Metabolically healthy obesity in adults with X-linked hypophosphatemia.

OBJECTIVES: 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. CONCLUSION: 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.

PTH like substance secreting mesenchymal tumor causing oncogenic osteomalacia; unravelling the difficulties in localization - A report of 2 cases.

Background: Oncogenic osteomalacia is a rare paraneoplastic association of Phosphaturic mesenchymal tumor (PMT) secreting excessive levels of a PTH like substance. They usually remain undiagnosed and patients suffer for years. The rarity of this tumor and its non-specific clinical presentations poses great challenge to the treating surgeons. Its management is poorly described in literature. We report two of such rare cases without much diagnostic delay. Case report: We had 2 cases; A 53-year-old south east Asian male with 6 months of debilitating pain over multiple sites, and another 44-year-old male patient with complaints of low back ache, and pain over both lower and upper limbs for 1.5 years. Both had low serum phosphorus and elevated FGF-23 values, but all other parameters were normal. A PMT was suspected and confirmed on a Ga68- DOTATOC scan in both cases, and on complete excision, their symptoms and the altered blood parameters got normalized. Histology was consistent with PMT. Conclusion: Accurate and timely diagnosis of a PMT with non-specific features are extremely challenging, but not without solutions. Even though a tumor of rarity, with the appropriate imaging modalities like Ga68- DOTATOC scan, and estimation of FGF-23 and serum phosphorus levels, they can be diagnosed. Once identified, complete removal is often curative within a few months.

Osteolytic mystery: A rare case of pathologic fracture from a phosphaturic mesenchymal tumor in hip and femur.

Phosphaturic mesenchymal tumor (PMT) is a rare tumor causing bone complications and myopathy. Histologically, PMT displays a mix of spindled cells, osteoclast-like giant cells, basophilic matrix, and flocculent or "grungy" calcification. Here we describe a case of PMT in the right hip and proximal femur, initially suspected to be multiple myeloma, presenting with osteolytic lesions and elevated alkaline phosphatase. Tests for malignancy were negative, but a subsequent biopsy confirmed PMT. The patient underwent hip biopsy, femur resection, and hemiarthroplasty, with follow-up MRI recommended.

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

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.

Nephrocalcinosis and Kidney Function in Children and Adults with X-linked Hypophosphatemia: Baseline Results from a Large Longitudinal Study.

BACKGROUND: In patients with X-linked hypophosphatemia (XLH), conventional therapy with oral phosphate salts and active vitamin D has been associated with nephrocalcinosis. However, the nature of the relationships among XLH, its treatment, nephrocalcinosis, and kidney function remain poorly understood. METHODS: Renal ultrasounds were performed and glomerular filtration rates were estimated (eGFR) at baseline in burosumab-naïve patients with XLH who participated in burosumab clinical trials (NCT02181764, NCT02526160, NCT02537431, NCT02163577, NCT02750618, NCT02915705) or enrolled in the XLH Disease Monitoring Program (XLH-DMP; NCT03651505). In this cross-sectional analysis, patient, disease, and treatment characteristics were described among patients with and without nephrocalcinosis. RESULTS: The analysis included 196 children (mean [SD] age 7.6 [4.0] years) and 318 adults (40.3 [13.1] years). Mean (SD) height z-score was -1.9 (1.2) for children and -2.3 (1.7) for adults. Nearly all children (97%) and adults (94%) had previously received conventional therapy. Nephrocalcinosis was detected in 22% of children and 38% of adults. In children, reduced eGFR <90 ml/min/1.73 m2 was more prevalent in those with nephrocalcinosis (25%) than in those without (11%), a finding that was not observed in adults. Children with nephrocalcinosis had lower mean values of TmP/GFR (P<.05), serum 1,25(OH)2D (P<.05), and eGFR (P<.001) and higher mean serum calcium concentrations (P<.05) than did those without nephrocalcinosis. Adults with nephrocalcinosis had lower mean serum phosphorus (P<.01) and 1,25(OH)2D (P<.05) concentrations than those without. Exploratory logistic regression analyses revealed no significant associations between the presence of nephrocalcinosis and other described patient or disease characteristics. CONCLUSIONS: Nephrocalcinosis was observed in nearly one quarter of children and more than one-third of adults with XLH. Further study is needed to better understand the predictors and long-term consequences of nephrocalcinosis, with surveillance for nephrocalcinosis remaining important in the management of XLH.

