Hypophosphatemic Rickets Research Articles

Genetic, Clinical, and Biochemical Characterization ofa Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome.

This study aims to investigate the clinical, biochemical, and genetic characteristics of Fanconi-Bickel syndrome (FBS) in a cohort of 20 individuals from Palestine and to identify novel pathogenic variants. A retrospective analysis was conducted on medical records from Al-Makassed Hospital's pediatric department spanning 2015 to 2023. Individuals diagnosed with FBS via molecular genetic testing were included in the study. Among the 20 genetically confirmed FBS patients, hepatomegaly was prevalent in 95%, whereas 70% exhibited both developmental delay and hypophosphatemic rickets, and 68.4% experienced growth retardation. Hypertriglyceridemia (HTG) was universal. Elevated liver enzymes and alkaline phosphatase were common, along with hypophosphatemia (95%) and urinary abnormalities. Genetic analysis revealed five distinct SLC2A2 pathogenic variants, including three previously unreported variants: p.Gln23Arg (c.68A > G), p.Thr353Arg (c.1058_1059delinsGG), and an exon 7 deletion. This study presents the largest single-center cohort of FBS patients, expanding our understanding of the disorder's phenotypic and genotypic spectrum. Despite FBS generally carrying a favorable prognosis, timely diagnosis remains crucial to prevent severe complications.

Bone microarchitecture evaluated by HR-pQCT in Chinese adolescent and pediatric patients with X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is the most common form of heritable hypophosphatemic rickets. Previous studies have found deteriorated bone microarchitecture in the XLH adults. Detailed studies on the skeletal microarchitecture of XLH adolescent and pediatric patients are still lacking. This study aimed to evaluate bone geometry, density, microarchitecture, stiffness in XLH adolescent and pediatric patients by using high-resolution peripheral quantitative computed tomography (HR-pQCT).Method: This study utilized HR-pQCT to assess bone geometry, density, microarchitecture, and stiffness in 106 Chinese adolescent and pediatric patients with XLH. Compared with the sex- and age-matched controls, XLH patients had significantly higher trabecular area (Tb.Ar), lower total volumetric bone mineral density (Tot.vBMD), lower cortical volumetric BMD (Ct.vBMD), and lower stiffness at both the distal radius and the tibia after adjusting for height and weight. Alkaline phosphatase Z score (ALP-Z), a marker to reflect the disease activity of rickets, was negatively correlated with Ct.vBMD and cortical thickness (Ct.Th) at the distal radius, and Ct.vBMD at the distal tibia, and positively correlated with cortical porosity (Ct.Po) at the distal tibia. We developed an online calculator to estimate Tb.Ar, Ct.vBMD, and stiffness of the distal tibia of XLH adolescent and pediatric patients based on clinical general characteristic and biochemical indicators. The bone microarchitecture of XLH adolescent and pediatric patients was deteriorated, and ALP-Z was negatively correlated with the skeletal quality of XLH adolescent and pediatric patients, especially in the cortical bone. HR-pQCT parameters can be estimated using clinical characteristics and biochemical indicators, which may assist physicians to monitor the disease progression in areas without HR-pQCT access.

CLINICAL CASE OF FAMILIAL HYPOPHOSPHATEMIC RICKETS IN A CHILD

X-linked hypophosphatemic rickets is an inherited disorder caused by mutations in the PHEX gene (phosphate- regulating proteinwith homology to endopeptidases on the X chromosome). Chronic hypophosphatemia leads to impaired bone mineralization, resulting ingrowth retardation, rickets, and damage to other organs and systems, including maxillofacial abnormalities. Clinically, these manifestationsbecome signifi cant when the child begins to walk.The purpose of the study is to describe a clinical case of congenital hypophosphatemic rickets in a child.Material and methods of the study. clinical, biochemical, genetic and imaging examination of the child Results of the study. The article presents a clinical case of a 9-year-old boy, who was adopted after being removed from an unfavorable psychosocial environment and admitted to the Odesa Regional Children’s Clinical Hospital to clarify the diagnosis and treatment tactics.On admission, the mother reported complaints of delayed psychophysical development, memory impairment, psychosocial dysfunction, deformities of the bones of the upper and lower extremities, chest and skull. The examination revealed a decrease in the level of phosphorus in the blood, increased levels of parathyroid hormone and alkaline phosphatase, and signs of osteomalacia in the x-ray. The diff erential diagnosis included vitamin D-dependent rickets, mucopolysaccharidosis, nanism, hyperparathyroidism, and metaphyseal chondrodystrophy. Based on the data obtained, the fi nal diagnosis was made and appropriate treatment was prescribed.Conclusions. The expanded diff erential diagnosis of rickets with rickets-like diseases contributed to the correct clinical diagnosis. Timely pathogenetic treatment reduces renal tubular phosphorus loss, improves mineral metabolism and quality of life. Prescription of growth hormone will reduce the manifestations of nanism.

