Lower limb bone geometry in adult individuals with X-linked hypophosphatemia: an observational study.

We assessed lower-limb geometry in adults with X-linked hypophosphatemia (XLH) and controls. We found large differences in multiple measures including femoral and tibial torsion, bowing and cross-sectional area and acetabular version and coverage which may contribute to clinical problems such as osteoarthritis, fractures and altered gait common in XLH. PURPOSE: Individuals with X-linked hypophosphatemia (XLH) are at risk of lower-limb deformities and early onset of osteoarthritis. These two factors may be linked, as altered biomechanics is a risk factor for osteoarthritis. This exploratory evaluation aims at providing clues and concepts for this association to facilitate future larger-scale and longitudinal studies on that aspect. METHODS: For this observational study, 13 patients with XLH, aged 18-65 years (6 female), were compared with sex-, age- and weight-matched healthy individuals at a single German research centre. Femoral and hip joint geometry, including femoral and tibial torsion and femoral and tibial shaft bowing, bone cross-sectional area (CSA) and acetabular version and coverage were measured from magnetic resonance imaging (MRI) scans. RESULTS: Total femoral torsion was 29° lower in individuals with XLH than in controls (p < 0.001), mainly resulting from lower intertrochanteric torsion (ITT) (p < 0.001). Femoral lateral and frontal bowing, tibial frontal bowing, mechanical axis, femoral mechanical-anatomical angle, acetabular version and acetabular coverage were all greater and tibial torsion lower in individuals with XLH as compared to controls (all p < 0.05). Greater femoral total and marrow cavity CSA, greater tibial marrow cavity CSA and lower cortical CSA were observed in XLH (all p < 0.05). DISCUSSION: We observed large differences in clinically relevant measures of tibia and particularly femur bone geometry in individuals with XLH compared to controls. These differences may plausibly contribute to clinical manifestations of XLH such as early-onset osteoarthritis, pseudofractures and altered gait and therefore should be considered when planning corrective surgeries.

Bone Deformities and Kidney Failure: Coincidence of PHEX-Related Hypophosphatemic Rickets and m.3243A>G Mitochondrial Disease.

X-linked hypophosphatemic rickets (XLH) and m.3243A>G mitochondrial disease share several clinical findings, including short stature, hearing impairment (HI), nephropathy, and hypertension. Here, we report on a case with the rare coincidence of these two genetic conditions. In early childhood, the patient presented with hypophosphatemia and bone deformities and was clinically diagnosed with XLH. This was genetically verified in adulthood with the identification of a de novo pathogenic deletion in phosphate-regulating endopeptidase homolog X-linked (PHEX). In addition, the patient developed HI and hypertension and when his mother was diagnosed with m.3243A>G, subsequent genetic testing confirmed the patient to carry the same variant. Over the next two decades, the patient developed progressive renal impairment however without nephrocalcinosis known to associate with XLH which could indicate an m.3243A>G-related kidney disease. Parallel with the progression of renal impairment, the patient developed hyperphosphatemia and secondary hyperparathyroidism. In conclusion, this case represents a complex clinical phenotype with the reversal of hypo- to hyperphosphatemia in XLH potentially mediated by the development of an m.3243A>G-associated nephropathy.

Cellular and Molecular Alterations Underlying Abnormal Bone Growth in X-Linked Hypophosphatemia.

X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets, is caused by inactivating mutations of the phosphate-regulating endopeptidase gene (PHEX). XLH is mainly characterized by short stature, bone deformities and rickets, while in hypophosphatemia, normal or low vitamin D levels and low renal phosphate reabsorption are the principal biochemical aspects. The cause of growth impairment in patients with XLH is not completely understood yet, thus making the study of the growth plate (GP) alterations necessary. New treatment strategies targeting FGF23 have shown promising results in normalizing the growth velocity and improving the skeletal effects of XLH patients. However, further studies are necessary to evaluate how this treatment affects the GP as well as its long-term effects and the impact on adult height.

Heterozygous recurrent HNF4A variant p.Arg85Trp causes Fanconi renotubular syndrome 4 with maturity onset diabetes of the young, an autosomal dominant phenocopy of Fanconi Bickel syndrome with colobomas.

