Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a complex disorder in need of precision medicine.

Hereditary hypophosphatemic rickets with hypercalciuria is an autosomal recessive phosphate-wasting disorder, associated with kidney and skeletal pathologies, which is caused by pathogenic variants of SLC34A3. In this issue, Zhu et al. describe a pooled analysis of 304 individuals carrying SLC34A3 variants. Their study underscores the complexity of hereditary hypophosphatemic rickets with hypercalciuria, as kidney and bone phenotypes generally do not coexist, heterozygous carriers of SLC34A3 variants also can be affected, and the response to oral phosphate supplementation is dependent on the genetic status.

Biallelic and monoallelic pathogenic variants in CYP24A1 and SLC34A1 genes cause idiopathic infantile hypercalcemia.

OBJECTIVE: Idiopathic infantile hypercalcemia (IIH) is a rare disorder of PTH-independent hypercalcemia. CYP24A1 and SLC34A1 gene mutations cause two forms of hereditary IIH. In this study, the clinical manifestations and molecular aspects of six new Chinese patients were investigated. METHODS: The clinical manifestations and laboratory study of six patients with idiopathic infantile hypercalcemia were analyzed retrospectively. RESULTS: Five of the patients were diagnosed with hypercalcemia, hypercalciuria, and bilateral medullary nephrocalcinosis. Their clinical symptoms and biochemical abnormalities improved after treatment. One patient presented at age 11 years old with arterial hypertension, hypercalciuria and nephrocalcinosis, but normal serum calcium. Gene analysis showed that two patients had compound heterozygous mutations of CYP24A1, one patient had a monoallelic CYP24A1 variant, and three patients had a monoallelic SLC34A1 variant. Four novel CYP24A1 variants (c.116G > C, c.287T > A, c.476G > A and c.1349T > C) and three novel SLC34A1 variants (c.1322 A > G, c.1697_1698insT and c.1726T > C) were found in these patients. CONCLUSIONS: A monoallelic variant of CYP24A1 or SLC34A1 gene contributes to symptomatic hypercalcemia, hypercalciuria and nephrocalcinosis. Manifestations of IIH vary with onset age. Hypercalcemia may not necessarily present after infancy and IIH should be considered in patients with nephrolithiasis either in older children or adults.

Family analysis and literature study of hereditary hypophosphatemic rickets with hypercalciuria.

BACKGROUND: Hereditary hypophosphatemia rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterised by reduced renal phosphate reabsorption leading to hypophosphataemia, rickets and bone pain. Here, we present a case of HHRH in a Chinese boy. CASE PRESENTATION: We report a 11-year-old female proband, who was admitted to our hospital with bilateral genuvarum deformity and short stature. Computed Tomography (CT) showed kidney stones, blood tests showed hypophosphatemia, For a clear diagnosis, we employed high-throughput sequencing technology to screen for variants. Our gene sequencing approach encompassed whole exome sequencing, detection of exon and intron junction regions, and examination of a 20 bp region of adjacent introns. Flanking sequences are defined as ±50 bp upstream and downstream of the 5' and 3' ends of the coding region.The raw sequence data were compared to the known gene sequence data in publicly available sequence data bases using Burrows-Wheeler Aligner software (BWA, 0.7.12-r1039), and the pathogenic variant sites were annotated using Annovar. Subsequently, the suspected pathogenic variants were classified according to ACMG's gene variation classification system. Simultaneously, unreported or clinically ambiguous pathogenic variants were predicted and annotated based on population databases. Any suspected pathogenic variants identified through this analysis were then validated using Sanger sequencing technology. At last, the proband and her affected sister carried pathogenic homozygous variant in the geneSLC34A3(exon 13, c.1402C > T; p.R468W). Their parents were both heterozygous carriers of the variant. Genetic testing revealed that the patient has anLRP5(exon 18, c.3917C > T; p.A1306V) variant of Uncertain significance, which is a rare homozygous variant. CONCLUSION: This case report aims to raise awareness of the presenting characteristics of HHRH. The paper describes a unique case involving variants in both theSLC34A3andLRP5genes, which are inherited in an autosomal recessive manner. This combination of gene variants has not been previously reported in the literature. It is uncertain whether the presence of these two mutated genes in the same individual will result in more severe clinical symptoms. This report shows that an accurate diagnosis is critical, and with early diagnosis and correct treatment, patients will have a better prognosis.