Midfoot and Forefoot Disorders in Adolescents and Adults with X-Linked Hypophosphatemia

Objectives: X-linked hypophosphatemia (XLH, OMIM 307800) is a rare genetic disorder that affects phosphate metabolism. While lower limb deformity represents a hallmark symptom of patients with XLH, the effect on the foot has not been investigated. This study aimed to characterise foot pathologies and assess related outcome scores in adolescents and adults with XLH. Methods: Patients aged ≥ 16 years with genetically verified XLH were included in this study. Physical examination was performed, and foot scores as well as foot X-rays were assessed. Radiographic analysis included the assessment of osteoarthritis, enthesopathies, and alignment abnormalities. Results: Twenty-six participants (51 limbs) with a mean age of 33.9 ± 15.4 years were eligible for the study. Patients with XLH presented with flatfoot deformity (reduced Meary angles > −4° in 84.3%), elevated first and fifth metatarsal angles > 30° (IM 1–5, 53.5%) and hallux valgus angles > 15° (36.0%). Moderate-to-severe joint space narrowing was observed in the talonavicular (49%) and cuneonavicular joints (41.2%). The American Orthopedic Foot and Ankle Society (AOFAS) score was associated with mildly reduced midfoot function. Conclusions: A high rate of bony deformity, joint degeneration, and decreased foot scores indicated the impact of forefoot and midfoot disorders in patients with XLH.

RNA-First Approach Identifies Deep Intronic PHEX Variants in X-Linked Hypophosphatemic Rickets.

Up to 20% of patients with X-linked hypophosphatemic rickets (XLH) have no causative variant identified on routine molecular diagnostic testing. To identify intronic variants causing PHEX mis-splicing in patients with XLH. The metabolic bone clinic of a paediatric orthopedic hospital. Four patients (age 6 to 12 years; 3 girls) with clinically diagnosed XLH and no PHEX variant on routine testing. RNA and DNA sequence analysis of PHEX. Urine-derived cells were cultured, and mRNA was extracted and transcribed to cDNA. PHEX cDNA was amplified by PCR, followed by sequencing of PCR products. Sequencing of PHEX intronic DNA regions was performed to identify variants causing mis-splicing observed on RNA analysis. PHEX mis-splicing was identified in 3 of the 4 participants, and an intronic variant was identified in all 3 cases. In a 12-year-old boy, transcript analysis showed skipping of PHEX exon 13, while sequencing of PHEX intronic regions revealed a de novo 18 bp deletion in intron 13. In a 7-year-old girl, a pseudoexon in PHEX intron 17 was found, associated with a de novo deep intronic variant (c.1768+173A>G) that activated a cryptic splice donor site. Finally, an 84 bp pseudoexon in PHEX intron 21 caused by a recurrent de novo deep intronic variant (c.2147+1197A>G) was identified in an 11-year-old girl. Analysis of RNA from urine-derived cells combined with sequencing of PHEX introns can identify deep intronic variants in individuals with XLH without a detectable PHEX variant in routine exon-centric molecular diagnosis.

Erratum: X-linked hypophosphatemic rickets and nephrocalcinosis: clinical characteriscs of a single-center pediatric cohort in North America before and after burosumab

Erratum: X-linked hypophosphatemic rickets and nephrocalcinosis: clinical characteriscs of a single-center pediatric cohort in North America before and after burosumab

Diagnostic and New Therapeutic Approaches to Two Challenging Pediatric Metabolic Bone Disorders: Hypophosphatasia and X-linked Hypophosphatemic Rickets.

The diagnosis and management of metabolic bone disease among children can be challenging. This difficulty could be due to many factors, including limited awareness of these rare conditions, the complex pathophysiology of calcium and phosphate homeostasis, the overlapping phenotype with more common disorders (such as rickets), and the lack of specific treatments for these rare disorders. As a result, affected individuals could experience delayed diagnosis or misdiagnosis, leading to improper management. In this review, we describe the challenges facing diagnostic and therapeutic approaches to two metabolic bone disorders (MBD) among children: hypophosphatasia (HPP) and X-linked hypophosphatemia (XLH). We focus on explaining the pathophysiological processes that conceptually underpin novel therapeutic approaches, as well as these conditions' clinical or radiological similarity to nutritional rickets. Particularly in areas with limited sun exposure and among patients not supplementing vitamin D, nutritional rickets are still more common than HPP and XLH, and pediatricians and primary physicians frequently encounter this disorder in their practices. More recently, our understanding of these disorders has significantly improved, leading to the development of novel therapies. Asfotas alfa, a recombinant, human- tissue, nonspecific alkaline phosphatase, improved the survival of patients with HPP. Burosumab, a human monoclonal anti-FGF23 antibody, was recently approved as a specific therapy for XLH. We also highlight the current evidence on these two specific therapies' safety and effectiveness, though long-term data are still needed. Both HPP and XLH are multisystemic disorders that should be managed by multidisciplinary teams. Finally, recognizing these conditions in early stages will enable affected children and young adults to benefit from newly introduced, specific therapies.

