatory drugs, articular and periarticular injections, physiotherapy, physical activity and non-pharmacological measures, always with patient education [12]. The reference calcium intakes cited are the 2001 recommended dietary allowances for the French population [12].

In therapeutic education, the PNDS emphasises adherence and the rules for taking phosphate, prevention of overweight, encouragement of regular sport in children, with selective exemptions from prolonged endurance efforts, and, in adults with reduced mobility, treatment of obesity and cardiovascular risk factors according to national recommendations; any bariatric surgery should be discussed with the reference centre, because of the effect of malabsorption on calcium–phosphate metabolism [12].

7.7. Orthopaedics, oral health, hearing and neurosurgery

Casts and insoles are not recommended for the deformity [5]. Elective surgery in children should only be performed with medical treatment optimised for at least 3–6 months and, on burosumab, should be postponed if possible, because straightening continues for at least 3 years; guided growth by temporary hemiepiphysiodesis requires 2–3 years of remaining growth (usually up to about 14 years in girls and 16 in boys), and osteotomies have fewer complications when performed later [5]. In one series, 57% of 49 patients had at least one surgical complication and 29% recurrence of the deformity [8]. In the study of 52 children on burosumab, the RSS fell by 0.9 by week 160 and the lower-limb RGI-C increased from 0.5 at week 64 to 1.05 at week 160 [5]. In adults, pseudofractures heal with metabolic optimisation and do not require surgery; hip or knee arthroplasty is indicated for osteoarthritis with disability, by surgeons experienced in dysplasias [5]. The French PNDS (French National Diagnosis and Care Protocol) provides for annual clinical monitoring of intercondylar (in genu varum) and intermalleolar (in genu valgum) distances, measured supine, and of internal tibial torsion by the thigh–foot angle in the prone position, and low-radiation standing whole-body radiographs at diagnosis, then every 5 years or when surgery is indicated. Surgery (femoral and/or tibial osteotomies) should ideally be postponed until the end of growth with biochemical balance; when a major deformity destabilises the knee before then, the risk of recurrence and of iatrogenic epiphysiodesis is high and requires pre- and postoperative biochemical control. After surgery, distances, tibial torsion, knee stability and height are monitored, with whole-body radiographs 1 year later and/or at the end of growth, at 20 years and then every 5 years. In adults, surgery includes realignment osteotomies, knee and hip arthroplasties and osteosynthesis of fractures, combined with osteotomy if necessary [12]. The PNDS does not mention guided growth by hemiepiphysiodesis, which the European update accepts with 2–3 years of remaining growth [5].

Oral health requires dental consultations at least every six months after eruption, sealing of pits and fissures with flowable composite resin, clinical and radiological investigation of pulp infection and optimisation of treatment before orthodontics; in adults, supportive periodontal therapy every six months and implants after at least 3 months of medical treatment, continued for 6 months afterwards [5]. The French PNDS (French National Diagnosis and Care Protocol) details early and repeated oral hygiene teaching, systematic sealing of fissures in primary and permanent molars, regular radiological screening for infectious foci, intensified to every 3 months during orthodontics, and orthodontics only with excellent hygiene and medical treatment balanced for more than 6 months; consultations are every six months in children and at least annually in adults, and the family should recognise signs of infection (swelling or a "white pimple" fistula). In adults, it favours endodontic treatment or retreatment, prevention and treatment of periodontitis and simple implants after resumption of well-adhered medical treatment, with extended healing times, considering bone grafts apparently contraindicated [12]. Treatment with active vitamin D and phosphate (grade B) or with burosumab (grade C) is recommended to reduce dental infections; in a retrospective study of 44 adults, phosphate with active vitamin D was associated with a 55.9% reduction and burosumab with an 86.4% reduction in infections, compared with untreated periods [5].

Hearing loss is treated like other peripheral hearing losses, with hearing aids, noise prevention and avoidance of ototoxic agents [5]. The French PNDS (French National Diagnosis and Care Protocol) calls for neonatal hearing screening, a more detailed assessment before 5 years of age and follow-up according to the results, with petrous bone CT in the presence of auditory or vestibular involvement; in adults, an audiogram whenever in doubt and vestibular assessment according to symptoms [12]. Annual neurological assessment and fundoscopy with brain or skull imaging are recommended in the presence of suggestive cranial morphology, intracranial hypertension or signs of brainstem or upper cervical cord compression [5]. Craniosynostosis is frequent but rarely surgical, and spinal cord compression due to spinal stenosis may require decompression [5, 11]. When suspected, the PNDS indicates brain MRI or cranial CT for craniosynostosis, MRI of the craniovertebral junction for Chiari malformation and spinal MRI for syringomyelia, with surgical treatment if symptomatic; in adults, symptomatic Chiari malformation is the main neurosurgical indication [12].

