Detection of nephrocalcinosis using ultrasonography, micro-computed tomography, and histopathology in cats.

BACKGROUND: Identification of nephrocalcinosis in cats with chronic kidney disease (CKD) is of clinical interest but the ability of ultrasonography to detect nephrocalcinosis is uncertain. OBJECTIVES: To compare ultrasonography, micro-computed tomography (µCT) and histopathology for identification of nephrocalcinosis. ANIMALS: Twelve kidneys from 7 euthyroid client-owned cats with CKD. METHODS: Descriptive study. Renal ultrasonography was performed ante-mortem for nephrocalcinosis detection. Kidneys were grouped based on nephrocalcinosis: present, suspected, or absent. When cats died, necropsy was performed. Renal tissue was evaluated using µCT for macroscopic nephrocalcinosis, and nephrocalcinosis volume-to-kidney tissue ratio (macro-VN:KT) and sagittal nephrocalcinosis area-to-kidney tissue ratio (macro-AN:KT) were calculated. Each kidney subsequently was bisected longitudinally, formalin-fixed, and paraffin-embedded for microscopic nephrocalcinosis assessment using von Kossa and Alizarin red staining with AN:KT (VK-micro-AN:KT and AR-micro-AN:KT) quantified using ImageJ. Data are presented as median (range). Relationships between macroscopic and microscopic AN:KT were assessed using Spearman's correlation. RESULTS: Nephrocalcinosis by ultrasonography was considered to be absent in 3, suspected in 3, and present in 5 kidneys; 1 kidney had nephrolithiasis with nephrocalcinosis. The macro-VN:KT was 0.001%, 0.001%, and 0.019%, and the macro-AN:KT was 0.08%, 0.30%, and 1.47%, respectively. Histologically, VK-micro-AN:KT was 0.21%, 2.85%, and 4.56%, and AR-micro-AN:KT was 1.73%, 5.82%, and 8.90% for kidneys where ultrasonographic macro-nephrocalcinosis was absent, suspected, or present, respectively. A strong correlation was identified between macroscopic (macro-AN:KT) and microscopic (VK-micro-AN:KT) nephrocalcinosis (rs = 0.76; P = .01). CONCLUSIONS AND CLINICAL IMPORTANCE: Ultrasonographically diagnosed nephrocalcinosis correlates well with macroscopic and microscopic nephrocalcinosis at necropsy despite their separation in time.

FAM20A mutations and transcriptome analyses of dental pulp tissues of enamel renal syndrome.

AIM: Biallelic loss-of-function FAM20A mutations cause amelogenesis imperfecta (AI) type IG, better known as enamel renal syndrome (ERS), characterized by severe enamel hypoplasia, delayed/failed tooth eruption, intrapulpal calcifications, gingival hyperplasia and nephrocalcinosis. FAM20A binds to FAM20C, the Golgi casein kinase (GCK) and potentiates its function to phosphorylate secreted proteins critical for biomineralization. While many FAM20A pathogenic mutations have been reported, the pathogeneses of orodental anomalies in ERS remain to be elucidated. This study aimed to identify disease-causing mutations for patients with ERS phenotypes and to discern the molecular mechanism underlying ERS intrapulpal calcifications. METHODOLOGY: Phenotypic characterization and whole exome analyses were conducted for 8 families and 2 sporadic cases with hypoplastic AI. A minigene assay was performed to investigate the molecular consequences of a FAM20A splice-site variant. RNA sequencing followed by transcription profiling and gene ontology (GO) analyses were carried out for dental pulp tissues of ERS and the control. RESULTS: Biallelic FAM20A mutations were demonstrated for each affected individual, including 7 novel pathogenic variants: c.590-5T>A, c.625T>A (p.Cys209Ser), c.771del (p.Gln258Argfs*28), c.832_835delinsTGTCCGACGGTGTCCGACGGTGTC CA (p.Val278Cysfs*29), c.1232G>A (p.Arg411Gln), c.1297A>G (p.Arg433Gly) and c.1351del (p.Gln451Serfs*4). The c.590-5T>A splice-site mutation caused Exon 3 skipping, which resulted in an in-frame deletion of a unique region of the FAM20A protein, p.(Asp197_Ile214delinsVal). Analyses of differentially expressed genes in ERS pulp tissues demonstrated that genes involved in biomineralization, particularly dentinogenesis, were significantly upregulated, such as DSPP, MMP9, MMP20 and WNT10A. Enrichment analyses indicated overrepresentation of gene sets associated with BMP and SMAD signalling pathways. In contrast, GO terms related to inflammation and axon development were underrepresented. Among BMP signalling genes, BMP agonists GDF7, GDF15, BMP3, BMP8A, BMP8B, BMP4 and BMP6 were upregulated, while BMP antagonists GREM1, BMPER and VWC2 showed decreased expression in ERS dental pulp tissues. CONCLUSIONS: Upregulation of BMP signalling underlies intrapulpal calcifications in ERS. FAM20A plays an essential role in pulp tissue homeostasis and prevention of ectopic mineralization in soft tissues. This critical function probably depends upon MGP (matrix Gla protein), a potent mineralization inhibitor that must be properly phosphorylated by FAM20A-FAM20C kinase complex.