Heterozygous pathogenic variants in HNF4A cause hyperinsulinism, maturity onset diabetes of the young type 1, and more rarely Fanconi renotubular syndrome. Specifically, the recurrent missense pathogenic variant c.253C>T (p.Arg85Trp) has been associated with a syndromic form of hyperinsulinism with additional features of macrosomia, renal tubular nephropathy, hypophosphatemic rickets, and liver involvement. We present an affected mother, who had been previously diagnosed clinically with the autosomal recessive Fanconi Bickel Syndrome, and her affected son. The son's presentation expands the clinical phenotype to include multiple congenital anomalies, including penile chordee with hypospadias and coloboma. This specific pathogenic variant should be considered in the differential diagnosis of Fanconi Bickel Syndrome when genetics are negative or the family history is suggestive of autosomal dominant inheritance. The inclusion of hyperinsulinism and maturity onset of the diabetes of the young changes the management of this syndrome and the recurrence risk is distinct. Additionally, this family also emphasizes the importance of genetic confirmation of clinical diagnoses, especially in adults who grew up in the premolecular era that are now coming to childbearing age. Finally, the expansion of the phenotype to include multiple congenital anomalies suggests that the full spectrum of HNF4A is likely unknown.

Crossfibrillar mineral tessellation in normal and Hyp mouse bone as revealed by 3D FIB-SEM microscopy.

In bone, structural components such as mineral extend across length scales to provide essential biomechanical functions. Using X-ray micro-computed tomography (µCT), and focused ion beam scanning electron microscopy (FIB-SEM) in serial-surface-view mode, together with 3D reconstruction, entire mouse skeletons and small bone tissue volumes were examined in normal wildtype (WT) and mutant Hyp mice (an animal model for X-linked hypophosphatemia/XLH, a disease with severe hypomineralization of bone). 3D thickness maps of the skeletons showed pronounced irregular thickening and abnormalities of many skeletal elements in Hyp mice compared to WT mice. At the micro- and nanoscale, near the mineralization front in WT tibial bone volumes, mineralization foci grow as expanding prolate ellipsoids (tesselles) to abut and pack against one another to form a congruent and contiguous mineral tessellation pattern within collagen bundles that contributes to lamellar periodicity. In the osteomalacic Hyp mouse bone, mineralization foci form and begin initial ellipsoid growth within normally organized collagen assembly, but their growth trajectory aborts. Mineralization-inhibiting events in XLH/Hyp (low circulating serum phosphate, and increased matrix osteopontin) combine to result in decreased mineral ellipsoid tessellation - a defective mineral-packing organization that leaves discrete mineral volumes isolated in the extracellular matrix such that ellipsoid packing/tessellation is not achieved. Such a severely altered mineralization pattern invariably leads to abnormal compliance, other aberrant biomechanical properties, and altered remodeling of bone, all of which indubitably lead to macroscopic bone deformities and anomalous mechanical performance in XLH/Hyp. Also, we show the relationship of osteocytes and their cell processes to this mineralization pattern.

Alterations of bone material properties in adult patients with X-linked hypophosphatemia (XLH).

X-linked hypophosphatemia (XLH) caused by PHEX mutations results in elevated serum FGF23 levels, renal phosphate wasting and low 1,25-dihydroxyvitamin D. The glycophosphoprotein osteopontin, a potent inhibitor of mineralization normally degraded by PHEX, accumulates within the bone matrix. Conventional therapy consisting of supplementation with phosphate and vitamin D analogs is burdensome and the effects on bone material poorly characterized. We analyzed transiliac bone biopsies from four adult patients, two of them severely affected due to no diagnosis and no treatment until adulthood. We used light microscopy, qBEI and FTIRI to study histology, histomorphometry, bone mineralization density distribution, properties of the organic matrix and size of hypomineralized periosteocytic lesions. Non-treatment resulted in severe osteomalacia, twice the amount of mineralized trabecular volume, multiple osteon-like perforations, continuity of lamellae from mineralized to unmineralized areas and distinctive patches of woven bone. Periosteocytic lesions were larger than in treated patients. The latter had nearly normal osteoid thicknesses, although surface was still elevated. The median calcium content of the matrix was always within normal range, although the percentage of lowly mineralized bone areas was highly increased in non-treated patients, resulting in a marked heterogeneity in mineralization. Divalent collagen cross-links were evident independently of the mineral content of the matrix. Broad osteoid seams lacked measurable pyridinoline, a mature trivalent cross-link and exhibited considerable acidic lipid content, typically found in matrix vesicles. Based on our results, we propose a model that possibly integrates the relationship between the observed mineralization disturbances, FGF23 secretion and the known osteopontin accumulation in XLH.

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.

