OBJECTIVE: X-linked hypophosphatemia (XLH) is characterized by increased concentrations of circulating fibroblast growth factor 23 (FGF-23) resulting in phosphate wasting, hypophosphatemia, atypical growth plate and bone matrix mineralization. Epidemiologic studies suggest a relationship between FGF-23, obesity, and metabolic dysfunction. The prevalence of overweight and obesity is high in children with XLH. We aimed to evaluate the prevalence of obesity and metabolic complications in adults with XLH.
METHODS: We conducted a prospective cohort study in adult XLH patients from a single tertiary referral center. The proportion of patients with a BMI >25 kg/m2 was the main outcome measure. Body fat mass percentage (FM%) and adipose tissue surfaces were secondary outcome measures. Glucose homeostasis (plasma glucose and insulin concentrations after fasting and 2 hours after an oral glucose tolerance test) was explored in a subgroup of patients and compared with age-, sex-, and BMI-matched healthy controls.
RESULTS: Among 113 evaluated patients, 85 (75%) were female and 110 (97%) carried a PHEX mutation. Sixty-three (56%) patients were overweight or obese, with a median BMI of 25.3 [IQR, 22.7; 29.2] kg/m2. BMI was correlated with FM%, abdominal and thigh subcutaneous and intra-abdominal adipose tissue surfaces. The prevalence of impaired fasting glucose, impaired glucose tolerance, and diabetes was not different between XLH patients and matched controls.
CONCLUSIONS: The prevalence of overweight and obesity is high among XLH patients and is associated with excess fat mass. However, the prevalence of glucose homeostasis abnormalities is not increased in patients compared to healthy controls, suggesting that metabolically healthy overweight or obesity predominates.

BACKGROUND: X-linked hypophosphatemia (XLH) is the most common inherited form of rickets. The presence of sequence variations in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene is associated with increased production of fibroblast growth factor 23 (FGF23). This results in renal phosphate wasting and impaired skeletal mineralization. Spontaneous dental abscesses, caused by endodontic infections resulting from hypomineralization of dentin, are a known dental complication of XLH. There is no objective method to evaluate the severity of dentin dysplasia. The purpose of this study was to develop a quantitative method to evaluate dentin dysplasia using orthopantomography that would allow the values in patients with XLH to be compared with the values in healthy participants of the same age.
METHODS: The severity of dentin dysplasia was analyzed by measuring the pulp cavity area of the tooth using orthopantomographic images. The teeth analyzed were mandibular second primary molars and mandibular first permanent molars with complete root formation. Teeth with dental caries, restorations, or root resorption were excluded.
RESULTS: This retrospective observational study included a total of 200 images of healthy participants (aged 2-15 years) divided into five age groups and 42 images of 17 patients with XLH. There was a significant tendency for the pulp cavity area to decrease with increasing age in primary and permanent teeth. The pulp chambers of patients with XLH were larger than those of healthy participants in primary and permanent teeth.
CONCLUSIONS: We have established a method of using orthopantomography for quantitative assessment of dentin dysplasia in XLH from the primary dentition to the permanent dentition. Evaluating the severity of dentin hypomineralization by this method is useful in the diagnosis of the dental manifestations of XLH. Early diagnosis of XLH enables oral management and leads to prevention of dental abscesses.

BACKGROUND: Hereditary vitamin D resistant rickets (HVDRR) is a rare autosomal recessive disorder marked by end-organ resistance of 1,25-dihydroxyvitamin D secondary to various mutations in the vitamin D receptor gene. The currently accepted treatment modality involves bypassing the affected receptors in the gut with high-dose intravenous calcium. In a few limited case reports, cinacalcet, a calcimimetic, has been used as an adjunctive therapy.
METHODS: Retrospective chart reviews were conducted to collect the clinical and biochemical data of 8 patients with HVDRR from 5 Saudi families. Four patients received only high-dose calcium, while the remaining 4 received adjuvant cinacalcet. Serum chemistry and PTH levels were measured before and during cinacalcet treatment. Gene sequencing was performed to identify the disease-causing mutation.
RESULTS: All 8 patients exhibited alopecia and secondary hyperparathyroidism. Other clinical and biochemical features of rickets were present to varying degrees. Genetic analysis revealed 3 distinct mutations: a ligand-binding domain mutation in 3 unrelated patients, a ligand-binding domain mutation in 2 sisters, and a missense DNA-binding domain mutation in 3 brothers. While the overall response to therapy was variable, none of the 4 patients who received adjunctive cinacalcet developed hypocalcaemia, and there was some initial promise in improving serum PTH levels.
CONCLUSIONS: This series provides new insight into the clinical and biochemical characteristics as well as treatment responses in Saudi children with HVDRR. The findings suggest that cinacalcet is a safe and potentially valuable adjuvant in this understudied population; however, further research is required to verify these results.