An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Urinary Acidification Does Not Explain the Absence of Nephrocalcinosis in a Mouse Model of Familial Hypomagnesaemia with Hypercalciuria and Nephrocalcinosis (FHHNC).

Patients with mutations in Cldn16 suffer from familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) which can lead to renal insufficiency. Mice lacking claudin-16 show hypomagnesemia and hypercalciuria, but no nephrocalcinosis. Calcium oxalate and calcium phosphate are the most common insoluble calcium salts that accumulate in the kidney in the case of nephrocalcinosis, however, the formation of these salts is less favored in acidic conditions. Therefore, urine acidification has been suggested to limit the formation of calcium deposits in the kidney. Assuming that urine acidification is causative for the absence of nephrocalcinosis in the claudin-16-deficient mouse model, we aimed to alkalinize the urine of these mice by the ablation of the subunit B1 of the vesicular ATPase in addition to claudin-16. In spite of an increased urinary pH in mice lacking claudin-16 and the B1 subunit, nephrocalcinosis did not develop. Thus, urinary acidification is not the only factor preventing nephrocalcinosis in claudin-16 deficient mice.

A previously healthy 3-year-old female with hypertension, proteinuria, and hypercalciuria.

A 3-year-old female patient with no significant medical history presented to her pediatrician with foamy urine. Initial testing revealed moderate proteinuria on qualitative testing, although she was incidentally noted to have severe hypertension (240/200 mmHg). Physical examination of the carotid and femoral areas revealed significant systolic vascular murmurs. Labs showed elevated serum creatinine, hypokalemia, metabolic alkalosis, elevated renin and aldosterone and hypercalciuria. Echocardiography identified ventricular hypertrophy. Computed tomography (CT) of the abdomen and magnetic resonance angiography of the head showed multiple tortuous or interrupted arteries and multiple calcifications in the renal sinus area. B-mode ultrasonography suggested thickening of the carotid and femoral artery walls, with numerous spotted calcifications. Genetic testing revealed that ABCC6 had a complex heterozygous mutation (exon 24: c.3340C > T and intron 30: c.4404-1G > A). Our panel of experts reviewed the evaluation of this patient with hypertension, proteinuria, hypercalciuria, and vascular abnormalities as well as the diagnosis and appropriate management of a rare disease.

Two novel heterozygous ADCY10 variants identified in Chinese pediatric patients with absorptive hypercalciuria: case report and literature review.

Absorptive hypercalciuria (AH) is a prevalent cause of kidney stones, and the adenylate cyclase 10 (ADCY10) gene is a rare causative gene of AH. This study aims to investigate the genotypic and phenotypic characteristics of patients with AH caused by ADCY10 gene mutations. Whole-exome sequencing and Sanger sequencing were performed on the probands and their family members, respectively. Clinical and genetic data of patients with AH caused by ADCY10 gene mutations were collected and analysed retrospectively from the present study and published literature. Two female patients (6 years old and 1 year old) with multiple bilateral kidney stones were found to have a heterozygous c.3304T>C mutation and a heterozygous c.1726C>T mutation in the ADCY10 gene. Urinary metabolite analysis revealed that urine calcium / creatinine ratios were 0.95 mmol/mmol and 1.61 mmol/mmol, respectively. Both patients underwent thiazide intake postoperatively, and upon reexamination, urine calcium decreased to within the normal range. A total of 61 patients with AH were reported from previous and present studies. The sex ratio was 7:5 for males to females, and the mean age of onset was 23.61±20.08 years. A total of 16 ADCY10 gene mutations were identified, including seven missense (43.75%), five splicing (31.25%), two frameshift (12.50%) and two nonsense mutations (12.50%). Only two cases were identified as homozygous mutations (c.1205_1206del), and the others were heterozygous mutations. In summary, we identified two novel ADCY10 gene candidate pathogenic variants in Chinese pediatric patients, which expands the mutational spectrum of the ADCY10 gene and provides a potential diagnostic and therapeutic target.