Autosomal recessive hypophosphatemic rickets type 1 (ARHR1) was reported to be caused by homozygous mutation of dentin matrix protein 1 (DMP1). To date, very few cases have been reported. Here, we summarized clinical, laboratory and imaging findings of ARHR1 patients in our hospital. Literature review was performed to analyze genotype-phenotype correlation. Five Chinese patients from three unrelated pedigrees presented with lower extremity deformity and short stature. Hypophosphatemia, elevated alkaline phosphatase, high intact fibroblast growth factor 23 and sclerostin were found. X-ray uncovered coexistence of osteomalacia and osteosclerosis. Although areal bone mineral density (aBMD) of axial bone measured by dual-energy X-ray absorptiometry was relatively high in all patients, volumetric BMD (vBMD) and microstructure of one adult patient's peripheral bone detected by HR-pQCT were damaged. Mutation analyses of DMP1 revealed three homozygous mutations including two novel mutations, c.54 + 1G > C and c.94C > A (p.E32X), and a reported mutation c.184-1G > A. Genotype-phenotype correlation analysis including 30 cases (25 from literature review and 5 from our study) revealed that patients harboring mutations affecting C-terminal fragment of DMP1 presented with shorter stature (Z score of height = - 3.4 ± 1.6 vs - 1.0 ± 1.6, p = 0.001) and lower serum phosphate level (0.70 ± 0.15 vs 0.84 ± 0.16, p = 0.03) than those harboring mutations only affecting N-terminal fragment. In summary, we reported five Chinese ARHR1 patients and identified two novel DMP1 mutations. High aBMD and local osteosclerosis in axial bone with low vBMD and damaged microstructure in peripheral bone were featured. Genotype-phenotype correlation analysis confirmed the important role of C-terminal fragment of DMP1.

MAPK inhibition and growth hormone: a promising therapy in XLH.

X-linked hypophosphatemia (XLH) leads to growth retardation and bone deformities, which are not fully avoided by conventional treatment with phosphate and vitamin D analogs. Pediatric patients have been treated with growth hormone (GH), and recent findings suggest that blocking fibroblast growth factor 23 actions may be the most effective therapy, but its effects on growth are not known. We here report the effect of MAPK inhibition alone or associated with GH on growth and growth plate and bone structure of young Hyp (the XLH animal model) mice. Untreated Hyp mice were severely growth retarded and had marked alterations in both growth plate structure and dynamics as well as defective bone mineralization. GH accelerated growth and improved mineralization and the cortical bone, but it failed in normalizing growth plate and trabecular bone structures. MAPK inhibition improved growth and rickets and, notably, almost normalized the growth plate organization. The administration of a MAPK pathway inhibitor plus GH was the most beneficial treatment because of the positive synergistic effect on growth plate and bone structures. Thus, the growth-promoting effect of GH is likely linked to increased risk of bone deformities, whereas the association of GH and MAPK inhibition emerges as a promising new therapy for children with XLH.-Fuente, R., Gil-Peña, H., Claramunt-Taberner, D., Hernández-Frías, O., Fernández-Iglesias, Á., Alonso-Durán, L., Rodríguez-Rubio, E., Hermida-Prado, F., Anes-González, G., Rubio-Aliaga, I., Wagner, C., Santos, F. MAPK inhibition and growth hormone: a promising therapy in XLH.

Mineralized tissues in hypophosphatemic rickets.

Hypophosphatemic rickets is caused by renal phosphate wasting that is most commonly due to X-linked dominant mutations in PHEX. PHEX mutations cause hypophosphatemia indirectly, through the increased expression of fibroblast growth factor 23 (FGF23) by osteocytes. FGF23 decreases renal phosphate reabsorption and thereby increases phosphate excretion. The lack of phosphate leads to a mineralization defect at the level of growth plates (rickets), bone tissue (osteomalacia), and teeth, where the defect facilitates the formation of abscesses. The bone tissue immediately adjacent to osteocytes often remains unmineralized ("periosteocytic lesions"), highlighting the osteocyte defect in this disorder. Common clinical features of XLH include deformities of the lower extremities, short stature, enthesopathies, dental abscesses, as well as skull abnormalities such as craniosynostosis and Chiari I malformation. For the past four decades, XLH has been treated by oral phosphate supplementation and calcitriol, which improves rickets and osteomalacia and the dental manifestations, but often does not resolve all aspects of the mineralization defects. A newer treatment approach using inactivating FGF23 antibodies leads to more stable control of serum inorganic phosphorus levels and seems to heal rickets more reliably. However, the long-term benefits of FGF23 antibody treatment remain to be elucidated.

