NR3C1 (nuclear receptor subfamily 3, group C, member 1/glucocorticoid receptor)

NR3C1 gene encodes the human glucocorticoid receptor(hGR), which is a ligand-dependent transcription factor and activates transcription of glucocorticoid-responsive genes through binding directly to glucocorticoid response elements(GREs) in their promoter region, or modulating transcriptional activity of other transcription factors through protein-protein interactions. hGR is implicated in a broad spectrum of biochemical physiologic functions, which are essential for life, and has also a key role in the maintenance of basal and stress-related homeostasis. Almost 20% of the genes expressed in human leukocytes are regulated positively or negatively by the hGR. Approximately every cellular, molecular and other physiologic network in the human body are influenced by this receptor and more specifically growth, reproduction, intermediary metabolism, immune and inflammatory reactions, as well as central nervous system and cardiovascular functions and lymphoproliferative disorders, cellular proliferation and differentiation in target tissues and normal renal tubular function and thus water and electrolyte homeostasis are only some of the examples where hGR is implicated(Nicolaides, Galata, Kino, Chrousos, and Charmandari, 2010)

Bone mineral density in patients with inherited bone marrow failure syndromes.

BackgroundPatients with inherited bone marrow failure syndromes (IBMFS) may have several risk factors for low bone mineral density (BMD). We aimed to evaluate the prevalence of low BMD in IBMFS and determine the associated risk factors.MethodsPatients with IBMFS with at least one dual-energy X-ray absorptiometry (DXA) scan were evaluated. Diagnosis of each IBMFS, Fanconi anemia (FA), dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome was confirmed by syndrome-specific tests. Data were gathered on age, height, and clinical history. DXA scans were completed at the lumbar spine, femoral neck, and forearm. BMD was adjusted for height (HAZ) in children (age ≤20 years). Low BMD was defined as a BMD Z-score and HAZ ≤-2 in adults and children, respectively, in addition to patients currently on bisphosphonate therapy.ResultsNine of thirty-five adults (26%) and eleven of forty children (27%) had low BMD. Adults with FA had significantly lower BMD Z-scores than those with other diagnoses; however, HAZ did not vary significantly in children by diagnosis. Risk factors included hypogonadism, iron overload, and glucocorticoid use.ConclusionsAdults and children with IBMFS have high prevalence of low BMD. Prompt recognition of risk factors and management are essential to optimize bone health

ARMC 5 Variants and Risk of Hypertension in Blacks: MH- GRID Study.

Background We recently found that ARMC 5 variants may be associated with primary aldosteronism in blacks. We investigated a cohort from the MH - GRID (Minority Health Genomics and Translational Research Bio-Repository Database) and tested the association between ARMC 5 variants and blood pressure in black s. Methods and Results Whole exome sequencing data of 1377 black s were analyzed. Target single-variant and gene-based association analyses of hypertension were performed for ARMC 5, and replicated in a subset of 3015 individuals of African descent from the UK Biobank cohort. Sixteen rare variants were significantly associated with hypertension ( P=0.0402) in the gene-based (optimized sequenced kernel association test) analysis; the 16 and one other, rs116201073, together, showed a strong association ( P=0.0003) with blood pressure in this data set. The presence of the rs116201073 variant was associated with lower blood pressure. We then used human embryonic kidney 293 and adrenocortical H295R cells transfected with an ARMC 5 construct containing rs116201073 (c.*920T>C). The latter was common in both the discovery ( MH - GRID ) and replication ( UK Biobank) data and reached statistical significance ( P=0.044 [odds ratio, 0.7] and P=0.007 [odds ratio, 0.76], respectively). The allele carrying rs116201073 increased levels of ARMC5 mRNA , consistent with its protective effect in the epidemiological data. Conclusions ARMC 5 shows an association with hypertension in black s when rare variants within the gene are considered. We also identified a protective variant of the ARMC 5 gene with an effect on ARMC 5 expression confirmed in vitro. These results extend our previous report of ARMC 5's possible involvement in the determination of blood pressure in blacks

Aortic pulse wave velocity in children with Cushing syndrome: A window into a marker of early cardiovascular disease.

ObjectiveTo investigate early signs of cardiovascular arterial remodelling in paediatric patients with Cushing syndrome (CS) in comparison with normative values from healthy children.Study designThe metrics used to assess cardiac health were from thoracic aorta and carotid MRI. Scans were performed on 18 children with CS (mean: 12.5 ± 3.1 years, range: 6.0-16.8 years, 10 female). Pulse wave velocity (PWV), aortic distensibility (AD) and carotid intima-media thickness (cIMT), well-validated measurements of cardiac compromise, were measured from the images and compared to normative age-matched values where available.ResultsPatients with CS had significantly higher PWV compared to age-adjusted normal median control values (4.0 ± 0.7 m/s vs. 3.4 ± 0.2 m/s, respectively, P = 0.0115). PWV was positively correlated with midnight plasma cortisol (r = 0.56, P = 0.02). Internal and common cIMT were negatively correlated with ascending AD (r = -0.75, P = 0.0022, r = -0.69, P = 0.0068, respectively).ConclusionPulse wave velocity data indicate that paediatric patients with CS have early evidence of cardiovascular remodelling. The results suggest the opportunity for monitoring as these changes begin in childhood

Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene.