BACKGROUND: Conventionally, patients with X-linked hypophosphatemia (XLH) were treated with phosphate and vitamin D taken by mouth. However, this therapy might lead to a buildup of calcium in the kidney, called nephrocalcinosis. Here, we tried to better understand how XLH, conventional therapy, nephrocalcinosis, and kidney function are related. METHODS: Nephrocalcinosis was detected with kidney ultrasounds. Kidney function, called the estimated glomerular filtration rate (eGFR), was determined using the blood level of creatinine. Patients had been part of burosumab clinical trials or part of the XLH Disease Monitoring Program. Data were collected from patients before they received burosumab. RESULTS: The study included 196 children and 318 adults. Almost all children and adults had received conventional therapy. 22% of children had nephrocalcinosis and 38% of adults had nephrocalcinosis. In children, low eGFR was more common in those with nephrocalcinosis (25%) than in those without (11%). In adults, levels of eGFR were similar among those with and without nephrocalcinosis.Some lab values were different among patients with versus those without nephrocalcinosis. Children with nephrocalcinosis had significantly greater loss of phosphate by the kidneys, lower blood levels of the active form of vitamin D (1,25(OH)2D), lower eGFR, and higher blood levels of calcium than those without nephrocalcinosis. Adults with nephrocalcinosis had significantly lower blood levels of phosphorus and 1,25(OH)2D concentrations than those without. CONCLUSIONS: Nearly one quarter of children and more than one-third of adults with XLH, most of whom had received conventional therapy, had nephrocalcinosis. Further study is needed to better understand what factors can predict who will get nephrocalcinosis and to understand the long-term consequences of nephrocalcinosis. It remains important to monitor patients with XLH for nephrocalcinosis.

Contributing factors to hypophosphatemia development in critically Ill ventilated patients: a retrospective cohort study.

Hypophosphatemia (serum phosphate < 2.5 mg/dL) is a major concern when initiating nutritional support. We evaluated which factors contribute to hypophosphatemia development in critically ill patients, as well as the association between hypophosphatemia and mortality. A retrospective cohort study of patients who were ventilated for at least 2 days in a 16-bed mixed ICU. Data collected includes demographics, Acute Physiology & Chronic Health Evaluation 2 (APACHE2) admission score, Sequential Organ Failure Assessment score at 24 h (SOFA24), hourly energy delivery, plasma phosphate levels during the first 2 weeks of admission, ICU length of stay (LOS), length of ventilation (LOV), and mortality (ICU and 90 days). For the hypophosphatemia development model, we considered mortality as a competing risk. For mortality analysis, we used the Cox proportional hazards model considering hypophosphatemia development as a time-varying covariate. 462 patients were used in the analysis. 59.52% of the patients developed hypophosphatemia. Several factors were associated with a decreased risk of hypophosphatemia: age, BMI, pre-admission diabetes diagnosis, APACHE2, SOFA24, first kidney SOFA score, hospital admission time before ICU admission, and admission after liver transplantation. Admission due to trauma was associated with an increased risk of hypophosphatemia. Survival analysis with hypophosphatemia as a time-varying covariate showed a protective effect of hypophosphatemia from mortality (HR 0.447, 95% CI 0.281, 0.712). Age, APACHE2, and SOFA24 score were found to be significantly associated with ICU mortality. Fasting duration in the ICU before nutritional support initiation was not found to be significantly associated with hypophosphatemia. We examined several fasting intervals (12 h, 24 h, 36 h, 48 h, 60 h, 72 h). In each fast interval, we compared the prevalence of hypophosphatemia among patients who fasted the specified length of time, with those who did not fast for the same length of time. In each fasting interval, hypophosphatemia prevalence was lower in the fasting group compared to the non-fasting group. However, this difference was insignificant. BMI, APACHE2, and hospital LOS before ICU admission were inversely associated with hypophosphatemia development. Fasting for up to 72 h in the ICU before starting nutritional support did not affect hypophosphatemia occurrence. Hypophosphatemia was associated with lower mortality.

