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OBJECTIVES: To explore the clinical value of the renal phosphorus threshold (ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate, TmP/GFR) in the diagnosis and treatment of children with X-linked hypophosphatemic rickets (XLH). METHODS: A retrospective study was conducted, including 83 children diagnosed with XLH at Children's Hospital of Nanjing Medical University from January 2010 to January 2023. Initial diagnosis and follow-up data were collected to investigate the correlation of TmP/GFR with the severity of rickets, calcium and phosphorus metabolism indicators, and the dosage of phosphate treatment. Children were divided into two groups based on the occurrence of renal calcification: the renal calcification group (n=47) and the non-renal calcification group (n=36). Clinical data between the two groups were compared. Multivariate logistic regression analysis was used to identify factors influencing renal calcification in XLH children. The predictive value of TmP/GFR for renal calcification in XLH children was evaluated using receiver operating characteristic (ROC) curves. RESULTS: In the 83 XLH children, the initial TmP/GFR was (0.78±0.21) mmol/L, with significant individual variation (range: 0.28-1.24 mmol/L). TmP/GFR showed no significant correlation with the severity of rickets (P>0.05). Parathyroid hormone was negatively correlated with TmP/GFR (rs=-0.020, P=0.008), while blood phosphorus (rs=0.384, P<0.001), blood calcium (rs=0.251, P<0.001), and 25-hydroxyvitamin D (rs=0.179, P<0.001) were positively correlated with TmP/GFR. No significant correlation was found between TmP/GFR and alkaline phosphatase (rs=-0.002, P=0.960) or phosphate treatment dosage (rs=0.012, P=0.800). Blood calcium and TmP/GFR levels were significantly lower in the renal calcification group than in the non-renal calcification group (P<0.05), while parathyroid hormone and urine calcium levels were significantly higher in the renal calcification group (P<0.05). Multivariate logistic regression analysis indicated that TmP/GFR and urine calcium levels were closely associated with renal calcification in XLH children (P<0.05). ROC curve analysis revealed that the areas under the curve for TmP/GFR, urine calcium, and their combined detection predicting renal calcification in XLH children were 0.696, 0.679, and 0.761, respectively. CONCLUSIONS: TmP/GFR may serve as an important diagnostic indicator for pediatric XLH; however, it does not reflect the severity or activity of rickets and cannot be used to judge the efficacy of traditional treatment. Urine calcium and TmP/GFR are valuable predictors for renal calcification in XLH children.

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BACKGROUND: Despite ample sunshine, vitamin D deficiency continues to be prevalent in the Middle East. This pilot study aimed to identify the rate of vitamin D deficiency at a tertiary hospital in Abu Dhabi and to identify the associated risk factors in children and adolescents. METHODOLOGY: A retrospective observational study was conducted using electronic medical records of paediatric patients who underwent 25-hydroxyvitamin D testing at Sheikh Shakhbout Medical City, Abu Dhabi between 1 January 2020 and 31 December 2021. Data on age, gender, ethnicity, weight, body mass index and other potential risk factors for vitamin D deficiency in children were recorded. Patients who were already receiving treatment for vitamin D deficiency were excluded. The collected data were analysed using standard statistical methods. RESULTS: Of 26,818 patients under 18 years of age who attended the outpatient clinic, 1519 underwent 25-hydroxyvitamin D testing; 51% were male (n = 755). After applying the exclusion criteria, 1311 participants were included, 755 (58%) of whom had vitamin D concentrations of ≤50 nmol/L. Vitamin D deficiency was more common in children aged ≥10 years (69%) than in those <10 years of age (53%) (p < 0.0001). The highest prevalence of vitamin D deficiency was in those older than 16 years (86%). More females (63%, n = 407) than males (52%, n = 348) were identified as vitamin D-deficient (p = 0.0001). Vitamin D deficiency was more commonly identified during summer and autumn (59%) than in winter and spring (44%, p < 0.00001). CONCLUSION: Vitamin D deficiency is prevalent in children seeking medical care in the UAE, especially in girls, older children and adolescents, and during the summer and autumn. Paediatricians should have a low screening threshold for hypovitaminosis D, or widespread supplementation should be considered.

