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Orphanet Journal of Rare Diseases logoLink to Orphanet Journal of Rare Diseases
. 2021 Feb 27;16:104. doi: 10.1186/s13023-021-01729-0

Phenotypic characterization of X-linked hypophosphatemia in pediatric Spanish population

Enrique Rodríguez-Rubio 1,, Helena Gil-Peña 2, Sara Chocron 3, Leire Madariaga 4, Francisco de la Cerda-Ojeda 5, Marta Fernández-Fernández 6, Carmen de Lucas-Collantes 7, Marta Gil 8, María Isabel Luis-Yanes 9, Inés Vergara 10, Juan David González-Rodríguez 11, Susana Ferrando 12, Montserrat Antón-Gamero 13, Marta Carrasco Hidalgo-Barquero 14, Angustias Fernández-Escribano 15, Mº Ángeles Fernández-Maseda 16, Laura Espinosa 17, Aniana Oliet 18, Antonio Vicente 19, Gema Ariceta 3, Fernando Santos 1,2; RenalTubeGroup
PMCID: PMC7912818  PMID: 33639975

Abstract

Background

X-linked hypophosphatemia (XLH) is a hereditary rare disease caused by loss-of-function mutations in PHEX gene leading tohypophosphatemia and high renal loss of phosphate. Rickets and growth retardation are the major manifestations of XLH in children, but there is a broad phenotypic variability. Few publications have reported large series of patients. Current data on the clinical spectrum of the disease, the correlation with the underlying gene mutations, and the long-term outcome of patients on conventional treatment are needed, particularly because of the recent availability of new specific medications to treat XLH.

Results

The RenalTube database was used to retrospectively analyze 48 Spanish patients (15 men) from 39 different families, ranging from 3 months to 8 years and 2 months of age at the time of diagnosis (median age of 2.0 years), and with XLH confirmed by genetic analysis. Bone deformities, radiological signs of active rickets and growth retardation were the most common findings at diagnosis. Mean (± SEM) height was − 1.89 ± 0.19 SDS and 55% (22/40) of patients had height SDS below—2. All cases had hypophosphatemia, serum phosphate being − 2.81 ± 0.11 SDS. Clinical manifestations and severity of the disease were similar in both genders. No genotype—phenotype correlation was found. Conventional treatment did not attenuate growth retardation after a median follow up of 7.42 years (IQR = 11.26; n = 26 patients) and failed to normalize serum concentrations of phosphate. Eleven patients had mild hyperparathyroidism and 8 patients nephrocalcinosis.

Conclusions

This study shows that growth retardation and rickets were the most prevalent clinical manifestations at diagnosis in a large series of Spanish pediatric patients with XLH confirmed by mutations in the PHEX gene. Traditional treatment with phosphate and vitamin D supplements did not improve height or corrected hypophosphatemia and was associated with a risk of hyperparathyroidism and nephrocalcinosis. The severity of the disease was similar in males and females.

Keywords: XLH, Inherited hypophosphatemia, Growth retardation, Bone deformities, Rickets

Background

X-linked hypophosphatemic rickets (XLH) (OMIM 307800) (ORPHA 89936) is the most common hereditary rickets [15] with an estimated prevalence of 1:20,000 [6, 7]. It follows an X-linked dominant transmission [8]. The disease is caused by a defective function of PHEX gene [1, 913], leading to elevated circulating concentrations of fibroblast growth factor 23 (FGF23) [14], relatively low levels of 1,25 dihydroxyvitamin d [1,25(OH)2D], hyperphosphaturia secondary to decreased proximal tubular reabsorption of phosphate and hypophosphatemia [8, 10, 15]. Classical, conventional treatment of XLH is based on the administration of phosphate supplements and 1-alpha hydroxylated derivates of vitamin D [16]. The wider availability of genetic studies and the recent development of an anti-FGF23 antibody, burosumab, as novel and promising therapy [10, 17] have resulted in a growing current interest for XLH.

