Prevalence of Enthesopathies in Adults With X-linked Hypophosphatemia: Analysis of Risk Factors

Abstract

Context

Enthesopathies are the determinant of a poor quality of life in adults with X-linked hypophosphatemia (XLH).

Objective

To describe the prevalence of patients with enthesopathies and to identify the risk factors of having enthesopathies.

Methods

Retrospective study in the French Reference Center for Rare Diseases of the Calcium and Phosphate Metabolism between June 2011 and December 2020. Adult XLH patients with full body X-rays performed using the EOS® low-dose radiation system and clinical data collected from medical records.

The main outcome measures were demographics, PHEX mutation, conventional treatment, and dental disease with the presence of enthesopathies.

Results

Of the 114 patients included (68% women, mean age 42.2 ± 14.3 years), PHEX mutation was found in 105 patients (94.6%), 86 (77.5%) had been treated during childhood. Enthesopathies (spine and/or pelvis) were present in 67% of the patients (n = 76). Patients with enthesopathies were significantly older (P = .001) and more frequently reported dental disease collected from medical records (P = .03). There was no correlation between the PHEX mutations and the presence of enthesopathies. Sixty-two patients had a radiographic dental examination in a reference center. Severe dental disease (number of missing teeth, number of teeth endodontically treated, alveolar bone loss, and proportion of patients with 5 abscesses or more) was significantly higher in patients with enthesopathies.

Conclusion

Adult XLH patients have a high prevalence of enthesopathies in symptomatic adults patients with XLH seen in a reference center. Age and severe dental disease were significantly associated with the presence of enthesopathies.

X-linked hypophosphatemia (XLH) is a rare genetic disease (incidence approximately 1/20 000) (1-4). In 75% to 90% of the cases, XLH is due to mutations in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene leading to an inadequate production of fibroblast growth factor-23 (FGF23) by osteocytes (4-10). As a consequence of elevated circulating FGF23 levels, the renal reabsorption of phosphate and the production of 1,25-dihydroxyvitamin D are limited (11). Most, but not all, patients are diagnosed at the age of walking because of lower limb deformities, delayed walking, and rickets (7-8). Children with XLH manifest with rickets and osteomalacia, short stature, bone pain, craniosynostosis, and dental anomalies (12, 13). In adulthood, the burden of disease is related to musculoskeletal symptoms due to osteomalacia, pseudofractures, osteoarthritis, and muscle weakness of lower limbs but also ossification of entheses (enthesopathies) (14-16). This last feature is a strong determinant of the altered quality of life in this population (14).

These enthesopathies have been described at the spine, peripheral joints, and tendon insertion at the Achilles tendon or plantar fascia ligament, and are responsible for chronic pain, stiffness, and disability (14). The prevalence of these different types of enthesopathies in adult XLH patients ranges between 30% and 100% (14, 17, 18), differing according to the characteristics of the population and the definition of enthesopathies. We distinguished an enthesopathy as a vertical ossification of the enthesis from osteophytes, defined as horizontal ossification coming from the joint between 2 vertebrae.

Clinical experience suggests that there is great variability in the phenotype of the disease in adults, with some patients tending to have pseudofractures and others enthesopathies, without it being possible to predict which patients will develop enthesopathies. Moreover, there is a confusion in the literature between the different terms (enthesopathies, osteophytes, ossifications, and calcifications), which do not necessarily refer to the same structure involved (17, 19, 20).

These discrepancies require a better description of the profile of patients with enthesopathies and to identify the risk factors of having enthesopathies. Dental abnormalities are reported with higher frequency in adults than in children. Spontaneous endodontic abscesses occur in children and in adults, whereas periodontitis, alveolar bone loss, and tooth loss are increased in adult XLH patients and contribute to reduced health-related quality of life (14). The PHEX gene is also expressed in odontoblasts. To our knowledge, no study has assessed the severity of the clinical phenotype compared with the severity of the dental phenotype. Our hypothesis is that there is a link between the severity of the dental disease and the presence of enthesopathies.