Osteocytes are embedded in lacunae and connected by canaliculi (lacuno-canalicular network, LCN). Bones from mice with X-linked hypophosphatemia (Hyp), which have impaired production of 1,25 dihydroxyvitamin D (1,25D) and hypophosphatemia, have abnormal LCN structure that is improved by treatment with 1,25D or an anti-FGF23 targeting antibody, supporting roles for 1,25D and phosphate in regulating LCN remodeling. Bones from mice lacking the vitamin D receptor (VDR) in osteocytes (Vdrf/f;Dmp1Cre+) and mice lacking the sodium phosphate transporter 2a (Npt2aKO), which have low serum phosphate with high serum 1,25D, have impaired LCN organization, demonstrating that osteocyte-specific actions of 1,25D and hypophosphatemia regulate LCN remodeling. In osteoclasts, nuclear factor of activated T cells cytoplasmic 1 (NFATc1) is critical for stimulating bone resorption. Since osteocytes also resorb matrix, we hypothesize that NFATc1 plays a role in 1,25D and phosphate-mediated LCN remodeling. Consistent with this, 1,25D and phosphate suppress Nfatc1 mRNA expression in IDG-SW3 osteocytes, and knockdown of Nfatc1 expression in IDG-SW3 cells blocks 1,25D- and phosphate-mediated suppression of matrix resorption gene expression and 1,25D- and phosphate-mediated suppression of RANKL-induced acidification of the osteocyte microenvironment. To determine the role of NFATc1 in 1,25D- and phosphate-mediated LCN remodeling in vivo, histomorphometric analyses of tibiae from mice lacking osteocyte-specific Nfatc1 in Vdrf/f;Dmp1Cre+ and Npt2aKO mice were performed, demonstrating that bones from these mice have decreased lacunar size and expression of matrix resorption genes, and improved canalicular structure compared to Vdrf/f;Dmp1Cre+ and Npt2aKO control. This study demonstrates that NFATc1 is necessary for 1,25D- and phosphate-mediated regulation of LCN remodeling.

An 18-month-old male presented with gross motor delay and poor growth (weight z-score -2.21, length z-score -4.26). Radiographs showed metaphyseal irregularities suggesting metaphyseal dysplasia and sagittal craniosynostosis. Biochemical evaluation supported hypophosphatemic rickets [serum phosphorus 2.3 mg/dL (reference range (RR) 4.3-6.8), alkaline phosphatase 754 unit/L (RR 156-369)] due to renal phosphate wasting (TmP/GFR 4.3 mg/dL, normal for age 4.3-6.8), with C-terminal fibroblast growth factor 23 (FGF23) 125 RU/mL (>90 during hypophosphatemia suggests FGF23-mediated hypophosphatemia). Treatment was initiated with calcitriol and phosphate. Genetic analysis showed a pathogenic variant of FGF23: c.527G > A (p.Arg176Gln) indicative of autosomal dominant hypophosphatemic rickets (ADHR). Consistent with reports linking iron deficiency with the ADHR phenotype, low ferritin was detected. Following normalization of ferritin level (41 ng/mL) with oral ferrous sulfate replacement, biochemical improvement was demonstrated (FGF23 69 RU/mL, phosphorus 5.0 mg/dL and alkaline phosphatase 228 unit/L). Calcitriol and phosphate were discontinued. Three years later, the patient demonstrated improved developmental milestones, linear growth (length Z-score -2.01), radiographic normalization of metaphyses, and stabilization of craniosynostosis. While the most common cause of hypophosphatemic rickets is X-linked hypophosphatemia, other etiologies should be considered as treatment differs. In ADHR, normalization of iron leads to biochemical and clinical improvement.

