Rodríguez‑Rubio et al. Orphanet J Rare Dis (2021) 16:104 https://doi.org/10.1186/s13023-021-01729-0 RESEARCH Open Access Phenotypic characterization of X‑linked hypophosphatemia in pediatric Spanish population Enrique Rodríguez‑Rubio1* , Helena Gil‑Peña2, Sara Chocron3, Leire Madariaga4, Francisco de la Cerda‑Ojeda5, Marta Fernández‑Fernández6, Carmen de Lucas‑Collantes7, Marta Gil8, María Isabel Luis‑Yanes9, Inés Vergara10, Juan David González‑Rodríguez11, Susana Ferrando12, Montserrat Antón‑Gamero13, Marta Carrasco Hidalgo‑Barquero14, Angustias Fernández‑Escribano15, Mº Ángeles Fernández‑Maseda16, Laura Espinosa17, Aniana Oliet18, Antonio Vicente19, Gema Ariceta3 and Fernando Santos1,2 on behalf of RenalTubeGroup 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 retarda‑ tion 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 correla‑ tion 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 *Correspondence: erodrr00@gmail.com 1 Pediatric Research, Medicine Department, University of Oviedo, Oviedo, Spain Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​ mmons​.org/publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Rodríguez‑Rubio et al. Orphanet J Rare Dis (2021) 16:104 Page 2 of 12 Background screening. Age at diagnosis of these patients was no dif- X-linked hypophosphatemic rickets (XLH) (OMIM ferent from that of the rest of the series as it ranged from 307800) (ORPHA 89936) is the most common hereditary 0.5 to 8 years with a median age of 1.04 years. rickets [1–5] with an estimated prevalence of 1:20,000 [6, Twenty-two out of40 patients (55%) in whom the height 7]. It follows an X-linked dominant transmission [8]. The was registered presented growth retardation (height ≤ 2 disease is caused by a defective function of PHEX gene SDS). Patients’ height (X ± SEM) was − 1.89 ± 0.19 SDS [1, 9–13], leading to elevated circulating concentrations (n = 40) (Fig. 2). In 87% (35/40) the height was below the of fibroblast growth factor 23 (FGF23) [14], relatively low 50th percentile. Weight was − 0.88 ± 0.14 SDS (n = 41) levels of 1,25 dihydroxyvitamin d [1,25(OH)2D], hyper- and body mass index 0.2 ± 0.15 SDS (n = 40). phosphaturia secondary to decreased proximal tubular Biochemical findings at diagnosis are shown in reabsorption of phosphate and hypophosphatemia [8, 10, Table 3. Mean values (± SEM) of available data were 15]. Classical, conventional treatment of XLH is based serum phosphate 2.7 ± 0.1 mg/dl; − 2.81 ± 0.11 SDS, on the administration of phosphate supplements and (n = 41), alkaline phosphatase (892 ± 84 mU/ml) (n = 39), 1-alpha hydroxylated derivates of vitamin D [16]. The 1,25(OH)2D62 ± 7 pg/ml (n = 34), parathyroid hormone wider availability of genetic studies and the recent devel- (PTH)70 ± 7 pg/ml (n = 33), and tubular phosphate reab- opment of an anti-FGF23 antibody, burosumab, as novel sorption (TPR) 69 ± 4% (n = 26). and promising therapy [10, 17] have resulted in a growing No differences were found between males and females current interest for XLH. for clinical manifestations, growth impairment or bio- We here report the clinical manifestations at diag- chemical data at diagnosis. Likewise, no genotype–phe- nosis and follow-up of a large series of Spanish patients notype correlation was found. Actually, even patients included in the online database RenalTube [18]. This within the same family presented different severity of study is justified at least by the following reasons: (1) clinical and biochemical manifestations. XLH is a rare disease and few publications provide data Growth and biochemical variables of 26 patients after on large series of patients; (2) XLH has a broad pheno- a median follow uptime of 7.42 years (IQR = 11.26) are typic variability and additional information is