The aim of our study was to describe the prevalence of enthesopathies in adults with X-linked hypophosphatemia and to identify the risk factors of having enthesopathies, with a special focus on dental phenotype.

Materials and Methods

Study Design

We conducted a retrospective study in the reference center for rare diseases of calcium and phosphate metabolism. The study was conducted according to French regulations. The need for written consent is waived by French regulations in this type of retrospective study. Patients were orally informed of the study and their consent obtained. They have a right to withdraw from the study at any time by contacting http://recherche.aphp.fr/eds/droit-opposition.

Patients

We included all consecutive XLH patients’ ≥18 years with a diagnosis of XLH defined by a PHEX mutation or a variant of unknown significance in the patient, or a family member with an appropriate X-linked dominant inheritance or rickets with hypophosphatemia with excess of FGF23. Different high-throughput sequencing (next-generation sequencing) technologies were used to detect PHEX variations in the 5 collaborating genetic diagnosis laboratories. The presence of the variants was verified using the Sanger technique or multiplex ligation-dependent probe amplification. Patients were referred by a specialist or consulting of their own free will in the Rheumatology Department for musculoskeletal features (pain/stiffness, disability) between June 2011 and December 2020. As a part of our routine procedure, all patients undergo at least 1 radiograph of the spine, pelvis, and lower limbs for the management of musculoskeletal symptoms, which are prominent at the hips, pelvis, and spine (14). Radiographs were performed using the low-dose biplanar imaging system EOS® (EOS Imaging, Paris, France).

Types of mutation were classified as plausible truncating mutations (nonsense and frameshift), nontruncating mutations (missense and inframe), and exon loss (exon deletion 1 or more and splice mutation). Mosaic mutation was not included in the analysis.

The following variables were assessed for each patient using standardized interviews and physical examinations conducted by the rheumatologist: age at visit, age at diagnosis, family history of XLH, history of orthopedic surgery of lower limbs, history of fracture, self-reported dental complications, persistence of lower limb deformities in adulthood, treatment during childhood with phosphate supplements and/or vitamin D analogs, current intake of phosphate and/or vitamin D analogs. Self-reported dental complications were reported by the patient and included periodontitis, teeth loss, and/or endodontically treatment.

EOS® Imaging Analysis Readers

EOS® images were assessed by 2 readers specializing in the field of bone and joint diseases: 1 radiologist and 1 rheumatologist using a reading grid. Radiological and dental findings were evaluated in a blinded fashion as the X-rays readers did not know the results of the dental findings and the dentists did know the presence of enthesopathies. However, the X-rays readers could access some clinical data such as age and gender but not medical data, as they did not have access to the medical file.

EOS® allows acquisition of images of the entire skeleton, in a standing position, as a single “snapshot,” using low radiation doses of about 20% to 30% of that of standard X-rays in accordance with EURATOM 2013/59 recommendations (21).

The focus was on some areas of EOS® imaging: spine, pelvis and heels. The concordance between readers was tested using 10 EOS® images, yielding a concordance of 0.89 at the spine, 1.00 at the ischial site, 0.67 at the iliac crest, 1.00 at the acetabulum, 0.67 at the sacroiliac joint, 0.89 at the Achilles tendon, and 0.78 for hip osteoarthritis.

In case of disagreement between the 2 readers, a third person (a pediatric radiologist experienced in reading EOS® radiographs in children and adults) also analyzed the images and a consensus was reached between the 3 readers.

Reading Grid

To describe the spine lesions, the reading grid was divided by spinal level into cervical, thoracic, and lumbar spine. At each level, the reader noted the presence or absence of enthesopathy. The presence of enthesopathy was defined as a vertical ossification coming from the enthesis. If the ossification was thin, it was described as a syndesmophyte (Fig. 1A); if it was a coarse ossification (Fig. 1B), it was described as a bony bridge (hyperostosis-like disease). In addition, at each level, the reader noted the presence or absence of an osteophyte and its localization (anterior, posterior, lateral). An osteophyte was defined as a horizontal ossification coming from the joint between 2 vertebrae (Fig. 1C). Because EOS® did not systematically include the calcanei, Achilles tendons were visible on 74 radiographs.