We here report the clinical manifestations at diagnosis and follow-up of a large series of Spanish patients included in the online database RenalTube [18]. This study is justified at least by the following reasons: (1) XLH is a rare disease and few publications provide data on large series of patients; (2) XLH has a broad phenotypic variability and additional information is required to better characterize the clinical spectrum of the disease and to explain why the number of cases diagnosed usually does not correspond to the estimated prevalence of the disease; (3) It is important to share data of patients with genetically confirmed XLH in order to facilitate the finding of a potential phenotype—genotype correlation and to have current data that can be compared for the assessment of the new therapies.

Results

Forty-eight patients included in the RenalTube database with the diagnosis of XLH confirmed by defect-of-function variants found in the PHEX gene were analyzed. All variants had been identified as pathogenic. Sixteen patients (33%) had variants with strong evidence of pathogenicity (nonsense, frameshift, deletions) while the other 32 (67%) harbored variants with very strong evidence of pathogenicity (SNPs). Demographic and genetic data from patients are shown in Table 1. Patients were from 39 families and were being followed in pediatric nephrology units of 17 Spanish hospitals (Fig. 1). Fifteen patients were males and 33 females. Median age at diagnosis was 2.0 (IQR 2.6) years and the age ranged from 3 months to 8 years 2 months.

Table 1.

Demographic and genetic data of 48 patients belonging to 39 families (Roman number indicates family)

Patient Relationship Sex cDNA mutation Protein mutation Variant type
I.1 Index F c.758_759delTT p.F26Cfs P (PVS1)
I.2 Sister F c.758_759delTT p.F26Cfs P (PVS1)
II.1 Index F c.2223_2224delAC p.A514Afs516X P (PVS1)
III.1 Index F c.1578_1579delAA p.K299Nfs304X P (PVS1)
IV.1 Index M c.893A>T p.N71I P (PS1)
IV.2 Brother M c.893A>T p.N71I P (PS1)
V.1 Index F c.2633G>C p.R651P P (PS1)
VI.1 Index F c.1885C>T p.Q402X P (PVS1)
VII.1 Index M c.?-2664dup2949-? Splice region variant P (PVS1)
VII.2 Brother M c.?-2664dup2949-? Splice region variant P (PVS1)
VII.3 Daughter F c.?-2664dup2949-? Splice region variant P (PVS1)
VII.4 Daughter F c.?-2664dup2949-? Splice region variant P (PVS1)
VIII.1 Index F c.886insT p.K69X P (PVS1)
IX.1 Index F c.2048G>A p.W456X P (PVS1)
X.1 Index F g.22099152G>T Splice region variant P (PVS1)
XI.1 Index M c.2648_?del p.A656_?del P (PVS1)
XII.1 Index F c.2327_?del p.R549_?del P (PVS1)
XIII.1 Index F g.22168393_delA Splice region variant P (PVS1)
XIV.1 Index F c.1552C>T p.R291X P (PVS1)
XV.1 Index F g.22190503G>A Splice region variant P (PVS1)
XVI.1 Index F c.889_893delGTAAA p.V70Sfs77X P (PVS1)
XVII.1 Index F c.2086_?del p.A469_?del P (PVS1)
XVIII.1 Index F c.1180T>C p.W167R P (PS1)
XIX.1 Index F c.2282C>T p.P534L P (PS1)
XX.1 Index F c.2416G>A p.G579R P (PS1)
XXI.1 Index F c.2920C>T p.R747X P (PVS1)
XXII.1 Index F c.2920C>T p.R747X P (PVS1)
XXIII.1 Index M c.1152delA p.L157Lfs220X P (PVS1)
XXIV.1 Index F c.1572C>A,c.1580_1582delTGA p.Y297X P (PVS1)
XXV.1 Index F g.22076478A>T Splice region variant P (PVS1)
XXVI.1 Index F g.22190507G>A Splice region variant P (PVS1)
XXVII.1 Index F c.889_893delGTAAA p.V70Sfs77X P (PVS1)
XXVII.2 Father M c.889_893delGTAAA p.V70Sfs77X P (PVS1)
XXVIII.1 Index M c.2879G>T p.C733F P (PS1)
XXVIII.2 Sister F c.2879G>T p.C733F P (PS1)
XXIX.1 Index F c.2642T>C p.F654S P (PS1)
XXX.1 Index M c.2387T>G p.L569R P (PS1)
XXX.2 Mother F c.2387T>G p.L569R P (PS1)
XXXI.1 Index F c.2085G>C p.K468N P (PS1)
XXXII.1 Index M c.2282C>T p.P534L P (PS1)
XXXIII.1 Index M g.22033125T>G Splice region variant P (PVS1)
XXXIV.1 Index M c.2380C>T p.R567X P (PVS1)
XXXV.1 Index M c.2005G>T p.V442P P (PS1)
XXXV.2 Mother F c.2005G>T p.V442P P (PS1)
XXXVI.1 Index F c.2416G>A G579R P (PS1)
XXXVII.1 Index M g.22099152G>A Splice region variant P (PVS1)
XXXVIII.1 Index F c.2617delG p.D646Ifs P (PVS1)
XXXIX.1 Index M c.1363_1364delTC p.S228Pfs236X P (PVS1)