Risk factors for the development of refeeding syndrome in adults: A systematic review.

Identifying patients with a particularly high risk of refeeding syndrome (RFS) is essential for taking preventive measures. To guide the development of clinical decision-making and risk prediction models or other screening tools for RFS, increased knowledge of risk factors is needed. Therefore, we conducted a systematic review to identify risk factors for the development of RFS. PubMed, EMBASE, Cochrane Library, and Web of Science were searched from January 1990 until March 2023. Studies investigating demographic, clinical, drug use, laboratory, and/or nutrition factors for RFS were considered. The Newcastle-Ottawa Scale was used to appraise the methodological quality of included studies. Of 1589 identified records, 30 studies were included. Thirty-three factors associated with increased risk of RFS after multivariable adjustments were identified. The following factors were reported by two or more studies, with 0-1 study reporting null findings: a previous history of alcohol misuse, cancer, comorbid hypertension, high Acute Physiology and Chronic Health Evaluation II score, high Sequential Organ Failure Assessment score, low Glasgow coma scale score, the use of diuretics before refeeding, low baseline serum prealbumin level, high baseline level of creatinine, and enteral nutrition. The majority of the studies (20, 66.7%) were of high methodological quality. In conclusion, this systematic review informs on several risk factors for RFS in patients. To improve risk stratification and guide development of risk prediction models or other screening tools, further confirmation is needed because there were a small number of studies and a low number of high-quality studies on each factor.

Expanding the Clinical Features of Schimke Immuno-Osseous Dysplasia: A New Patient with a Novel Variant and Novel Clinical Findings.

Schimke Immuno-Osseous Dysplasia (SIOD) (MIM:242900) is an ultra-rare autosomal recessive pan-ethnic pleiotropic disease. Typical findings of this syndrome are steroid-resistant nephrotic syndrome, cellular immunodeficiency and spondyloepiphyseal dysplasia and facial dysmorphism. Biallelic variants in the SMARCAL1 gene cause SIOD. The five-and-half-year-old female patient was evaluated because of short stature, dysmorphism, hypercalcemia, hypophosphatemia and elevated FSH levels. Karyotype analysis and array-CGH testing were normal. Clinical Exome Sequencing was performed via next-generation sequencing to analyze genes associated with hypophosphatemia. No pathogenic variant was detected. The subsequent detection of proteinuria during her follow-up for cross-fused ectopic left kidney ultimately facilitated the diagnosis of SIOD, although no obvious spondyloepiphyseal dysplasia was detected. Re-analysis of CES revealed a novel homozygous c.2422_2427+9delinsA pathogenic variant in the SMARCAL1. One hundred twenty-five SIOD cases from 38 literature reporting SMARCAL1 gene pathogenic variants were reviewed to investigate whether hypercalcemia, hypophosphatemia and elevated FSH levels had been previously reported in SIOD patients. This review revealed that this was the first time these findings had been reported in a SIOD patient. This report expands not only the phenotypic but also genotypic spectrum of SIOD.

Epidemiology of Hypophosphatemia in Critical Illness: A Multicentre, Retrospective Cohort Study.

