X-linked hypophosphatemia (XLH) is the most common form of inherited rickets, resulting in short stature despite treatment with oral phosphate and active vitamin D. Detailed data of anthropometric parameters at birth, during infancy, and on the influence of an affected parent on outcome are lacking. In this prospective multicenter observational study, conducted from 1998 to 2023 in Germany, Austria, and Switzerland, body length, body weight, and head circumference were investigated in 198 children with XLH from birth until the age of 18 years, all being only on supplementation therapy. XLH newborns presented with disproportionate body shape characterized by decreased birth length relative to weight and head circumference with a 2.4-fold increased risk to be born small for gestational age (SGA). A positive family history for XLH was associated with lower anthropometric characteristics at birth. Body disproportion increased during 0–2 years old, resulting in significantly increased head circumference (+ 0.82 SD) and reduced body length (−2.00 SD) compared to healthy 2-year-old patients. Supplementation therapy failed to prevent progressive growth failure and reduced final height, regardless of whether treatment was started early due to an affected family member, which was associated with overall poor control of metabolic bone disease indicated by persistent hypophosphatemia and rising alkaline phosphatase z-score. XLH is associated with an increased risk for SGA and progressive disproportional body growth during infancy. Routine medical check-ups may soon use this unique growth pattern to identify children with XLH. Supplemental therapy fails to prevent progressive growth failure.

Magnesium plays a vital role in virtually all cellular processes as a cofactor of enzymes, a structural element of proteins and nucleic acids, and a modulator of receptors and ion channels. The control of magnesium homeostasis primarily resides in the kidney tubules. Nephron segments critical for renal magnesium conservation mainly comprise the thick ascending limb and the distal convoluted tubule where different control mechanisms act. Over the past two decades, genetic and molecular studies in patients with hereditary forms of hypomagnesemia led to the identification of important components of epithelial magnesium transport. These discoveries have greatly advanced our understanding not only of inherited but also of acquired disorders of magnesium metabolism at the molecular level. This chapter highlights the different transport pathways involved in tubular magnesium reabsorption and their regulation; it also summarizes important discoveries in hereditary disorders of renal magnesium handling and provides an overview on acquired forms of hypomagnesemia.

Burosumab is effective for treatment of rickets in children with X-linked hypophosphatemia (XLH). The effects of burosumab on markers and regulators of osteoblast and osteoclast acitivity are largely unknown. In this cross-sectional observational study, we investigated 7 key markers and regulators of osteoblast and osteoclast activity in 107 burosumab-treated children with XLH. We calculated z-scores for bone-specific alkaline phosphatase (BAP), procollagen-1-N-terminal propeptide (P1NP), carboxy-terminal telopeptide of type 1 collagen (CTX), tartrate-resistant acid phosphatase type 5b (TRAP5b), soluble receptor activator of NF-κB ligand (sRANKL), osteoprotegerin (OPG), and sclerostin. The median age at investigation and duration of burosumab treatment were 10.7 and 2.2 yr, respectively, with 18.7% of patients on primary burosumab treatment and 81.3% with prior treatment with phosphate and active vitamin D. Height and body mass index improved by approx. 0.3 z-score from baseline with burosumab treatment, and serum phosphate, 1,25-dihydroxyvitamin D, and alkaline phosphatase improved by 2 z-scores (each p < .01 versus prior burosunab), but phosphate (-1.8 z-score) and calcium (-0.65 z-score) remained reduced (each p < .001 versus age and sex specific reference values). The z-scores for osteoblast (BAP, P1NP) and osteoclast (CTX, TRAP5b) activity markers and for the osteoblast suppressor sclerostin were increased (each p < .001). Standardized sRANKL was reduced (p < .05), while the RANKL inhibitor OPG was increased resulting in a reduced sRANKL/OPG ratio (each p < .001). Multivariate analysis revealed significant associations between serum sclerostin and serum phosphate (negative), serum calcium and vitamin D sufficiency (positive), and primary burosumab treatment with BAP (negative). In this real-world setting, pediatric XLH patients receiving burosumab treatment showed persisting mild hypophosphatemia and increased markers of osteoblast and osteoclast acitivity despite negative counter-regulation of osteoblasts by sclerostin and osteoclasts by OPG/RANKL. Our data suggest a more pronounced normalization osteoblast activity when children are primarily treated with burosumab and underscore the need for adequate vitamin D supplementation.