Burosumab (Crysvita)

Canada’s Drug Agency recommends that Crysvita be reimbursed by public drug plans for the treatment of X-linked hypophosphatemia (XLH) in adult patients if certain conditions are met. The previous recommendation for Crysvita when initiated in pediatric patients who are at least 1 year of age and in whom epiphyseal closure has not yet occurred, continues to apply to those patients. Crysvita should only be covered to treat patients aged 18 years or older who have a diagnosis of XLH supported by classic clinical features of adult XLH and a confirmed PHEX gene variant, and who have not previously received it. Patients should also have a specific threshold for kidney function or reduced kidney function if it is confirmed not to be due to nephrocalcinosis, bone pain that is caused by XLH or osteomalacia, and have not had a sufficient response to conventional therapy (therapy with active vitamin D and oral phosphate). If a PHEX gene variant is not confirmed, XLH diagnosis can be confirmed with a serum intact fibroblast growth factor 23 (FGF23) level by a Kainos assay. Crysvita should only be reimbursed if it is prescribed by a physician who works in a comprehensive team of health care providers experienced in the diagnosis and management of XLH and if the cost of Crysvita is reduced. Reimbursement may be renewed on an annual basis for patients who do not meet any of the discontinuation criteria, which are the development of hyperparathyroidism, nephrocalcinosis, fasting hypophosphatemia, or fractures or pseudofractures based on X-ray.

Educational Series: Vitamin D-Resistant Rickets, Helicobacter pylori, Hypothyroidism, Tuberculosis, Upper Airway Obstruction, Haemorrhagic Disease of the Newborn

Educational Series: Vitamin D-Resistant Rickets, Helicobacter pylori, Hypothyroidism, Tuberculosis, Upper Airway Obstruction, Haemorrhagic Disease of the Newborn

Real-World Clinical and Healthcare Resource Burden Among Burosumab-Naïve Patients With Familial Hypophosphatemia.

To examine the real-world clinical and healthcare resource burden of familial hypophosphatemia (FH). In a retrospective, observational cohort study using MarketScan claims data from 2017 to 2021, clinical characteristics and healthcare resource utilization (HCRU) and costs were compared between burosumab-naïve pediatric and adult patients with ≥ 1 FH diagnosis code and matched controls without FH. Patient characteristics were evaluated at baseline, and disease characteristics, HCRU, and costs were evaluated over a 12-month follow-up period. Outcomes were analyzed descriptively. Costs were additionally analyzed using multivariate regression models. Overall, 570 patients with FH and 1710 non-FH matched controls were included. Approximately 10% of study participants were aged < 18 years. Patients with FH had 7.8-fold higher mean baseline comorbidity (Charlson Comorbidity Index). The prevalence of morbidities over the 12-month follow-up period was higher in patients with FH than controls, including renal disease (33% vs 3%), arthralgia (25% vs 10%), osteoarthritis (17% vs 6%), and delayed growth/walking difficulty (16% vs 2%; all P < .001). All-cause HCRU was significantly greater for patients with FH than controls over follow-up, including the proportion of patients with at least one inpatient admission (60% vs 4%), outpatient emergency room visit (52% vs 16%), and outpatient pharmacy prescription (96% vs 71%; all P < .001). The mean annual total healthcare cost per patient was also 22.6-fold higher for patients with FH than controls (adjusted cost difference = $129 643; P < .001). Differences were apparent across all age groups. Compared with non-FH matched controls, burosumab-naïve patients with FH experienced multiple morbidities and had substantially higher HCRU and costs.

Model-Informed Approach to Recommend Burosumab Dosing Regimens for Pediatric and Adult Patients With the Ultrarare Disease Tumor-Induced Osteomalacia.