INTRODUCTION: Hypophosphatemia is common in critically ill patients. We have described the epidemiology of hypophosphatemia in patients admitted to the Intensive Care Units. METHODS: A multicentre, retrospective cohort study of 12 ICUs in Queensland, Australia from January 1st, 2015, to December 31st, 2021. Exclusions included readmissions, renal replacement therapy, end-stage renal disease, and palliative intent admissions and transfers from other ICUs. Patients were classified into four groups based on the severity of the first episode of low serum phosphate (PO4): "None" (PO4: ≥ 0.81 mmol/L, ``Mild" (PO4: ≥ 0.50 & < 0.81 mmol/L) "Moderate" (PO4: ≥ 0.30 & < 0.50 mmol/L) and "Severe" (PO4: < 0.30 mmol/L). A mixed-effect logistic regression model, including hospital as a random effect, was developed to examine factors associated with 90-day case fatality. RESULTS: Of the 89,776 patients admitted, 68,699 patients were included in this study, with 23,485 (34.2%) having hypophosphatemia with onset mostly on Day 2 of ICU admission and correcting to normal 3 days after hypophosphatemia was identified. There was substantial variation among participating ICUs in phosphate replacement; the threshold, and the route by which it was replaced. Day-90 case fatality increased with severity of hypophosphatemia (None: 3,974 (8.8%), Mild: 2,306 (11%), Moderate: 377 (14%); Severe: 108 (21%) (p < 0.001)). Multivariable regression analysis showed that compared to those without hypophosphatemia, patients with moderate (odds ratio (OR) 1.24; 95% confidence intervals (CI) 1.07-1.44; p = 0.004) or severe (OR 1.49; 95% CI 1.13-1.97; p = 0.005) hypophosphatemia had increased risk of 90-day case fatality. CONCLUSION: Hypophosphatemia was common, and mostly occurred on day 2 with early correction of serum phosphate. Phosphate replacement practices were variable among ICUs. Moderate and severe hypophosphatemia was associated with increased 90-day case fatality.

Tumor-Induced Osteomalacia: A Case Report.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome with a variable presentation. We present a case of a 55-year-old female who presented with pain in the bilateral hip region for the last two years. On routine biochemical evaluation, she was found to have hypophosphatemia with an X-ray of the bilateral hip region showing an acute stress fracture in the bilateral intertrochanteric region of the femur. An evaluation for the cause of hypophosphatemia revealed renal phosphate loss with low percentage tubular reabsorption of phosphate (% TRP) of 83% (reference range: 85-95%), with tubular maximum phosphate reabsorption per unit glomerular filtration rate (TmP/GFR) of 2.07 mg/dL (reference range: 2.5-4.5 mg/dL (0.67 mmol/L; range: 0.84-1.23 mmol/L)). Further evaluation revealed elevated levels of intact fibroblast growth factor, 445.7 pg/mL (reference range: 23-95 pg/mL). A 68-Gallium DOTA-1-Nal3-octreotide (DOTANOC) PET-CT revealed a focal increased tracer uptake with a lytic lesion at the lateral metaphyseal aspect of the proximal right tibia, suspicious of somatostatin receptor avid mesenchymal tumor, leading to the diagnosis of TIO. Definitive treatment with complete surgical excision of the tumor was done. Postoperatively, her phosphorus level was within the normal target range even without oral phosphate supplementation. While it is a rare condition, a proper and systemic workup can lead to timely diagnosis and management of this debilitating benign condition.

Long-term Evolution of Hypophosphatemia and Osteomalacia in a Patient With Multiple Myeloma.

Multiple myeloma commonly manifests with symptoms arising from the involvement of various organs, particularly the bone and kidneys. In this report, we detail the case of a 44-year-old man who was diagnosed with multiple myeloma associated with reduced bone density. He exhibited clinical findings of osteomalacia due to Fanconi syndrome (characterized clinically by bone pain and proximal weakness and biochemically by elevated serum alkaline phosphatase, hypophosphatemia, hypouricemia, and glucosuria). With phosphate replacement, there was a notable improvement in bone pain, osteomalacia, and bone mineral density. Nevertheless, the patient continued to experience renal wasting of phosphate, uric acid, and glucose despite achieving remission from multiple myeloma for nearly 2 years. Our case highlights several important clinical features of myeloma-associated Fanconi syndrome, including the need to recognize this complication to appropriately treat the underlying bone disease while avoiding osteoclast inhibitors and the long-term persistence of the proximal renal tubulopathy despite achieving remission from myeloma and correction of osteomalacia.