Pathogenesis of Enamel-Renal Syndrome Associated Gingival Fibromatosis: A Proteomic Approach.

The enamel renal syndrome (ERS) is a rare disorder featured by amelogenesis imperfecta, gingival fibromatosis and nephrocalcinosis. ERS is caused by bi-allelic mutations in the secretory pathway pseudokinase FAM20A. How mutations in FAM20A may modify the gingival connective tissue homeostasis and cause fibromatosis is currently unknown. We here analyzed conditioned media of gingival fibroblasts (GFs) obtained from four unrelated ERS patients carrying distinct mutations and control subjects. Secretomic analysis identified 109 dysregulated proteins whose abundance had increased (69 proteins) or decreased (40 proteins) at least 1.5-fold compared to control GFs. Proteins over-represented were mainly involved in extracellular matrix organization, collagen fibril assembly, and biomineralization whereas those under-represented were extracellular matrix-associated proteins. More specifically, transforming growth factor-beta 2, a member of the TGFß family involved in both mineralization and fibrosis was strongly increased in samples from GFs of ERS patients and so were various known targets of the TGFß signaling pathway including Collagens, Matrix metallopeptidase 2 and Fibronectin. For the over-expressed proteins quantitative RT-PCR analysis showed increased transcript levels, suggesting increased synthesis and this was further confirmed at the tissue level. Additional immunohistochemical and western blot analyses showed activation and nuclear localization of the classical TGFß effector phospho-Smad3 in both ERS gingival tissue and ERS GFs. Exposure of the mutant cells to TGFB1 further upregulated the expression of TGFß targets suggesting that this pathway could be a central player in the pathogenesis of the ERS gingival fibromatosis. In conclusion our data strongly suggest that TGFß -induced modifications of the extracellular matrix contribute to the pathogenesis of ERS. To our knowledge this is the first proteomic-based analysis of FAM20A-associated modifications.

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Bartter and Gitelman Syndromes: A Primer for Clinicians.

Gitelman and Bartter syndromes are rare inherited diseases that belong to the category of renal tubulopathies. The genes associated with these pathologies encode electrolyte transport proteins located in the nephron, particularly in the Distal Convoluted Tubule and Ascending Loop of Henle. Therefore, both syndromes are characterized by alterations in the secretion and reabsorption processes that occur in these regions. Patients suffer from deficiencies in the concentration of electrolytes in the blood and urine, which leads to different systemic consequences related to these salt-wasting processes. The main clinical features of both syndromes are hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia and hyperaldosteronism. Despite having a different molecular etiology, Gitelman and Bartter syndromes share a relevant number of clinical symptoms, and they have similar therapeutic approaches. The main basis of their treatment consists of electrolytes supplements accompanied by dietary changes. Specifically for Bartter syndrome, the use of non-steroidal anti-inflammatory drugs is also strongly supported. This review aims to address the latest diagnostic challenges and therapeutic approaches, as well as relevant recent research on the biology of the proteins involved in disease. Finally, we highlight several objectives to continue advancing in the characterization of both etiologies.

XIST Inhibition Attenuates Calcium Oxalate Nephrocalcinosis-Induced Renal Inflammation and Oxidative Injury via the miR-223/NLRP3 Pathway.