Hereditary Hypophosphatemic Rickets with Hypercalciuria Presenting with Enthesopathy, Renal Cysts, and High Serum c-Terminal FGF23: Single-Center Experience and Systematic Review.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of phosphate homeostasis. We describe a single-center experience of genetically proven HHRH families and perform systematic review phenotype-genotype correlation in reported biallelic probands and their monoallelic relatives. Detailed clinical, biochemical, radiological, and genetic data were retrieved from our center and a systematic review of Pub-Med and Embase databases for patients and relatives who were genetically proven. Total of nine subjects (probands:5) carrying biallelic SLC34A3 mutations (novel:2) from our center had a spectrum from rickets/osteomalacia to normal BMD, with hypophosphatemia and hypercalciuria in all. We describe the first case of genetically proven HHRH with enthesopathy. Elevated FGF23 in another patient with hypophosphatemia, iron deficiency anemia, and noncirrhotic periportal fibrosis led to initial misdiagnosis as tumoral osteomalacia. On systematic review of 58 probands (with biallelic SLC34A3 mutations; 35 males), early-onset HHRH and renal calcification were present in ~ 70% and late-onset HHRH in 10%. c.575C > T p.(Ser192Leu) variant occurred in 53% of probands without skeletal involvement. Among 110 relatives harboring monoallelic SLC34A3 mutation at median age 38 years, renal calcification, hypophosphatemia, high 1,25(OH)2D, and hypercalciuria were observed in ~30%, 22.3%, 40%, and 38.8%, respectively. Renal calcifications correlated with age but were similar across truncating and non-truncating variants. Although most relatives were asymptomatic for bone involvement, 6/12(50%) had low bone mineral density. We describe the first monocentric HHRH case series from India with varied phenotypes. In a systematic review, frequent renal calcifications and low BMD in relatives with monoallelic variants (HHRH trait) merit identification.

Identification of a Novel Homozygous Missense Mutation in the CLDN16 Gene to Decipher the Ambiguous Clinical Presentation Associated with Autosomal Dominant Hypocalcaemia and Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis in an Indian Family.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHNNC) is a rare autosomal recessive renal tubulopathy disorder characterized by excessive urinary loss of calcium and magnesium, polyuria, polydipsia, bilateral nephrocalcinosis, progressive chronic kidney disease, and renal failure. Also, sometimes amelogenesis imperfecta and severe ocular abnormalities are involved. The CLDN-16 and CLDN-19 genes encode the tight junction proteins claudin-16 and claudin-19, respectively, in the thick ascending loop of Henle in the kidney, epithelial cells of the retina, dental enamel, etc. Loss of function of the CLDN-16 and/or CLDN-19 genes leads to FHHNC. We present a case of FHHNC type 1, which was first confused with autosomal dominant hypocalcaemia (ADH) due to the presence of a very low serum parathyroid hormone (PTH) concentration and other similar clinical features before the genetic investigations. After the exome sequencing, FHHNC type 1 was confirmed by uncovering a novel homozygous missense mutation in the CLDN-16 gene (Exon 2, c.374 T > C) which causes, altered protein structure with F55S. Associated clinical, biochemical, and imaging findings also corroborate final diagnosis. Our findings expand the spectrum of the CLDN-16 mutation, which will further help in the genetic diagnosis and management of FHNNC.

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Renal calculus is a common disease with complex etiology and high recurrence rate. Recent studies have revealed that gene mutations may lead to metabolic defects which are associated with the formation of renal calculus, and single gene mutation is involved in relative high proportion of renal calculus. Gene mutations cause changes in enzyme function, metabolic pathway, ion transport, and receptor sensitivity, causing defects in oxalic acid metabolism, cystine metabolism, calcium ion metabolism, or purine metabolism, which may lead to the formation of renal calculus. The hereditary conditions associated with renal calculus include primary hyperoxaluria, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Bartter syndrome, primary distal renal tubular acidosis, infant hypercalcemia, hereditary hypophosphatemic rickets with hypercalciuria, adenine phosphoribosyltransferase deficiency, hypoxanthine-guanine phosphoribosyltransferase deficiency, and hereditary xanthinuria. This article reviews the research progress on renal calculus associated with inborn error of metabolism, to provide reference for early screening, diagnosis, treatment, prevention and recurrence of renal calculus.

Kidney stones, hypercalciuria, and recent insights into proximal tubule calcium reabsorption.