Introduction: Variants in the Ras-related GTPase D (RRAGD) gene have been associated with autosomal dominant kidney hypomagnesemia (ADKH) characterized by hypokalemia, nephrocalcinosis, and dilated cardiomyopathy (DCM). RRAGD, which encodes for the RagD protein, is involved in the activation of the mechanistic target of rapamycin complex 1 (mTORC1). Owing to the limited characterization of patients’ phenotypes, the understanding of RRAGD-associated ADKH (ADKH-RRAGD) remains incomplete. Consequently, available treatment strategies are primarily symptomatic and insufficient. Methods: In the present case series, 13 new patients and 3 novel RRAGD variants, that is, p.(Ser77Phe), p.(Thr91Ile), and p.(Ile100Arg), are described. To assess the pathogenicity of the novel variants, an in vitro assay of mTORC1 activity was performed. In addition, the clinical response to diuretics (furosemide and thiazide, n = 4) and Na+-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (n = 6) was evaluated in patients carrying the RRAGD p.(Thr97Pro) variant during routine. Results: The patients presented with kidney tubulopathies, including hypomagnesemia, hypercalciuria, and nephrocalcinosis. Five patients also exhibited DCM. In vitro assays demonstrated constitutive activation of noncanonical mTORC1 signaling caused by the p.(Ser77Phe) and p.(Ile100Arg) variants. Clinically, patients remained sensitive to diuretic challenges, whereas dapagliflozin treatment increased serum magnesium (Mg2+) levels by 0.04 mM but exacerbated hypokalemia. Conclusion: To date, 37 patients with ADKH-RRAGD have been identified. Kidney tubulopathy is the most prominent feature within the phenotypic spectrum of ADKH-RRAGD. Molecularly, constitutive activation of noncanonical mTORC1 is present in most RRAGD variants. From a therapeutic perspective, dapagliflozin may increase serum Mg2+ levels in patients with RRAGD variants.

Children with X-linked hypophosphatemia (XLH) present with rickets, leg deformities, and growth failure. Bone stability depends on balanced bone growth in both length and width. Data on body proportions, including transverse body dimensions, in children with XLH treated with phosphate supplements and active vitamin D are lacking. Six major transverse body dimensions of the trunk and extremities, and the frame index (FI), i.e., ratio between bicondylar humerus diameter and height, were measured annually along with clinical characteristics in 109 pediatric patients with XLH, all on supplementation therapy, participating in a prospective multicenter observational study conducted since 1998. Associations between anthropometric and clinical parameters were investigated using linear mixed-effects models. Children with XLH exhibited persistent hypophosphatemia and elevated alkaline phosphatase z scores despite supplementation treatment. This was associated with disproportionate transversal skeletal growth, which was most pronounced during adolescence (13–17 years). Bicondylar diameter z scores (tubular bone width) and FI progressively increased with age (each p < 0.05). In addition, FI was identified as a superior indicator of stunting when compared to other measures of transversal dimensionality across all age groups. In young children (2–6 years), transversal growth was most synchronized and associated most strongly with clinical characteristics. Our data show disproportionate growth in transversal body dimensions despite supplementation treatment in children with XLH, suggesting compensatory widening of tubular bones as adaptation for mineral loss caused by persisting rickets. The FI can be used as a general indicator of bone health in children with XLH in clinical practice and trials.

X-linked hypophosphatemia (XLH) is the most common inherited form of hypophosphatemic rickets. Children with XLH have an increased risk of obesity, which may promote high blood pressure, but data on blood pressure in XLH are inconclusive. We aimed to assess blood pressure and its determinants in pediatric XLH patients. We conduct a prospective, multicenter observational study of children with XLH in Germany and Switzerland. Office blood pressure and body mass index (BMI) were annually measured in 128 pediatric XLH patients with a median follow-up of 2 years (range 1-6). Potential predictors of blood pressure were investigated by Spearman correlation. Seventeen percent of patients were treated with phosphate supplements and active vitamin D for a median of 8 years, 83% of patients received burosumab for 2.3 years with 3.1 years of prior treatment with phosphate supplements and active vitamin D. Median systolic (0.75 z-score) and diastolic (0.32 z-score) blood pressure and BMI (0.72 z-score) were increased compared to healthy children (each p < 0.01). The prevalence of obesity (9.8% vs. 3%), arterial hypertension (26.2% vs. 5%), and high-normal blood pressure (22.9% vs. 5%) was higher in the XLH cohort compared to the general pediatric population (each p < 0.001). Spearman rank correlation analysis revealed significant associations between both systolic (r = 0.24; p < 0.01) and diastolic (r = 0.20; p < 0.05) blood pressure with BMI, while the mode of treatment, i.e. burosumab versus phosphate supplements and active vitamin D, was no significant correlate. Children with XLH present with elevated office blood pressure values, associated with elevated BMI.