Impaired mineral quality in dentin in X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is a skeletal disorder arising from mutations in the PHEX gene, transmitted in most cases as an X-linked dominant trait. PHEX deficiency leads to renal phosphate wasting and hypophosphatemia, as well as impaired mineralization of bone and dentin, resulting in severe skeletal and dental complications. Dentin mineralization defects appear as characteristic, large interglobular spaces resulting from the lack of fusion of calculospherites in the circumpulpal region during the mineralization process. Here, we examined changes in the composition and structure of dentin using Raman spectroscopy on XLH human teeth, and using transmission electron microscopy on the dentin of Hyp mice (the murine model of XLH). The dentin of patients with XLH showed changes in the quality of the apatitic mineral, with greater carbonate substitution and lower crystallinity compared to the dentin of age-matched control teeth. In addition, ultrastructural analysis by transmission electron microscopy revealed a major disorganization of the peri- and intertubular structure of the dentin, with odontoblast processes residing within an unmineralized matrix sheath in the Hyp mouse. Taken together, these results indicate that like for bone and tooth cementum, there are impaired mineral quality and matrix changes in XLH dentin reflecting high sensitivity to systemic serum phosphate levels and possibly other local changes in the dentin matrix.

Craniofacial and dental characteristics of patients with vitamin-D-dependent rickets type 1A compared to controls and patients with X-linked hypophosphatemia.

ᅟOBJECTIVES: Vitamin-D-dependent rickets type 1A (VDDR1A) is a rare inherited disease caused by defective activation of vitamin D. The aim of the study was to describe the craniofacial characteristics and the dental phenotype of patients with genetically confirmed VDDR1A. The VDDR1A findings were compared to findings in patients with X-linked hypophosphatemia (XLH) and healthy controls. MATERIAL AND METHODS: Ten patients with VDDR1A were identified. The reference group for the comparison of cephalometric findings was 49 adults without chronic disease. The reference group for the comparison of dental findings was 30 adults with XLH. Clinical examination, clinical photos, and radiographs were obtained. Cephalometric analysis was performed. Photos and radiographs were visually evaluated. RESULTS: The depth of the posterior cranial fossa (d-p and d-s-iop) in VDDR1A adults was reduced compared to the reference group (p < 0.05). Five (83%) of six adults with VDDR1A and one (4%) of 25 adults with XLH had enamel hypoplasia on several incisors and/or canines (p < 0.001). Three (75%) of four adults with VDDR1A and none of 16 adults with XLH had several first molars with enamel hypoplasia (p = 0.004). Five of 7 (71%) adults with VDDR1A and 24 of 30 (80%) adults with XLH had endodontically affected teeth. CONCLUSIONS: The dental aberration of VDDR1A is more in line with the dental aberration of nutritional rickets than with the dental aberrations in XLH, suggesting the combination of low availability of both calcium and phosphate to be critical in periods of enamel formation. CLINICAL RELEVANCE: Knowledge on craniofacial and dental aberration in patients with rare diseases, e.g., inherited rickets, is of importance to the dental practitioner, especially during diagnostics and treatment in special care units.

[Rickets/Osteomalacia. FGF23-related hypophosphatemic rickets/osteomalacia.]

FGF23 is a hormone that reduces blood phosphate level. Excessive actions of FGF23 result in several kinds of hypophosphatemic rickets/osteomalacia such as X-linked hypophosphatemic rickets and tumor-induced osteomalacia. It is not clear how excessive actions of FGF23 are induced in these diseases. The inhibition of excessive FGF23 actions is a promising new treatment for FGF23-related hypophosphatemic rickets/osteomalacia.

Evaluation of bone mineral density and microarchitectural parameters by DXA and HR-pQCT in 37 children and adults with X-linked hypophosphatemic rickets.