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Abstract Objective: To estimate the prevalence of vitamin D deficiency and severe deficiency in children and adolescents, in a large Brazilian sample. Methodology: Results of 413,988 25(OH)D measurements in children and adolescents aged 0 to 18 years collected between 01/2014 and 10/2018 were obtained from the database of a Clinical Laboratory. In this population, 25 hydroxyvitamin D concentrations below 20 ng/mL are considered deficient, and below 12 ng/mL as severe deficiency. All measurements were performed by immunoassay and the results were distributed by gender, age group, seasonality, and latitude. Results: The mean of 25(OH)D levels was 29.2 ng/mL with a standard deviation of 9.2 ng/mL. Of the total samples, 0.8% had a concentration < 12 ng/mL, and 12.5% of the samples had a concentration < 20 ng/mL, with a higher prevalence in females. Children under 2 years of age had the lowest prevalence. The effects of latitude and seasonality were quite evident. In samples of female adolescents from the southern region in winter, 36% of vitamin D deficiency and 5% of severe deficiency were found. Conclusion: In this large number of measurements of 25(OH)D in children and adolescents, 12.5% had a deficiency and 0.8% had severe deficiency. A greater deficiency was observed among adolescents, especially females, which raises questions about the need for supplementation during this period of life.

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Purpose: Metabolic Bone Disease of Infancy (MBDI) is a multifactorial disorder of bone fragility that presents with multiple unexplained fractures (MUF) and is often misdiagnosed as child abuse. The diagnosis of MBDI is made by the finding of radiographic features of healing rickets and risk factors for MBDI. Our anecdotal experience indicates blood 1,25-dihydroxyvitamin D (1,25-DiOHVD) is sometimes elevated. The purpose of this retrospective study was to review cases of MBDI in which child abuse was alleged and the alleged perpetrator denied wrongdoing. Methods: We reviewed forensic cases of MBDI born between 2015 and 2021. The diagnosis was based on radiographic findings of healing rickets. Records were reviewed for blood 1,25-DiOHVD testing. Results: 22 of the 76 infants (29 %) had a blood 1,25-DiOHVD level performed at the time of presentation with fractures. The average age of presentation with fractures was 11 weeks.3 of the 22 infants (14 %) had a normal 1,25-DiOHVD blood level, and 19 of the 22 infants (86 %) had an elevated level. None had low levels. Conclusion: Blood 1,25-DiOHVD is often elevated in infants with MBDI. Elevated blood 1,25-DiOHVD levels cause increased bone resorption and decreased bone mineralization, and thus this finding is not unexpected since all infants had evidence of healing rickets on imaging studies. These results indicate blood 1,25-DiOHVD should be done in contested cases of child abuse in infants with MUF as an elevated level indicates bone fragility.

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Catherine Chisholm BA MB ChB MD FRCP CBE (1879-1952) is celebrated as the first woman to qualify in medicine from Manchester University in 1904 and is remembered for founding the Manchester Babies Hospital in 1914 (later renamed in 1935 as the Duchess of York Hospital for Babies). She was indefatigable in her pursuit to improve the education and status of women doctors; the first woman member and president of the British Paediatric Society; first woman president of the Manchester Medical Society and was mainly responsible for establishing the Medical Women's Federation in 1917. Her career was a complex mixture of medical and social networks that linked her work as a children's physician to the Manchester Public Health Committee, Liberal politics and feminist groups. These networks played an important role in Dr Chisholm's successful career and are at the centre of this paper.