The roles of the lncRNA X inactive specific transcript (XIST) in many diseases, including cancers and inflammatory sickness, have been previously elucidated. However, renal calculus remained poorly understood. In this study, we revealed the potential effects of XIST on kidney stones that were exerted via inflammatory response and oxidative stress mechanisms. We established a glyoxylate-induced calcium oxalate (CaOx) stone mouse model and exposed HK-2 cells to calcium oxalate monohydrate (COM). The interactions among XIST, miR-223-3p, and NOD-like receptor protein 3 (NLRP3) and their respective effects were determined by RNAs and protein expression, luciferase activity, and immunohistochemistry (IHC) assays. Cell necrosis, reactive oxygen species (ROS) generation, and inflammatory responses were detected after silencing XIST, activating and inhibiting miR-223-3p, and both knocking down XIST and activating miR-223-3p in vitro and in vivo. The XIST, NLRP3, caspase-1, and IL-1ß levels were notably increased in kidney samples from glyoxylate-induced CaOx stone model mice. XIST knockdown significantly suppressed the inflammatory damage and ROS production and further attenuated oxalate crystal deposition. miRNA-223-3p mimics also exerted the same effects. Moreover, we verified the interactions among XIST, miRNA-223-3p and NLRP3, and the subsequent effects. Our results suggest that the lncRNA XIST participates in the formation and progression of renal calculus by interacting with miR-223-3p and the NLRP3/Caspase-1/IL-1ß pathway to mediate the inflammatory response and ROS production.

[18F]-sodium fluoride autoradiography imaging of nephrocalcinosis in donor kidneys and explanted kidney allografts.

Nephrocalcinosis is present in up to 43% of kidney allograft biopsies at one-year after transplantation and is associated with inferior graft function and poor graft survival. We studied [18F]-sodium fluoride ([18F]-NaF) imaging of microcalcifications in donor kidneys (n = 7) and explanted kidney allografts (n = 13). Three µm paraffin-embedded serial sections were used for histological evaluation of calcification (Alizarin Red; Von Kossa staining) and ex-vivo [18F]-NaF autoradiography. The images were fused to evaluate if microcalcification areas corresponded with [18F]-NaF uptake areas. Based on histological analyses, tubulointerstitial and glomerular microcalcifications were present in 19/20 and 7/20 samples, respectively. Using autoradiography, [18F]-NaF uptake was found in 19/20 samples, with significantly more tracer activity in kidney allograft compared to deceased donor kidney samples (p = 0.019). Alizarin Red staining of active microcalcifications demonstrated good correlation (Spearman's rho of 0.81, p < 0.001) and Von Kossa staining of consolidated calcifications demonstrated significant but weak correlation (0.62, p = 0.003) with [18F]-NaF activity. This correlation between ex-vivo [18F]-NaF uptake and histology-proven microcalcifications, is the first step towards an imaging method to identify microcalcifications in active nephrocalcinosis. This may lead to better understanding of the etiology of microcalcifications and its impact on kidney transplant function.

Do the Heterozygous Carriers of a CYP24A1 Mutation Display a Different Biochemical Phenotype Than Wild Types?

CONTEXT: Human cytochrome P450 24 subfamily A member 1 (CYP24A1) loss-of-function mutations result in impaired activity of the 24-hydroxylase involved in vitamin D catabolism, thus inducing a vitamin D-dependent hypercalcemia. Homozygotes often present an overt clinical phenotype named idiopathic infantile hypercalcemia (IIH), whereas it is debated whether heterozygotes display an abnormal phenotype. OBJECTIVE: To compare the clinical and biochemical features of heterozygous carriers of CYP24A1 variant and healthy wild-type controls sharing the same genetic and environmental exposure. METHODS: A large family harboring the nonsense c.667A>T, p.Arg223* pathogenic variant in the CYP24A1 gene was evaluated. All subjects underwent clinical and biochemical evaluation and complete analysis of vitamin D metabolites using mass spectroscopy including 1,24,25(OH)3D3. Subjects were divided into 2 groups according to their genotype: heterozygotes and wild-type for the CYP24A1 variant. RESULTS: The proband, a 40-year-old man, homozygous for p.Arg223* pathogenic variant, had a history of mild hypercalcemia with a seasonal trend, recurrent nephrolithiasis, and no episodes of acute hypercalcemia. He showed the highest serum levels of fibroblast growth factor 23, the highest 25(OH)D3/24,25(OH)2D3 ratio and undetectable levels of 1,24,25(OH)3D3, which represent indicators of a loss-of-function CYP24A1. Compared with the wild-types, heterozygotes had higher serum calcium and 25(OH)D3 concentrations (P = .017 and P = .025, respectively), without any difference in the other biochemical parameters and in the rate of nephrolithiasis. CONCLUSION: Heterozygotes exhibit a biochemical phenotype different from that of wild-type subjects. In clinical practice, these individuals might require surveillance because of the potential risk of developing hypercalcemia and related clinical manifestations if exposed to triggering factors.

