Severe Hypercalcemia Due to Primary Hyperparathyroidism and Heterozygous Pathogenic Variant of CYP24A1.

Pathogenic variants of CYP24A1 are associated with hypercalcemia due to disruptions in the ability of 24-hydroxylase to break down 1,25-dihydroxyvitamin D (1,25-DHVD). A case involving a heterozygous pathogenic variant of CYP24A1 and primary hyperparathyroidism leading to severe hypercalcemia has not been previously reported. A 23-year-old woman presented with fatigue and was found to be hypercalcemic at 13.8 mg/dL [reference range, 8.4-10.2 pg/mL]. Her parathyroid hormone (PTH) was 62 pg/mL [reference range, 19-88 pg/mL] and 1,25-DHVD was elevated to 242.7 pg/mL [reference range, 18-72 pg/mL]. Other laboratory workup was unrevealing. She had a bone scan, whole body CT scan, and thyroid ultrasound that were normal. Her 25-hydroxy-vitamin D to 24,25-dihydroxy-vitamin D ratio was elevated at 25.18 (normal, < 25). Because of concern for primary hyperparathyroidism, she was referred to an endocrine surgeon and underwent a parathyroidectomy with the removal of a 3.5-gram adenoma. Pathology showed a parafibromin-deficient parathyroid neoplasm. Genetic testing demonstrated a heterozygous pathogenic variant in CYP24A1. Three weeks after surgery, PTH was 14 pg/mL (1.48 pmol/L), calcium and 1,25-DHVD normalized. In summary, we report a case where a patient with severe symptomatic hypercalcemia was found to have primary hyperparathyroidism exacerbated by an underlying heterozygous pathogenic variant in CYP24A1.

Periodontal Disease and Incident CKD in US Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos.

RATIONALE & OBJECTIVE: Recent studies suggest that periodontal disease may be associated with incident chronic kidney disease (CKD). However, studies have focused on older populations, and US Hispanics/Latinos were not well represented. STUDY DESIGN: Observational cohort. SETTING & PARTICIPANTS: We analyzed data from the Hispanic Community Health Study/Study of Latinos who completed a baseline visit with a periodontal examination and a follow-up visit, and did not have CKD at baseline. PREDICTORS: Predictors included ≥30% of sites with clinical attachment loss ≥3 mm, ≥30% of sites with probing depth ≥4 mm, percentage of sites with bleeding on probing, and absence of functional dentition (<21 permanent teeth present). OUTCOMES: Outcomes were incident low estimated glomerular filtration rate (eGFR) (eGFR <60 mL/min/1.73 m2 and decline in eGFR ≥1 mL/min/year); incident albuminuria (urine albumin:creatinine ratio [ACR] ≥30 mg/g); and change in eGFR and ACR. ANALYTIC APPROACH: Poisson and linear regression. RESULTS: For the sample (n = 7.732), baseline mean age was 41.5 years, 45.2% were male, 11.7% had ≥30% of sites with clinical attachment loss ≥3 mm, 5.1% had ≥30% of sites with probing depth ≥4 mm, 30.7% had ≥50% of sites with bleeding on probing, and 16.2% had absent functional dentition. During a median follow-up of 5.9 years, 149 patients developed low eGFR and 415 patients developed albuminuria. On multivariable analysis, presence versus absence of ≥30% of sites with probing depth ≥4 mm and absence of functional dentition were each associated with increased risk for incident low eGFR (incident density ratio, 2.31; 95% CI, 1.14-4.65 and 1.65, 95% CI, 1.01-2.70, respectively). None of the other predictors were associated with outcomes. LIMITATIONS: Only a single kidney function follow-up measure. CONCLUSIONS: In this cohort of US Hispanics/Latinos, we found that select measures of periodontal disease were associated with incident low eGFR. Future work is needed to assess whether the treatment of periodontal disease may prevent CKD.

Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease.

Renal disease variability in autosomal dominant polycystic kidney disease (ADPKD) is strongly influenced by the gene locus (PKD1 versus PKD2). Recent studies identified nontruncating PKD1 mutations in approximately 30% of patients who underwent comprehensive mutation screening, but the clinical significance of these mutations is not well defined. We examined the genotype-renal function correlation in a prospective cohort of 220 unrelated ADPKD families ascertained through probands with serum creatinine ≤1.4 mg/dl at recruitment. We screened these families for PKD1 and PKD2 mutations and reviewed the clinical outcomes of the probands and affected family members. Height-adjusted total kidney volume (htTKV) was obtained in 161 affected subjects. Multivariate Cox proportional hazard modeling for renal and patient survival was performed in 707 affected probands and family members. Overall, we identified pathogenic mutations in 84.5% of our families, in which the prevalence of PKD1 truncating, PKD1 in-frame insertion/deletion, PKD1 nontruncating, and PKD2 mutations was 38.3%, 4.3%, 27.1%, and 30.3%, respectively. Compared with patients with PKD1 truncating mutations, patients with PKD1 in-frame insertion/deletion, PKD1 nontruncating, or PKD2 mutations have smaller htTKV and reduced risks (hazard ratio [95% confidence interval]) of ESRD (0.35 [0.14 to 0.91], 0.10 [0.05 to 0.18], and 0.03 [0.01 to 0.05], respectively) and death (0.31 [0.11 to 0.87], 0.20 [0.11 to 0.38], and 0.18 [0.11 to 0.31], respectively). Refined genotype-renal disease correlation coupled with targeted next generation sequencing of PKD1 and PKD2 may provide useful clinical prognostication for ADPKD.

FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.

BACKGROUND: Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. METHODS: We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples from patients. RESULTS: Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. CONCLUSIONS: Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.).