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Background: X-linked hypophosphatemic rickets (XLH) is a rare genetic disease characterized by inappropriately elevated circulating fibroblast growth factor 23 (FGF-23) and subsequent urinary phosphate wasting. The primary clinical manifestations of XLH include short stature, lower extremity bowing, dental abscesses, and rickets. Historical treatment includes phosphate and vitamin D supplementation, but recently, targeted therapy with burosumab has gained widespread acceptance. Burosumab is an FGF-23 blocking antibody. Conventional therapy options have been associated with the development of nephrocalcinosis (NC), with reported rates varying between 33% and 80% in XLH patients. Previous studies have noted that the phosphate supplementation dose correlates with the presence of NC, although this finding is not consistent across studies. It remains unclear whether nephrocalcinosis occurs in patients now treated with burosumab. Our aim was to identify XLH-associated nephrocalcinosis risk factors in our cohort of children with XLH and provide an updated analysis in the era of burosumab. Methods: We identified 13 children with XLH who received routine medical care for XLH at our institution between 2015 and 2023. All were initially treated with conventional therapy and were transitioned to burosumab either upon its US Food and Drug Administration (FDA) approval in 2018 or at 6 months of age if this occurred after 2018. All patients were routinely monitored and this included laboratory tests and renal ultrasonography. Phosphate and calcitriol dosages were regularly adjusted to minimize serum and urinary laboratory abnormalities. Burosumab was administered according to its FDA package insert directions. Medication doses and laboratory values were analyzed between the group with NC and the group without NC. Results: Three patients were noted to have evidence of NC within the study timeline. Two children developed NC while receiving conventional therapy and one while prescribed burosumab. None of the variables, including a positive family history of XLH, average age at diagnosis of XLH, duration or dosage of treatment with conventional therapy, average age at the initiation of burosumab, and all measured laboratory values, were significantly different between the groups with and without NC. Female sex was the only identified significant risk factor for a diagnosis of XLH-associated NC. Conclusion: XLH-associated NC remains a clinical concern even with modern treatment, although the traditional risk factors (dose of phosphate supplements and degree of urinary phosphate excretion) may not always correlate with the onset of nephrocalcinosis. XLH patients receiving burosumab, which has been hypothesized to eliminate the risk factors for NC, can still develop NC. It is important to continue screening patients treated with burosumab for nephrocalcinosis. In addition, more research is needed to better understand the risk factors that cause XLH-associated NC and determine whether children with XLH never exposed to conventional therapy will develop NC.

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OBJECTIVE: Compare the efficacy and safety of daily versus fortnightly oral vitamin D3 in treating symptomatic vitamin D deficiency in children aged 1-10 years. DESIGN: Open labelled randomized controlled trial. PATIENTS: Eighty children with symptomatic vitamin D deficiency were randomized into group daily (D) and group bolus (B) [40 in each group] to receive oral vitamin D3, 4000 IU daily or 60,000 IU fortnightly for 12 weeks respectively. Both groups received daily oral calcium of 500 mg/day. MEASUREMENTS: Serum calcium (Ca), phosphate (P), alkaline phosphatase (ALP), 25-hydroxy cholecalciferol (25(OH)D), parathyroid hormone (PTH) levels, urine calcium: creatinine ratio and radiological score were assessed at baseline, 4 weeks and 12 weeks. At the end of 12 weeks, 74 children were available for evaluation of the efficacy and safety of both regimens. RESULTS: Both regimens led to a significant increase in Ca and P levels and a fall in ALP and PTH levels from baseline to 4 and 12 weeks of therapy, with no intergroup difference. At 4- and 12-week assessments, all children in both treatment arms achieved 25(OH)D level in sufficiency range, with no significant difference in their geometric mean. Both regimens were associated with asymptomatic transient hypercalcemia [group D-51.4% vs. group B-34.3%; p -0.14] and hypercalciuria (5.7%) in group D that resolved spontaneously on follow-up. CONCLUSIONS: Daily and fortnightly oral vitamin D3 in similar cumulative doses are efficacious for treating symptomatic vitamin D deficiency in children (1-10 years). Treated children should be monitored for serum 25(OH)D, Ca and urinary calcium creatinine ratio.

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BACKGROUND: Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function variants in the ALPL gene, leading to deficient tissue-nonspecific alkaline phosphatase (ALP) activity. This results in a distinctive biochemical profile marked by low serum ALP levels and elevated pyridoxal-5-phosphate (PLP). The clinical spectrum of HPP ranges from perinatal lethality to asymptomatic cases, presenting significant diagnostic and therapeutic challenges. SUMMARY: Diagnosis of HPP relies on identifying the characteristic biochemical signature (low ALP, high PLP), concomitant with skeletal (osteomalacia, rickets, pseudofracture) or extraskeletal (muscle weakness, musculoskeletal pain, dental) manifestations. Current diagnostic frameworks lack uniformity, highlighting the imperative for a standardized diagnostic approach. Molecular genetic testing plays a pivotal role in making the diagnosis of HPP, but difficulties persist in diagnosing milder cases and correlating genotypes with phenotypes. Comprehensive multidisciplinary care is indispensable, with enzyme replacement therapy (ERT) proving efficacious in severe cases and more nuanced management approaches for milder presentations. Overcoming challenges in ERT initiation, treatment response assessment, dose titrations, and long-term surveillance necessitates further refinement of management guidelines. KEY MESSAGE: Mild forms of HPP and asymptomatic carriers of pathogenic ALPL variants pose substantial diagnosis and management challenges. Developing consensus-driven guidelines is crucial to enhance clinical outcomes and patient care.