Burosumab is approved for the treatment of hypophosphatemia in persistent tumor-induced osteomalacia. This work exemplifies a model-informed drug development approach that evaluated burosumab pharmacokinetics and pharmacokinetic/pharmacodynamics in the ultrarare tumor-induced osteomalacia population to support adult and pediatric dosing. Data from tumor-induced osteomalacia participants were combined with data from X-linked hypophosphatemia to understand pharmacokinetic and pharmacokinetic/pharmacodynamic characteristics and covariates specific to tumor-induced osteomalacia. Pharmacokinetic and pharmacokinetic/pharmacodynamic simulations were performed using final models to support dosing recommendations for adults and extrapolation to pediatric patients. Burosumab pharmacokinetics were described using a one-compartment model with first-order absorption and body weight as a significant covariate. Pharmacokinetic/pharmacodynamic relationships were described using a sigmoidal Emax model with significant covariates of baseline fibroblast growth factor 23 on baseline fasting serum phosphate and potency of burosumab response and tumor-induced osteomalacia disease state resulting in a steep slope of response; however, the covariates are not clinically meaningful. Simulations demonstrated that, in pediatric patients, starting doses of burosumab 0.3 and 0.4 mg/kg every 2 weeks at steady state would achieve normal serum phosphate levels in ≥ 30% of patients with relatively low risk of hyperphosphatemia (< 3%). In adults, burosumab 0.3 and 0.5 mg/kg every 4 weeks achieves similar percentages of responders and a relative low risk of hyperphosphatemia (< 7%). Serum phosphate titration-based burosumab dosing increased the probability of achieving normal serum phosphate levels. The models supported a model-informed drug development approach for global approvals of titration-based burosumab dosing, guided by monitoring fasting serum phosphate levels.

Burosumab in adults with X-linked hypophosphatemia: real-world experience from a retrospective study in Sydney

Abstract X-linked hypophosphatemia (XLH) is a chronic disabling hereditary musculoskeletal disorder associated with inactivating PHEX mutations and elevated circulating FGF-23 concentrations. In a placebo-controlled trial of adults with XLH, burosumab (anti-FGF-23 antibody) demonstrated durable improvements in phosphate concentrations, and self-reported stiffness and physical limitation. However, real-world data regarding burosumab efficacy and tolerability in adults with XLH is lacking. A retrospective audit was performed of patients (age ≥ 18-years) who commenced four-weekly subcutaneous burosumab for XLH at Royal North Shore and Westmead Hospitals, Sydney, between January 2021 and June 2024. Patients were managed per standard clinical care and burosumab dose adjusted as necessary according to manufacturer instructions. Electronic medical records were reviewed to collate data regarding patient demographics, XLH-related complications and prior treatment, burosumab dosage and side effects, and pre- and post-burosumab biochemistry and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores. Of thirteen adults with XLH, all had hypophosphatemia before commencing burosumab (mean 0.64 ± 0.08 mmol/L). Mean WOMAC scores demonstrated baseline impairments in stiffness, pain and physical limitation. Burosumab was administered for median 15 months during follow-up (median dose 70 mg). Hypophosphatemia resolved in all patients within three months of burosumab (mean 1.03 ± 0.38 mmol/L). Two patients developed hyperphosphatemia two weeks after commencing burosumab requiring dose reduction. One patient ceased burosumab in the setting of hypercalcaemia and constipation secondary to pre-existing tertiary hyperparathyroidism. Adverse events were mild, including transient musculoskeletal discomfort (n = 4), restless legs (n = 2), injection site reaction (n = 2) and headache (n = 1). Repeat WOMAC within 12 months of commencing burosumab (n = 9) demonstrated clinically meaningful improvements in stiffness (-33.3 ± 12.5, P&amp;lt;.001) and physical function (-14.3 ± 16.2, P=.029). This study reports real-world outcomes of adults with XLH treated with burosumab. Clinical experience from two centres in Sydney support trial findings that burosumab is well-tolerated and associated with improved serum phosphate concentrations and self-reported stiffness and physical function.

Effect of Mutation Type on Ectopic Ossification Among Adult Patients With X-Linked Hypophosphatemia.

Causative factors for ectopic ossifications in X-linked hypophosphatemia (XLH) remain to be elucidated. This work aimed to investigate the genotype-phenotype correlations between the phosphate-regulating endopeptidase homologue, X-linked gene (PHEX) and ectopic ossifications in XLH. Biochemical data, spinal computed tomography scans, and x-rays of hip/knee joints were retrospectively reviewed. Genetic analysis and the measurement of plasma inorganic pyrophosphate (PPi)-a potent inhibitor of tissue calcification-were performed. The effect of PHEX mutations on protein function was predicted using nonsense-mediated decay (NMD) and 3-dimensional structure modeling. The index of ossification of the anterior/posterior longitudinal ligament and yellow ligament (OA/OP/OY index) and the sum of the OA/OP/OY index (OS index) were used to quantify the severity of spinal ligament ossification. The severity of the hip/knee osteoarthritis was evaluated by the Kellgren-Lawrence classification. We examined 24 distinct pathogenic PHEX variants in 28 patients from a study population of 33 individuals in 27 unrelated, nonconsanguineous families. Among the 31 patients whose plasma samples were analyzed for PPi, 14 patients (45%) showed decreased plasma PPi concentrations; however, PPi concentrations did not correlate with mutation type or ectopic ossification. Fibroblast growth factor 23 levels in women with NMD-insensitive mutations trended lower than in men with NMD-sensitive mutations but failed to reach statistical significance. Both models revealed no correlations between PHEX pathogenic variant and ectopic ossification. Neither modeling found correlates between PHEX pathogenic variants and ectopic ossification. The effects of PPi on ectopic ossifications in adults with XLH revealed trends that should be investigated with a large sample size.