X-linked Hypophosphatemia (XLH) is the most common type of inherited rickets. Although the clinical features are well characterized, bone structure, mineralization, and biomechanical properties are poorly known. Our aim was to analyze bone properties in the appendicular and axial skeleton of adults with XLH. In this observational case-control study, each affected patient (N = 14; 9 females; age 50 ± 15 years) was matched by sex, age and body mass index to a minimum of two healthy controls (N = 34). Dual-energy X-ray Absorptiometry (DXA) analyses revealed that areal bone mineral density (aBMD) was higher in XLH patients at the lumbar spine (Z score mean difference = +2.47 SD, P value = 1.4 × 10-3). Trabecular Bone Score was also higher at the lumbar spine (P value = 1.0 × 10-4). High Resolution peripheral Quantitative Computed Tomography (HRpQCT) demonstrated that bone cross-sectional area was larger at the distal radius (P value = 6 × 10-3). Total and trabecular volumetric BMD were lower at both sites. Trabecular bone volume fraction was also lower with fewer trabecular numbers at both sites. However, bone strength evaluated by micro-finite element analyzes revealed unaffected bone stiffness and maximum failure load. Evaluation of bone mineralization with aBMD by DXA at the distal radius correlated with vBMD by HRpQCT measurements at both sites. PTH levels were inversely correlated with trabecular vBMD and BV/TV at the tibia. We then followed a subset of nine patients (median follow-up of 4 years) and reassessed HRpQCT. At the tibia, we observed a greater decrease than expected from an age and sex standardized normal population in total and cortical vBMD as well as a trabecularization of the cortical compartment. In conclusion, in adult patients with XLH, bone mineral density is high at the axial skeleton but low at the appendicular skeleton. With time, microarchitectural alterations worsen. We propose that noninvasive evaluation methods of bone mineralization such as DXA including the radius should be part of the management of XLH patients. Larger studies are needed to evaluate the clinical significance of BMD changes in XLH patients under conventional or targeted therapies.