7.8. Agents and circumstances to avoid

Phosphate without 1,25-dihydroxyvitamin D should be avoided; calcitriol alone increases the risk of hypercalcaemia, hypercalciuria and nephrocalcinosis; bisphosphonates and other osteoporosis drugs may worsen osteomalacia [1]. Densitometry, scintigraphy and routine serial radiographs are not recommended, and FGF23 is not useful for monitoring [1, 5]. In Schmid metaphyseal chondrodysplasia mistakenly treated as rickets, vitamin D is contraindicated [51]. The French PNDS (French National Diagnosis and Care Protocol) contraindicates bisphosphonates and denosumab at menopause, because of the risk of worsening hypophosphataemia and osteomalacia, and advises avoiding alkalinising agents, such as potassium citrate, in children and adults [12]; on this point it agrees with the warning of the 2019 guidelines and differs from the 2025 European update, which proposes potassium citrate for hypercalciuria [5, 8]. At menopause, the PNDS indicates a new osteoarticular assessment with densitometry, interpreted bearing in mind that osteomalacia is not osteoporosis; with bone fragility, phosphate with alfacalcidol is resumed, and in the event of an osteoporotic-type fracture (wrist, vertebra, proximal femur) hormone replacement therapy is proposed, subject to its contraindications [12].

7.9. Treatment of the other hereditary forms

In ARHR2, bilateral medullary nephrocalcinosis was found in 5 of 10 patients treated with the conventional regimen and in none of 7 untreated patients [29].

7.10. Developments in the last 12 months and research

The most recent regulatory changes are decisions by authorities and not new published results: on 23 April 2026 the FDA approved an optional dose increase in adults with an inadequate response to 1.0 mg/kg every 4 weeks (0.5 mg/kg and then 1 mg/kg every 2 weeks, maximum of 90 mg per dose) [9], and on 29 May 2026, after a CHMP opinion of 23 April, the European Commission decided to extend the indication to infants under 1 year of age; in 2025, both agencies added warnings on hypercalcaemia [25, 52]. In June 2026 ClinGen published version 2.0.0 of actionability report AC009, classified as strong actionability in the paediatric setting and limited in adults [59].

Regarding trials, a phase 1/2 dose-escalation study of KK8123, administered subcutaneously to adults with XLH, has been recruiting since October 2024, with a primary safety outcome and completion expected in 2029 (NCT06525636); no results have been published [58]. The trial of calcitriol monotherapy without phosphate in children and adults (NCT03748966), with 16 participants, ended in 2025 and has results posted in the registry, without a peer-reviewed publication identified in this search [58]. In ENPP1 deficiency, the phase 3 trials ENERGY 3 (children, 27 participants) and ENERGY 2 (infants) of INZ-701, a recombinant ENPP1 enzyme, were terminated by the sponsor in 2026, which decided to discontinue development for reasons unrelated to safety; the ENABLE study was withdrawn [58]. In murine models, recombinant ENPP1 enzyme prevented calcification and mortality as well as osteomalacia [29]. Sclerostin inhibition and calcitonin have been studied, the former only in an animal model and the latter with disappointing randomised trials [1]. The absence of other programmes in this search does not prove that none exist.

8. Reproductive Options and Family Counselling

8.1. X-linked hypophosphataemia

XLH is transmitted in an X-linked dominant manner, with hemizygous males and heterozygous females similarly affected and complete penetrance [1]. An affected man transmits the variant to all his daughters, who will be affected, and to none of his sons; an affected woman has a 50% probability of transmitting the variant in each pregnancy, and children of either sex who inherit it will be affected [1, 4]. Severity varies among relatives with the same variant and does not correlate with sex, so it cannot be predicted for an offspring [1, 11].

In simplex cases, the variant may be inherited from a parent with an undiagnosed mild phenotype, arise de novo or result from parental gonadal or somatic mosaicism. Therefore, an apparently negative family history can only be confirmed by molecular or biochemical testing of the parents: in an isolated affected male, the mother is tested; in an isolated affected female, both parents are tested [1]. Leucocyte DNA testing does not detect all somatic mosaicism or exclusively gonadal mosaicism, and a father with somatic and germline mosaicism for the variant designated in the article as R567X (historical numbering, = NM_000444.6:c.1699C>T p.(Arg567Ter)) has been described, who transmitted the variant to one of his two daughters and mimicked autosomal dominant inheritance [1, 2, 62]. In the French series of 118 pedigrees, analysis of relatives of 13 sporadic cases detected the variant in an apparently healthy mother [26]. When the proband's variant is not found in either parent, the risk to siblings is low, but higher than that of the general population [1].

The European update recommends investigating all at-risk relatives (grade D), noting that sons and fathers of affected males are not at risk, and offering genetic counselling, especially at transition to adult care and to families planning a pregnancy (grade C) [5]. Prenatal diagnosis and preimplantation genetic testing are possible when the familial variant is known, and should follow the ethical and legal standards of each country (grade D) [1, 5]. In France, the PNDS (French National Diagnosis and Care Protocol) assigns genetic counselling to an expert physician from the reference centre, who provides information on the mode of transmission according to the gene (X-linked dominant, autosomal dominant, autosomal recessive or unknown); after each diagnosis, it recommends family screening by phosphataemia and genetic study, refers preimplantation genetic testing to authorised centres and discusses indications for prenatal diagnosis case by case in the multidisciplinary prenatal diagnosis centres (CPDPN) [12]. The appropriate time to discuss risk and options is before pregnancy, and DNA banking should be considered in probands without a molecular diagnosis [1]. Newborns from affected families should be tested early, because diagnostic delay delays treatment [11].

