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Familial hypocalciuric hypercalcemia (FHH) causes hypercalcemia by three genetic mechanisms: inactivating mutations in the calcium-sensing receptor, the G-protein subunit α11, or adaptor-related protein complex 2, sigma 1 subunit. While hypercalcemia in other conditions causes significant morbidity and mortality, FHH generally follows a benign course. Failure to diagnose FHH can result in unwarranted treatment or surgery for the mistaken diagnosis of primary hyperparathyroidism (PHPT), given the significant overlap of biochemical features. Determinations of urinary calcium excretion greatly aid in distinguishing PHPT from FHH, but overlap still exists in certain cases. It is important that 24-h urine calcium and creatinine be included in the initial workup of hypercalcemia. FHH should be considered if low or even low normal urinary calcium levels are found in what is typically an asymptomatic hypercalcemic patient. The calcimimetic cinacalcet has been used to treat hypercalcemia in certain symptomatic causes of FHH.

Matrix metalloproteinase-2 (MMP-2; gelatinase A) is known to degrade a broad range of extracellular matrix components and chemokines, and has important roles in the processes of cell migration, invasion, and involution during development, as well as during tumor growth and metastasis and in inflammation and repair. To better elucidate the roles of this matrix metalloproteinase in the development and progression of experimental autoimmune encephalomyelitis, we used MMP-2-deficient (KO) mice. Surprisingly, we found that MMP-2 KO mice exhibited an earlier onset and more severe disease than did their wild-type (WT) counterparts. WT mice engrafted with MMP-2 KO bone marrow exhibited a similar earlier onset and more severe clinical disease score than WT mice engrafted with WT bone marrow. Lymphocytes derived from MMP-2 KO mice exhibited increased transmigration through endothelial cell monolayers as well as through collagen type IV and laminin-coated BD BIOCOAT inserts, which correlated with a 3-fold increase in expression of MMP-9 and was abrogated by inhibition of MMP activity. We demonstrated a correlation between expression levels of MMP-9 and MT1-MMP expression and suggest a signaling pathway involving tethering of MMP-2 to MT1-MMP as a modulator of MMP-9 expression. Last, we discuss other possible MMP-2-mediated mechanisms which may contribute to the observed phenotype.

SUMMARYPersistent down-regulation in the expression of the hyperpolarization-activated HCN1 cation channel, a key determinant of intrinsic neuronal excitability, has been observed in febrile seizure, temporal lobe epilepsy, and generalized epilepsy animal models, as well as in patients with epilepsy. However, the role and importance of HCN1 down-regulation for seizure activity is unclear. To address this question we determined the susceptibility of mice with either a general or forebrain-restricted deletion of HCN1 to limbic seizure induction by amygdala kindling or pilocarpine administration. Loss of HCN1 expression in both mouse lines is associated with higher seizure severity and higher seizure-related mortality, independent of the seizure-induction method used. Therefore, down-regulation of HCN1 associated with human epilepsy and rodent models may be a contributing factor in seizure behavior.

We compared the expression profiles of the mRNAs of both estrogen receptors, ER-alpha and the recently cloned ER-beta, in the midgestational human fetus by semiquantitative RT-PCR. ER-alpha was most abundant in the uterus, and smaller quantities were detected in the ovary, testis, skin and gut. High amounts of ER-beta mRNA were present in fetal ovaries, testes, adrenals and spleen. In these tissues, the levels of ER-beta mRNA were higher than ER-alpha. In the uterus, however, ER-alpha mRNA was more abundant, and ER-beta mRNA was expressed only moderately. ER-beta mRNA was present at moderate to low levels in the thymus, pituitary gland, skin, lung, kidney and brain cortex. In the course of our work, using the ER-beta primers on genomic DNA, an intron of 2468 bp in length, located between nt 222 and 223 in the A/B domain of ER-beta cDNA, was detected, cloned and sequenced. The study shows that the expression profile of the two ERs is different, and ER-beta is expressed in a variety of tissues during human fetal development, suggesting different, organ-specific roles for the two receptors.

Abstract Context Transgender youth may initiate gonadotropin-releasing hormone agonists (GnRHa) to suppress puberty, a critical period for bone-mass accrual. Low bone mineral density (BMD) has been reported in late-pubertal transgender girls prior to gender-affirming therapy, but little is known about BMD in early-pubertal transgender youth. Objective To describe BMD in early-pubertal transgender youth. Design Cross-sectional analysis of the prospective, observational, longitudinal Trans Youth Care Study cohort. Setting Four multi-disciplinary academic pediatric gender centers in the United States. Participants Early-pubertal transgender youth initiating GnRHa. Main Outcome Measures Areal and volumetric BMD Z-scores. Results Designated males at birth (DMAB) had below-average BMD Z-scores when compared with male reference standards, and designated females at birth (DFAB) had below-average BMD Z-scores when compared with female reference standards except at hip sites. At least one BMD Z-score was < -2 in 30% of DMAB and 13% of DFAB. Youth with low BMD scored lower on the Physical Activity Questionnaire for Older Children than youth with normal BMD, 2.32 ± 0.71 vs. 2.76 ± 0.61 (p = 0.01). There were no significant deficiencies in vitamin D, but dietary calcium intake was suboptimal in all youth. Conclusions In early-pubertal transgender youth, BMD was lower than reference standards for sex designated at birth. This lower BMD may be explained, in part, by suboptimal calcium intake and decreased physical activity – potential targets for intervention. Our results suggest a potential need for assessment of BMD in pre-pubertal gender-diverse youth and continued monitoring of BMD throughout the pubertal period of gender-affirming therapy.