For the description of peri-articular structural damage, the reader documented the presence or absence of enthesopathies at the Achilles tendon, iliac crests, and ischial sites. We assessed sacroiliac joint damage (joint space widening and/or ankylosis) (Fig. 1D) and hip osteoarthritis defined by the presence of osteophytes and/or joint space narrowing. Presence or absence of pseudofractures at the lower limb were also documented by the reader. Pseudofracture was defined as a cortical infraction surrounded by a thickened periosteum.

Dental Disease Evaluation

A complete dental examination by a specialist in rare bone diseases was carried out on 62 of 114 patients. Dental evaluation was carried out using a panoramic radiograph or cone beam computerized tomography or a full mouth series of periapical radiographs. The dental findings were performed in a blinded fashion for the EOS® radiological findings. As the specialists had access to the medical files, the evaluation was not blinded for the medical data (age, sex, treatments).

Number of teeth, number of missing teeth (except wisdom teeth), number of teeth treated endodontically, and alveolar bone loss were collected. The teeth treated endodontically indirectly indicated the occurrence of dental abscesses. The percent of teeth treated endodontically was the number of teeth treated under the number of teeth present. As defined by Connor et al. (22), severe dental disease was defined by a history of more than 5 dental abscesses (more than 5 teeth treated endodontically) or by more than 5 missing teeth. Alveolar bone loss was used as a radiographic sign of periodontitis. Bone loss was classified as mild, moderate, or severe (bone loss ≤1/3, >1/3 to ≤1/2, or >1/2 of the root length, respectively) (23).

Statistical Analysis

Descriptive statistical analyses of the population and results were made using mean and standard deviation. Descriptive analyses were also realized according to the age of the patients (under 30, between 30 and 40, between 40 and 50, and over 50). One spinal enthesopathy or 1 pelvis enthesopathy was sufficient to be included in the enthesopathies group. Spinal enthesopathy was defined as an ossification thin (syndesmophyte-like) or coarse. Factors associated with enthesopathies were assessed using multiple logistical regression. The first model was adjusted on age because of the importance of age in the natural history of XLH. To identify the variables to be included in multiple logistical regression, a step-by-step multiple regression was performed, using stepAIC backward selection. Variables from the model were progressively removed to obtain the lowest AIC. Age, history of lower limb surgery, dental disease (collected in medical records as yes or no), treatment during childhood with phosphate and/or vitamin D analogs, pseudofractures, and hip osteophytes were the variables included in the multivariate model.

A good correlation, assessed with the chi-squared test, was found between self-reported dental complications and dental complications reported by dental examination (P = 10^–7).

Bivariate analysis was performed to assess the association between dental disease assessed by a complete dental examination and the presence of enthesopathies. Age-adjusted and multivariate analyses were performed. Multiple imputation was performed for missing data.

For all the analyses, P < .05 was considered statistically significant. All analyses were performed on the statistical software R, version 3.5.2.

Results

Characteristics of the Population

Of the 143 adult patients with XLH from 114 families with a PHEX mutation or a related family member referred from rheumatology between June 2011 and December 2020, EOS® radiographs were performed for 114 patients (68% women, mean age 42.2 ± 14.3 years) and were analyzed for this study (Table 1).

Screening for PHEX mutation was performed for 111 adults. The types of mutation were “frameshift,” “nonsense,” “missense,” “splice,” “in-frame,” and “deletion” for 12 (11.0%), 25 (22.9%), 19 (17.4%), 25 (22.9%), 3 (2.8%), and 19 (17.4%) adult patients with XLH, respectively. Six of them had no mutation and 2 had a PHEX mutation notified in the medical file but the type of mutation was not found in the collaborating genetic diagnosis laboratories. We have categorized the types of mutation into truncating (40 [39.2%]), non-truncating (22 [21.6%]), and exon loss (40 [39.2%]).