The association between serum phosphate and length of hospital stay and all-cause mortality in adult patients: a cross-sectional study.

BACKGROUND: Data is limited on the prevalence of hypophosphatemia in general hospitalized patients, and its association with length of hospital stay (LOS) and mortality remained unclear. We aimed to investigate the prevalence of admission phosphate abnormality and the association between serum phosphate level and length of hospital stay and all-cause mortality in adult patients. METHODS: This was a multi-center retrospective study based on real-world data. Participants were classified into five groups according to serum phosphate level (inorganic phosphorus, iP) within 48 h after admission: G1, iP < 0.64 mmol/L; G2, iP 0.64-0.8 mmol/L; G3, iP 0.8-1.16 mmol/L; G4, iP 1.16-1.45 mmol/L; and G5, iP ≥ 1.45 mmol/L, respectively. Both LOS and in-hospital mortality were considered as outcomes. Clinical information, including age, sex, primary diagnosis, co-morbidity, and phosphate-metabolism related parameters, were also abstracted from medical records. RESULTS: A total number of 23,479 adult patients (14,073 males and 9,406 females, aged 57.7 ± 16.8 y) were included in the study. The prevalence of hypophosphatemia was 4.74%. An "L-shaped" non-linear association was determined between serum phosphate level and LOS and the inflection point was 1.16 mmol/L in serum phosphate level. Compared with patients in G4, patients in G1, G2 or G3 were significantly associated with longer LOS after full adjustment of covariates. Each 0.1 mmol/L decrease in serum phosphate level to the left side of the inflection point led to 0.64 days increase in LOS [95% confidence interval (CI): 0.46, 0.81; p for trend < 0.001]. But there was no association between serum phosphate and LOS where serum levels of phosphate ≥ 1.16 mmol/L. Multivariable logistic regression analysis showed that adjusted all-cause in-hospital mortality was 3.08-fold greater in patients in G1 than those in G4 (95% CI: 1.52, 6.25; p for trend = 0.001). Similarly, no significant association with either LOS or mortality were found in patients in G5, comparing with G4. CONCLUSIONS: Hypophosphatemia, but not hyperphosphatemia, was associated with LOS and all-cause mortality in adult inpatients. It is meaningful to monitor serum levels of phosphate to facilitate early diagnosis and intervention.

Sclerostin inhibition in rare bone diseases: Molecular understanding and therapeutic perspectives.

Sclerostin emerges as a novel target for bone anabolic therapy in bone diseases. Osteogenesis imperfecta (OI) and X-linked hypophosphatemia (XLH) are rare bone diseases in which therapeutic potential of sclerostin inhibition cannot be ignored. In OI, genetic/pharmacologic sclerostin inhibition promoted bone formation of mice, but responses varied by genotype and age. Serum sclerostin levels were higher in young OI-I patients, while lower in adult OI-I/III/IV. It's worth investigating whether therapeutic response of OI to sclerostin inhibition could be clinically predicted by genotype and age. In XLH, preclinical/clinical data suggested factors other than identified FGF23 contributing to XLH. Higher levels of circulating sclerostin were detected in XLH. Sclerostin inhibition promoted bone formation in Hyp mice, while restored phosphate homeostasis in age-/gender-dependent manner. The role of sclerostin in regulating phosphate metabolism deserves investigation. Sclerostin/FGF23 levels of XLH patients with/without response to FGF23-antibody warrants study to develop precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy. Notably, OI patients were associated with cardiovascular abnormalities, so were XLH patients receiving conventional therapy. Targeting sclerostin loop3 promoted bone formation without cardiovascular risks. Further, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety. The Translational Potential of this Article. Preclinical data on the molecular understanding of sclerostin inhibition in OI and therapeutic efficacy in mouse models of different genotypes, as well as clinical data on serum sclerostin levels in patients with different phenotypes of OI, were reviewed and discussed. Translationally, it would facilitate to develop clinical prediction strategies (e.g. based on genotype and age, not just phenotype) for OI patients responsive to sclerostin inhibition. Both preclinical and clinical data suggested sclerostin as another factor contributing to XLH, in addition to the identified FGF23. The molecular understanding and therapeutic effects of sclerostin inhibition on both promoting bone anabolism and improving phosphate homostasis in Hyp mice were reviewed and discussed. Translationaly, it would facilitate the development of precise sclerostin/FGF23 inhibition strategy or synergistic/additive strategy for the treatment of XLH. Cardiovascular risk could not be ruled out during sclerostin inhibition treatment, especially for OI and XLH patients with cardiovascular diseases history and cardiovascular abnormalities. Studies on the role of sclerostin in inhiting bone formation and protecting cardiovascular system were reviewed and discussed. Translationaly, blockade of sclerostin loop3-LRP4 interaction while preserving sclerostin loop2-ApoER2 interaction could be a potential precise sclerostin inhibition strategy for OI and XLH with cardiovascular safety.