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OBJECTIVE: To use the prevalence of prenatal/infancy interglobular dentine (IGD) as a proxy for suboptimal vitamin D status and explore its link to mortality, biological sex, cultural behaviours and environmental factors during the end of the pre-industrial/ beginning of the industrial period. MATERIALS: 50 skeletons from the St. Antoine cemetery (1799-1854), Montreal, Quebec with a well-preserved first mandibular molar. METHODS: Thin sections were prepared for histological examination of IGD in crown dentine. RESULTS: IGD prevalence was 74 % (37/50) and not significantly correlated statistically to sex and age-at-death. Most IGD occurred at birth and up to 3 years-old, six individuals were affected in utero, 54 % of the sample (27/50) presented longstanding IGD and six individuals displayed multiple IGD episodes. CONCLUSIONS: Prenatal IGD episodes revealed suboptimal maternal vitamin D levels, which, alongside a high frequency of IGD episodes around birth/from birth until a certain age, suggest cultural influences. Multiple and longstanding IGD episodes might also reflect suboptimal seasonal vitamin D attainment. SIGNIFICANCE: This study provides in-depth data on IGD within a relatively large archaeological North American sample, proving relevant to epidemiological studies on suboptimal vitamin status in 19th century Montreal. LIMITATIONS: The total number of IGD episodes is underestimated due to methodological biases; first-generation migrants in this study could not be identified and excluded from the sample. SUGGESTIONS FOR FURTHER RESEARCH: Use of a larger sample with a wider age-at-death range; further research on infants and children to investigate links between growth and lesion formation and visibility.

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CONTEXT: Hereditary distal renal tubular acidosis caused by SLC4A1 gene mutation (SLC4A1-dRTA) is a rare hereditary form of renal tubular acidosis. Rickets or osteomalacia is a common complication of SLC4A1-dRTA, and seriously affects patients' daily life. However, studies on the bone microstructure in SLC4A1-dRTA are limited. OBJECTIVE: This work aimed to evaluate the bone microstructure of SLC4A1-dRTA patients, compared to age- and sex-matched healthy controls and X-linked hypophosphatemic rickets (XLH) patients. METHODS: This was a retrospective study on eleven SLC4A1-dRTA patients. Clinical manifestations, biochemical and radiographical examinations were characterized. Bone microstructure was examined in seven SLC4A1-dRTA patients, seven healthy controls and twenty-one XLH patients using high-resolution peripheral quantitative computed tomography (HR-pQCT). RESULTS: Skeletal symptoms, including fracture, bone pain, and lower limb deformity, were presented in 72.7% of SLC4A1-dRTA patients. Short stature was presented in 63.6% of the patients. SLC4A1-dRTA patients had significantly lower volumetric BMD in the distal tibia, and more severe deteriorated trabecular bone in the distal radius and tibia than healthy controls. SLC4A1-dRTA patients had significantly more severe deteriorated trabecular bone in the distal radius and distal tibia compared to XLH patients. With long-term alkaline therapy, SLC4A1-dRTA patients had alleviation in bone pain, increase in height. CONCLUSIONS: Skeletal lesions were common clinical manifestations in SLC4A1-dRTA patients. Compared with XLH, another common type of rickets, SLC4A1-dRTA patients had more severe trabecular bone microstructure damage, further supporting the necessity of early diagnosis and timely treatment of the disease.

