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X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients’ experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease.This Consensus Statement provides robust clinical evidence on the multidisciplinary management of children and adults with X-linked hypophosphataemia, with an emphasis on patients’ experiences and needs. It is the outcome of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases.

Abstract Disclosure: S. Dickerman: None. F.A. Al-Khayer: None. Introduction: Hereditary hypophosphatemia rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder with an estimated prevalence of 1 in 250,000 caused by mutations in the SLC34A3 gene that clinically manifests as rickets, bone pain, and hypercalciuria. This disorder may present similarly to more common disease states such as osteomalacia or osteoporosis, making its diagnose difficult and often tenuous. Clinical Case: This is the case of a 39-year-old female patient with a complex past medical history significant for renal stones since childhood and pancreatoduodenectomy in 2022 due to a dysplastic pancreatic lesion who initially presented to the office in 2024 with low phosphate, normal alkaline phosphatase, normal B6, high calcitriol, and hypercalciuria. Initial diagnoses considered based on these results included Fanconi syndrome, x-linked hypophosphatemia, nutritional or tumor-induced osteomalacia, and hereditary Vitamin D resistance. However, none of these conditions were consistent with her presenting symptoms and lab values. To work up the etiology of her presentation, the tubular reabsorption of phosphorus (TRP) was calculated using TRP=100(1-[quarinePO4/UCr])(serum Cr/serum PO4). When serum phosphate is low, it is expected that renal phosphate absorption and TRP will increase, yet this patient had a calculated TRP of 15. The tubular maximum reabsorption of phosphate (TmP) was then calculated using TmP=(TRP)(serum PO4), yielding 27. The ratio of TmP/eGFR was calculated to be 0.4, with a normal ratio for females being 3-4.45, 5-4 standard deviations below the age-related mean. Further, the upper limit of normal calcium excretion in 24 hours is 4mg/kg and this patient’s excretion was calculated to be 9.4mg/kg. An excretion rate greater than 8.6mg/kg is consistent with HHRH, as is the low ratio of Tmp/eGFR. The patient was treated with potassium phosphate supplementation. This successfully led to the correction of all the above abnormalities except for the decreased TmP/eGFR ratio and improvement of her symptoms. The diagnosis was later confirmed by detecting the pathogenic SLC34A3 mutation. Conclusion: Making the diagnosis of HHRH is challenging and requires an extensive and often timely workup. This case details the diagnostic process and key findings associated with HHRH: phosphate wasting which causes an appropriately elevated level of calcitriol, increased calcium intestinal absorption, suppression of PTH, hypercalciuria, and phosphate deficiency acting as a potent and direct stimulus to renal 25-hydroxyvitamin D-1-alpha hydroxylase (CYP27B1) activity. Treatment of HHRH and correction of these abnormalities may be accomplished utilizing phosphate supplementation. This case report offers a diagnostic schema for making an obscure diagnosis. Presentation: Sunday, July 13, 2025

X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1–12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8–1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. Ultragenyx Pharmaceutical and Kyowa Kirin International.

X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH. Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003-0.3 mg/kg i.v. or 0.1-1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days. KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P<0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8-15 days) compared with that seen with i.v. dosing (0.5-4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8-12 days after i.v. administration and 13-19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine. KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674. Funding. Kyowa Hakko Kirin Pharma, Inc.

Hypophosphatemic rickets typically presents in infancy or early childhood with skeletal deformities and growth plate abnormalities. The most common causes are genetic (such as X-linked hypophosphatemia), and these typically will result in lifelong hypophosphatemia and osteomalacia. Knowledge of phosphate metabolism, including the effects of fibroblast growth factor 23 (FGF23) (an osteocyte produced hormone that downregulates renal phosphate reabsorption and 1,25-dihydroxyvitamin-D (1,25(OH)2D) production), is critical to determining the underlying genetic or acquired causes of hypophosphatemia and to facilitate appropriate treatment. Serum phosphorus should be measured in any child or adult with musculoskeletal complaints suggesting rickets or osteomalacia. Clinical evaluation incudes thorough history, physical examination, laboratory investigations, genetic analysis (especially in the absence of a guiding family history), and imaging to establish etiology and to monitor severity and treatment course. The treatment depends on the underlying cause, but often includes active forms of vitamin D combined with phosphate salts, or anti-FGF23 antibody treatment (burosumab) for X-linked hypophosphatemia. The purpose of this article is to explore the approach to evaluating hypophosphatemic rickets and its treatment options.

In patients with X-linked hypophosphatemia, which is caused by PHEX mutations and is characterized by high FGF-23 and rickets, burosumab, an FGF-23 monoclonal antibody, improved renal phosphate reabsorption, serum phosphorus levels, and linear growth and reduced rickets severity.

Yenidoğanın yaygın arteriyel kalsifikasyonu (GACI), sıklıkla ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) genindeki mutasyonlara bağlı gelişen, nadir ve ölümcül seyirli bir hastalıktır. Hastalık genellikle erken bebeklik döneminde arterlerde yaygın kalsifikasyon, miyokard enfarktüsü, konjestif kalp yetmezliği ve hipertansiyon gibi kardiyovasküler komplikasyonlarla ortaya çıkar. Hayatta kalan hastalarda zamanla hipofosfatemik raşitizm (ARHR2) gelişebilir. Tanı; klinik, biyokimyasal, radyolojik ve genetik bulgularla konur. Görüntülemede bilgisayarlı tomografi, ekokardiyografi ve vasküler ultrasonografi önemli rol oynar. Tedavide fosfat ve aktif D vitamini desteği, bazı olgularda bifosfonatlar ve deneysel olarak rekombinant ENPP1 kullanımı söz konusudur. ENPP1 eksikliği sıklıkla tanınmaz ya da başka raşitizm nedenleriyle karıştırılır; bu nedenle genetik doğrulama hem doğru tanı hem de yeni tedavi olanaklarına erişim açısından kritik önemdedir.

Nutritional rickets, caused by vitamin D and/or calcium deficiency is by far the most common cause of rickets. In resource-limited settings, it is therefore not uncommon to treat rickets with vitamin D and calcium. If rickets fails to heal and/or if there is a family history of rickets, then refractory rickets should be considered as a differential diagnosis. Chronic low serum phosphate is the pathological hallmark of all forms of rickets as its low concentration in extracellular space leads to the failure of apoptosis of hypertrophic chondrocytes leading to defective mineralisation of the growth plate. Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) control serum phosphate concentration by facilitating the excretion of phosphate in the urine through their action on the proximal renal tubules. An increase in PTH, as seen in nutritional rickets and genetic disorders of vitamin D-dependent rickets (VDDRs), leads to chronic low serum phosphate, causing rickets. Genetic conditions leading to an increase in FGF23 concentration cause chronic low serum phosphate concentration and rickets. Genetic conditions and syndromes associated with proximal renal tubulopathies can also lead to chronic low serum phosphate concentration by excess phosphate leak in urine, causing rickets. In this review, authors discuss an approach to the differential diagnosis and management of refractory rickets.