For all patients with negative mutations, the absence of variants was verified using the Sanger technique.

Eighty-six (77.5%) patients had been treated during childhood with phosphate supplements and/or vitamin D analogs. At the time of the study, 67 (59.8%) were still receiving phosphate supplements and/or vitamin D analogs.

Pseudofractures were found in 31 (27.2%) patients (mean age 42.8 [±13.3] years). Hip osteoarthritis was found in 96 patients (84.2%) (mean age 44.8 [±13.7] years) with hip joint space narrowing and hip osteophytes in 71 (62.3%) and 89 (78.1%) patients respectively.

Prevalence of Enthesopathies

Enthesopathies (spine and/or pelvis) were present in 76 patients (67%). Spinal enthesopathies were found in 60 patients (53%) and 44% had enthesopathies of pelvis. These ossifications were thin (syndesmophyte-like in SpA) in 48 patients (80%) and coarse in 45 (75%). Thirty-five patients (58%) had spinal osteophytes. All patients with spinal osteophytes had spinal enthesopathies or pelvic enthesopathies, except 1 who had only 1 lumbar osteophyte.

Of the 60 patients with the spinal enthesopathies, the average number of enthesopathies was 4.25 ± 3.04 per patient. Most of them were localized at the cervical (88%) or lumbar (65%) spine (vs 18% at the thoracic spine).

Fifty (44%) patients had peripheral enthesopathies localized at the ischial region (29%) or iliac crests (34%). Calcanei were visible on 74 radiographs. Enthesopathies were present on the Achilles tendon in 24 cases (32%).

Spondyloarthritis-like Pattern

Among patients with enthesopathies, 48 (63%) patients had syndesmophytes, which are thin bony structures observed in ankylosing spondylitis; 13 (11%) of these patients had a complete sacroiliac ankylosis and 10 patients a joint space widening (8.8%), suggesting a radiographical diagnosis of ankylosing spondylitis.

Characteristics of Patients With Enthesopathies

The prevalence of syndesmophytes and spine bony bridges increased with age (Fig. 2). Indeed, we found them in 34% and 25% of patients between 30 and 40 years, in 54% and 41% of patients between 40 and 50 years, and in 94% and 70% of patients over 50 years, respectively. Only 2 subjects below 30 years of age had spinal enthesopathies.

Patients with enthesopathies were significantly older (mean age of 47.4 vs 31.7 years old, P < .0001) and more frequently reported a delay of treatment initiation (age of onset of treatment of 14.0 vs 6.0 year olds, P = .04), a lower limb deformity (80% vs 60%, P = .03), a history of lower limb surgery (75% vs 49%, P = .005), dental complications (87% vs 54%, P = .003), and less frequently received treatment during childhood with phosphate and/or vitamin D analogs (71% vs 89%, P = .03) (Table 2). Patients with enthesopathies more frequently had pseudofractures (33% vs 16%), hip joint space narrowing (70% vs 47%), and hip osteophytes (91% vs 52%) assessed by the EOS® imaging (P = .04, P = .02, and P <.0001, respectively).

Univariate analysis adjusted for age showed that some risk factors were associated with the presence of enthesopathies (Table 2): pseudofractures, hip osteophytes, history of lower limb surgery, and self-reported dental complications (P = .05, P = .03, P = .02, and P = .01 respectively).

In multivariate analysis, age and self-reported dental disease were the only factors associated with the presence of enthesopathies (OR 1.09, CI 1.04-1.15, P = .001; OR 4.05, CI 1.22-14.6, P = .03 respectively).

The percentage in the various categories of mutation varied between 20% and 43% for the group with enthesopathies and between 18% and 48% for the group without enthesopathies. We did not find an effect of mutational categories of PHEX on the development of enthesopathy in adults with XLH (P = .49).