8.2. Pregnancy and lactation

There is no consensus on phosphate and active vitamin D use during pregnancy; most women already receiving treatment continue it, with urinary calcium/creatinine ratio monitoring every 1–2 months, because the physiological rise in 1,25-dihydroxyvitamin D increases the risk of hypercalcaemia, hypercalciuria and stones; treatment is generally not initiated in women untreated at conception, and additional fetal monitoring or caesarean delivery because of XLH is not required [1]. The European update suggests considering phosphate with active vitamin D during pregnancy and lactation and treating in the last trimester (grade D) [5]; the 2019 guidelines allowed phosphate doses up to 2,000 mg/day during pregnancy and encouraged breastfeeding regardless of treatment [8]. The ESCEO consensus notes that phosphate requirements increase in the third trimester and that newborns of mothers with XLH have no skeletal abnormalities at birth [11]. The 2026 ClinGen summary records, based on the guidelines, assessment of corrected total or ionised calcium in each trimester, monthly creatinine and GFR in treated women, fasting phosphate at least once during pregnancy and calcium monitoring during lactation in the presence of hyperparathyroidism, because PTHrP may rise [59].

Burosumab should be stopped when pregnancy is planned or diagnosed (grade X, strong) and requires contraception in sexually active women of childbearing potential [5]. The European SmPC requires effective contraception during treatment and for at least 14 weeks after the last dose, does not recommend the drug during pregnancy and allows its use during breastfeeding only after the first few days, if clinically necessary [10]. The US label states that no human data are available, that monkeys exposed to 15 times the maximum human exposure had late fetal loss, shorter gestation and preterm deliveries associated with maternal hyperphosphataemia and placental mineralisation, without teratogenicity, and that the antibody crosses the placenta [9]. The European update considers that burosumab is not contraindicated during breastfeeding and may be considered in severe cases, including pseudofractures (grade D) [5]. In the phase 3 adult trial, two participants withdrew because of pregnancy and delivered healthy term newborns [5].

The French PNDS (French National Diagnosis and Care Protocol) considers, based on the authors' experience, that XLH carries no particular maternal–fetal risk, but advises close monitoring, obstetric and ultrasound follow-up in a level 3 maternity unit and resumption of the conventional regimen throughout pregnancy, especially in the third trimester, in untreated women (phosphate 2,000 mg/day in 2 doses, the maximum foreseen for adults, and alfacalcidol 1–1.5 µg/day in 1 dose, below the maximum of 2.0 µg/day), with clinical and biochemical monitoring every 2 months; treatment is permitted and advised during breastfeeding. The newborn is screened on the third day with phosphate, phosphaturia, blood and urinary creatinine and ALP [12]. It differs from GeneReviews, which usually does not start treatment in a woman untreated at conception and does not require additional fetal monitoring [1], and from the ESCEO consensus, which assesses the newborn at 7 days and at 1 month [11].

8.3. Other forms

ADHR is transmitted in an autosomal dominant manner, with a 50% risk for each offspring, but with variable penetrance and iron-dependent late onset, and some carriers lose the defect after puberty [15, 28]. Recessive forms (DMP1, ENPP1, FAM20C) carry a 25% risk for each sibling when both parents are carriers; in ENPP1 deficiency, the carrier frequency estimated from population databases is 1 in 228 to 1 in 290, and rarely an affected parent and a carrier parent produce a 50% risk [29]. In HHRH, heterozygotes are not merely carriers: 38% have idiopathic hypercalciuria and 23% a skeletal phenotype, justifying biochemical assessment of relatives [30].

9. Special Considerations: Population Diversity and Epidemiology

9.1. XLH frequency

The lower estimates in recent series are considered underestimates due to misdiagnosis and diagnostic delay [1]. In Australian and New Zealand surveillance, 49% of children were diagnosed after 2 years despite a family history in most, and only 3% received psychological support and 68% dental care [65]. The ESCEO consensus attributes the variation between 1 in 20,000 and 1 in 60,000 to selection bias or differences in genetic background [11]. These rates refer to XLH and should not be transferred to the other forms.

9.2. Other forms

Orphanet classifies ADHR and HHRH (the latter for Europe) in the prevalence class below 1 per 1,000,000, and the prevalence of ARHR is unknown [3]. For ARHR1, only approximately 30 published cases existed up to 2020 [34]. The genetic prevalence of ENPP1 deficiency associated with GACI, calculated from allele frequencies, is 1 in 206,123 to 1 in 334,177 pregnancies; this is a genetic estimate rather than observed prevalence [29]. HHRH was first described in a consanguineous Bedouin family [23].

9.3. Founder populations and recurrent variants

The PHEX c.*231A>G allele in cis with duplication of exons 13–15 is the prevalent variant in North America; carriers may have normal stature and normophosphataemia and are frequently diagnosed with ankylosing spondylitis, which has implications for family screening and lower treatment doses [1, 27]. The FGF23 p.(Arg176Gln) variant was present in all six adults in the North American iron replacement trial [28]. No PHEX founder effects in European populations were identified in the sources consulted.