Extrahematopoietic manifestations of the short telomere syndromes.

The short telomere syndromes encompass a spectrum of clinical manifestations that present from infancy to late adulthood. They are caused by mutations in telomerase and other telomere maintenance genes and have a predominantly degenerative phenotype characterized by organ failure across multiple systems. They are collectively one of the most common inherited bone marrow failure syndromes; however, their most prevalent presentations are extrahematopoietic. This review focuses on these common nonhematologic complications, including pulmonary fibrosis, liver pathology, and immunodeficiency. The short telomere syndrome diagnosis informs clinical care, especially in guiding diagnostic evaluations as well as in the solid organ transplant setting. Early recognition allows an individualized approach to screening and management. This review illustrates a myriad of extrahematopoietic presentations of short telomere syndromes and how they impact clinical decisions.

A novel PIK3R1 mutation of SHORT syndrome in a Chinese female with diffuse thyroid disease: a case report and review of literature.

BACKGROUND: SHORT syndrome is a rare genetic disease named with the acronyms of short stature, hyper-extensibility of joints, ocular depression, Rieger anomaly and teething delay. It is inherited in an autosomal dominant manner confirmed by the identification of heterozygous mutations in PIK3R1. This study hereby presents a 15-year-old female with intrauterine growth restriction, short stature, teething delay, characteristic facial gestalts who was identified a novel de novo nonsense mutation in PIK3R1. CASE PRESENTATION: The proband was admitted to our department due to irregular menstrual cycle and hirsutism with short stature, who had a history of intrauterine growth restriction and presented with short stature, teething delay, characteristic facial gestalts, hirsutism, and thyroid disease. Whole-exome sequencing and Sanger sequencing revealed c.1960C > T, a novel de novo nonsense mutation, leading to the termination of protein translation (p. Gln654*). CONCLUSIONS: This is the first case report of SHORT syndrome complicated with thyroid disease in China, identifying a novel de novo heterozygous nonsense mutation in PIK3R1 gene (p. Gln654*). The phenotypes are mildly different from other cases previously described in the literature, in which our patient presents with lipoatrophy, facial feature, and first reported thyroid disease. Thyroid disease may be a new clinical symptom of patients with SHORT syndrome.

Disturbances of calcium homeostasis in a child with acute lymphoblastic leukemia.

Hypercalcemia is a rare presentation of childhood acute lymphoblastic leukemia (ALL), and presents with nonspecific symptoms. A 11-year old boy developed severe hypercalcemia during initial presentation and relapse of ALL. Both times, he subsequently developed transient symptomatic hypocalcemia, associated with hypomagnesemia and renal tubulopathy. Disturbances in calcium homeostasis may rarely be the sole presenting feature of ALL in children, as a paraneoplastic syndrome, or may arise as a consequence of the malignancy and its treatment. Along with other measures, early recognition of malignancy and initiation of treatment play a key role in correcting calcium disturbances.

Novel compound heterozygous mutations of CLDN16 in a patient with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

BACKGROUND: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubulopathy characterized by excessive urinary wasting of magnesium and calcium, bilateral nephrocalcinosis, and progressive chronic renal failure in childhood or adolescence. FHHNC is caused by mutations in CLDN16 and CLDN19, which encode the tight-junction proteins claudin-16 and claudin-19, respectively. Most of these mutations are missense mutations and large deletions are rare. METHODS: We examined the clinical and biochemical features of a Spanish boy with early onset of FHHNC symptoms. Exons and flanking intronic segments of CLDN16 and CLDN19 were analyzed by direct sequencing. We developed a new assay based on Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF) to investigate large CLDN16 deletions. RESULTS: Genetic analysis revealed two novel compound heterozygous mutations of CLDN16, comprising a missense mutation, c.277G>A; p.(Ala93Thr), in one allele, and a gross deletion that lacked exons 4 and 5,c.(840+25_?)del, in the other allele. The patient inherited these variants from his mother and father, respectively. CONCLUSIONS: Using direct sequencing and our QMPSF assay, we identified the genetic cause of FHHNC in our patient. This QMPSF assay should facilitate the genetic diagnosis of FHHNC. Our study provided additional data on the genotypic spectrum of the CLDN16 gene.