Dental Disease and Enthesopathies

Sixty-two patients had a complete dental evaluation (Table 3). This sample population had similar characteristics to the study population (data not shown). Abnormal dental examination, defined by alveolar bone loss or dental treatment endodontically or by missing teeth, was found in 54 patients (87%). Mean number of teeth was 24.3 (7.3), mean number of missing teeth was 5.2 (6.7), and mean number of teeth treated endodontically was 5.6 (5.4). Forty-five percent (n = 5) had a normal dental examination before the age of 30 years.

Patients with enthesopathies had a significantly higher number of missing teeth (mean of 6.5 vs 2.3, P = .02), number of teeth treated endodontically (6.2 vs 4.2, P = .04), and moderate to severe alveolar bone loss (40% vs 16%, P = .08).

Severe dental disease defined by the prevalence of more than 5 abscesses or 5 missing teeth was higher in patients with enthesopathies (77% vs 47%, P = .02). Age-adjusted and multivariate analysis were no longer statistically significant (data not shown).

Patients with hip osteoarthritis (n = 55, 89%) had a higher frequency of severe dental disease (more than 5 teeth treated endodontically or more than 5 missing teeth (73% vs 28%, P = .03). Patients with pseudofractures (n = 12, 19%) did not have associated severe dental disease (data not shown).

Alveolar Bone Loss

Forty-four patients (71%) had an alveolar bone loss (Table 4), classified as mild (n = 24), moderate (n = 11), or severe (n = 9). Only 1 patient aged <30 years presented with alveolar bone loss. Patients with alveolar bone loss (normal, mild, moderate, and severe) were older (mean 27.8 vs 44,1 vs 48.7 vs 46.7, respectively, P < .0001), had a higher prevalence of enthesopathies (37% vs 75% vs 100% vs 67%, respectively, P = .005), a higher number of enthesopathies (0,56 vs 3.17 vs 4.54 vs 2.78, respectively, P = .02), a higher prevalence of hip joint space narrowing (31% vs 54% vs 82% vs 100%, respectively, P = .003), and hip osteophytes (56% vs 87% vs 82% vs 100%, respectively), P = .03. We did not find an effect of mutational categories of PHEX on the dental phenotype in adult with XLH (P = .11).

Discussion

This is the largest study conducted in adult patients with XLH showing a high prevalence of enthesopathies with a radiographic assessment in symptomatic adult patients with XLH seen in a reference center. Age and severe dental disease were the main risk factors of having enthesopathies.

In our study, 67% of adult patients (mean age of 42 years) with XLH had at least 1 enthesopathy. According to our data, the disease develops during the fourth decade, as only 2 patients <30 years displayed enthesopathies on radiographs.

We reported a higher prevalence of enthesopathies in the cervix and lumbar spine than in the thorax spine. Our explanation is that enthesophytes develop in areas with excess mechanical stress. The dorsal spine is probably less subjected to these constraints because it is less mobile due to the presence of the ribs.

In our first study conducted in 52 adults with XLH, 64% of them had enthesopathies, and we showed that enthesopathies were significantly associated with impaired quality of life (14). In the study by Skrinar et al., the presence of enthesopathies was self-reported in 27% of participants (18), a difference that can be explained by the method of data collection and an older population (mean age of 46 years)

Difference of prevalence of enthesopathies between studies can also be explained by the definition of enthesopathies. In some patients, we observed coarse ossifications that can be observed in degenerative diseases, such as diffuse idiopathic skeletal hyperostosis. Both radiological types of enthesopathies can be observed within a single patient.

We paid careful attention to the differences between enthesopathies and osteophytes. In this population, enthesopathies were more frequent than osteophytes. We also found that a high proportion of adults with XLH had thin enthesopathies similar to syndesmophytes described in ankylosing spondylitis. This is relevant as some adult patients with XLH mimicked ankylosing spondylitis (14). In our study, 49% of adult patients with XLH had radiological features that can be observed in ankylosing spondylitis, such as syndesmophytes and/or sacroiliac ankylosis. In adulthood, the diagnosis of XLH can be delayed because the radiological phenotype of enthesopathies can lead to a diagnosis of axial spondyloarthritis. Physicians should be aware of the different patterns of radiographic features to avoid misdiagnosis, and to eventually reach a diagnosis of XLH and avoid the use of inappropriate medications such as tumor necrosis factor inhibitors as previously reported (24).