9.4. Brazil, Portugal and other regions

In Brazil, a single-centre study at Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, assessed 39 patients with a confirmed PHEX variant (16 children and 23 adults, aged 3 to 76 years) using ultrasonography and computed tomography: nephrocalcinosis was identified in 15 (38.4%), more frequently in children (56.2%) than adults (26.1%); nephrolithiasis in four adults (10.2%); hypocitraturia was the most common metabolic factor (28.2%) and hypercalciuria occurred in two patients (5.1%) [66]. Children had started treatment earlier and used phosphate more intensively, and adults were shorter (z-score −3.4 versus −2.4) [66]. This hospital series measures complications at a referral centre rather than population prevalence. The Brazilian textbook of genetic syndromes considers the prevalence unknown [4]. The international paediatric guideline compares nephrocalcinosis in series from Canada (47.8%), Brazil (38.5%), Japan (83.3%) and the United States (17.1%), and hypertension in Japanese (27.2%) and US (19.5%) series [6]. No epidemiological data from Portugal were found in the sources consulted.

The international paediatric guideline acknowledges the absence of representatives from Africa and Australia and limited representation from Asia and South America on the panel [6], and unequal access to burosumab between countries is described as an equity issue [6].

10. Illustrative Clinical Case

10.1. Burosumab interruption in an adult with femoral pseudofractures (Switzerland, 2025)

Bandir and colleagues described a 36-year-old woman with XLH due to a de novo heterozygous variant in exon 16 of PHEX [53]. In childhood, despite early phosphate and calcitriol treatment, she underwent surgery on both tibiae for bowing and developed bilateral coxa vara. After a period of poor phosphate adherence because of digestive intolerance, pseudofractures of the medial cortex of the femoral shafts developed at 24 and 26 years, managed conservatively without complete healing. In 2020, with increasing leg pain, sleep disturbance, a need for two elbow crutches and sick leave, phosphate was 0.73 mmol/L (normal 0.80–1.40), ALP and 25-hydroxyvitamin D were normal, and there was mild secondary hyperparathyroidism and renal phosphate wasting with intact FGF23 of 135.1 pg/mL (normal 10–50); single-photon emission computed tomography with computed tomography showed a new impending fracture of the lateral cortex of the right femur, and orthopaedics proposed surgical realignment [53].

After 2 weeks off phosphate and calcitriol (phosphate 0.40 mmol/L, TmP/GFR 0.31 mmol/L), she started burosumab in January 2021, every 4 weeks, with increasing doses up to 90 mg per month from August 2021. Phosphate and TmP/GFR never normalised 2 weeks after injection, but 1,25-dihydroxyvitamin D rose, pain, stiffness and disability measured by WOMAC improved rapidly, the patient stopped regular analgesics within 2 months and returned to part-time work, and the pseudofractures healed after two doses; surgery was abandoned in October 2021 [53]. Hip radiographs before and after treatment initiation are in Figure 1 of the article (Figure 1).

The insurer stopped reimbursement, and the last injection was on 11 October 2021. Six weeks later, pain and stiffness returned; at 12 weeks, phosphate was 0.33 mmol/L, TmP/GFR 0.26 mmol/L and intact FGF23 approximately 100 times higher than the patient's usual values, and phosphate with calcitriol was reintroduced. Imaging showed almost complete healing of old fractures but a new distal medial fracture of the right femur in January 2022 and another in the left femur in September 2022 despite maximum tolerated doses of the conventional regimen (Figure 2) [53]. With compassionate-use burosumab from November 2022, phosphate reached the lower limit of normal within 2 weeks, pain decreased and the new fractures healed almost completely by March 2023 [53].

The case illustrates three points discussed by the authors and guidelines: the benefit of burosumab for adult pseudofractures, the dependence of its effect on treatment continuity and the uselessness of FGF23 measured during and shortly after treatment, because of analytical interference or accumulation of antibody-bound FGF23, hypotheses the authors could not distinguish [5, 53]. The authors suggest that reintroducing the conventional regimen before the scheduled next injection, or tapering, might reduce relapse, but there is no validated discontinuation protocol; this is an isolated case that does not establish the frequency of the phenomenon [53]. The publication was supported by an unrestricted grant from the marketing authorisation holder [53].

10.2. Hypophosphataemic rickets without a molecular diagnosis (Brazil, 2018)

Maia and colleagues described, at a São Paulo tubulopathy outpatient clinic, a boy with bone deformities and respiratory infections from 9 months and motor regression, investigated at 3 years after a pathological humeral fracture: tubular phosphate reabsorption 70.8% (normal > 80%), phosphate 2.2 mg/dL and calcium 7.5 mg/dL; bone biopsy showed osteomalacia, without a family history and without vitamin D measurement available [67]. After 20 months bedridden, with tracheostomy and mechanical ventilation, treatment was readjusted at 7 years with phosphorus 65 mg/kg/day, calcitriol 0.06 µg/kg/day and calcium 127 mg/kg/day; within 3 months phosphate rose from 1.7 to 5.7 mg/dL and ALP fell from 12,660 to 430 U/L, the patient was decannulated and began walking without support, and height z-score rose from −6.05 to −3.64 over 12 months, with transient gallstones [67]. After two years without follow-up, he lost the ability to walk, with worsening deformities and recurrent hypophosphataemia and raised ALP [67]. The case, cited by the Brazilian textbook [4], lacks molecular confirmation, featured hypocalcaemia and received calcium supplementation and phosphate doses above the recommended limits for XLH; it should therefore not be read as a typical XLH example or prescribing model; it shows the severity of untreated or poorly controlled disease and the effect of loss of adherence.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