required to shown in Table 4, Figs. 3 and 4. Anthropometric data better characterize the clinical spectrum of the disease were − 1.94 ± 0.16 SDS for height (n = 24), − 0.82 ± 0.10 and to explain why the number of cases diagnosed usu- SDS for weight (n = 22) and 0.14 ± 0.19 SDS for BMI ally does not correspond to the estimated prevalence of (n = 22). Comparison of data from patients with infor- the disease; (3) It is important to share data of patients mation both at diagnosis and last follow-up showed with genetically confirmed XLH in order to facilitate the mean variations of 0.13 ± 0.23 SDS for height (p > 0.05) finding of a potential phenotype—genotype correlation (n = 20), 0.35 ± 0.14 SDS for weight (p = 0.02) (n = 20) and to have current data that can be compared for the and 0.13 ± 0.20 SDS for BMI (p > 0.05) (n = 20). assessment of the new therapies. Mean SDS for serum phosphate was − 2.72 ± 0.20 (n = 25). Alkaline phosphatases, 1,25 (OH)2D and PTH Results levels were 525 ± 82 mU/ml (n = 14), 53 ± 7 pg/ml Forty-eight patients included in the RenalTube database (n = 15) and 68 ± 8 pg/ml (n = 26) respectively. Mean with the diagnosis of XLH confirmed by defect-of-func- tubular phosphate reabsorption was 65 ± 3% (n = 22). tion variants found in the PHEX gene were analyzed. Comparison between diagnosis and last follow-up data All variants had been identified as pathogenic. Sixteen revealed a variation of 0.20 ± 0.28 SDS for serum phos- patients (33%) had variants with strong evidence of phate (p > 0.05) (n = 20), 5 ± 7 pg/ml for 1,25 (OH)2D pathogenicity (nonsense, frameshift, deletions) while the (p > 0.05) (n = 10), 0 ± 11 pg/ml for PTH (p > 0.05) other 32 (67%) harbored variants with very strong evi- (n = 16) and − 7 ± 8 for tubular phosphate reabsorption dence of pathogenicity (SNPs). Demographic and genetic (p > 0.05) (n = 11). data from patients are shown in Table 1. Patients were Eight out of 24 patients with renal ultrasounds at last from 39 families and were being followed in pediatric follow-up presented nephrocalcinosis (Table 5). nephrology units of 17 Spanish hospitals (Fig. 1). Fifteen patients were males and 33 females. Median age at diag- Discussion nosis was 2.0 (IQR 2.6) years and the age ranged from This study provides a current description of the phe- 3 months to 8 years 2 months. notypic characteristics of a large cohort of Caucasian Presenting manifestations are shown in Table 2 for pediatric patients with XLH genetically confirmed. The each patient. Bone deformities and radiological signs of sample is a broad representation of the Spanish chil- active rickets were the most frequent findings leading to dren with XLH, coming from several hospitals scattered diagnosis. Ten patients were diagnosed because of family through the country and provides data at diagnosis and Rodríguez‑Rubio et al. Orphanet J Rare Dis (2021) 16:104 Page 3 of 12 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 Rodríguez‑Rubio et al. Orphanet J Rare Dis (2021) 16:104 Page 4 of 12 Table 1 (continued) PVS1: very strong evidence of pathogenicity according to reference 19 PS1: strong evidence of pathogenicity according to reference 19 Fig. 1 Geographical distribution of the Spanish hospitals participating in the study after a median follow-up of 7.42 years. The study con- of calcitriol. Unfortunately, this study does not provide firms that growth retardation, bone deformities and information on circulating FGF23 levels, given its ret- active lesions of rickets are the main presenting manifes- rospective design. At the last follow-up visit, 11 out of tations of the disease, within a wide spectrum of symp- 25 patients had serum PTH values mildly elevated. In toms. No significant differences were found between XLH, development of