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INTRODUCTION: Childhood hypophosphatemia is a rare condition and may be caused by malabsorption, malignancies, or genetic factors. Prolonged hypophosphatemia leads to impaired growth and radiographic signs of rickets. METHODS: We performed a detailed clinical and genetic evaluation of an adolescent boy with repeatedly low plasma phosphate concentrations (below 0.60 mmol/L) and growth failure. RESULTS: At 14 years, the patient presented with decelerating growth and delayed puberty. Biochemistry showed hypophosphatemia due to increased urinary phosphate loss; kidney function and vitamin D status were normal. Radiographs showed mild metaphyseal changes. A gene panel for known genetic hypophosphatemia was negative. Trio exome analysis followed by Sanger sequencing identified a pathogenic heterozygous de novo stop-gain variant in PRPF8 gene, c.5548C>T p.(Arg1850*), in the conserved RNase H homology domain. PRPF8 encodes the pre-RNA protein 8, which has a role in RNA processing. Heterozygous PRPF8 variants have been associated with retinitis pigmentosa and neurodevelopmental disorders but not with phosphate metabolism. The patient underwent growth hormone (GH) stimulation tests which confirmed GH deficiency. Head MRI indicated partially empty sella. GH treatment was started at 15 years. Surprisingly, phosphate metabolism normalized during GH treatment, suggesting that hypophosphatemia was at least partly secondary to GH deficiency. CONCLUSION: The evaluation of an adolescent with profound long-term hypophosphatemia revealed a pituitary developmental defect associated with a stop-gain variant in PRPF8. Hypophosphatemia alleviated with GH treatment. The pathological PRPF8 variant may contribute to abnormal pituitary development; however, its role in phosphate metabolism remains uncertain.

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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.

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BACKGROUND AND 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. DISCUSSION: 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.

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INTRODUCTION: 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. MATERIAL AND 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.

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BACKGROUND: Vitamin D-dependent rickets type 1 A (VDDR1A) is an autosomal recessive disorder due to mutations in the CYP27B1 gene which result in inability to generate 1,25(OH)2D. CASE PRESENTATION: An 18-month-old boy with VDDR1A presented with hypotonia and respiratory distress. He had been diagnosed 2 months earlier, having been evaluated for stunted growth, hypotonia, and delayed developmental milestones. He was stabilized with oxygen and bronchodilators for his bronchiolitis and high doses of alfacalcidol, calcium, and phosphate supplements for his hungry bone syndrome. Of note, the patient sustained upper limb fractures after a fall from his bed during admission. Overall, he had a protracted disease course; however, his bone profile gradually improved and he steadily recovered. CONCLUSION: VDDR1A causes failure to thrive, hypotonia, and increased fracture risk and may complicate the clinical course of lower respiratory tract infections. Furthermore, management of hungry bone syndrome requires supraphysiologic doses of vitamin D metabolites and calcium.

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INTRODUCTION: Tyrosinemia type 1 is a rare disease with autosomal recessive inheritance, featuring various clinical manifestations. These may encompass acute neonatal liver failure, neonatal cholestatic syndrome, chronic hepatitis, cirrhosis, hepatocellular carcinoma, and, alternatively, kidney disorders like renal tubular acidosis, Fanconi syndrome, hypophosphatemic rickets, among other alterations. Diagnosis relies on detecting toxic metabolites in the blood and urine, ideally confirmed through molecular testing. METHOD: A consensus was reached with experts in the field of inborn errors of metabolism (EIM), including eight pediatric gastroenterologists, two EIM specialists, two geneticists, three pediatric nutritionists specialized in EIM, and a pediatric surgeon specializing in transplants. Six working groups were tasked with formulating statements and justifications, and 32 statements were anonymously voted on using the Likert scale and the Delphi method. The first virtual vote achieved an 80% consensus, with the remaining 20% determined in person. RESULTS: The statements were categorized into epidemiology, clinical presentation, diagnosis, nutritional and medical treatment, and genetic counseling. CONCLUSIONS: This consensus serves as a valuable tool for primary care physicians, pediatricians, and pediatric gastroenterologists, aiding in the prompt diagnosis and treatment of this disease. Its impact on the morbidity and mortality of patients with tyrosinemia type 1 is substantial.