XLH does not affect intellectual development [4]. Functional prognosis depends on age at treatment initiation and continuity: treatment before 1 year was associated with better stature and less rachitic activity, without complete skeletal normalisation [61], and even with the conventional regimen most adults have reduced stature [5]. In adulthood, complications tend to worsen: osteomalacia is demonstrable by biopsy in untreated patients with few complaints, and early osteoarthritis and enthesopathy, which are almost universal, restrict mobility and do not appear to reverse with treatment [6]. Many adults who stopped treatment at the end of growth experience a minimally symptomatic phase before developing pain, stiffness and limitation, and it is unknown whether long-term treatment of asymptomatic adults modifies these outcomes [1]. Quality of life is lower than in the general population; in a Spanish series of 21 children, 61.9% reported mobility problems and 23.8% moderate anxiety or depression [6]. Observed mortality in the United Kingdom was higher than in controls [45]. Progressive renal function decline is rare and usually preceded by hyperparathyroidism and hypertension [6]. With burosumab, height stops declining and deformities improve over years, but long-term effects on teeth, hearing, enthesopathy, osteoarthritis and spinal stenosis are not established [5].

11.2. Follow-up plan

The two 2025 guidelines differ on the 6-minute walk test, systematic quality-of-life assessment and growth hormone; international monitoring recommendations are based on an expert survey and have very low certainty [6].

The 2018 French PNDS (French National Diagnosis and Care Protocol), designed for the conventional regimen, defines its own age-specific schedule [12].

This schedule is more intensive than the 2025 European one in the first years (monthly consultations and biochemistry at the start) and differs from it on three points: it includes densitometry at transition and in adults, which the European update and the international guideline do not recommend routinely; it maintains orthopantomography every 18 months at school age, whereas the European update reserves it for clinical indications from 6 years; and it proposes whole-body radiographs every 5 years after surgery, whereas the 2025 guidelines advise against routine radiographs [5, 6, 12]. Annual renal ultrasonography with nephrocalcinosis and biennial without it coincides with the European update [5]. Transition to adult care should include information on the disease, treatment options, patient associations and specialties involved, and medical treatment should continue for several years after growth plate closure to optimise bone mass [5, 6]. Patients should receive contact details of patient associations, such as the International XLH Alliance and the XLH Network, and information on research; the European networks ERN BOND, Endo-ERN and ERKNet endorse the European recommendations [1, 5]. In France, the PNDS defines the goals of follow-up as quality of life, prevention of complications and handicap, adherence, detection of treatment effects, therapeutic education, school and occupational integration and support through life stages, and refers patients to the RVRH-XLH association and to the reference centre and competence centres of the OSCAR network [12].

12. Summary and Final Considerations

X-linked hypophosphataemia is an X-linked dominant disease with complete penetrance, caused by PHEX loss of function and mediated by excess FGF23, with renal phosphate wasting and relative calcitriol deficiency [1]. The autosomal dominant (FGF23), autosomal recessive (DMP1, ENPP1, FAM20C) and rare KL-associated forms share the same axis and biochemistry, whereas HHRH (SLC34A3) and tubulopathies are FGF23-independent, with raised 1,25-dihydroxyvitamin D and hypercalciuria [5, 7]. This division guides diagnosis — phosphate, TmP/GFR, urinary calcium, 1,25-dihydroxyvitamin D and intact FGF23, followed by genetic testing with copy-number analysis — and treatment, because burosumab and active vitamin D analogues have opposite roles depending on the mechanism [5, 6, 39].

In children, the 2025 guidelines recommend burosumab as first line, based on a randomised trial of 61 children in which it improved rickets and deformities compared with phosphate and active vitamin D [5, 6, 56]. In adults, burosumab raised phosphate and accelerated fracture and pseudofracture healing, with significant benefit only in stiffness at 24 weeks, and European recommendations reserve it for pseudofractures, insufficient response or intolerance to the conventional regimen [5, 57]. The regimen of divided phosphate and calcitriol or alfacalcidol remains in use where burosumab is unavailable and in specific populations, with doses adjusted according to ALP and response rather than phosphate normalisation [5]. Labels differ: the USA authorises treatment from 6 months and, since April 2026, an every-2-week regimen in adults with an inadequate response; the EU authorises treatment from 1 month with hypophosphataemia since May 2026 and retains every-4-week dosing in adults [9, 10, 52].

Follow-up is multidisciplinary and lifelong and includes a dentist, orthopaedic surgeon, neurosurgeon, nephrologist, rheumatologist and geneticist. Unresolved areas include the long-term effect of burosumab on enthesopathy, osteoarthritis, hearing and teeth, the best approach to transition and possible discontinuation, treatment of recessive forms — in which burosumab is used off-label in ARHR1 and should be avoided in ENPP1 deficiency — and equitable access to treatment [5, 6, 29, 35].