The Manifestations and Complications of X-linked Hypophosphatemia in Saudi Arabia: A Retrospective Study

Background: X-linked hypophosphatemia (XLH) is a genetic disease of phosphate metabolism in which inactivating mutations of the phosphate regulating endopeptidase homolog, X-linked (PHEX) gene lead to local and systemic effects. In our pediatric clinics, XLH was observed to be associated with multiple complications despite conventional treatment. There is a need for novel treatment modalities to prevent disease progression and aid in the resolution of symptoms. Methods: This retrospective cross-sectional study aimed to understand the manifestations and complications of XLH in patients followed up at the endocrinology clinics in King Faisal Specialist Hospital and Research Center in Saudi Arabia. The study was conducted by reviewing the medical files of all XLH patients at the King Faisal Specialist Hospital and Research Center. Results: All the patients (N=24) who were included in this study had PHEX gene mutations. The mean age was 18.7 13.6 years and 68% were females. The mean height standard deviation score (HSDS) was ‑2.96 (-5.25 to -0.97) and 12 patients reached their final height (mean final HSDS, -3.28 [-1.39 to ‑5.39]). Skeletal deformities (mainly genu varum) were observed in 68% of the patients and 29% had craniosynostosis; 54% had undergone corrective osteotomy. Hyperparathyroidism was observed in 54% of the patients and 45% of the patients had nephrocalcinosis (grades 2/3). Conclusions: In our study, a majority of the XLH patients suffered from complications arising from the use of conventional therapy, thus indicating the need for novel treatment modalities for these patients. Additionally, no correlation between genotype and phenotype was found.

Areas of uncertainty on the diagnosis, treatment, and follow-up of hypophosphatemia in adults: an Italian Delphi consensus.

The study aimed to present the results of a Delphi consensus involving Italian experts focusing on the management of hypophosphatemia in adults. A multidisciplinary advisory board of nine physicians, experts in hypophosphatemia management, was established. Next, a literature search was performed to identify international guidelines, consensus, and clinical pathways, which were later presented to the advisory board. Collaboratively, the advisory board and authoring team selected key statements for the consensus process and focused on areas of uncertainty related to the management of hypophosphatemia. The advisory board also indicated the experts to be invited to participate in the consensus process. The Delphi method was employed to reach a consensus. The literature search yielded one guideline, five consensus documents, and one clinical pathway. While our search strategy aimed to identify documents on the management of all types of hypophosphatemia, most of the guidelines and consensus documents retrieved focused on X-linked hypophosphatemia. The consensus process focused on 11 key issues, achieving strong convergence (over 70% consensus) in the first Delphi round for 8 out of the 11 statements. Three statements proceeded to the second round, with strong agreement reached for two. Notably, consensus was not reached for the statement concerning the measurement of fibroblast growth factor 23 for diagnostic purposes. The study revealed that the community of clinical experts is well-informed and in agreement regarding hypophosphatemia management. It emphasized the importance of developing clear national guidance documents to support clinicians and multidisciplinary teams in patient management. These documents are crucial not only for healthcare professionals but also for those responsible for defining pathways and services, facilitating a more accurate management of hypophosphatemic patients.

Evaluation of the impact of specific oral health parameters on the quality of life in children with rare disorders of phosphorus-calcium metabolism