F: female, M: male

P: pathogenic

PVS1: very strong evidence of pathogenicity according to reference 19

PS1: strong evidence of pathogenicity according to reference 19

Fig. 1.

Fig. 1

Geographical distribution of the Spanish hospitals participating in the study

Presenting manifestations are shown in Table 2 for each patient. Bone deformities and radiological signs of active rickets were the most frequent findings leading to diagnosis. Ten patients were diagnosed because of family screening. Age at diagnosis of these patients was no different from that of the rest of the series as it ranged from 0.5 to 8 years with a median age of 1.04 years.

Table 2.

Clinical manifestations at diagnosis

Patient Age at diagnosis Bone deformities Active rickets Longitudinal growth retardation (≤ 2 SDS) Dental problems
I.1 3 m No No
I.2 1 y Yes Yes
II.1 1 y 5 m Yes Yes Yes No
III.1 1 y 6 m Yes Yes Yes
IV.1 1 y 4 m No No Yes Yes
IV.2 4 y No No No No
V.1 5 y Yes Yes Yes No
VI.1 2 y Yes No No No
VII.1 8 y
VII.2 2 y Yes No
VII.3 11 m Yes Yes No
VII.4 1 y Yes
VIII.1 4 y Yes Yes No No
IX.1 5 y Yes Yes No No
X.1 5 y Yes Yes Yes No
XI.1 2 y 3 m Yes Yes Yes No
XII.1 2 y Yes Yes
XIII.1 5 y Yes
XIV.1 9 m Yes Yes No No
XV.1 1 y 1 m Yes Yes Yes
XVI.1 4 y Yes Yes No
XVII.1 5 y Yes
XVIII.1 2 y Yes Yes Yes No
XIX.1 7 m Yes Yes No
XX.1 2 y 1 m Yes Yes
XXI.1 4 y 5 m Yes Yes No No
XXII.1 4 y Yes Yes Yes No
XIII.1 2 y Yes Yes No No
XXIV.1 3 y Yes No
XXV.1 1 y 6 Yes Yes No No
XXVI.1 4 y Yes Yes Yes No
XXVII.1 6 m Yes Yes No No
XXVII.2 8 y Yes No
XXVIII.1 1 y 6 m Yes No
XXVIII.2 6 m Yes Yes No No
XXIX.1 1 y 9 m Yes Yes Yes No
XXX.1 1 y 1 m Yes Yes Yes
XXX.2 1 y 6 m Yes No
XXXI.1 8 y2 m Yes Yes Yes No
XXXII.1 1 y 6 m Yes Yes No No
XXXIII.1 5 y Yes
XXXIV.1 2 y 2 m Yes Yes No No
XXXV.1 7 m Yes Yes No
XXXV.2 2 y 6 m Yes Yes Yes
XXXVI.1 6 m Yes Yes No No
XXXVII.1 1 y 9 m Yes Yes Yes Yes
XXXVIII.1 1 y 6 m Yes Yes No No
XXXIX.1 2 y 2 m Yes Yes No
Percentage of patients P/A/U P/A/U P/A/U P/A/U
73/6/21 73/6/21 46/38/17 6/63/31

m: month, y: year

SDS: standard deviation score. Dash: information in this field was missing from the database

P/A/U: present/absent/unreported

Twenty-two out of40 patients (55%) in whom the height was registered presented growth retardation (height ≤ 2 SDS). Patients’ height (X ± SEM) was − 1.89 ± 0.19 SDS (n = 40) (Fig. 2). In 87% (35/40) the height was below the 50th percentile. Weight was − 0.88 ± 0.14 SDS (n = 41) and body mass index 0.2 ± 0.15 SDS (n = 40).