13. Bibliographical References

1. Laurent MR, Harvengt P, Mortier GR, Böckenhauer D. X-Linked Hypophosphatemia. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Published on 9 Feb 2012; full revision on 14 Dec 2023. NBK83985. PMID:22319799.
2. VariantValidator (version 4.0.1; databases vvta_2025_02 and vvdb_2025_3). Validation of NM_000444.6:c.*231A>G, NM_000444.6:c.1699C>T and NM_020638.3:c.527G>A on GRCh38. variantvalidator.org. Accessed on 6 Oct and 1 Nov 2026.
3. Orphanet/Orphadata. X-linked hypophosphatemia (ORPHA:89936); Hypophosphatemic rickets (ORPHA:437); Autosomal dominant hypophosphatemic rickets (ORPHA:89937); Autosomal recessive hypophosphatemic rickets (ORPHA:289176); Hereditary hypophosphatemic rickets with hypercalciuria (ORPHA:157215). Epidemiology records dated 23 Jun 2026. Orphadata API. Accessed on 6 Oct 2026.
4. Ribeiro LO, Ribeiro EM. 5.5 Raquitismo hipofosfatêmico. In: Ribeiro EM, coordinator. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 116–117. Local book.
5. Haffner D, Emma F, Seefried L, Högler W, Javaid KM, Bockenhauer D, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2025;21(5):330–354. doi:10.1038/s41581-024-00926-x. PMID:39814982. Correction: doi:10.1038/s41581-025-00939-0.
6. Ali DS, Carpenter TO, Imel EA, Ward LM, Appelman-Dijkstra NM, Chaussain C, et al. X-Linked Hypophosphatemia Management in Children: An International Working Group Clinical Practice Guideline. J Clin Endocrinol Metab. 2025;110(7):2055–2070. doi:10.1210/clinem/dgaf093. PMID:39960858; PMCID:PMC12187519.
7. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Hereditary rickets (MIM 307800, 193100, 241520, 613312, 241530, 264700, 600081, 277440, 600785, 300554, 612089). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 568–574. Local chapter.
8. Haffner D, Emma F, Eastwood DM, Biosse Duplan M, Bacchetta J, Schnabel D, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019;15(7):435–455. doi:10.1038/s41581-019-0152-5. PMID:31068690; PMCID:PMC7136170.
9. Kyowa Kirin, Inc. CRYSVITA (burosumab-twza) injection, for subcutaneous use. Prescribing Information. Revision 4/2026 (SPL set id 102f96a0-6e3a-4fc1-b204-34d604683af6, version 7, effective time 22 Apr 2026). openFDA and PDF label. Accessed on 6 Oct 2026.
10. European Medicines Agency. CRYSVITA (burosumab): Summary of Product Characteristics, Annex I–III. EMEA/H/C/004275. First authorisation 19 Feb 2018; renewal 21 Feb 2022; document dated 14 May 2026. EPAR — product information. Accessed on 6 Oct 2026.
11. Trombetti A, Al-Daghri N, Brandi ML, Cannata-Andía JB, Cavalier E, Chandran M, et al. Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia. Nat Rev Endocrinol. 2022;18(6):366–384. doi:10.1038/s41574-022-00662-x. PMID:35484227.
12. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Hypophosphatémies héréditaires à FGF23 élevé (dont hypophosphatémies liées à l'X). Centre de référence des maladies rares du métabolisme du calcium et du phosphate. Saint-Denis La Plaine: HAS; 2018 May 14 (text dated March 2018). Available from: https://www.has-sante.fr/jcms/c_2849263
13. Winters RW, Graham JB, Williams TF, McFalls VW, Burnett CH. A genetic study of familial hypophosphatemia and vitamin D resistant rickets with a review of the literature. Medicine (Baltimore). 1958;37(2):97–142. doi:10.1097/00005792-195805000-00001. PMID:13565132.
14. The HYP Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet. 1995;11(2):130–136. doi:10.1038/ng1095-130. PMID:7550339.
15. Econs MJ, McEnery PT. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab. 1997;82(2):674–681. doi:10.1210/jcem.82.2.3765. PMID:9024275.
16. ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26(3):345–348. doi:10.1038/81664. PMID:11062477.
17. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A. 2001;98(11):6500–6505. doi:10.1073/pnas.101545198. PMID:11344269.
18. Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003;348(17):1656–1663. doi:10.1056/NEJMoa020881. PMID:12711740.
19. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006;38(11):1310–1315. doi:10.1038/ng1905. PMID:17033621.
20. Lorenz-Depiereux B, Bastepe M, Benet-Pagès A, Amyere M, Wagenstaller J, Müller-Barth U, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet. 2006;38(11):1248–1250. doi:10.1038/ng1868. PMID:17033625.
21. Lorenz-Depiereux B, Schnabel D, Tiosano D, Häusler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet. 2010;86(2):267–272. doi:10.1016/j.ajhg.2010.01.006. PMID:20137773.
22. Rafaelsen SH, Raeder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S, et al. Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification. J Bone Miner Res. 2013;28(6):1378–1385. doi:10.1002/jbmr.1850. PMID:23325605.
23. Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, et al. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaP(i)-IIc in maintaining phosphate homeostasis. Am J Hum Genet. 2006;78(2):179–192. doi:10.1086/499409. PMID:16358214.
24. Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet. 2006;78(2):193–201. doi:10.1086/499410. PMID:16358215.
25. U.S. Food and Drug Administration. Drugs@FDA: BLA 761068, Crysvita (burosumab-twza) — approval history (ORIG-1, 17 Apr 2018; SUPPL-3 and SUPPL-4, 27 Sep 2019; SUPPL-5, 18 Jun 2020; SUPPL-9, 28 Aug 2025; SUPPL-11, 23 Apr 2026) and approval letters. openFDA drugsfda; SUPPL-11 letter; SUPPL-4 letter. Accessed on 6 Oct 2026.
26. Gaucher C, Walrant-Debray O, Nguyen TM, Esterle L, Garabédian M, Jehan F. PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets. Hum Genet. 2009;125(4):401–411. doi:10.1007/s00439-009-0631-z. PMID:19219621.
27. Dahir KM, Black M, Gottesman GS, Imel EA, Mumm S, Nichols CM, et al. X-linked hypophosphatemia caused by the prevailing North American PHEX variant c.*231A>G; exon 13-15 duplication is often misdiagnosed as ankylosing spondylitis and manifests in both men and women. JBMR Plus. 2022;6(12):e10692. doi:10.1002/jbm4.10692. PMID:36530187.
28. Imel EA, Liu Z, Coffman M, Acton D, Mehta R, Econs MJ. Oral iron replacement normalizes fibroblast growth factor 23 in iron-deficient patients with autosomal dominant hypophosphatemic rickets. J Bone Miner Res. 2020;35(2):231–238. doi:10.1002/jbmr.3878. PMID:31652009.
29. Ziegler SG, Ferreira CR. Generalized Arterial Calcification of Infancy. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Published on 13 Nov 2014; updated on 19 May 2026. NBK253403.
30. Zhu Z, Bo-Ran Ho B, Chen A, Amrhein J, Apetrei A, Carpenter TO, et al. An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Kidney Int. 2024;105(5):1058–1076. doi:10.1016/j.kint.2024.01.031. PMID:38364990.
31. Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, et al. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci U S A. 2008;105(9):3455–3460. doi:10.1073/pnas.0712361105. PMID:18308935.
32. Lieske JC, Milliner DS, Beara-Lasic L, Harris P, Cogal A, Abrash E. Dent Disease. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Updated on 14 Dec 2017. NBK99494.
33. National Center for Biotechnology Information. ClinVar. Variation 5025: NM_020638.3(FGF23):c.527G>A (p.Arg176Gln), pathogenic (criteria provided, single submitter). ClinVar 5025. Accessed on 6 Oct 2026.
34. Ni X, Li X, Zhang Q, Liu C, Gong Y, Wang O, et al. Clinical characteristics and bone features of autosomal recessive hypophosphatemic rickets type 1 in three Chinese families: report of five Chinese cases and review of the literature. Calcif Tissue Int. 2020;107(6):636–648. doi:10.1007/s00223-020-00755-7. PMID:32920683.
35. Bai X, Levental M, Karaplis AC. Burosumab treatment for autosomal recessive hypophosphatemic rickets type 1 (ARHR1). J Clin Endocrinol Metab. 2022;107(10):2777–2783. doi:10.1210/clinem/dgac433. PMID:35896139.
36. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 39, section 39.1.1 Disorders of Ectonucleotide Metabolism – Prototype: Ectopic Calcification.
37. Ferreira CR, Hackbarth ME, Nitschke Y, Botschen U, Gafni RI, Mughal MZ, et al. Phenotypic characterization of ENPP1 deficiency: generalized arterial calcification of infancy and autosomal recessive hypophosphatemic rickets type 2. JBMR Plus. 2025;9(5):ziaf019. doi:10.1093/jbmrpl/ziaf019. PMID:40176950.
38. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Raine dysplasia (MIM 259775). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 577–578. Local chapter.
39. Bergwitz C, Miyamoto KI. Hereditary hypophosphatemic rickets with hypercalciuria: pathophysiology, clinical presentation, diagnosis and therapy. Pflugers Arch. 2019;471(1):149–163. doi:10.1007/s00424-018-2184-2. PMID:30109410.
40. Gordon RJ, Li D, Doyle D, Zaritsky J, Levine MA. Digenic heterozygous mutations in SLC34A3 and SLC34A1 cause dominant hypophosphatemic rickets with hypercalciuria. J Clin Endocrinol Metab. 2020;105(7):2392–2400. doi:10.1210/clinem/dgaa217. PMID:32311027.
41. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 43, section 43.2.2 GALNT3 Deficiency (GALNT3-CDG).
42. Polisson RP, Martinez S, Khoury M, Harrell RM, Lyles KW, Friedman N, et al. Calcification of entheses associated with X-linked hypophosphatemic osteomalacia. N Engl J Med. 1985;313(1):1–6. doi:10.1056/NEJM198507043130101. PMID:4000222.
43. Herrou J, Picaud AS, Lassalle L, Pacot L, Chaussain C, Merzoug V, et al. Prevalence of enthesopathies in adults with X-linked hypophosphatemia: analysis of risk factors. J Clin Endocrinol Metab. 2022;107(1):e224–e235. doi:10.1210/clinem/dgab580. PMID:34406383.
44. Rothenbuhler A, Fadel N, Debza Y, Bacchetta J, Diallo MT, Adamsbaum C, et al. High incidence of cranial synostosis and Chiari I malformation in children with X-linked hypophosphatemic rickets (XLHR). J Bone Miner Res. 2019;34(3):490–496. doi:10.1002/jbmr.3614. PMID:30352126.