PURPOSE OF REVIEW: Most kidney stones are composed of calcium, and the greatest risk factor for kidney stone formation is hypercalciuria. Patients who form kidney stones often have reduced calcium reabsorption from the proximal tubule, and increasing this reabsorption is a goal of some dietary and pharmacological treatment strategies to prevent kidney stone recurrence. However, until recently, little was known about the molecular mechanism that mediates calcium reabsorption from the proximal tubule. This review summarizes newly uncovered key insights and discusses how they may inform the treatment of kidney stone formers. RECENT FINDINGS: Studies examining claudin-2 and claudin-12 single and double knockout mice, combined with cell culture models, support complementary independent roles for these tight junction proteins in contributing paracellular calcium permeability to the proximal tubule. Moreover, a family with a coding variation in claudin-2 causing hypercalciuria and kidney stones have been reported, and reanalysis of Genome Wide Association Study (GWAS) data demonstrates an association between noncoding variations in CLDN2 and kidney stone formation. SUMMARY: The current work begins to delineate the molecular mechanisms whereby calcium is reabsorbed from the proximal tubule and suggests a role for altered claudin-2 mediated calcium reabsorption in the pathogenesis of hypercalciuria and kidney stone formation.

Activating calcium-sensing receptor gene variants in China: a case report of hypocalcaemia and literature review.

OBJECTIVES: Autosomal dominant hypocalcaemia 1 (ADH1) is a rare autosomal dominant genetic disease, due to the activating mutations of the calcium-sensing receptor (CASR) gene. The current paper presents a severe case of ADH1 with intellectual backwardness, and systematically reviews the reported 17 ADH1 patients in China. CASE PRESENTATION: A 7 years old boy with recurrent seizures over 1 year was admitted at Yuying children' hospital, the clinical centre of south province of Zhejiang. Auxiliary examinations demonstrated hypocalcaemia, hyperphosphatemia, hypomagnesemia, hypercalciuria, low parathyroid hormone (PTH), basal ganglia calcifications, normal range of serum creatinine, and 25-hydroxyvitamin D. Wechsler's intelligence test result indicated intellectually backward. The patient's genotype found a heterozygous variant in CASR gene, c.T416C p. (Ile139Thr). This article also systematically reviews the literatures on ADH1 in China and summarises the clinical characteristics and treatment. CONCLUSIONS: ADH1 can be a cause of idiopathic hypoparathyroidism. Recognition and rational treatment is important for symptom improvement and reducing high potential adverse effects.

Novel Calcium-Sensing Receptor (CASR) Mutation in a Family with Autosomal Dominant Hypocalcemia Type 1 (ADH1): Genetic Study over Three Generations and Clinical Characteristics.

INTRODUCTION: Activating mutation of the calcium-sensing receptor gene (CASR) reduces parathyroid hormone secretion and renal tubular reabsorption of calcium, defined as autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 may present with hypocalcemia-induced seizures. Calcitriol and calcium supplementation in symptomatic patients may exacerbate hypercalciuria, leading to nephrocalcinosis, nephrolithiasis, and compromised renal function. METHODS: We report on a family with seven members over three generations with ADH1 due to a novel heterozygous mutation in exon 4 of CASR: c.416T>C. RESULTS: This mutation leads to substitution of isoleucine with threonine in the ligand-binding domain of CASR. HEK293T cells transfected with wild type or mutant cDNAs demonstrated that p.Ile139Thr substitution led to increased sensitivity of the CASR to activation by extracellular calcium relative to the wild-type CASR (EC50 of 0.88 ± 0.02 mM vs. 1.1 ± 0.23 mM, respectively, p < 0.005). Clinical characteristics included seizures (2 patients), nephrocalcinosis and nephrolithiasis (3 patients), and early lens opacity (2 patients). In 3 of the patients, serum calcium and urinary calcium-to-creatinine ratio levels obtained simultaneously over 49 patient-years were highly correlated. Using the age-specific maximal-normal levels of calcium-to-creatinine ratio in the correlation equation, we obtained age-adjusted serum calcium levels that are high enough to reduce hypocalcemia-induced seizures and low enough to reduce hypercalciuria. CONCLUSION: We report on a novel CASR mutation in a three-generation kindred. Comprehensive clinical data enabled us to suggest age-specific upper limit of serum calcium levels, considering the association between serum calcium and renal calcium excretion.