hyperparathyroidism is thought males and females as for the severity of the disease. It is to be related with the pharmacological administration of interest that a broad spectrum of PHEX gene variants, of phosphate [22]. Eight patients developed nephrocalci- all of them already described as pathogenic, was found nosis during the follow-up period, a finding linked to the and no mutation was specifically prevalent in Spanish administration of phosphate and vitamin D that usually population. All variants were classified as pathogenic does not result in subsequent clinical complications [16]. according to the American College of Medical Genetics Though conventional treatment has been described and Genomics consensus [19]. There was a high pheno- to heal active signs of rickets and may improve bone typical variability even among family members harbor- deformities [23], this study confirms that it does not lead ing the same mutations, suggesting that other genes and to catch-up growth. Mean height Z score of the group of environmental factors may affect the severity of XLH, as patients remained low, − 1.89 at diagnosis versus − 1.94 reported by other authors [20, 21]. at the last visit, although Fig. 3 indicates that the indi- In addition, the study shows that conventional treat- vidual patients’ response varied from marked improve- ment with phosphate supplements and vitamin D ment to worsening of growth impairment. Two patients, metabolites does not lead to persistent correction of VII.3 and XV.1, transiently received growth hormone hypophosphatemia or reduction of renal wasting of treatment and their heights improved + 2.19and + 0.66 phosphate and does not modify the circulating levels SDS, respectively. It is of note that 4 out of 16 patients Rodríguez‑Rubio et al. Orphanet J Rare Dis (2021) 16:104 Page 5 of 12 Table 2 Clinical manifestations at diagnosis Patient Age at diagnosis Bone deformities Active rickets Longitudinal growth Dental problems retardation (≤ 2 SDS) I.1 3m No – No – I.2 1y Yes – Yes – II.1 1y5m Yes Yes Yes No III.1 1y6m – Yes Yes Yes IV.1 1y4m No No Yes Yes IV.2 4y No No No No V.1 5y Yes Yes Yes No VI.1 2y Yes No No No VII.1 8y – – – – VII.2 2y – Yes – No VII.3 11 m – Yes Yes No VII.4 1y – – Yes – VIII.1 4y Yes Yes No No IX.1 5y Yes Yes No No X.1 5y Yes Yes Yes No XI.1 2y3m Yes Yes Yes No XII.1 2y Yes Yes – – XIII.1 5y – Yes – – XIV.1 9m Yes Yes No No XV.1 1y1m Yes Yes Yes – XVI.1 4y Yes – Yes No XVII.1 5y – – Yes – XVIII.1 2y Yes Yes Yes No XIX.1 7m Yes Yes – No XX.1 2y1m Yes – Yes – XXI.1 4y5m Yes Yes No No XXII.1 4y Yes Yes Yes No XIII.1 2y Yes Yes No No XXIV.1 3y Yes – No – XXV.1 1y6 Yes Yes No No XXVI.1 4y Yes Yes Yes No XXVII.1 6m Yes Yes No No XXVII.2 8y – Yes – No XXVIII.1 1y6m Yes – No – XXVIII.2 6m Yes Yes No No XXIX.1 1y9m Yes Yes Yes No XXX.1 1y1m Yes Yes Yes – XXX.2 1y6m – Yes – No XXXI.1 8 y2 m Yes Yes Yes No XXXII.1 1y6m Yes Yes No No XXXIII.1 5y – – Yes – XXXIV.1 2y2m Yes Yes No No XXXV.1 7m Yes Yes No – XXXV.2 2y6m Yes Yes Yes – XXXVI.1 6m Yes Yes No No XXXVII.1 1y9m Yes Yes Yes Yes XXXVIII.1 1y6m Yes Yes No No XXXIX.1 2y2m 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 Rodríguez‑Rubio et al. Orphanet J Rare Dis (2021) 16:104 Page 6 of 12 Table 2 (continued) m: month, y: year SDS: standard deviation score. Dash: information in this field was missing from the database P/A/U: present/absent/unreported Fig. 2 Height at diagnosis (n = 40). Black line: 0 SD; red line: − 2 SD had BMI greater than + 1.00 SDS at the last follow-up treatment. Our findings could be used as reference for visit. This percentage of 25% corresponds to the normal further studies using burosumab treatment. distribution of reference population and it indicates that tendency to overweight and obesity was not found