Lessons learned from the real-world diagnosis and management of hereditary hypophosphatemic rickets.

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.

Hypophosphatemic osteomalacia due to cadmium toxicity in silverware industry: A curious case of aches and pains.

Hypophosphatemic osteomalacia in an adult often gives clinical diagnostic challenges. Usually, they are caused by either tumor-induced osteomalacia or due to genetically mediated hypophosphatemia, particularly X-linked hypophosphatemia. However, heavy metal toxicity, leading to global proximal renal tubular dysfunction, is a rare cause, and in particular, cadmium toxicity is rarely encountered in clinical practice. The presence of bony pain and neurological deficit, along with a classical exposure history, provides the diagnostic clue. In this background, here we present a middle-aged man who had severe bony pains all over his body and lower back stiffness for five years. He underwent an initial workup as a suspected spondyloarthropathy but was later on, found to have hypophosphatemic osteomalacia and severe proximal renal tubular dysfunction. Further, the workup revealed elevated FGF-23. His occupational history revealed prolonged exposure to cadmium fumes in the silverware industry. He improved moderately with treatment; however, significant renal damage is still present. This case highlights the importance of considering cadmium toxicity in proper clinical and occupational contexts in the evaluation of hypophosphatemic osteomalacia in an adult.

Etiology of hypophosphatemia in adults. / Etiología de la hipofosfatemia en el adulto.

Long-term hypophosphatemia, defined by serum phosphorus (P) levels <2.5mg/dL, impairs the development and quality of mineralized tissue of the skeletal, dental, and auditory systems. P homeostasis depends mainly on intestinal absorption and renal excretion. Hypophosphatemia may be due to the redistribution of P to the intracellular space, increased renal losses, or decreased intestinal absorption. Hypophosphatemia can be categorized as acute or chronic, depending on the time course. Most cases, either acute or chronic, are due to acquired causes. However, some chronic cases may have a genetic origin. Accurate and early diagnosis, followed by adequate treatment, is essential to limit its negative effects on the body.

Longitudinal assessment of physical function in adults with X-linked hypophosphatemia following initiation of burosumab therapy.