Introduction: Gitelman syndrome (GS) is a rare inherited salt-losing tubulopathy with limited clinical data. Methods: Surveys were conducted with GS physicians in Europe and patients with GS in the Netherlands to compare findings with the general population. Results: Data from 587 patients (25% pediatric) across 13 countries showed 93% were genotyped, with 94% having variants in SLC12A3. Children with GS were shorter and lighter than the general population, with lower bodyweight persisting into adulthood. The sex distribution was uneven, with more males in childhood and more females in adulthood. Patients with GS had the expected electrolyte disorders as well as significantly lower blood phosphate levels. Positive correlations were found between blood magnesium and potassium, and potassium and aldosterone. Physicians reported muscle cramps, salt craving, and muscle weakness as most common GS symptoms. Patients with GS scored worse than the general population in fatigue, physical, and cognitive function; and ranked salt craving and polydipsia-polyuria as the most severe symptoms. Symptom burden was higher in adult females and patients with lower blood magnesium. Treatment mainly consisted of potassium (94%) and magnesium (50%) supplementation. Potassium-sparing medication (used in 33%) slightly increased blood potassium levels (3.2 vs. 3.1 mmol/l). Adult patients with GS had a high prevalence of chondrocalcinosis (15%) and elevated blood cell counts (26%). Compared with the general population, adult patients with GS had lower rates of chronic kidney disease (CKD) and hypertension, a similar rate of diabetes, but a higher rate of albuminuria or proteinuria (28%). Conclusions: These findings provide new insights into GS, highlight disease burden, and suggest areas for future research.

Abstract Background and Aims X-linked hypophosphatemia (XLH) is the most common genetic cause of hypophosphatemia. Mutations in the PHEX gene cause elevated circulating levels of fibroblast growth factor 23 (FGF23), phosphaturia, rickets and osteomalacia. Conventional treatment with phosphate salts and active vitamin D is associated with nephrocalcinosis and preclinical studies in mice have shown that a chronic high phosphate load causes proximal tubular injury and fibrosis. There is no detailed analysis on kidney health in XLH patients yet. Method We conduct a prospective observational multicenter study in Germany and Switzerland to evaluate kidney health in pediatric XLH patients. Patients receive conventional therapy or burosumab, a fully humanized anti-FGF23 antibody. Clinical and biochemical data, blood and urine samples are collected annually. Results To date, 137 patients (80 girls, mean age 10.5 years) from 40 centers are included. 22% of patients have been treated conventionally for 7.5 years, 78% of patients have received burosumab for 2.3 years with 3.7 years of conventional therapy beforehand. Children with XLH show increased systolic blood pressure and body mass index (BMI), and overweight (BMI >90th percentile) and hypertension (systolic blood pressure >95th percentile) were each found in 20% of patients. A reduced eGFR (<90 ml/min/1.73 m2) and/or nephrocalcinosis was noted in 7% and 28% of patients, respectively. Microalbuminuria is twice as prevalent in children with XLH as in healthy children (14% vs 7%). Urinary lithogenic substances (calcium, oxalate, glycolate) are increased in 1.8-22.8%, and citrate is decreased in 12.3% of XLH patients. Tubular injury markers neutrophil gelatinase-associated lipocalin (NGAL) and Dickkopf-3 (DKK3) are elevated in urine of children with XLH, Chitinase 3-like 1 (CHl3L1) is comparable to children with chronic kidney disease, while kidney injury molecule-1 (Kim-1), indicating proximal tubule cell injury, is within a normal range. The renal inflammation marker monocyte chemoattractant protein-1 (MCP-1) is elevated in children with XLH, and epidermal growth factor (EGF), a marker of tubular cell repair, is decreased compared to healthy adults. Conclusion Pediatric XLH patients on conventional or burosumab therapy show enhanced systolic blood pressure slightly associated with elevated BMI, and significant renal comorbidity, i.e. reduced eGFR, nephrocalcinosis, increased urinary lithogenic substances, elevated urinary markers of glomerular and tubular injury and inflammation. The impact of conventional versus burosumab treatment are still being investigated.