INTRODUCCIÓN: La tirosinemia tipo 1 es una enfermedad rara, con herencia autosómica recesiva, con múltiples manifestaciones clínicas, que pueden comprender desde falla hepática aguda neonatal, síndrome colestásico neonatal, hepatitis crónica, cirrosis o hepatocarcinoma, hasta alteraciones renales como acidosis tubular renal, síndrome de Fanconi o raquitismo hipofosfatémico, entre otras. El diagnóstico se basa en la presencia de metabolitos tóxicos en la sangre y la orina, idealmente con la confirmación molecular de la enfermedad. MÉTODO: Se realizó un consenso con expertos en el área de los errores innatos del metabolismo (EIM): ocho gastroenterólogos pediatras, dos médicos especialistas en EIM, dos genetistas, tres nutriólogas pediatras especializadas en EIM y un cirujano pediatra especialista en trasplantes. Se formaron seis mesas de trabajo encargadas de desarrollar los enunciados con sus justificaciones y fueron votados anónimamente 32 enunciados en una escala Likert con un método Delphi. La primera votación fue virtual, obteniendo consenso del 80% de los enunciados, y la segunda fue presencial, obteniendo el 20% restante. RESULTADOS: Los enunciados fueron divididos en epidemiología, cuadro clínico, diagnóstico, tratamiento nutricional y médico, y consejo genético. CONCLUSIONES: Este consenso constituye una valiosa herramienta para los médicos de atención primaria, pediatras y gastroenterólogos pediátricos, ya que ayuda a diagnosticar y tratar rápidamente esta enfermedad. Su impacto en la morbilidad y mortalidad de los pacientes con tirosinemia tipo 1 es sustancial.

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X-linked hypophosphatemia (XLH) is a genetic disease that results in excessive FGF23, chronic hypophosphatemia, and musculoskeletal abnormalities, with affected patients experiencing symptoms such as bone pain, bone deformity, fracture, and pseudofracture. Burosumab is a fully human monoclonal antibody that binds to FGF23, improving lowered serum 1,25(OH)2D and phosphate levels in patients with XLH. There are insufficient data on the use of burosumab, its safety, and the outcomes of treated patients in a real-world setting. The SUNFLOWER (Study of longitUdinal observatioN For patients with X-Linked hypOphosphatemic rickets/osteomalacia in collaboration With Asian partnERs) study is an ongoing longitudinal, observational cohort study of patients with XLH in Japan and South Korea. Enrollment occurred between April 2018 and December 2020. This interim analysis compared the background characteristics of patients who received burosumab with those who did not, and assessed improvements in biomarkers, physical and motor function, health-related quality-of-life (HRQOL) and other patient-reported outcome (PRO) measures, as well as the safety of burosumab treatment in 143 Japanese patients from 15 institutions over 6 mo. The patients had a median [interquartile range] age of 17.5 [11.0, 38.8] yr and 98 (68.5%) were female. Among patients aged <18 and ≥18 yr, 40/73 (54.8%) and 25/70 (35.7%) received burosumab, respectively. More patients aged ≥18 who received burosumab had bone pain at baseline vs those not treated with burosumab (6/25, 24.0% vs 2/45, 4.4%, p=.021). Patients treated with burosumab had improved serum phosphate and 1,25(OH)2D levels; moreover, rickets severity and HRQOL/PRO measures, such as pain, appeared to improve over 6 mo of burosumab treatment, and no new safety concerns were identified. This study identified trends in the background characteristics of patients with XLH who receive burosumab in real-world clinical practice. Furthermore, the results support the use of burosumab therapy in real-world settings.

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Hypophosphatemic rickets, which is often hereditary, is still under- or misdiagnosed in both children and adults, denying these individuals access to optimal management and genetic counseling. There have been recent calls to compile real-world data and share best practice on these rare conditions to guide clinical decision-making. Here we present eight clinical vignettes of patients with hypophosphatemic rickets encountered in our tertiary pediatric endocrinology practice. We describe the clinical features, genetics, and management of four cases of X-linked hypophosphatemia (PHEX mutations), one each of autosomal recessive hypophosphatemic rickets (DMP1 mutation) and autosomal recessive vitamin D-dependent rickets type 1A (CYP27B1 mutation), and two cases of distal renal tubular acidosis with FOXI1 mutation-associated hypophosphatemic rickets. Our cases prompt consideration of the (i) frequent misdiagnosis of hypophosphatemic rickets in clinical practice and the importance of comprehensive genetic testing; (ii) variable expressivity of the causative mutations; and (iii) a lack of responsiveness and/or compliance to conventional therapy and the value of burosumab in modern management, provided access is equitable. These cases highlight common real-world themes and challenges to managing patients presenting with these diverse conditions, especially the burden of disease hidden by misdiagnosis. In sharing these cases, we hope to raise awareness of these conditions, promote best practice in genetic diagnosis and management, and further advocate for reimbursement equity for the best available therapies.

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