45. Hawley S, Shaw NJ, Delmestri A, Prieto-Alhambra D, Cooper C, Pinedo-Villanueva R, et al. Prevalence and mortality of individuals with X-linked hypophosphatemia: a United Kingdom real-world data analysis. J Clin Endocrinol Metab. 2020;105(3):e871–e878. doi:10.1210/clinem/dgz203. PMID:31730177.
46. Firth HV, Hurst JA. Skeletal dysplasias; Suspected non-accidental injury. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 316–318, 326.
47. Hartley IR, Gafni RI, Roszko KL, Brown SM, de Castro LF, Saikali A, et al. Determination of FGF23 levels for the diagnosis of FGF23-mediated hypophosphatemia. J Bone Miner Res. 2022;37(11):2174–2185. doi:10.1002/jbmr.4702. PMID:36093861.
48. Jones KL, Jones MC, del Campo M. McCune-Albright syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 720.
49. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Fibrous dysplasia (MIM 174800). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 717–718.
50. Jones KL, Jones MC, del Campo M. Linear sebaceous nevus syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 702–704.
51. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Metaphyseal chondrodysplasia, Schmid type (MIM 156500). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 33–34.
52. European Medicines Agency. Crysvita: EPAR — Procedural steps taken and scientific information after authorisation (updated 10 Jun 2026) and its historical archive. Current document; archive. Accessed on 6 Oct 2026.
53. Bandir R, Zanisi L, Nicod-Lalonde M, Gonzalez-Rodriguez E. Case Report: Increased FGF23 and new insufficiency fractures at burosumab discontinuation in X-linked hypophosphatemia. Front Endocrinol (Lausanne). 2025;16:1665649. doi:10.3389/fendo.2025.1665649. PMID:41210504; PMCID:PMC12588828.
54. Carpenter TO, Whyte MP, Imel EA, Boot AM, Högler W, Linglart A, et al. Burosumab therapy in children with X-linked hypophosphatemia. N Engl J Med. 2018;378(21):1987–1998. doi:10.1056/NEJMoa1714641. PMID:29791829.
55. Whyte MP, Carpenter TO, Gottesman GS, Mao M, Skrinar A, San Martin J, et al. Efficacy and safety of burosumab in children aged 1–4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019;7(3):189–199. doi:10.1016/S2213-8587(18)30338-3. PMID:30638856.
56. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019;393(10189):2416–2427. doi:10.1016/S0140-6736(19)30654-3. PMID:31104833.
57. Insogna KL, Briot K, Imel EA, Kamenický P, Ruppe MD, Portale AA, et al. A randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy of burosumab, an anti-FGF23 antibody, in adults with X-linked hypophosphatemia: week 24 primary analysis. J Bone Miner Res. 2018;33(8):1383–1393. doi:10.1002/jbmr.3475. PMID:29947083.
58. ClinicalTrials.gov (API v2). Records NCT06525636 (KK8123), NCT03748966 (calcitriol monotherapy), NCT04188964 (burosumab in infants), NCT07183579, NCT06046820 (ENERGY 3), NCT07473973 (ENERGY 2), NCT05734196 (ENERGY), NCT06462547 (ADAPT) and NCT06739980 (ENABLE). clinicaltrials.gov. Accessed on 6 Oct 2026.
59. Clinical Genome Resource (ClinGen) Actionability Working Group. X-linked hypophosphatemia, report AC009, paediatric and adult settings, version 2.0.0 (published 18 and 24 Jun 2026). Paediatric; adult. Actionability classifications according to the GeneGuidance database (dump of 26 Sep 2026). Accessed on 6 Oct 2026.
60. Rising Pharma Holdings, Inc. Calcitriol Oral Solution (ANDA 209798). Prescribing Information, section Indications and Usage (effective time 18 Apr 2025). openFDA. Accessed on 6 Oct 2026.
61. Mäkitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 2003;88(8):3591–3597. doi:10.1210/jc.2003-030036. PMID:12915641.
62. Goji K, Ozaki K, Sadewa AH, Nishio H, Matsuo M. Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait. J Clin Endocrinol Metab. 2006;91(2):365–370. doi:10.1210/jc.2005-1776. PMID:16303832.
63. Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol. 2009;160(3):491–497. doi:10.1530/EJE-08-0818. PMID:19095780.
64. Rafaelsen S, Johansson S, Ræder H, Bjerknes R. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol. 2016;174(2):125–136. doi:10.1530/EJE-15-0515. PMID:26543054.
65. Sandy JL, Nunez C, Wheeler BJ, Jefferies C, Morris A, Siafarikas A, et al. Prevalence and characteristics of paediatric X-linked hypophosphataemia in Australia and New Zealand: results from the Australian and the New Zealand Paediatric Surveillance Units survey. Bone. 2023;173:116791. doi:10.1016/j.bone.2023.116791. PMID:37263386.
66. Colares Neto GP, Ide Yamauchi F, Hueb Baroni R, de Andrade Bianchi M, Cavalanti Gomes A, Chammas MC, et al. Nephrocalcinosis and nephrolithiasis in X-linked hypophosphatemic rickets: diagnostic imaging and risk factors. J Endocr Soc. 2019;3(5):1053–1061. doi:10.1210/js.2018-00338. PMID:31065622; PMCID:PMC6497922.
67. Maia MLA, Abreu ALS, Nogueira PCK, Val MLDMD, Carvalhaes JTA, Andrade MC. Raquitismo hipofosfatêmico: relato de caso. Rev Paul Pediatr. 2018;36(2):242–247. doi:10.1590/1984-0462/;2018;36;2;00009. PMID:29617471; PMCID:PMC6038795.