In X-linked hypophosphatemic (XLH) rickets, dual-energy X-ray absorptiometry (DXA) measurements must be analyzed with caution. High-resolution peripheral quantitative computed tomography (HR-pQCT) analysis suggested that XLH primarily affects the cancellous compartment, with the tibia more affected than the radius. Effective treatment of XLH appears to positively affect bone mineralization, mainly in the bone cortex. INTRODUCTION: The purpose of this study is to evaluate bone mineral density (BMD) and microarchitecture in 37 patients (13 children and 24 adults) with XLH confirmed by PHEX mutations from a tertiary center compared to healthy controls. METHODS: Areal BMD (aBMD) was evaluated by DXA, whereas volumetric BMD (vBMD) and microarchitectural parameters were analyzed by HR-pQCT. RESULTS: Adult XLH patients had higher lumbar aBMD (p < 0.01) than the controls. At the radius, the vBMD was similar between XLH patients and controls. At the tibia, XLH patients had lower total vBMD (p = 0.04), likely resulting from decreased trabecular vBMD (p < 0.01), and this difference was observed in the children and adult groups. Analysis based on metabolic status showed that the adult XLH patients with non-compensated disease had lower cortical vBMD at the tibia than the compensated XLH patients (p = 0.03). The microarchitectural differences at the radius and tibia included lower trabecular number (p < 0.01), greater trabecular separation (p < 0.01), and higher trabecular network inhomogeneity (p < 0.01) in XLH patients compared to their controls. At the radius, adults exhibited greater trabecular deficits than were seen in children. CONCLUSIONS: In XLH patients, DXA measurements must be analyzed with caution due to the interference of anatomic and anthropometric factors. HR-pQCT analysis suggested that XLH primarily affects the cancellous compartment, with the tibia more affected than the radius. Effective treatment of XLH appears to positively affect bone mineralization, mainly in the bone cortex.

Review of the dental implications of X-linked hypophosphataemic rickets (XLHR).

OBJECTIVES: The aim of this article was to review the dental implications of X-linked hypophosphataemic rickets (XLHR) and to provide suggestions regarding the dental treatment of these patients. MATERIALS AND METHODS: The following search items "x-linked hypophosphataemia, hypophosphataemic rickets, vitamin D-resistant rickets" were used for literature search. Only full-text articles were analysed and summarized to get an overview of the different treatments and outcomes of hypophosphataemic patients. RESULTS: Radiographically, very large pulp chambers with an abnormally high pulp volume/tooth volume ratio, suggesting taurodontism, are often evident. The affected teeth are characterised by a thin enamel layer and dentinal defects. The gender distribution of hypophosphataemic patients is almost equal, but postpubertary males seem to show a trend to develop more severe dental symptoms of the disease. Abscesses without any signs of dental caries or trauma are frequent findings. The most often affected teeth are incisors followed by molars and premolars. CONCLUSIONS: Treatment options include frequent dental examination, application of topical fluoride varnish and sealing of pits and fissures to prevent microbial invasion that may result in pulpitis and further endodontic complications. CLINICAL RELEVANCE: X-linked hypophosphataemic rickets is associated with marked structural alterations of dental hard tissues and the development of multiple abscesses and sinus tracts of dental origin. Therefore, profound knowledge of the various dental implications of XLHR is required to provide these patients with the best possible treatment options.

Vitamin D receptor mutations in patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets.

CONTEXT: Hereditary vitamin D resistant rickets (HVDRR), also known as vitamin D-dependent rickets type II, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia, secondary hyperparathyroidism and hypophosphatemia and is caused by mutations in the vitamin D receptor (VDR) gene. The human gene encoding the VDR is located on chromosome 12 and comprises eight coding exons and seven introns. OBJECTIVES, PATIENTS, AND METHODS: We analyzed the VDR gene of 5 previously unreported patients, two from Singapore and one each from Macedonia (former Yugoslav Republic), Saudi Arabia and Turkey. Each patient had clinical and radiographic features of rickets, hypocalcemia, and the 4 cases that had the measurement showed elevated serum concentrations of 1,25-dihydroxyvitamin D (1,25(OH)(2)D). Mutations were re-created in the WT VDR cDNA and examined for 1,25(OH)(2)D(3)-mediated transactivation in COS-7 monkey kidney cells. RESULTS: Direct sequencing identified four novel mutations and two previously described mutations in the VDR gene. The novel mutations included a missense mutation in exon 3 causing the amino acid change C60W; a missense mutation in exon 4 causing the amino acid change D144N; a missense mutation in exon 7 causing the amino acid change N276Y; and a 2bp deletion in exon 3 5'-splice site (IVS3∆+4-5) leading to a premature stop. CONCLUSIONS: These 4 unique mutations add to the previous 45 mutations identified in the VDR gene in patients with HVDRR.

Establishing a human-induced pluripotent stem cell line SMUSHi005-A from a patient with hypophosphatemic vitamin D-resistant rickets carrying the PHEX c.1586-1586+1 delAG mutation.