Fig. 2.

Fig. 2

Height at diagnosis (n = 40). Black line: 0 SD; red line: − 2 SD

Biochemical findings at diagnosis are shown in Table 3. Mean values (± SEM) of available data were serum phosphate 2.7 ± 0.1 mg/dl; − 2.81 ± 0.11 SDS, (n = 41), alkaline phosphatase (892 ± 84 mU/ml) (n = 39), 1,25(OH)2D62 ± 7 pg/ml (n = 34), parathyroid hormone (PTH)70 ± 7 pg/ml (n = 33), and tubular phosphate reabsorption (TPR) 69 ± 4% (n = 26).

Table 3.

Biochemical manifestations at diagnosis

Patient Serum phosphate Serum alkaline phosphatases (mU/ml) Serum 1,25(OH)2D (pg/ml) Serum intact PTH (pg/ml) TPR (%)
mg/dl SDS
I.1 3.4 − 2.21 1230 87
I.2 3.8 − 1.05 1916 76
II.1 2.6 − 2.68 695 57 81 79
III.1 2.1 − 3.36 1646 16 68 32
IV.1 2.8 − 2.41 378 73 29 78
IV.2 3.0 − 2.44 232 40 43 82
V.1 2.1 − 3.99 1513 147 78 85
VI.1 2.6 − 2.68 525 33 64 78
VII.1
VII.2 2.4 − 2.95 516
VII.3 991 28 30
VII.4
VIII.1 3.1 − 2.27 598 55 39 38
IX.1 3.0 − 2.44 1824 47 59 67
X.1 2.9 − 2.61 639 33 136 74
XI.1 2.3 − 3.09 58
XII.1 2.7 − 2.54 48
XIII.1
XIV.1 3.3 − 2.34 892 64 65 75
XV.1 2.0 − 3.49 704 20 39
XVI.1 2.4 − 3.47 571 108 71 26
XVII.1 2.5 − 3.30 28 30
XVIII.1 2.3 − 3.09 1864 31 64 73
XIX.1
XX.1 2.9 − 2.27 446 88 116 93
XXI.1 3.1 − 2.27 470 56 49 86
XXII.1 2.8 − 2.78 697 74 32 76
XXIII.1 2.1 − 3.36 733 68 82
XXIV.1 2.2 − 3.22 514 61 78 58
XXV.1 2.9 − 2.27 1940 40 57 58
XXVI.1 2.3 − 3.64 423 82
XXVII.1 2.9 − 2.86 432 31 23
XXVII.2
XXVIII.1 3.0 − 2.14 236 78 54
XXVIII.2 3.3 − 2.34 426 171 57 90
XXIX.1 1.8 − 3.77 1555
XXX.1 3.1 − 2.00 829 183 101 88
XXX.2 2.2 − 3.22 158 25
XXXI.1
XXXII.1 2.8 − 2.41 692 41 111
XXXIII.1 2.1 − 3.99 76 54
XXXIV.1 2.3 − 3.09 856 64 101 46
XXXV.1 3.5 − 2.08 916 227 82
XXXV.2 2.2 − 3.22 1620 70
XXXVI.1 2.8 − 2.41 1093 65 66
XXXVII.1 2.4 − 2.95 1527 46 94
XXXVIII.1 2.4 − 2.95 856 40 58
XXXIX.1 3.0 − 2.14 759 51 43

1,25(OH)2D: 1,25 dihydroxyvitamin D. PTH: Parathyroid hormone

TPR: tubular phosphate reabsorption. Dash: information in this field was missing from the database

No differences were found between males and females for clinical manifestations, growth impairment or biochemical data at diagnosis. Likewise, no genotype–phenotype correlation was found. Actually, even patients within the same family presented different severity of clinical and biochemical manifestations.