3' Untranslated Region Structural Elements in CYP24A1 Are Associated With Infantile Hypercalcemia Type 1.

Loss-of-function mutations in the CYP24A1 protein-coding region causing reduced 25 hydroxyvitamin D (25OHD) and 1,25 dihydroxyvitamin D (1,25(OH)2 D) catabolism have been observed in some cases of infantile hypercalcemia type 1 (HCINF1), which can manifest as nephrocalcinosis, hypercalcemia and adult-onset hypercalciuria, and renal stone formation. Some cases present with apparent CYP24A1 phenotypes but do not exhibit pathogenic mutations. Here, we assessed the molecular mechanisms driving apparent HCINF1 where there was a lack of CYP24A1 mutation. We obtained blood samples from 47 patients with either a single abnormality of no obvious cause or a combination of hypercalcemia, hypercalciuria, and nephrolithiasis as part of our metabolic and stone clinics. We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine serum vitamin D metabolites and direct sequencing to confirm CYP24A1 genotype. Six patients presented with profiles characteristic of altered CYP24A1 function but lacked protein-coding mutations in CYP24A1. Analysis upstream and downstream of the coding sequence showed single nucleotide variants (SNVs) in the CYP24A1 3' untranslated region (UTR). Bioinformatics approaches revealed that these 3' UTR abnormalities did not result in microRNA silencing but altered the CYP24A1 messenger RNA (mRNA) secondary structure, which negatively impacted translation. Our experiments showed that mRNA misfolding driven by these 3' UTR sequence-dependent structural elements was associated with normal 25OHD but abnormal 1,25(OH)2 D catabolism. Using CRISPR-Cas9 gene editing, we developed an in vitro mutant model for future CYP24A1 studies. Our results form a basis for future studies investigating structure-function relationships and novel CYP24A1 mutations producing a semifunctional protein. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Mechanisms of paracellular transport of magnesium in intestinal and renal epithelia.

Magnesium is the fourth most abundant cation in the body. It plays a critical role in many biological processes, including the process of energy release. Paracellular transport of magnesium is mandatory for magnesium homeostasis. In addition to intestinal absorption that occurs in part across the paracellular pathway, magnesium is reabsorbed by the kidney tubule. The bulk of magnesium is reabsorbed through the paracellular pathway in the proximal tubule and the thick ascending limb of the loop of Henle. The finding that rare genetic diseases due to pathogenic variants in genes encoding specific claudins (CLDNs), proteins located at the tight junction that determine the selectivity and the permeability of the paracellular pathway, led to an awareness of their importance in magnesium homeostasis. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is caused by a loss of function of CLDN16 or CLDN19. Pathogenic CLDN10 variants cause HELIX syndrome, which is associated with a severe renal loss of sodium chloride and hypermagnesemia. The present review summarizes the current knowledge of the mechanisms and factors involved in paracellular magnesium permeability. The review also highlights some of the unresolved questions that need to be addressed.

Idiopathic infantile hypercalcemia in children with chronic kidney disease due to kidney hypodysplasia.

BACKGROUND: Idiopathic infantile hypercalcemia (IIH) etiologies include pathogenic variants in CYP24A1, leading to increased 1,25(OH)2 D, hypercalciuria and suppressed parathyroid hormone (PTH), and in SLC34A1 and SLC34A3, leading to the same metabolic profile via increased phosphaturia. IIH has not been previously described in CKD due to kidney hypodysplasia (KHD). METHODS: Retrospective study of children with bilateral KHD and simultaneously tested PTH and 1,25(OH)2D, followed in a tertiary care center between 2015 and 2021. RESULTS: Of 295 screened patients, 139 had KHD, of them 16 (11.5%) had IIH (study group), 26 with normal PTH and any 1,25(OH)2D were controls. There were no differences between groups' gender, obstructive uropathy rate and baseline eGFR. Study patients were younger [median (IQR) age: 5.2 (3.2-11.3) vs. 61 (13.9-158.3) months, p < 0.001], had higher 1,25(OH)2D (259.1 ± 91.7 vs. 156.5 ± 46.4 pmol/l, p < 0.001), total calcium (11.1 ± 0.4 vs. 10.7 ± 0.3 mg/dl, p < 0.001), and lower phosphate standard deviation score (P-SDS) [median (IQR): - 1.4 (- 1.9, - 0.4) vs. - 0.3 (- 0.8, - 0.1), p = 0.03]. During 12 months of follow-up, PTH increased among the study group (8.8 ± 2.8 to 22.7 ± 12.4 pg/ml, p < 0.001), calcium decreased (11 ± 0.5 to 10.3 ± 0.6 mg/dl, p = 0.004), 1,25(OH)2D decreased (259.5 ± 91.7 to 188.2 ± 42.6 pmol/l, p = 0.1), P-SDS increased [median (IQR): - 1.4 (- 1.9, - 0.4) vs. - 0.3 (- 0.9, 0.4), p = 0.04], while eGFR increased. Five of 9 study group patients with available urine calcium had hypercalciuria. Five patients had nephrocalcinosis/lithiasis. Genetic analysis for pathogenic variants in CYP24A1, SLC34A1 and SLC34A3 had not been performed. CONCLUSIONS: Transient IIH was observed in infants with KHD, in association with hypophosphatemia, resembling SLC34A1 and SLC34A3 pathogenic variants' metabolic profile. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical and genetic characteristics of Dent's disease type 1 in Europe.