Identifying optimal magnesium replenishment points based on risk of severe hypomagnesemia in colorectal cancer patients treated with cetuximab or panitumumab.

PURPOSE: Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR). Treatment with cetuximab and panitumumab commonly causes hypomagnesemia, and optimal management of this adverse effect remains unclear. Here, we evaluated the optimal magnesium replacement points based on the risk of severe hypomagnesemia in colorectal cancer patients who received cetuximab or panitumumab. METHODS: We retrospectively evaluated 184 patients who received cetuximab or panitumumab for colorectal cancer at Ogaki Municipal Hospital (Ogaki, Japan) between January 2010 and December 2019. Univariate analyses were conducted to evaluate the relationship between patient baseline characteristics and development of hypomagnesemia following cetuximab or panitumumab treatment. Variables that were significantly associated with hypomagnesemia in the univariate analyses as well as previously reported risk factors were entered into a multivariate logistic regression model. RESULTS: The incidence of hypomagnesemia was associated with panitumumab treatment, pre-replenishment serum magnesium concentration, treatment duration, and treatment line. Severe hypomagnesemia post-cetuximab or panitumumab treatment was significantly associated with low baseline magnesium concentrations (< 1.8 mg/dL; odds ratio 18.100, 95% confidence interval 1.570-210.000; p = 0.020) and low serum magnesium concentrations during treatment (< 1.1 mg/dL; odds ratio 93.800, 95% confidence interval 3.510-2510.000; p = 0.007). CONCLUSION: To minimize the risk of severe hypomagnesemia during anti-EGFR treatment, magnesium replenishment should be initiated in patients with pre-replenishment concentrations of < 1.8 mg/dL, preferably before reaching intra-treatment concentrations of < 1.1 mg/dL.

Two new families with enamel renal syndrome: A novel FAM20A gene mutation and review of literature.

Enamel renal syndrome (ERS) or so-called amelogenesis imperfecta type IG is a very rare disorder characterized by the triad of amelogenesis imperfecta, gingival enlargement and nephrocalcinosis. It is caused by biallelic mutations in the FAM20A gene. Herein, we report two unrelated patients with ERS. Our patients presented with the characteristic features of the syndrome, and amelogenesis imperfecta and gingival hyperplasia were the main complaint. Strikingly, they both had long face, thick lips, notched upper central incisors, and thick alveolar ridge which have never been reported before in patients with ERS. Gingival biopsy showed psammomatous calcifications, and renal ultrasound revealed bilateral nephrocalcinosis in the two patients. Mutational analysis of the FAM20A gene identified two homozygous mutations including a novel one (c.915_918delCTTT, p.Phe305Leufs*76 and c.1219 + 3_1219+6delAGGT). Our data expand the phenotypic and mutational spectrum of FAM20A gene and reinforce the importance of kidney examination and follow up for all patients with amelogenesis imperfecta unless FAM20A mutations were ruled out.

SHORT syndrome in two Chinese girls: A case report and review of the literature.

BACKGROUND: SHORT syndrome is a rare inherited multisystem disease that includes characteristic facial features, growth retardation, and metabolic anomalies and is related to heterozygous mutations in the PIK3R1 gene. However, it is difficult to ascertain the relationship between the phenotype and the genotype quickly and efficiently. METHODS: We report two Chinese girls with SHORT syndrome who presented with growth retardation, dysmorphic features, insulin resistance, and diabetes. Comprehensive medical evaluations were collected, including anthropometric measurements, laboratory measurements, and imaging examinations. Whole exome and Sanger sequencing was performed to detect and confirm the underlying genetic mutations in these patients. We prescribed metformin for the patients. RESULTS: The patients both presented diabetes, insulin resistance, short stature, lipodystrophy, and characteristic facial dysmorphic features. A heterozygous mutation was detected in the PIK3R1 gene (c.1615_1617del) of Patient 1. The analysis of patient 2 revealed another PIK3R1 mutation (c.1945C>T). After family validation, neither their parents nor their brothers had similar clinical presentations or carried the same mutation. CONCLUSION: We identified two de novo heterozygous mutations in PIK3R1 as the cause of SHORT syndrome in two Chinese girls. Additionally, in terms of diabetes control, metformin works well in the early treatment stage.