Growth and biochemical variables of 26 patients after a median follow uptime of 7.42 years (IQR = 11.26) are shown in Table 4, Figs. 3 and 4. Anthropometric data were − 1.94 ± 0.16 SDS for height (n = 24), − 0.82 ± 0.10 SDS for weight (n = 22) and 0.14 ± 0.19 SDS for BMI (n = 22). Comparison of data from patients with information both at diagnosis and last follow-up showed mean variations of 0.13 ± 0.23 SDS for height (p > 0.05) (n = 20), 0.35 ± 0.14 SDS for weight (p = 0.02) (n = 20) and 0.13 ± 0.20 SDS for BMI (p > 0.05) (n = 20).

Table 4.

Biochemical manifestations at last follow up

Patient Follow-up Time Serum phosphate Serum alkaline phosphatases (mU/ml) Serum 1,25(OH)2D
(pg/ml)
Serum intact PTH (pg/ml) TPR (%)
mg/dl SD (Z score)
I.1 7 y 2 m 2.9 − 2.07 787 30 72
I.2 10 y 1 m 2.7 − 2.90 1035 35 50
II.1 1 y 1 m 3.8 − 1.05 34 70
III.1
IV.1 7 y 6 m 3.0 − 1.91 231 78 32 60
IV.2 7 y 6 m 2.6 − 3.06 266 73 44 48
V.1
VI.1
VII.1
VII.2
VII.3 8 y 4 m 1.9 − 3.69 77 42
VII.4 8 y 3 m 1.8 − 3.85 665 108 73
VIII.1 2 y 7 m 2.4 − 3.47 868 15 84 81
IX.1
X.1 7 y 5 m 3.0 − 2.41 962 50 93 85
XI.1 5 y 11 m 2.8 − 2.78 632 45 49 42
XII.1 11 y 5 m 2.8 − 2.23 636 112 86
XIII.1 17 y 6 m 1.7 − 4.22 29 86 64
XIV.1 2 y 1 m 2.8 − 2.41 96 20 70
XV.1 25 y 5 m 2.0 − 3.55 20 75 45
XVI.1
XVII.1 18 y 8 m 1.7 − 4.22 120 32 99 42
XVIII.1
XIX.1 26 y 2 m 2.4 − 2.66 200
XX.1 1 y 9 m 3.3 − 1.73 312 72 53 45
XXI.1 3 y 5 m 2.6 − 2.56 348 43 26 53
XXII.1
XXIII.1 2 y 10 m 3.0 − 2.44 29 28
XXIV.1
XXV.1 16 y 1.9 − 3.77 37
XXVI.1 2 y 4 m 2.8 − 2.78 240 86 25 70
XXVII.1 1 y 10 m 2.8 − 2.41 58 49 76
XXVII.2 37 y 4 m 2.3 − 2.88 117 80
XXVIII.1
XXVIII.2
XXIX.1 1 y 10 m 4.8 0.31 244 68 73 89
XXX.1
XXX.2
XXXI.1
XXXII.1
XXXIII.1 4 y 2.1 − 3.36 114 76
XXXIV.1
XXXV.1
XXXV.2
XXXVI.1
XXXVII.1
XXXVIII.1
XXXIX.1

1,25(OH)2D: 1,25 dihydroxyvitamin D

m: month, y: year

PTH: parathyroid hormone

TPR: tubular phosphate reabsorption. Dash: information in this field was missing from the database

Fig. 3.

Fig. 3

Biochemical and growth data at diagnosis and last follow-up. TPR: tubular phosphate reabsorption. BMI: Body Mass Index. Mean values are connected by red dots line. Vertical bars represent ± SEM

Fig. 4.

Fig. 4

Height at last follow-up (n = 24). Black line: 0 SD; red line: − 2 SD

Mean SDS for serum phosphate was − 2.72 ± 0.20 (n = 25). Alkaline phosphatases, 1,25 (OH)2D and PTH levels were 525 ± 82 mU/ml (n = 14), 53 ± 7 pg/ml (n = 15) and 68 ± 8 pg/ml (n = 26) respectively. Mean tubular phosphate reabsorption was 65 ± 3% (n = 22). Comparison between diagnosis and last follow-up data revealed a variation of 0.20 ± 0.28 SDS for serum phosphate (p > 0.05) (n = 20), 5 ± 7 pg/ml for 1,25 (OH)2D (p > 0.05) (n = 10), 0 ± 11 pg/ml for PTH (p > 0.05) (n = 16) and − 7 ± 8 for tubular phosphate reabsorption (p > 0.05) (n = 11).