Moreover, from a pathophysiological perspective, the presence of syndesmophytes in a noninflammatory disease illustrated that syndesmophyte formation is possible without inflammation but may be explained by other hypotheses, such as an excess of mechanical stress on poorly mineralized bone. Similar to adult patients with XLH, Hyp mice developed calcaneal enthesophytes, hip joint alterations, erosions of the sacroiliac joints, and periarticular calcifications. Hyp mice provide a mouse model for X-linked hypophosphatemic rickets. We showed that these lesions were already present at month 3 and gradually worsened over time. Histological analyses confirmed the presence of bone erosions, calcifications, and expansion of mineralizing enthesis fibrocartilage in Hyp mice, suggesting that new bone formation is driven by altered mechanical strain. Interestingly, despite strong deformation of the curvature of the spine, none of the Hyp mice displayed enthesophyte at the spine (25). In a mouse model of ankylosing spondylitis, tail suspension limits the development of enthesophytes on lower limbs, suggesting a link between mechanical stress and bone formation in this inflammatory condition (26). An elevated expression of FGFR3 and Klotho in the fibrocartilage where enthesis mineralization starts was found in hypophosphatemic mice, suggesting that high circulating levels of FGF23 may have a role in the ossification of enthesis (17, 20). Finally, recent experimental studies suggest that enhancing bone morphogenetic proteins (BMP) and Indian hedgehog (IHH) signaling due to impaired 1,25 dihydroxyvitamin D activity in XLH is involved in the development of enthesopathy (25, 27).

In univariate analysis we found that patients with enthesopathies were significantly older and more frequently reported a delay in treatment initiation, had a lower limb deformity, a history of lower limb surgery, dental complications, and less frequently received treatment during childhood with phosphate and/or vitamin D analogs. They more frequently had pseudofractures, hip joint space narrowing, and hip osteophytes assessed by EOS®. When we adjusted for age and self-reported dental complications, pseudofractures and hip osteophytes remained statistically significant. These data suggest that enthesopathies are associated with severity of osteomalacia and with other severe radiological manifestations (pseudofractures and hip osteoarthritis). After multivariate adjustment, age and self-reported dental complications were significantly associated with enthesopathies. We did not find any association with the intake of phosphate and vitamin D analogs. This is in accordance with other studies, suggesting that treatments do not seem prevent or worsen enthesopathies (22).

A study with hypophosphatemic mice found an exacerbation of mineralizing enthesopathy with conventional treatment but this was not confirmed in clinical studies (20).

We also found that the prevalence of enthesopathies increased with age, from 5% before 30 years up to 83% after the age of 50 years. We did not find factors to prevent the occurrence of enthesopathies, such as beginning treatment before age of 2 or continued treatment after adolescence.

Dental disease was assessed by a single dentist, expert in the field of rare bone diseases, in 62 patients. To date, studies have described only self-reported dental manifestations in adults. Connor et al. presented dental manifestations in 52 patients with XLH according to both medical records and extensive questioning, and reported a history of more than 5 abscesses in 61.5% of patients (22). Our findings confirmed the high prevalence of past or present periodontitis and dental abscesses using radiographic evaluation. A shorter duration of conventional treatment in childhood was associated with alveolar bone loss in univariate analysis. Conventional treatment prevents dental manifestations in childhood and improves dental mineralization (28, 29). In adulthood, continued supplementation could be beneficial to dental health. Continued conventional treatment during adulthood improved periodontal health in 34 adults with XLH (29). Two others studies reported a beneficial effect (22, 28). We did not find an association between conventional treatment and dental disease, probably because data on conventional treatment were collected retrospectively and not at the time of the dental examination.