X-linked hypophosphatemia (XLH) is a rare inherited phosphate-wasting disorder associated with bone and dental complications. Health-related quality of life (HRQoL) is reduced in XLH patients on conventional treatment with phosphate supplements and active vitamin D, while information on patients treated with burosumab is rare. HRQoL was assessed in 63 pediatric XLH patients participating in a prospective, observational study and patient registry in Germany using the KIDSCREEN-52 survey instrument and standardized qualitative interviews. The median age of the XLH patients was 13.2 years (interquartile range 10.6 – 14.6). At the time of the survey, 55 (87

Background Long-read sequencing is increasingly used to uncover structural variants in the human genome, both functionally neutral and deleterious. Structural variants occur more frequently in regions with a high homology or repetitive segments, and one rearrangement may predispose to additional events. Bartter syndrome type 3 (BS 3) is a monogenic tubulopathy caused by deleterious variants in the chloride channel gene CLCNKB , a high proportion of these being large gene deletions. Multiplex ligation-dependent probe amplification, the current diagnostic gold standard for this type of mutation, will indicate a simple homozygous gene deletion in biallelic deletion carriers. However, since the phenotypic spectrum of BS 3 is broad even among biallelic deletion carriers, we undertook a more detailed analysis of precise breakpoint regions and genomic structure. Methods Structural variants in 32 BS 3 patients from 29 families and one BS4b patient with CLCNKB deletions were investigated using long-read and synthetic long-read sequencing, as well as targeted long-read sequencing approaches. Results We report a ~3 kb duplication of 3′-UTR CLCNKB material transposed to the corresponding locus of the neighbouring CLCNKA gene, also found on ~50 % of alleles in healthy control individuals. This previously unknown common haplotype is significantly enriched in our cohort of patients with CLCNKB deletions (45 of 51 alleles with haplotype information, 2.2 kb and 3.0 kb transposition taken together, p =9.16×10 −9 ). Breakpoint coordinates for the CLCNKB deletion were identifiable in 28 patients, with three being compound heterozygous. In total, eight different alleles were found, one of them a complex rearrangement with three breakpoint regions. Two patients had different CLCNKA/CLCNKB hybrid genes encoding a predicted CLCNKA/CLCNKB hybrid protein with likely residual function. Conclusions The presence of multiple different deletion alleles in our cohort suggests that large CLCNKB gene deletions originated from many independently recurring genomic events clustered in a few hot spots. The uncovered associated sequence transposition haplotype apparently predisposes to these additional events. The spectrum of CLCNKB deletion alleles is broader than expected and likely still incomplete, but represents an obvious candidate for future genotype/phenotype association studies. We suggest a sensitive and cost-efficient approach, consisting of indirect sequence capture and long-read sequencing, to analyse disease-relevant structural variant hotspots in general.

Background Gitelman syndrome is a salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. It is caused by homozygous recessive or compound heterozygous pathogenic variants in SLC12A3, which encodes the Na+-Cl- cotransporter (NCC). In up to 10% of patients with Gitelman syndrome, current genetic techniques detect only one specific pathogenic variant. This study aimed to identify a second pathogenic variant in introns, splice sites, or promoters to increase the diagnostic yield.Methods Long-read sequencing of SLC12A3 was performed in 67 DNA samples from individuals with suspected Gitelman syndrome in whom a single likely pathogenic or pathogenic variant was previously detected. In addition, we sequenced DNA samples from 28 individuals with one variant of uncertain significance or no candidate variant. Midigene splice assays assessed the pathogenicity of novel intronic variants.Results A second likely pathogenic/pathogenic variant was identified in 45 (67%) patients. Those with two likely pathogenic/pathogenic variants had a more severe electrolyte phenotype than other patients. Of the 45 patients, 16 had intronic variants outside of canonic splice sites (nine variants, mostly deep intronic, six novel), whereas 29 patients had an exonic variant or canonic splice site variant. Midigene splice assays of the previously known c.1670-191C > T variant and intronic candidate variants demonstrated aberrant splicing patterns.Conclusion Intronic pathogenic variants explain an important part of the missing heritability in Gitelman syndrome. Long-read sequencing should be considered in diagnostic workflows for Gitelman syndrome.

This article has been withdrawn due to a publisher error that caused it to be duplicated. The definitive version of this article is published under https://doi.org/10.1210/clinem/dgad147.