Purpose Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome of abnormal phosphate and vitamin D metabolism caused by typically small endocrine tumors that secrete fibroblast growth factor 23 (FGF23). TIO is characterized clinically by progressive musculoskeletal pain, fatigue, proximal muscle weakness, and multiple fractures, leading to long-term disability. Misdiagnosis and delayed diagnosis are common because of the non-specific symptoms, and several years may elapse before patients receive an accurate diagnosis and appropriate treatment. Thus, it is vital that awareness of the appropriate recognition and management of TIO is increased among healthcare professionals who may encounter patients with suspected TIO. Methods A roundtable meeting was held on 10 January 2020 in Dallas, TX, USA to gather perspectives on the diagnosis and treatment of TIO. The following topics were considered: clinical presentation, patient history, differential diagnosis, laboratory assessment, imaging, venous sampling, and treatment. Results This report provides a summary of our collective experiences in the management of TIO. Main conclusions Laboratory tests are mandatory to expedite TIO diagnosis and should include measurement of fasting serum phosphorus, renal phosphate reabsorption, serum 1,25-dihydroxyvitamin D, and serum FGF23 levels. Functional and anatomical imaging are essential to locate the FGF23-secreting tumor(s) causing TIO. Surgical resection is often a curative treatment when the tumor can be localized; however, better management of non-operable patients with targeted therapies is needed. Further efforts to increase awareness of TIO within the medical community, and education on recommended diagnostic and treatment pathways are required to improve the management of this debilitating disease.

Developmental changes in the responsiveness of the fetal adrenals to corticotropin (ACTH) play an important role in the regulation of the fetal hypothalamic-pituitary-adrenal axis. Responsiveness of adrenal cortical cells to ACTH is dependent on the extent of ACTH receptor expression. Therefore, we examined the localization and regulation of ACTH receptor expression in the midgestation (16-24 weeks) human fetal adrenal cortex. In situ hybridization analysis was used to localize messenger RNA (mRNA) encoding the ACTH receptor in sections of human fetal adrenal glands. Messenger RNA encoding the ACTH receptor was localized in cells from all cortical zones; abundance was higher in definitive zone than in fetal zone cells and was least abundant in the more central portions of the cortex. Regulation of ACTH receptor expression was studied using Northern blot analysis of total RNA extracted from primary cultures of fetal and definitive zone cells. Two major (1.5 and 3.5 kilobases) and, upon stimulation with ACTH, 3 minor (4.0, 6.0 and 10.0 kb) ACTH receptor mRNA transcripts were detected in RNA from fetal and definitive zone cells. In both cell types, ACTH-(1-24) increased the abundance of mRNA encoding the ACTH receptor 10- to 20-fold compared with untreated cells. The effects of ACTH-(1-24) on ACTH receptor expression in fetal zone cells were time- and dose-dependent. The ED50 for the stimulation of ACTH receptor expression by ACTH-(1-24) was 1-10 pM, and maximal response to 0.1 nm ACTH-(1-24) was detected after 12-16 h. Eight-bromoadenosine cAMP and forskolin also stimulated ACTH receptor expression in fetal zone cells and closely mimicked the effects of ACTH-(1-24). In contrast, stimulation of protein kinase C with 12-O-tetradecanoyl phorbol 13-acetate had no effect on ACTH receptor expression. Changes in ACTH receptor expression in response to ACTH-(1-24), cAMP and forskolin were paralleled by changes in expression of the P450 cholesterol side chain cleavage (P450scc) enzyme. These data demonstrate that expression of the ACTH receptor by the human fetal adrenal cortex is up-regulated by its own ligand and that this effect is mediated by a cAMP-dependent mechanism. In addition, the coordinate stimulation of ACTH receptor and P450scc expression by ACTH indicates that the gene for the ACTH receptor is one of a specific cohort of genes regulated by ACTH that are required to facilitate fetal adrenal cortical response to ACTH. ACTH regulation of its own receptor may represent a mechanism by which fetal adrenal responsiveness to ACTH is maintained and possibly enhanced during fetal development.