Relevance. Understanding the impact of oral health problems on the quality of life in children with rare metabolic disorders that affect mineral metabolism is critically important.Materials and methods. An oral health assessment was conducted on 59 children aged 6 to 17 years with rare diseases affecting mineral metabolism, each with a genetically confirmed diagnosis. The children were divided into two study groups: the first group (24 children) comprised those with bone mineralization disorders (hypophosphatemic rickets, hypophosphatasia), while the second group (35 children) included those with disorders of bone and cartilage formation (osteogenesis imperfecta, Marfan syndrome, achondroplasia, etc.). The clinical condition of the children's dental tissues was assessed by evaluating oral hygiene levels and caries intensity in permanent teeth, using the OHI-S and DMFT indices, respectively. The pufa/PUFA index was used to document complications arising from dental caries. To assess the perception of oral health problems, a survey was administered to parents and legal guardians using the Oral Health-Related Quality of Life (OHRQoL) questionnaire.Results. The average DMFT and OHI-S index values did not show statistically significant differences, with values of 4.26 ± 0.28 and 1.96 ± 0.15 in the first group, and 3.76 ± 0.40 and 1.75 ± 0.10 in the second group, respectively. However, the mean pufa/PUFA index values were significantly higher in children with bone and cartilage formation disorders (p = 0.003), being three times greater than those in the group with bone mineralization disorders, with values of 1.03 ± 0.18 and 0.30 ± 0.11, respectively. This increase was associated with higher correlation coefficients between the DMFT and PUFA indices and the modules for physical discomfort, oral functional status, and emotional well-being, with values of 0.38 and 0.41, and 0.49 and 0.27, compared to 0.07 and 0.02, and 0.29 and -0.21 in the first group. These differences were statistically significant at p &lt; 0.05 and p &lt; 0.005.Conclusion. The study revealed that existing oral health conditions have the greatest impact on the quality of life in children with rare diseases affecting bone and cartilage formation.

6864 Genetic Profile And Identification Of A Novel Mutation In PHEX In X-Linked Hypophosphatemia (XLH) Patients At A Brazilian Research Center: Insights And Implications

Abstract Disclosure: M. Monseff Rodrigues da silva: None. I.M. de Araújo: None. F.J. de Paula: None. Background: X-Linked Hypophosphatemia (XLH) is a rare genetic disorder characterized by low phosphate levels in the blood, primarily caused by mutations in the PHEX gene, leading to bone skeletal deformities and reduced quality of life. XLH genetics is extensively studied with over 500 pathogenic mutations in the PHEXgene having been identified. Common mutations include missense, nonsense, and splicing, accounting for approximately 50% of cases. However, genotype-phenotype correlations remain unclear. Methods: We conducted a cross-sectional study using a convenience sample selected from the osteometabolism an outpatient clinic in Brazil. Genetic analysis was performed using next-generation sequencing (NGS; Ilumina) in collaboration with Mendelics Laboratory. Results: In our study, 9 out of 10 patients showed previously known and reported mutations, with 60% exhibiting common mutation types. The mutations occur in different codons; however, the most prevalent consequence was the substitution of glycine (G) with adenine (A), present in 40% of the patients. One patient, however, showed a unique missense mutation in PHEX gene (arginine to glutamate at codon 266), which leads to a premature stop codon, a mutation absent in over 183,000 X chromosomes from XLH individuals. Even though this mutation was novel, no significant diferences in the phenotype of this patient were seen in comparision with the rest of the cohort. Discussion: The findings of our study underscore the genetic heterogeneity characteristic of XLH, as evidenced by the fact that 90% of our patient cohort exhibited mutations previously identified in the literature, with a significant 60% showing common mutation types. This highlights the recurring genetic patterns in XLH, which can be instrumental for diagnostic and - perhaps in the future - therapeutic strategies. Particularly notable is the predominant mutation involving the substitution of glycine with adenine, found in 40% of our patients, underscoring its potential role as a key mutation in the pathogenesis of XLH. Furthermore, the discovery of a novel missense mutation in one patient, resulting in a premature stop codon, enriches the mutation spectrum of XLH and suggests a deeper complexity in the genetic landscape of the disease. This mutation, not previously documented in the extensive database of over 183,000 X chromosomes from XLH individuals, opens new avenues for research into the disease's molecular mechanisms and potential genotype-phenotype correlations. Conclusion: This study underlines the genetic diversity within XLH, emphasizing the need for comprehensive genetic analysis to understand the full spectrum of the disease. More studies are yet necessary to elucidate if there is a genotype-phenotype correlation. Presentation: 6/1/2024