in the Conclusions group of XLH patients here reported, unlike other series This study confirms that growth retardation and rickets that have recently drawn attention to these complications were the most prevalent clinical manifestations at diag- likely related with the sedentary life and restricted mobil- nosis in a large series of Spanish pediatric patients with ity of these patients [11]. In this regard, a slight but signif- XLH confirmed by identification of pathogenic variants icant increase in weight was found during the follow-up in the PHEX gene. Traditional treatment with phosphate period in our series. supplements and calcitriol did not improve height or cor- Our study presents methodological limitations inherent rected hypophosphatemia and was associated with a risk to the retrospective analysis and to the fact that patients’ of hyperparathyroidism and nephrocalcinosis. The sever- information was extracted from a database in which some ity of the disease was similar in males and females and no data were missing and cannot be recovered. It is also of phenotype-genotype association was found. note the lack of information on the degree of adherence to medication of each patient as well as the different Patients and methods monitoring protocols among the participating centers. The RenalTube database including 48 patients, 15 males However, it is an observational clinical study describing a and 33 females, with the diagnosis of XLH confirmed by large cohort of Spanish pediatric patients with genetically defect-of-function mutations found in the PHEX gene confirmed XLH and it provides current and interesting was retrospectively reviewed to obtain demographic information on the clinical and biochemical features of information and clinical and biochemical manifestations the disease, at diagnosis and follow-up after conventional at diagnosis and at the last annual follow-up. Genetic information was confirmed and formatted according to Rodríguez‑Rubio et al. Orphanet J Rare Dis (2021) 16:104 Page 7 of 12 Table 3 Biochemical manifestations at diagnosis Patient Serum phosphate Serum alkaline phosphatases Serum 1,25(OH)2D (pg/ Serum intact PTH (pg/ TPR (%) (mU/ml) ml) ml) 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 Rodríguez‑Rubio et al. Orphanet J Rare Dis (2021) 16:104 Page 8 of 12 Table 4 Biochemical manifestations at last follow up Patient Follow-up Time Serum phosphate Serum alkaline Serum Serum intact PTH TPR (%) phosphatases (mU/ml) 1,25(OH)2D (pg/ml) mg/dl SD (Z score) (pg/ml) I.1 7y2m 2.9 − 2.07 787 – 30 72 I.2 10 y 1 m 2.7 − 2.90 1035 – 35 50 II.1 1y1m 3.8 − 1.05 – – 34 70 III.1 – – – – – – – IV.1 7y6m 3.0 − 1.91 231 78 32 60 IV.2 7y6m 2.6 − 3.06 266 73 44 48 V.1 – – – – – – – VI.1 – – – – – – – VII.1 – – – – – – – VII.2 – – – – – – – VII.3 8y4m 1.9 − 3.69 – – 77 42 VII.4 8y3m 1.8 − 3.85 665 – 108 73 VIII.1 2y7m 2.4 − 3.47 868 15 84 81 IX.1 – – – – – – – X.1 7y5m 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 2y1m 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 1y9m 3.3 − 1.73 312 72 53 45 XXI.1 3y5m 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 2y4m 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 4y 2.1 − 3.36 – – 114 76 XXXIV.1 – – – – – – – XXXV.1 – – – – – – – XXXV.2 – – – – – – – XXXVI.1 – – – – – – – XXXVII.1 – – – – – – – XXXVIII.1 – – – – – – – XXXIX.1 – – – – – – – Rodríguez‑Rubio et al. Orphanet J Rare Dis (2021) 16:104 Page 9 of 12 Table 4 (continued) 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 a Serum Phosphate (Z Score) b Alkaline Phosphatases (mU/ml) c TPR (%) Diagnosis Last Follow-Up Diagnosis Last Follow-Up Diagnosis Last Follow-Up d Height (SDS) e Weight (SDS) f BMI (SDS) Diagnosis Last Follow-Up Diagnosis Last Follow-Up Diagnosis Last Follow-Up 