Eight out of 24 patients with renal ultrasounds at last follow-up presented nephrocalcinosis (Table 5).

Table 5.

Treatment and clinical data at last follow-up

Patient Phosphorus element dose (mg/kg/day) Vitamin D dose (µg/day) Nephrocalcinosis
I.1 38a 0.50c No
I.2 40a 0.50c No
II.1 86a 1.20d Yes
III.1
IV.1 83a 0.60d No
IV.2 62a 1.00d No
V.1
VI.1
VII.1 No
VII.2
VII.3 55b 0.50c Yes
VII.4 52b 0.50c Yes
VIII.1 90a 1.50d Yes
IX.1
X.1 40a 0.25d No
XI.1 83a 0.50c No
XII.1 44b 0.29d No
XIII.1 41b 0.25c Yes
XIV.1 52a 1.20d
XV.1 41b 1.00c No
XVI.1
XVII.1 45b 0.25c Yes
XVIII.1
XIX.1 27b 0.50c Yes
XX.1 32a 0.50c No
XXI.1 63a 1.50d No
XXII.1
XXIII.1 65a 1.10d No
XXIV.1
XXV.1 38a 1.40c
XXVI.1 58b 0.25c No
XXVII.1 48b 0.60d No
XXVII.2
XXVIII.1
XXVIII.2
XXIX.1 0.10d No
XXX.1
XXX.2 Yes
XXXI.1
XXXII.1
XXXIII.1 49b 0.75c No
XXXIV.1
XXXV.1
XXXV.2
XXXVI.1
XXXVII.1
XXXVIII.1
XXXIX.1

aPhosphate was administered as a solution

bPhosphate was administered as tablets

cCorresponds to 1,25 dihydroxy vitamin D

dCorresponds to 1 hydroxy vitamin D

Discussion

This study provides a current description of the phenotypic characteristics of a large cohort of Caucasian pediatric patients with XLH genetically confirmed. The sample is a broad representation of the Spanish children with XLH, coming from several hospitals scattered through the country and provides data at diagnosis and after a median follow-up of 7.42 years. The study confirms that growth retardation, bone deformities and active lesions of rickets are the main presenting manifestations of the disease, within a wide spectrum of symptoms. No significant differences were found between males and females as for the severity of the disease. It is of interest that a broad spectrum of PHEX gene variants, all of them already described as pathogenic, was found and no mutation was specifically prevalent in Spanish population. All variants were classified as pathogenic according to the American College of Medical Genetics and Genomics consensus [19]. There was a high phenotypical variability even among family members harboring the same mutations, suggesting that other genes and environmental factors may affect the severity of XLH, as reported by other authors [20, 21].

In addition, the study shows that conventional treatment with phosphate supplements and vitamin D metabolites does not lead to persistent correction of hypophosphatemia or reduction of renal wasting of phosphate and does not modify the circulating levels of calcitriol. Unfortunately, this study does not provide information on circulating FGF23 levels, given its retrospective design. At the last follow-up visit, 11 out of 25 patients had serum PTH values mildly elevated. In XLH, development of hyperparathyroidism is thought to be related with the pharmacological administration of phosphate [22]. Eight patients developed nephrocalcinosis during the follow-up period, a finding linked to the administration of phosphate and vitamin D that usually does not result in subsequent clinical complications [16].

Though conventional treatment has been described to heal active signs of rickets and may improve bone deformities [23], this study confirms that it does not lead to catch-up growth. Mean height Z score of the group of patients remained low, − 1.89 at diagnosis versus − 1.94 at the last visit, although Fig. 3 indicates that the individual patients’ response varied from marked improvement to worsening of growth impairment. Two patients, VII.3 and XV.1, transiently received growth hormone treatment and their heights improved + 2.19and + 0.66 SDS, respectively. It is of note that 4 out of 16 patients had BMI greater than + 1.00 SDS at the last follow-up visit. This percentage of 25% corresponds to the normal distribution of reference population and it indicates that tendency to overweight and obesity was not found in the group of XLH patients here reported, unlike other series that have recently drawn attention to these complications likely related with the sedentary life and restricted mobility of these patients [11]. In this regard, a slight but significant increase in weight was found during the follow-up period in our series.