Objective: To evaluate the effectiveness and safety of treatment with Burosumab in pediatric X-linked hypophosphatemia (XLH) patients. Methods: In this retrospective case study, 4 children with pediatric XLH, who were treated with Burosumab in Beijing Children\'s Hospital, Capital Medical University and Shandong Provincial Hospital affiliated to Shandong First Medical University from July 2022 to December 2023, were selected as the study objects. We collected and analyzed their clinical characteristics, biochemical indicators, imaging results, and treatment. The children were followed up every 3 months until December 2023, and the clinical outcomes and adverse drug reactions after treatment were evaluated. Results: Of the 4 patients, 3 were males and 1 was female; they were aged 6.7, 2.9, 2.1, and 2.3 years, respectively. Three patients had previously received treatment with phosphate supplements and active vitamins, but their wadding gait and lower limb deformities did not improve significantly, neither did their imaging changes of active richets. The initial dose of Burosumab in the 4 patients was 0.8 mg/kg, administered subcutaneously every 2 weeks, with a treatment course of 0.8-1.3 years. The fasting serum phosphorus and tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) of the 4 patients before treatment were 0.72, 0.95, 0.81, 0.66 mmol/L and 0.67, 0.85, 0.87, 0.61 mmol/L, respectively. At the last follow-up, the fasting serum phosphorus and TmP/GFR levels were significantly increased (0.96, 1.09, 1.09, 0.90 mmol/L, and 0.85, 0.79, 1.03, 0.98 mmol/L, respectively). Among them, only the TmP/GFR level (1.17 mmol/L) in case 2 achieved normal values at 3 months post-therapy, while the rest did not reach the normal range for children of the same age. After treatment, the alkaline phosphatase levels of all patients gradually decreased (the values were 461, 240, 423, and 237 U/L, respectively), and the ALP levels in cases 2 and 4 returned to normal at the last visit. Case 4 showed a slight increase in parathyroid hormone (PTH) levels after 9 months of treatment, while the PTH levels in the rest 3 cases remained normal. Case 1 underwent a 6-minute walking test, and the walking distance increased from 245 m to 570 m. Abnormal gait, lower limb deformity, and the severity of rickets in the 4 patients had all improved. No adverse drug reactions such as nephrocalcinosis, local skin injection reaction, hyperphosphatemia, or vitamin D deficiency were observed. Conclusion: Burosumab can improve clinical symptoms in children with XLH with a good safety profile.
目的： 评估X连锁低磷性佝偻病（XLH）患儿布罗索尤单抗治疗的有效性及安全性。 方法： 回顾性病例总结。以2022年7月至2023年12月首都医科大学附属北京儿童医院和山东第一医院大学附属省立医院收治的4例布罗索尤单抗治疗的XLH患儿为研究对象，收集其临床特征、生化指标、影像学资料、治疗及随访（每3个月随访1次，截至2023年12月）情况，分析患儿治疗后的临床转归及药物不良反应。 结果： 4例患儿中男3例、女1例，治疗前年龄分别为6.7、2.9、2.1、2.3岁。其中3例曾使用磷酸盐合剂及活性维生素D治疗，但患儿的步态异常、双下肢弯曲改善不明显，活动性佝偻病影像学变化未修复。4例患儿布罗索尤单抗起始剂量为0.8 mg/kg，每2周皮下注射1次，治疗周期为0.8~1.3年。4例患儿治疗前的空腹血清磷和肾磷阈分别为0.72、0.95、0.81、0.66 mmol/L和0.67、0.85、0.87、0.61 mmol/L，末次随访时血清磷和肾磷阈均明显升高（分别为0.96、1.09、1.09、0.90 mmol/L，0.85、0.79、1.03、0.98 mmol/L），其中仅例2肾磷阈治疗3个月时达到了正常值（1.17 mmol/L），其余均未达到同年龄儿童的正常范围。经过治疗，全部患儿的碱性磷酸酶水平均逐渐下降（分别为461、240、423、237 U/L），例2、例4末次访视时降至正常。例4治疗9个月时甲状旁腺激素水平轻度升高（81.0 ng/L），其余3例未见异常。例1行6 min步行试验，步行距离从245 m提高至570 m。4例患儿步态异常、双下肢弯曲及佝偻病严重程度均得到改善，未见肾脏钙质沉积、局部皮肤注射反应、高磷血症、维生素D缺乏等药物不良反应。 结论： 布罗索尤单抗治疗可改善XLH患儿临床症状，尚未见药物不良反应。.

OBJECTIVE: X-linked hypophosphatemic rickets (XLH) is due to loss-of-function mutations in the phosphate-regulating endopeptidase homologue on the X chromosome (PHEX) that lead to increased fibroblast growth factor 23 (FGF23) production. FGF23 excess causes renal phosphate wasting and insufficient 1,25-dihydroxyvitamin D (1,25(OH)2D) synthesis with reduced intestinal phosphate absorption, ultimately resulting in chronic hypophosphatemia. Children with XLH show typical skeletal lesions of rickets, deformities of the lower limbs, stunted growth with disproportionate short stature, bone pain, and physical dysfunctions. Burosumab, a fully human IgG1 monoclonal antibody that binds to FGF23 to inhibit its activity, is more effective to improve the biochemical and clinical signs of XLH than conventional treatment with phosphate supplements and vitamin D active metabolites. Data on adolescents with XLH during the transition period to young adulthood are few. In this prospective case series, we aimed to assess safety and efficacy of burosumab in adolescents with XLH who discontinued long-term conventional therapy.
METHODS: Five Caucasian adolescents (4 males, 1 female; mean age 15.4 ± 1.5 years) with XLH were recruited and switched from conventional treatment to burosumab (0.8-1.2 mg/kg, s. c. QW2). Burosumab was continued for 12-48 months and, once discontinued, patients were followed-up for 6-12 months. In all patients, serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 1,25(OH)2D levels, and renal tubular reabsorption of phosphate (TmP/GFR) values were assessed at entry and during burosumab. Intact FGF23 plasma levels were measured at entry. Patient-reported outcomes (PROs) were assessed at entry and every 3-6 months to evaluate the impact of low extremity pain, stiffness, and difficulties performing daily activities.
RESULTS: At entry, all patients showed hypophosphatemia, increased intact FGF23 levels, reduced TmP/GFR, insufficient 1,25(OH)2D levels, and in four out of five increased ALP levels. Two patients had radiological signs of rickets. During burosumab, all patients showed a significant increase in serum phosphate and 1,25(OH)2D levels, and in TmP/GFR values (P < 0.05 - P < 0.0001). Serum ALP levels significantly declined (P < 0.05) to normal values. No changes of serum calcium and PTH levels (PNS) were found during burosumab. PROs significantly improved (P < 0.02 - P < 0.0001) in all patients. Four patients discontinued burosumab when they turned 18 or 19, whereas one continued the treatment since he was still younger than 18 during the study period. Four patients who suspended burosumab showed a rapid decline in serum phosphate and 1,25(OH)2D levels and in TmP/GFR values; serum ALP levels increased, and PROs progressively worsened with a significant reduction in quality of life. These consequences were not observed in the patient who continued burosumab treatment.
CONCLUSIONS: Our data showed that conventional treatment improved only in part the signs and symptoms of XLH. Burosumab was well tolerated and was effective in improving phosphate metabolism, bone health, and PROs. All the benefits of burosumab were lost after its discontinuation. These results suggested that continuing burosumab is required to achieve and maintain the clinical benefits of the treatment during the transition to young adulthood in patients with XLH.