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 Height at last follow-up (n = 24). Black line: 0 SD; red line: − 2 SD Rodríguez‑Rubio et al. Orphanet J Rare Dis (2021) 16:104 Page 10 of 12 Table 5 Treatment and clinical data at last follow-up Table 5 (continued) a Phosphate was administered as a solution Patient Phosphorus element Vitamin D Nephrocalcinosis b dose (mg/kg/day) dose (µg/day) Phosphate was administered as tablets c Corresponds to 1,25 dihydroxy vitamin D I.1 38a 0.50c No d Corresponds to 1 hydroxy vitamin D a I.2 40 0.50c No II.1 86a 1.20d Yes III.1 – – – Genome Reference Consortium Human Build 38 patch IV.1 83 a 0.60d No release 13 (GRCh38.p13) [24]. Variants were analyzed IV.2 62a 1.00d No in silico and classified according to recommendations V.1 – – – from the consensus of the American College of Medical VI.1 – – – Genetics and Genomics and the Association for Molec- VII.1 – – No ular Pathology [19] as pathogenic, likely pathogenic, VII.2 – – – benign or likely benign. Results for the age are presented VII.3 55b 0.50c Yes as median and interquartile range (IQR). Other variables VII.4 52b 0.50c Yes are presented for the group as mean (X) ± standard error VIII.1 90a 1.50d Yes of the mean (SEM). Z score (SDS) of anthropometric val- IX.1 – – – ues was calculated using Spanish age and sex-matched X.1 40a 0.25d No reference values [25]. Patients with height ≤ 2 SDS XI.1 83 a 0.50c No were considered to have longitudinal growth retarda- XII.1 44b 0.29d No tion according to World Health Organization standards XIII.1 41b 0.25c Yes [26]. Reference values for biochemical parameters were XIV.1 52a 1.20d – obtained from the laboratory of the Hospital Universi- XV.1 41b 1.00c No tario Central de Asturias (HUCA) [27]. XVI.1 – – – All patients received treatment with phosphate sup- XVII.1 45b 0.25c Yes plementation (dose range of phosphorus element: XVIII.1 – – – 27–90 mg/kg/day at last follow-up) and vitamin D XIX.1 27b 0.50c Yes metabolites (dose range: 0.25–1.5 µg/day at last follow- XX.1 32a 0.50c No up), according to the criteria and indications given by XXI.1 63a 1.50d No their physicians (Table 5). Two patients (VII.3 and XV.1) XXII.1 – – – received growth hormone treatment. None of them XXIII.1 65a 1.10d No received burosumab treatment. XXIV.1 – – – Information in RenalTube database was downloaded XXV.1 38a 1.40c – b and formatted to an Excel database. All fields but reasons XXVI.1 58 0.25c No for consultation and genetic information were multi- XXVII.1 48b 0.60d No choice or numeric format. XXVII.2 – – – Chi squared test was used to analyze differences XXVIII.1 – – – between sex for binary (Yes/No) fields (growth retarda- XXVIII.2 – – – tion, bone deformities). F-test was used to assess variance XXIX.1 – 0.10d No equality between sex for anthropometric and biochemi- XXX.1 – – – cal values. T-test was used to analyze differences between XXX.2 – – Yes sex for anthropometric and biochemical values. Paired XXXI.1 – – – T-test for means was used to analyze differences between XXXII.1 – – – XXXIII.1 49b 0.75c No diagnosis and last follow-up for anthropometric and bio- XXXIV.1 – – – chemical values. T-test for unequal variances was used to XXXV.1 – – – compare age at diagnosis for patients with and without XXXV.2 – – – family history of the disease. XXXVI.1 – – – Phenotype—genotype correlation was assessed by iso- XXXVII.1 – – – lating the most severe phenotypes (lowest serum concen- XXXVIII.1 – – – trations, most severe growth retardation, highest levels of XXXIX.1 – – – alkaline phosphatases) and comparing genetic mutations in these patients looking for big deletions, SNPs with entirely different amino acids or nonsense mutations. Rodríguez‑Rubio et al. Orphanet J Rare Dis (2021) 16:104 Page 11 of 12 Acknowledgements 