7293 An Unusual Case Of Adult-Onset Heterozygous HHRH In A Male With Normal Phosphorus And Severe Osteoporosis

Abstract Disclosure: M. El Najjar: None. A. Sabet: None. D. Willard: None. Introduction: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare genetic disorder characterized by renal phosphate wasting, which can affect bone metabolism. Although onset is typically in childhood, adult-onset forms have been described, and the manifestation depends on the zygosity of each patient. Most commonly, adults with HHRH demonstrate markedly reduced bone density and multiple fractures. Heterozygotes have milder presentations with mild hypophosphatemia, hypercalciuria, and nephrolithiasis, usually without bone disease; however, it is less well characterized. Case report: A 73-year-old man suffered an L1 vertebral compression fracture while playing golf. Bone mineral density testing revealed T-scores of -0.9 at the lumbar spine and -3.4 at the femoral neck (Z-score -2.6). He started alendronate 70 mg weekly for osteoporosis treatment. A year later, the patient sustained an L3 vertebral compression fracture while on treatment with no improvement in his bone density. His family history was remarkable for osteoporosis in his mother but no nephrolithiasis or hypercalcemia. Physical examination was unremarkable. Laboratory evaluation was notable for a 1,25-dihydroxyvitamin D of 87 pg/mL (18-72 pg/mL) , a 24-hour urine calcium of 240 mg/g Cr (30-210 mg/g),a serum PTH of 9 pg/mL (16-77 pg/ml) , but otherwise a normal serum calcium level of 9.4 mg/dL (8.6-10.3 mg/dL) and serum phosphate level of 2.2 mg/dl (2.1-4.3 mg/dl). Genetic testing revealed heterozygosity for SLC34A3 mutation, which is associated with HHRH. The patient discontinued alendronate and started 250 mg phosphorus supplementation 4 times daily. At 6 months follow up, he reported improvement in his body aches, and biochemical testing showed normalization of his 24-hour urine calcium to 171 mg/g Cr and serum PTH to 21 pg/mL. Repeat bone density scan after 1 year of phosphorus supplementation showed T-scores of -0.3 at the lumbar spine (5.8% increase) and -2.6 at the femoral neck (15.5% increase). Clinical Lesson: HHRH is an autosomal recessive hypophosphatemic rickets associated with mutations of the SLC34A3 sodium-phosphate cotransporter, where it is believed that selective phosphate wasting leads to increased calcitriol, in contrast to other forms of hypophosphatemic rickets, causing increased intestinal calcium absorption and resulting hypercalciuria. Adult-onset forms of HHRH have been described in heterozygous carriers of the SLC34A3 mutation and usually present with low to low-normal phosphate levels, hypercalciuria, and nephrolithiasis but without bone disease. However, clinical variations of heterozygous carriers have also been recognized, and therefore are likely underdiagnosed. Our patient’s serum phosphorus level was within the normal range, and hypophosphatemic rickets could have been missed if a more extensive laboratory evaluation had not been performed. Presentation: 6/1/2024

12324 Clinical Features And PHEX Variants Of Adults With X-Linked Hypophosphatemia

Abstract Disclosure: L.P. Valadares: None. D.R. Carvalho: None. F.S. Lopes: None. R.S. Oliveira: None. L.G. Castro: None. X-linked hypophosphatemia (XLH), caused by loss-of-function PHEX mutations, is a lifelong renal phosphate-wasting disorder and the main cause of inherited hypophosphatemia. In adults, chronic hypophosphatemia leads to impaired bone mineralization and persistent osteomalacia. Short stature, lower limb deformities and musculoskeletal chronic pain can significantly impact the daily lives of affected individuals. This study aimed to describe the clinical and molecular profiles of 23 adults with genetically proven XLH who are being followed at a tertiary medical center in Brazil. We conducted a retrospective analysis of their medical records. The median age at diagnosis was 3.0 years (IQR 2.0-8.0) and the mean age at first visit at the adult care unit was 30.5 years (±12.7). Their mean final height was 144.2 cm (±10.5), with a mean body mass index (BMI) of 28.1 kg/m2 (±4.9). Nine patients were overweight, and seven were obese. Sixteen patients had a positive family history of rickets, and nine had offspring with XLH. Among the 14 different PHEX mutations that were identified, six had not been previously reported. Hypophosphatemia was observed in 21 patients at presentation at the adult care unit, increased serum alkaline phosphatase levels in 19, and 12 showed increased PTH levels. Chronic bone and muscular pain were reported by sixteen patients, eighteen had lower limb deformities, and six had a history of fractures and/or pseudofractures. Seventeen patients underwent orthopedic surgeries, with an average of 3.8 surgical interventions per patient. Nephrolithiasis and/or nephrocalcinosis were observed in nine patients, but none had glomerular filtration rate below 60 mL/min adjusted to 1.73 m2 of body surface. Three patients were on conventional treatment (phosphate and calcitriol) upon presentation at the adult care unit, five patients had never received XLH-specific treatment, and fifteen discontinued conventional therapy after completing skeletal growth, with a mean therapy duration of 12.1 years (±3.5). Out of the 20 patients without treatment, 16 were initiated on pharmacological therapy based on symptoms and signs of persistent osteomalacia. Eleven started combined phosphate and calcitriol supplementation, while five received calcitriol monotherapy. This cohort underscores that adults with XLH experience significant musculoskeletal morbidity throughout their lives, and require long-term follow-up, including assessment of energy metabolism. Importantly, most of them benefits from maintaining pharmacological treatment in adulthood. Presentation: 6/2/2024