X-linked hypophosphatemia (XLH) is a rare inherited disorder of renal phosphate wasting with a highly variable phenotype caused by loss-of-function variants in the PHEX gene. The diagnosis of individuals with mild phenotypes can be challenging and often delayed. Here, we describe a three-generation family with a very mild clinical presentation of XLH. The diagnosis was unexpectedly found in a 39-year-old woman who was referred for genetic testing due to an unclear childhood diagnosis of a tubulopathy. Genetic testing performed by next-generation sequencing using a kidney disease gene panel identified a novel non-canonical splice site variant in the PHEX gene. Segregation analysis detected that the consultand\'s father, who presented with hypophosphatemia and decreased tubular phosphate reabsorption, and the consultand\'s son also carried this variant. RNA studies demonstrated that the non-canonical splice site variant partially altered the splicing of the PHEX gene, as both wild-type and aberrant splicing transcripts were detected in the two male members with only one copy of the PHEX gene. In conclusion, this case contributes to the understanding of the relationship between splicing variants and the variable expressivity of XLH disease. The mild phenotype of this family can be explained by the coexistence of PHEX transcripts with aberrant and wild-type splicing.

UNASSIGNED: Hereditary Vitamin D-dependent rickets type II (HVDDR-type II) is a rare autosomal recessive disorder caused by molecular variation in the gene encoding the vitamin D receptor (VDR). This study aims to evaluate phenotype and genotype characteristics and long-term follow-up of the largest group of patients with (HVDDR-type II) in Saudi Arabia.
UNASSIGNED: We conducted a retrospective chart review to collect the clinical, biochemical, and genetic data for all HVDDR-type II patients currently receiving treatment at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
UNASSIGNED: A total of 42 patients, 57.1% female, and 42.9% male were included in the study. Seven patients were treated with high doses of oral calcium, while 35 patients were treated with IV calcium infusion. The median age at presentation was 15.5 months. Alopecia was found in 97.6%, 21.4% presented with bowing legs, 14.3% with delayed walking, 9.5% with seizure, and 2.4% presented with respiratory failure, while a family history of the disease was positive in 71.4% of total patients. Molecular genetic testing of the VDR gene in our cohort identified six different gene variants c.885 C>A (p.Tyr295Ter), c.88 C>T (p.Arg30Ter), c.1036G>A (p.Val346Met), c.820C>T (p.Arg274Cys), c.803 T>C (p.Ile268Thr), and c.2T>G (p.Met1?).
UNASSIGNED: We are describing the largest cohort of patients with HVDDR-type II, their clinical biochemical findings, and the most prevalent genetic variants in our population.