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.

Research progress on renal calculus associate with inborn error of metabolism / 浙江大学学报·医学版

Renal calculus is a common disease with complex etiology and high recurrence rate. Recent studies have revealed that gene mutations may lead to metabolic defects which are associated with the formation of renal calculus, and single gene mutation is involved in relative high proportion of renal calculus. Gene mutations cause changes in enzyme function, metabolic pathway, ion transport, and receptor sensitivity, causing defects in oxalic acid metabolism, cystine metabolism, calcium ion metabolism, or purine metabolism, which may lead to the formation of renal calculus. The hereditary conditions associated with renal calculus include primary hyperoxaluria, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Bartter syndrome, primary distal renal tubular acidosis, infant hypercalcemia, hereditary hypophosphatemic rickets with hypercalciuria, adenine phosphoribosyltransferase deficiency, hypoxanthine-guanine phosphoribosyltransferase deficiency, and hereditary xanthinuria. This article reviews the research progress on renal calculus associated with inborn error of metabolism, to provide reference for early screening, diagnosis, treatment, prevention and recurrence of renal calculus.

Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism due to activating variants of the calcium-sensing receptor gene (CASR). Inherited or de novo activating variants of the CASR alter the set point for extracellular calcium, resulting in inadequate parathyroid hormone (PTH) secretion and inappropriate renal calcium excretion leading to hypocalcemia and hypercalciuria. Conventional therapy includes calcium and activated vitamin D, which can worsen hypercalciuria, resulting in renal complications. A systematic literature review, using published reports from 1994 to 2021, was conducted to catalog CASR variants, to define the ADH1 clinical spectrum, and to determine the effect of treatment on patients with ADH1. There were 113 unique CASR variants reported, with a general lack of genotype/phenotype correlation. Clinical data were available in 191 patients; 27% lacked symptoms, 32% had mild/moderate symptoms, and 41% had severe symptoms. Seizures, the most frequent clinical presentation, occurred in 39% of patients. In patients with blood and urine chemistries available at the time of diagnosis (n = 91), hypocalcemia (99%), hyperphosphatemia (59%), low PTH levels (57%), and hypercalciuria (34%) were observed. Blood calcium levels were significantly lower in patients with severe symptoms compared with asymptomatic patients (6.8 ± 0.7 versus 7.6 ± 0.7 mg/dL [mean ± SD]; p < 0.0001), and the age of presentation was significantly lower in severely symptomatic patients (9.1 ± 15.0 versus 19.3 ± 19.4 years; p < 0.01). Assessments for complications including nephrocalcinosis, nephrolithiasis, renal impairment, and brain calcifications in 57 patients on conventional therapy showed that 75% had at least one complication. Hypercalciuria was associated with nephrocalcinosis, nephrolithiasis, renal impairment, or brain calcifications (odds ratio [OR] = 9.3; 95% confidence interval [CI] 2.4-37.2; p < 0.01). In 27 patients with urine calcium measures before and after starting conventional therapy, the incidence of hypercalciuria increased by 91% (p < 0.05) after therapy initiation. ADH1 is a condition often associated with severe symptomatology at presentation with an increase in the risk of renal complications after initiation of conventional therapy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).