3. Morey M, Castro-Feijóo L, Barreiro J, Cabanas P, Pombo M, Gil M, et al. Not applicable. Genetic diagnosis of X-linked dominant hypophosphatemic rickets in a cohort study: Tubular reabsorption of phosphate and 1,25(OH)2D Authors’ contributions serum levels are associated with PHEX mutation type. BMC Med Genet. ER gathered, formattedand analyzed data from patients included in RenalTube 2011;12(1):116. database and was a major contributor in writing the manuscript. FS and HG 4. Zhang C, Zhao Z, Sun Y, Xu L, JiaJue R, Cui L, et al. Clinical and contributed on analyzing data and were major contributors on writing the genetic analysis in a large Chinese cohort of patients with X-linked manuscript. Every other author introduced information of at least 1 patient hypophosphatemia. Bone. 2019;121:212–20. https​://doi.org/10.1016/j. from this study in RenalTube database. All authors read and approved the final bone.2019.01.021. manuscript. 5. Capelli S, Donghi V, Maruca K, Vezzoli G, Corbetta S, Brandi ML, et al. Clinical and molecular heterogeneity in a large series of patients Funding with hypophosphatemic rickets. Bone. 2015;79:143–9. https​://doi. This research has been partially funded by Kyowa Kirin Farmacéutica S.L.U., org/10.1016/j.bone.2015.05.040. Fondo de Investigaciones Sanitarias (FIS) and Fundación Nutrición y Crec‑ 6. Francis F, Hennig S, Korn B, Reinhardt R, de Jong P, Poustka A, et al. A imiento (FUNDNYC). gene (PEX) with homologies to endopeptidases is mutated in patients with X–linked hypophosphatemic rickets. Nat Genet. 1995;11(2):130–6. Availability of data and materials 7. Fuente R, Gil-Peña H, Claramunt-Taberner D, Hernández O, Fernández- The datasets used and/or analyzed during the current study are available from Iglesias A, Alonso-Durán L, et al. X-linked hypophosphatemia and the corresponding author on reasonable request. growth. Rev Endocr Metab Disord. 2017. https​://doi.org/10.1007/s1115​ 4-017-9408-1. Ethics approval and consent to participate 8. Gattineni J, Baum M. Genetic disorders of phosphate regulation. Pedi‑ Patients information has been processed via RenalTube database where atr Nephrol. 2012;27(9):1477–87. patients signed their consent to participate in scientific studies. 9. Bitzan M, Goodyer PR. Hypophosphatemic rickets. Pediatr Clin North Am. 2019;66(1):179–207. https​://doi.org/10.1016/j.pcl.2018.09.004. Consent for publication 10. Carpenter TO, Whyte MP, Imel EA, Boot AM, Högler W, Linglart A, et al. Patients or parents signed consent for publication of their data through Burosumab therapy in children with X-linked hypophosphatemia. N RenalTube consent form. Engl J Med. 2018;378(21):1987–98. 11. Zhukouskaya VV, Rothenbuhler A, Colao A, Di SC, Kamenický P, Trabado Competing interests S, et al. Increased prevalence of overweight and obesity in children company produces the drug Crysvita® (burosumab). Nevertheless, no patients The study has been partially funded by Kyowa Kirin Farmacéutica S.L.U. This with x-linked hypophosphatemia. Endocr Connect. 2020;9(2):144–53. 12. Emma F, Cappa M, Antoniazzi F, Bianchi ML, Chiodini I, Eller Vainicher in this study had been or were being treated with burosumab at the time of C, et al. X-linked hypophosphatemic rickets: An Italian experts’ opinion data collection. survey. Ital J Pediatr. 2019;45(1):1–7. 13. Cho HY, Lee BH, Kang JH, Ha IS, Cheong HI, Choi Y. A clinical and Author details molecular genetic study of hypophosphatemic rickets in children. 1 Pediatric Research, Medicine Department, University of Oviedo, Oviedo, Pediatr Res. 2005;58(2):329–33. Spain. 2 AGC Pediatría, Hospital Universitario Central de Asturias, Oviedo, 14. Endo I, Fukumoto S, Ozono K, Namba N, Inoue D, Okazaki R, et al. 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