Clinical Evidence for the Benefits of Burosumab Therapy for X-Linked Hypophosphatemia (XLH) and Other Conditions in Adults and Children.

Burosumab (KRN23) is an FGF23 neutralizing antibody that has been the subject of several recent clinical trials principally focused on the treatment of hypophosphatemic rickets in patients with X-linked hypophosphatemia (XLH). Since the first publications in 2014, these trials have demonstrated efficacy with minimal safety concerns in both adult and pediatric cohorts. These studies have used dose-escalation to establish a dosing regimen that is well-tolerated in clinical use. This review summarizes the clinical trial data with respect to burosumab treatment in adults and children as well as noting several clinical trials currently underway. While burosumab appears transformative for the treatment of XLH, long term follow-up studies would be required to allay concerns over the potential for nephrocalcinosis and cardiac calcification. While these do not appear to be problematic in current trials, the effects of chronic or lifelong treatment have yet to be established.

Effects of bodybuilding supplements on the kidney: A population-based incidence study of biopsy pathology and clinical characteristics among middle eastern men.

BACKGROUND: The incidence of kidney diseases among bodybuilders is unknown. METHODS: Between January 2011 and December 2019, the Iraqi Kurdistan 15 to 39 year old male population averaged 1,100,000 with approximately 56,000 total participants and 25,000 regular participants (those training more than 1 year). Annual age specific incidence rates (ASIR) with (95% confidence intervals) per 100,000 bodybuilders were compared with the general age-matched male population. RESULTS: Fifteen male participants had kidney biopsies. Among regular participants, diagnoses were: focal segmental glomerulosclerosis (FSGS), 2; membranous glomerulonephritis (MGN), 2; post-infectious glomeruonephritis (PIGN), 1; tubulointerstitial nephritis (TIN), 1; and nephrocalcinosis, 2. Acute tubular necrosis (ATN) was diagnosed in 5 regular participants and 2 participants training less than 1 year. Among regular participants, anabolic steroid use was self-reported in 26% and veterinary grade vitamin D injections in 2.6%. ASIR for FSGS, MGN, PIGN, and TIN among regular participants was not statistically different than the general population. ASIR of FSGS adjusted for anabolic steroid use was 3.4 (- 1.3 to 8.1), a rate overlapping with FSGS in the general population at 2.0 (1.2 to 2.8). ATN presented as exertional muscle injury with myoglobinuria among new participants. Nevertheless, ASIR for ATN among total participants at 1.4 (0.4 to 2.4) was not significantly different than for the general population at 0.3 (0.1 to 0.5). Nephrocalcinosis was only diagnosed among bodybuilders at a 9-year cumulative rate of one per 314 vitamin D injectors. CONCLUSIONS: Kidney disease rates among bodybuilders were not significantly different than for the general population, except for nephrocalcinosis that was caused by injections of veterinary grade vitamin D compounds.

Four novel mutations of FAM20A in amelogenesis imperfecta type IG and review of literature for its genotype and phenotype spectra.