We assessed multiple components of muscle function in ten adults with X-linked hypophosphatemia (XLH) receiving burosumab treatment. Lower limb power (+ 9%), short physical performance battery (SPPB) score (+ 1.2 points), and physical activity (+ 65%) increased following 6 months of treatment, and hand grip increased (+ 10%) between 6 and 12 months of treatment. PURPOSE: X-linked hypophosphatemia (XLH) is a rare genetic disorder of phosphate metabolism. Burosumab is a monoclonal antibody treatment shown to improve phosphate homeostasis and improve symptoms as well as fracture healing when used as a therapy for XLH in adults. However, little is known about its effects on the large deficits in multiple components of physical function previously reported in XLH. METHODS: Ten adults (6 females, age 41.1 ± 15.7 y) were recruited from specialist centres in London and Bristol. During clinical visits for initial burosumab treatment and at 6-month and 12-month follow-up, physical function, and physical activity (PA) assessments were performed. In detail, lower limb power was assessed by mechanography via a countermovement jump, mobility by short physical performance battery (SPPB), functional capacity by 6-min walk test (6MWT), upper limb strength by hand grip dynamometry, and PA via an International Physical Activity Questionnaire (IPAQ). Differences between baseline and 6-month follow-up, and in a subset of 5 patients between 6- and 12-month follow-up, were assessed. RESULTS: Lower limb power increased by 9% (P = 0.049) from baseline to 6 months, as did SPPB score (+ 1.2 points, P = 0.033) and total PA (+ 65%, P = 0.046) although hand grip and 6MWT did not differ. Only for hand grip was a significant improvement (+ 10%, P = 0.023) seen between 6 and 12 months. CONCLUSIONS: Burosumab treatment is associated with improved lower limb function and mobility at 6 months, with improvement in hand grip strength at 12 months. Future studies should explore the underlying mechanisms and describe on function and other patient outcomes.

Prospective multicenter study to describe the prevalence, outcomes, and management of phosphate disorders in intensive care patients: Study protocol for part B of the international GUTPHOS study.

BACKGROUND: Aberrations in blood phosphate (Pi) levels, whether presenting as hypo- or hyperphosphatemia, appear to be associated with clinical complications and adverse outcomes in patients admitted to an intensive care unit (ICU). However, the prevalence of Pi disorders and the association with subsequent factors and organ failures leading to death in ICU patients are poorly described. Despite endeavors to understand the etiology and treatment of low Pi levels from systematic reviews and meta-analyses, the literature lacks comprehensive guidance for managing hypophosphatemia. Hyperphosphatemia, on the other hand, appears to be associated with higher mortality among critically ill patients, yet its prevalence among ICU patients, particularly following phosphate repletion, remains unknown. The present study aims to investigate the prevalence of Pi abnormalities upon ICU admission and their incidence during the first week of ICU stay, the factors associated with Pi alterations, and the effect of phosphate repletion on the normalization of Pi levels, and its associations with clinical outcomes. METHODS: This multicentre, prospective, non-interventional cohort study will include at least 1000 consecutive adult ICU patients (≥18 years) as part B of the GUTPHOS study. Sites are eligible if an anticipated minimal inclusion of 50 eligible patients during eight weeks from January 2024 until June 2024 and daily phosphate measurements during the first seven days of ICU stay are expected. All consecutive adult patients admitted to a participating ICU during the recruitment period, lasting up to eight weeks, or up to 120 patients if enrollment reaches that limit earlier, will be included. Study parameters include study site characteristics, patient demographics, daily assessment of Pi levels, Pi-related treatment, feeding details, renal replacement therapy details, the incidence of refeeding-associated hypophosphatemia and administered medication (during the first seven calendar days of ICU stay). There will be a follow-up period of a maximum of 90 days to document 28- and 90-day all-cause mortality as the primary outcome. Multiple logistic regression will be used to assess independent associations with mortality in addition to Receiver Operating Characteristics curves to identify cut-off Pi values associated with mortality and overcorrection. Linear mixed models will be conducted to assess Pi treatment effects. Subgroup analyses will be performed based on Pi abnormalities observed during ICU admission, categorized as normo-, hypo-, hyper-, or mixed, along with its severity (mild, moderate, or severe). DISCUSSION: The GUTPHOS study will be the first multicentre, prospective observational cohort study to investigate the prevalence, management practices, and consequent outcomes associated with Pi abnormalities during the first week of ICU admission. Its results may bridge the current evidence gap in repletion protocols while establishing the groundwork for a subsequent randomized controlled trial. CLINICAL TRIAL REGISTRY: NCT05909722.