Our study presents methodological limitations inherent to the retrospective analysis and to the fact that patients’ information was extracted from a database in which some data were missing and cannot be recovered. It is also of note the lack of information on the degree of adherence to medication of each patient as well as the different monitoring protocols among the participating centers. However, it is an observational clinical study describing a large cohort of Spanish pediatric patients with genetically confirmed XLH and it provides current and interesting information on the clinical and biochemical features of the disease, at diagnosis and follow-up after conventional treatment. Our findings could be used as reference for further studies using burosumab treatment.

Conclusions

This study confirms that growth retardation and rickets were the most prevalent clinical manifestations at diagnosis in a large series of Spanish pediatric patients with XLH confirmed by identification of pathogenic variants in the PHEX gene. Traditional treatment with phosphate supplements and calcitriol did not improve height or corrected hypophosphatemia and was associated with a risk of hyperparathyroidism and nephrocalcinosis. The severity of the disease was similar in males and females and no phenotype-genotype association was found.

Patients and methods

The RenalTube database including 48 patients, 15 males and 33 females, with the diagnosis of XLH confirmed by defect-of-function mutations found in the PHEX gene was retrospectively reviewed to obtain demographic information and clinical and biochemical manifestations at diagnosis and at the last annual follow-up. Genetic information was confirmed and formatted according to Genome Reference Consortium Human Build 38 patch release 13 (GRCh38.p13) [24]. Variants were analyzed in silico and classified according to recommendations from the consensus of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [19] as pathogenic, likely pathogenic, benign or likely benign. Results for the age are presented as median and interquartile range (IQR). Other variables are presented for the group as mean (X) ± standard error of the mean (SEM). Z score (SDS) of anthropometric values was calculated using Spanish age and sex-matched reference values [25]. Patients with height ≤ 2 SDS were considered to have longitudinal growth retardation according to World Health Organization standards [26]. Reference values for biochemical parameters were obtained from the laboratory of the Hospital Universitario Central de Asturias (HUCA) [27].

All patients received treatment with phosphate supplementation (dose range of phosphorus element: 27–90 mg/kg/day at last follow-up) and vitamin D metabolites (dose range: 0.25–1.5 µg/day at last follow-up), according to the criteria and indications given by their physicians (Table 5). Two patients (VII.3 and XV.1) received growth hormone treatment. None of them received burosumab treatment.

Information in RenalTube database was downloaded and formatted to an Excel database. All fields but reasons for consultation and genetic information were multichoice or numeric format.

Chi squared test was used to analyze differences between sex for binary (Yes/No) fields (growth retardation, bone deformities). F-test was used to assess variance equality between sex for anthropometric and biochemical values. T-test was used to analyze differences between sex for anthropometric and biochemical values. Paired T-test for means was used to analyze differences between diagnosis and last follow-up for anthropometric and biochemical values. T-test for unequal variances was used to compare age at diagnosis for patients with and without family history of the disease.

Phenotype—genotype correlation was assessed by isolating the most severe phenotypes (lowest serum concentrations, most severe growth retardation, highest levels of alkaline phosphatases) and comparing genetic mutations in these patients looking for big deletions, SNPs with entirely different amino acids or nonsense mutations.

Acknowledgements

Not applicable.

Authors’ contributions

ER gathered, formattedand analyzed data from patients included in RenalTube database and was a major contributor in writing the manuscript. FS and HG contributed on analyzing data and were major contributors on writing the manuscript. Every other author introduced information of at least 1 patient from this study in RenalTube database. All authors read and approved the final manuscript.

Funding

This research has been partially funded by Kyowa Kirin Farmacéutica S.L.U., Fondo de Investigaciones Sanitarias (FIS) and Fundación Nutrición y Crecimiento (FUNDNYC).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

Patients information has been processed via RenalTube database where patients signed their consent to participate in scientific studies.

Consent for publication

Patients or parents signed consent for publication of their data through RenalTube consent form.

Competing interests

The study has been partially funded by Kyowa Kirin Farmacéutica S.L.U. This company produces the drug Crysvita® (burosumab). Nevertheless, no patients in this study had been or were being treated with burosumab at the time of data collection.

Footnotes

Publisher's Note

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.


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