Amelogenesis imperfecta type IG (AI1G) is caused by mutations in FAM20A. Genotypic and phenotypic features of AI1G are diverse and their full spectra remain to be characterized. The aim of this study was to identify and summarize variants in FAM20A in a broad population of patients with AI1G. We identified a Thai female (Pt-1) and a Saudi male (Pt-2) affected with AI1G. Both had hypoplastic enamel, gingival hyperplasia, and intrapulpal calcification. Pt-1 also had rapidly progressive embedding of unerupted teeth, early eruption of permanent teeth, and spontaneous dental infection. Uniquely, Pt-2 had all permanent teeth erupted which was uncommon in AI1G patients. Whole exome sequencing (WES) identified that Pt-1 was heterozygous for FAM20A, c.758A > G (p.Tyr253Cys), inherited from her father. The mutation on maternal allele was not detected by WES. Pt-2 possessed compound heterozygous mutations, c.1248dupG (p.Phe417Valfs*7); c.1081C > T (p.Arg361Cys) in FAM20A. Array comparative genomic hybridization (aCGH), cDNA sequencing, and whole genome sequencing successfully identified 7531 bp deletion on Pt-1's maternal allele. This was the largest FAM20A deletion ever found. A review of all 70 patients from 50 independent families with AI1G (including two families in this study) showed that the penetrance of hypoplastic enamel and gingival hyperplasia was complete. Unerupted permanent teeth were found in all 70 patients except Pt-2. Exons 1 and 11 were mutation-prone. Most mutations were frameshift. Certain variants showed founder effect. To conclude, this study reviews and expands phenotypic and genotypic spectra of AI1G. A large deletion missed by WES can be detected by WGS. Hypoplastic enamel, gingival hyperplasia, and unerupted permanent teeth prompt genetic testing of FAM20A. Screening of nephrocalcinosis, early removal of embedded teeth, and monitoring of dental infection are recommended.

Nephrocalcinosis: A Review of Monogenic Causes and Insights They Provide into This Heterogeneous Condition.

The abnormal deposition of calcium within renal parenchyma, termed nephrocalcinosis, frequently occurs as a result of impaired renal calcium handling. It is closely associated with renal stone formation (nephrolithiasis) as elevated urinary calcium levels (hypercalciuria) are a key common pathological feature underlying these clinical presentations. Although monogenic causes of nephrocalcinosis and nephrolithiasis are rare, they account for a significant disease burden with many patients developing chronic or end-stage renal disease. Identifying underlying genetic mutations in hereditary cases of nephrocalcinosis has provided valuable insights into renal tubulopathies that include hypercalciuria within their varied phenotypes. Genotypes affecting other enzyme pathways, including vitamin D metabolism and hepatic glyoxylate metabolism, are also associated with nephrocalcinosis. As the availability of genetic testing becomes widespread, we cannot be imprecise in our approach to nephrocalcinosis. Monogenic causes of nephrocalcinosis account for a broad range of phenotypes. In cases such as Dent disease, supportive therapies are limited, and early renal replacement therapies are necessitated. In cases such as renal tubular acidosis, a good renal prognosis can be expected providing effective treatment is implemented. It is imperative we adopt a precision-medicine approach to ensure patients and their families receive prompt diagnosis, effective, tailored treatment and accurate prognostic information.

Nephrocalcinosis, Renal Dysfunction, and Calculi in Patients With Primary Hypoparathyroidism on Long-Term Conventional Therapy.

CONTEXT: There are concerns about the long-term safety of conventional therapy on renal health in patients with hypoparathyroidism. Careful audit of these would help comparisons with upcoming parathyroid hormone therapy. OBJECTIVE: We investigated nephrocalcinosis, renal dysfunction, and calculi, their predictors and progression over long-term follow-up in patients with primary hypoparathyroidism (PH). DESIGN AND SETTING: An observational study at a tertiary care center was conducted. PARTICIPANTS AND METHODS: A total of 165 PH patients receiving conventional therapy were evaluated by radiographs, ultrasonography, and computed tomography. Their glomerular filtration rate (GFR) was measured by Tc-99m-diethylenetriamine penta-acetic acid clearance. Clinical characteristics, serum total calcium, phosphorus, creatinine, hypercalciuria, and fractional excretion of phosphorus (FEPh) at presentation and during follow-up were analyzed as possible predictors of renal complications. Controls were 165 apparently healthy individuals. RESULTS: Nephrocalcinosis was present in 6.7% of PH patients but not in controls. Patients younger than 15 years at presentation and with higher serum calcium-phosphorus product were at higher risk. Nephrocalcinosis showed no significant association with cataract and intracranial calcification. Prevalence of renal calculi was comparable between hypoparathyroid patients and controls (5% vs 3.6%, P = .58). Fourteen percent of patients had a GFR less than 60 mL/min/1.73 m2. Increased FEPh during follow-up was the significant predictor of low GFR. Nephrocalcinosis developed in 9% of patients over 10 years of conventional therapy. CONCLUSION: A total of 6.7% of PH patients had nephrocalcinosis, and 14% showed renal dysfunction. Prevalence of renal calculi was similar in patients and controls. Nine percent of patients developed nephrocalcinosis over 10 years of conventional therapy.