AbstractContextKenny–Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by pathogenic variants in TBCE and FAM111A, respectively. Clinically the phenotypes are difficult to distinguish.ObjectiveThe objective was to determine and expand the phenotypic spectrum of KCS1 and KCS2 in order to anticipate complications that may arise in these disorders.MethodsWe clinically and genetically analyzed 10 KCS2 patients from 7 families. Because we found unusual phenotypes in our cohort, we performed a systematic review of genetically confirmed KCS cases using PubMed and Scopus. Evaluation by 3 researchers led to the inclusion of 26 papers for KCS1 and 16 for KCS2, totaling 205 patients. Data were extracted following the Cochrane guidelines and assessed by 2 independent researchers.ResultsSeveral patients in our KCS2 cohort presented with intellectual disability (3/10) and chronic kidney disease (6/10), which are not considered common findings in KCS2. Systematic review of all reported KCS cases showed that the phenotypes of KCS1 and KCS2 overlap for postnatal growth retardation (KCS1: 52/52, KCS2: 23/23), low parathyroid hormone levels (121/121, 16/20), electrolyte disturbances (139/139, 24/27), dental abnormalities (47/50, 15/16), ocular abnormalities (57/60, 22/23), and seizures/spasms (103/115, 13/16). Symptoms more prevalent in KCS1 included intellectual disability (74/80, 5/24), whereas in KCS2 bone cortical thickening (1/18, 16/20) and medullary stenosis (7/46, 27/28) were more common.ConclusionOur case series established chronic kidney disease as a new feature of KCS2. In the literature, we found substantial overlap in the phenotypic spectra of KCS1 and KCS2, but identified intellectual disability and the abnormal bone phenotype as the most distinguishing features.

This article has been withdrawn due to a publisher error that caused it to be duplicated. The definitive version of this article is published under https://doi.org/10.1210/clinem/dgad147.

Context Burosumab has been approved for the treatment of children and adults with X-linked hypophosphatemia (XLH). Real-world data and evidence for its efficacy in adolescents are lacking. Objective To assess the effects of 12 months of burosumab treatment on mineral metabolism in children (aged <12 years) and adolescents (aged 12-18 years) with XLH. Design Prospective national registry. Setting Hospital clinics. Patients A total of 93 patients with XLH (65 children, 28 adolescents). Main Outcome Measures Z scores for serum phosphate, alkaline phosphatase (ALP), and renal tubular reabsorption of phosphate per glomerular filtration rate (TmP/GFR) at 12 months. Results At baseline, patients showed hypophosphatemia (-4.4 SD), reduced TmP/GFR (-6.5 SD), and elevated ALP (2.7 SD, each P < .001 vs healthy children) irrespective of age, suggesting active rickets despite prior therapy with oral phosphate and active vitamin D in 88% of patients. Burosumab treatment resulted in comparable increases in serum phosphate and TmP/GFR in children and adolescents with XLH and a steady decline in serum ALP (each P < .001 vs baseline). At 12 months, serum phosphate, TmP/GFR, and ALP levels were within the age-related normal range in approximately 42%, 27%, and 80% of patients in both groups, respectively, with a lower, weight-based final burosumab dose in adolescents compared with children (0.72 vs 1.06 mg/kg, P < .01). Conclusions In this real-world setting, 12 months of burosumab treatment was equally effective in normalizing serum ALP in adolescents and children, despite persistent mild hypophosphatemia in one-half of patients, suggesting that complete normalization of serum phosphate is not mandatory for substantial improvement of rickets in these patients. Adolescents appear to require lower weight-based burosumab dosage than children.

ABSTRACT Background Dent's disease type 1 (DD1) is a rare X-linked nephropathy caused by CLCN5 mutations, characterized by proximal tubule dysfunction, including low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis–nephrocalcinosis, progressive chronic kidney disease (CKD) and kidney failure (KF). Current management is symptomatic and does not prevent disease progression. Here we describe the contemporary DD1 picture across Europe to highlight its unmet needs. Methods A physician-based anonymous international e-survey supported by several European nephrology networks/societies was conducted. Questions focused on DD1 clinical features, diagnostic procedure and mutation spectra. Results A total of 207 DD1 male patients were reported; clinical data were available for 163 with confirmed CLCN5 mutations. Proteinuria was the most common manifestation (49.1%). During follow-up, all patients showed LMWP, 66.4% nephrocalcinosis, 44.4% hypercalciuria and 26.4% nephrolithiasis. After 5.5 years, ≈50% of patients presented with renal dysfunction, 20.7% developed CKD stage ≥3 and 11.1% developed KF. At the last visit, hypercalciuria was more frequent in paediatric patients than in adults (73.4% versus 19.0%). Conversely, nephrolithiasis, nephrocalcinosis and renal dysfunction were more prominent in adults. Furthermore, CKD progressed with age. Despite no clear phenotype/genotype correlation, decreased glomerular filtration rate was more frequent in subjects with CLCN5 mutations affecting the pore or CBS domains compared with those with early-stop mutations. Conclusions Results from this large DD1 cohort confirm previous findings and provide new insights regarding age and genotype impact on CKD progression. Our data strongly support that DD1 should be considered in male patients with CKD, nephrocalcinosis/hypercalciuria and non-nephrotic proteinuria and provide additional support for new research opportunities.