12605 Two Systematic Reviews Of Treatment Efficacy On Patient Important Outcomes In Children X-linked Hypophosphatemia

Abstract Disclosure: D.S. Ali: None. R. Mirza: None. S. Hussein: None. F. Alsarraf: None. R. Alexander: Consulting Fee; Self; Ultragenyx. Grant Recipient; Self; Ardylex Inc.. H. AbuAlrob: None. M. Brandi: Consulting Fee; Self; Aboca, Alexion, Amolyt, Bruno Farmaceutici, Calcilytix, Echolight, Kyowa Kirin, Personal Genomics,. Speaker; Self; Kyowa Kirin, Abiogen, Alexion, Amgen, Amolyt, Amorphical, Bruno Farmaceutici, Eli Lilly &amp; Company. T.O. Carpenter: Advisory Board Member; Self; Kyowa Kirin, Ultragenyx. Consulting Fee; Self; Kyowa Kirin, Ultragenyx. Grant Recipient; Self; Ultragenyx. Other; Self; Assoc. Editor JBMR, President Ped Endo Soc, Author UpToDate (royalties), XLH-Network (Patient Advisory Org). K. Dandurand: Speaker; Self; Amgen Inc, Kyowa Kirin. G. Filler: Consulting Fee; Self; Kyowa Kirin, Ultragenyx, ProKidney. Speaker; Self; Ultragenyx, ProKidney. P.F. Florenzano: ; Institutional Research Grants: Ultragenyx. ; Advisory Boards: Ultragenyx, Kyowa Kirin. S. Fukumoto: Consulting Fee; Self; Kyowa Kirin. C. Grasemann: Speaker; Self; Kyowa Kirin. E.A. Imel: ; Ultragenyx (Research funding and consulting). ; Kyowa Kirin (research funding and consulting). ; Inozyme (consulting). ; Amgen (research funding). S.M. Jan De Beur: Consulting Fee; Self; Ultragenyx, Kyowa Kirin. Research Investigator; Self; Ultragenyx. E. Morgante: None. L.M. Ward: ; clinical trials with Ultragenyx. ; consultancy to Kyowa Kirin and Ultragenyx. ; unrestricted educational grants from Ultragenyx and Kyowa Kirin (with funds to Dr. Ward’s instituition). A.A. Khan: Advisory Board Member; Self; Amgen Inc, Ascendis, Alexion. Grant Recipient; Self; Takeda, Amolyt, Calcilytix. Speaker; Self; Amgen Inc, Ascendis, Alexion. G. Guyatt: None. Objective: We sought to examine the highest certainty evidence on managing X-linked hypophosphatemia (XLH) in children, aiming to inform treatment recommendations of XLH international guidelines. Data Sources: We searched Embase, MEDLINE, Web of Science, and Cochrane Central from inception to March 2023. We also reviewed reference lists of eligible studies and pertinent review articles. Study eligibility criteria: Eligible studies included randomized controlled trials (RCTs) and observational studies enrolling individuals younger than 18 years old with XLH diagnosed on clinical grounds or with a confirmed pathogenic variant in PHEX. Articles were selected according to specific criteria evaluating the effectiveness of burosumab compared to either no treatment or conventional therapy (phosphate salts and active vitamin D) or evaluating conventional therapy compared to no treatment. Methods: Two reviewers independently determined eligibility, conducted data extraction, and assessed the risk of bias (RoB) in eligible articles. We employed the GRADE methodology to evaluate the certainty of the evidence. Results: After removing duplicates from 7,043 citations, we screened 4,114 records and assessed 254 full texts, of which in the systematic review (SR) addressing burosumab one RCT and one post-Hoc study proved eligible. Being open-label design, the RoB was high, with certainty of evidence on individual outcomes ranging from moderate to very low. Burosumab, compared to conventional therapy, probably prevents lower limb deformity, and improves physical health quality of life (QoL) (moderate certainty). It might also increase height and possibly improve the burden of symptoms related to chronic hypophosphatemia (low certainty). Conversely, burosumab probably increases Treatment-Emergent adverse events after the first administration (moderate certainty), and it may increase dental abscesses (low certainty). In the second SR, one observational study assessing conventional therapy versus no treatment was at high RoB providing very low certainty of evidence regarding the impact of conventional therapy compared to no treatment on final height. Conclusion: Our review indicates that burosumab likely offers benefits in preventing lower limb deformity and improving physical health QoL, while potentially increasing height and improving the burden of symptoms related to chronic hypophosphatemia (low certainty). However, it may also increase adverse events, including dental abscesses. Additionally, our review found limited evidence regarding the impact of conventional therapy compared to no treatment on final height in children. These findings highlight the need for further research to better understand the long-term impact of conventional therapy and burosumab in children. Presentation: 6/2/2024