Hypophosphatemic vitamin D-resistant rickets typically presents in infancy or early childhood with skeletal deformities and growth plate abnormalities. In this report, the SMUSHi005-A human induced pluripotent stem cell (hiPSC) line was successfully established from the PBMCs of a female patient carrying the PHEX mutation with c.1586-1586+1 delAG. The iPSC line has been confirmed to have a normal karyotype. The displayed cells clearly exhibit characteristics similar to embryonic stem cells, expressing pluripotency markers and demonstrating the ability to differentiate into three germ layers.

Increased Col10a1 expression is not causative for the phenotype of Phex-deficient Hyp mice.

X-linked hypophosphatemic rickets (XLHR) is a severe disorder of phosphate homeostasis and skeletal mineralization caused by mutations of PHEX, encoding a bone-specific endopeptidase. Phex-deficient Hyp mice have been extensively studied to understand the molecular bases of XLHR, and here it was found that Fgf23, encoding a major phosphaturic hormone, was transcriptionally activated in bone-forming osteoblasts. We and others could additionally show that Col10a1 expression is increased in Hyp osteoblasts and bones, thereby raising the possibility that ectopic production of type X collagen could contribute to the impaired mineralization of the Hyp bone matrix. Here we show that an additional deficiency of the Col10a1 gene does not overtly affect the skeletal phenotype of Hyp mice. More specifically, Col10a1-deficient Hyp mice displayed severe disturbances of skeletal growth, bone mass acquisition and bone matrix mineralization, and they were essentially indistinguishable from Hyp littermates. This was confirmed by non-decalcified histology and bone-specific histomorphometry quantifying all relevant parameters of growth plate maturation, trabecular bone architecture and osteoid accumulation. Taken together, our results show that increased Col10a1 expression in Phex-deficient osteoblasts is not a major cause of the XLHR phenotype, which was an important issue to address based on the previous findings.

Changes in adipose bone marrow and bone morphology in X-linked hypophosphatemic rickets.

INTRODUCTION: X-linked hypophosphatemic (XLH) rickets causes significant bone deformities in the lower limbs resulting from a bone mineralization defect. According to Frost's Mechanostat theory, compensatory modeling of the bones takes place during increased mechanical loads. In addition, mechanical stimuli modulate the differentiation of mesenchymal stem cells; common precursors to bone marrow adipocytes and osteoblasts. HYPOTHESIS: Bone deformities of the lower limbs lead to increased femoral bone mass and decreased fatty infiltration of the bone marrow (FIBM) in children with XLH rickets compared to a control group. PATIENTS AND METHODS: Eleven children (10.3years [6-17]) with XLH rickets and 22 healthy children (10.2years [5-15.5]) underwent lower limb Magnetic Resonance Imaging. A calculation of FIBM was performed at the mid-femur, as well as a calculation of the total bone cross-sectional area (CSA), the cortical CSA, the anteroposterior and mediolateral axes of the femur, bone marrow and the thickness of the femoral cortices. RESULTS: Total bone CSA, total cortical CSA and bone marrow CSA were higher in the XLH group than in the control group (p<0.05). The mid-lateral diameters of the femur and bone marrow were more elongated than those of the control group (p<0.001). Only the anterior cortex was thinned in the XLH group (p=0.001), while there was no difference with the control group for the posterior, medial and lateral cortices. The total percentage of FIBM was 72.81% [±3.95] and 77.4% [±5.52] for the XLH and control groups respectively (p<0.001). DISCUSSION: The increase in bone mass in the XLH population reflects an adaptation of bone tissue to the bone deformities present in this pathology. The decrease in FIBM indicates a lower risk of osteoporosis in the XLH population and may constitute a new monitoring parameter in this pathology. LEVEL OF STUDY: III; Case-control study.

X-linked hypophosphatemia in 4 generations due to an exon 13-15 duplication in PHEX, in the absence of the c.*231A>G variant.

X-linked hypophosphatemia is the most common cause of inherited rickets, due to inactivating variants of PHEX. More than 800 variants have been described to date and one which consists of a single base change in the 3' untranslated region (UTR) (c.*231A>G) is reported as prevalent in North America. Recently an exon 13-15 duplication has been found to occur in concert with the c.*231A>G variant, and thus it is unclear whether the pathogenicity is solely a function of the UTR variant. We present a family with XLH who harbors the exon 13-15 duplication but does not carry the 3'UTR variant, providing evidence that the duplication itself is the pathogenic variant when these two variants are found in cis.