We found that patients with enthesopathies had a higher number of missing teeth or teeth treated endodontically. Severe dental disease defined by the prevalence of more than 5 abscesses or 5 missing teeth was higher in patients with enthesopathies. Hip osteoarthritis was also associated with severe dental disease, but not pseudofractures; this result should be confirmed because of our small sample size (only 12 events in this subgroup). Alveolar bone loss was also associated with severe radiological manifestations of hip osteoarthritis and enthesopathies but not with pseudofractures. To our knowledge, this is the first study to assess the association between the severity of radiological phenotype and the severity of dental disease in adults with XLH. Our hypothesis is that the presence of enthesopathies that reflect severe disease is due to the severity of the osteomalacia, which also explains the severity of dental involvement. These results are indeed important because they show that age is not the only determinant. We focused on enthesopathies and not osteophytes or other causes of ossification.

The strengths of our study are the following: (1) data from the largest database of adult patients with XLH; (2) it is the largest study using EOS® radiographic assessment and accurate readings by 2 readers specialized in the field. In these patients who likely have been exposed to multiple radiographs and are at high risk of rheumatological complications, EOS® can be considered as an interesting imaging tool; (3) it has the largest dental description by an expert in bone rare disease derived from clinical and radiographic examinations.

The main limitation of this study is that the data were collected retrospectively from medical records, which leads to difficulties analyzing the exposition to a medical treatment, such as phosphate supplements and vitamin D analogs, in a retrospective analysis spanning several decades of treatment intake. The results of the radiographic evaluation (presence of enthesopathies in particular) were not known to the dentists and, conversely, the X-ray readers did not know the results of the dental findings. However, the evaluators could access clinical data, such as age and gender, and dentists could access the medical records, which might have biased the findings. Heels, upper limbs, and knees could not be extensively analyzed using the EOS® imaging approach.

Another limitation was that as a tertiary referral center we deal with patients with more severe disease and our group of patients could have more disability than the average adult population affected by XLH. In vivo studies suggested the possible role of FGF23 in the development of ossification in the enthesis. Analyses between the serum level of FGF23 and the presence of enthesopathies would be of interest, but few FGF23 assays were available (only for 28 patients).

In conclusion, using an accurate definition, we reported that 67% of adult patients with XLH, attending a specialized center with a mean age of 42 years, had at least 1 enthesopathy at the spine and/or pelvis. Age and severe dental disease were significantly associated with the presence of enthesopathies. Because of the consequences of enthesopathies on quality of life, further studies are needed to understand the mechanisms and the risk factors of enthesopathies.

Abbreviations

Abbreviations
 
• FGF

  fibroblast growth factor

 
• XLH

  X-linked hypophosphatemia

Acknowledgment

The authors thank the 5 collaborating genetic diagnosis laboratories: (Hopital Sud, Rennes, France; Cochin hospital, Paris, France; CHU de Lille, Lille, France; Hopital Bicêtre, Le Kremlin Bicêtre, France; CHU de Poitiers, Poitiers, France).

Financial Support: No grant has been received for this study.

Additional Information

Disclosures: Dr. Herrou, Dr. A. Salcion-Picaud, and Dr. L. Lassalle have not received honoraria. Pr. Chaussain has received research grants from Kyowa Kirin. Dr. V. Merzoug has received honoraria from Alexion. Ms. Hervé and Ms. Gadion have not received honoraria. Dr. A. Rothenbuhler has received honoraria from Kyowa Kirin, Ultragenyx, and Alexion. Dr. P. Kamenicky has received honoraria from Kyowa Kirin and Ultragenyx. Pr. C. Roux has received honoraria from Alexion, Sanofi, and UCB and research grants from Alexion and Regeneron. Pr. A. Linglart has received research grants and/or honoraria from Kyowa Kirin, Ultragenyx, and Alexion. Dr. Biosse Duplan has received research grants or honoraria from Alexion and Kyowa Kirin. Pr. K. Briot has received research grants or honoraria from Amgen, Kyowa Kirin, Lilly, Medtronic, MSD, and UCB.

Data Availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

References