UnlabelledAutosomal recessive pseudohypoaldosteronism type 1 (PHA1) is a rare disorder characterized by sodium wasting, failure to thrive, hyperkalemia, hypovolemia and metabolic acidosis. It is due to mutations in the amiloride-sensitive epithelial sodium channel (ENaC) and is characterized by diminished response to aldosterone. Patients may present with life-threatening hyperkalemia, which must be recognized and appropriately treated. A 32-year-old female was referred to the National Institutes of Health (NIH) for evaluation of hyperkalemia and muscle pain. Her condition started in the second week of life, when she was brought to an outside hospital lethargic and unresponsive. At that time, she was hypovolemic, hyperkalemic and acidotic, and was eventually treated with sodium bicarbonate and potassium chelation. At the time of the presentation to the NIH, her laboratory evaluation revealed serum potassium 5.1 mmol/l (reference range: 3.4-5.1 mmol/l), aldosterone 2800 ng/dl (reference range: ≤21 ng/dl) and plasma renin activity 90 ng/ml/h (reference range: 0.6-4.3 ng/ml per h). Diagnosis of PHA1 was suspected. Sequencing of the SCNN1B gene, which codes for ENaC, revealed that the patient is a compound heterozygote for two novel variants (c.1288delC and c.1466+1 G>A), confirming the suspected diagnosis of PHA1. In conclusion, we report a patient with novel variants of the SCNN1B gene causing PHA1 with persistent, symptomatic hyperkalemia.Learning pointsPHA1 is a rare genetic condition, causing functional abnormalities of the amiloride-sensitive ENaC.PHA1 was caused by previously unreported SCNN1B gene mutations (c.1288delC and c.1466+1 G>A).Early recognition of this condition and adherence to symptomatic therapy is important, as the electrolyte abnormalities found may lead to severe dehydration, cardiac arrhythmias and even death.High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment

Lipoprotein particles in patients with pediatric Cushing disease and possible cardiovascular risks.

BackgroundCardiovascular (CV) complications are the most significant cause of mortality in adults with Cushing disease (CD); little is known about CV risk factors in children with CD. Measurement of lipoprotein particles by nuclear magnetic resonance (NMR) spectroscopy is a novel technology to assess CV risk. The objective of the current study is to analyze the NMR lipid profile in pediatric CD patients before and 1 year after remission.MethodsNMR lipid profile was obtained via the Vantera NMR analyzer, using frozen serum samples from 33 CD patients (mean age 13.8 ± 4.0 years) evaluated between 1997 and 2017 at the National Institutes of Health (NIH) Clinical Center (CC).ResultsGlycA (glycosylated acute-phase proteins), triglyceride-rich particles (TRLP medium and very small sizes), low-density lipoprotein (LDL) particles (LDLP total and large size), high-density lipoprotein (HDL) particles (HDLP total, medium and small sizes), total cholesterol, LDL-cholesterol, HDL-cholesterol, GlycA inflammatory biomarker, and apolipoprotein B and apolipoprotein A1 (ApoA1) concentrations showed statistically significant changes after remission of CD (p < 0.05).ConclusionIn our study population, most of the lipid variables improved post-CD remission, with the exception of HDL and ApoA1, indicating that NMR lipoprotein profile may be a helpful tool in assessing the CV risk in pediatric patients with CD

Corticotropinoma as a Component of Carney Complex.

Known germline gene abnormalities cause one-fifth of the pituitary adenomas in children and adolescents, but, in contrast with other pituitary tumor types, the genetic causes of corticotropinomas are largely unknown. In this study, we report a case of Cushing disease (CD) due to a loss-of-function mutation in PRKAR1A, providing evidence for association of this gene with a corticotropinoma. A 15-year-old male presenting with hypercortisolemia was diagnosed with CD. Remission was achieved after surgical resection of a corticotropin (ACTH)-producing pituitary microadenoma, but recurrence 3 years later prompted reoperation and radiotherapy. Five years after the original diagnosis, the patient developed ACTH-independent Cushing syndrome, and a diagnosis of primary pigmented nodular adrenocortical disease was confirmed. A PRKAR1A mutation (c.671delG, p.G225Afs*16) was detected in a germline DNA sample from the patient, which displayed loss of heterozygosity in the corticotropinoma. No other germline or somatic mutations of interest were found. As corticotropinomas are not a known component of Carney complex (CNC), we performed loss of heterozygosity and messenger RNA stability studies in the patient's tissues, and analyzed the effect of Prkar1a silencing on AtT-20/D16v-F2 mouse corticotropinoma cells. No PRKAR1A defects were found among 97 other pediatric CD patients studied. Our clinical case and experimental data support a role for PRKAR1A in the pathogenesis of a corticotroph cell tumor. This is a molecularly confirmed report of a corticotropinoma presenting in association with CNC. We conclude that germline PRKAR1A mutations are a novel, albeit apparently infrequent, cause of CD

Novel polymorphisms and lack of mutations in the ACD gene in patients with ACTH resistance syndromes

Objective  ACTH resistance is a feature of several human syndromes with known genetic causes, including familial glucocorticoid deficiency (types 1 and 2) and triple A syndrome. However, many patients with ACTH resistance lack an identifiable genetic aetiology. The human homolog of the Acd gene, mutated in a mouse model of adrenal insufficiency, was sequenced in 25 patients with a clinical diagnosis of familial glucocorticoid deficiency or triple A syndrome. Design  A 3·4 kilobase genomic fragment containing the entire ACD gene was analysed for mutations in all 25 patients. Setting  Samples were obtained by three investigators from different institutions. Patients  The primary cohort consisted of 25 unrelated patients, primarily of European or Middle Eastern descent, with a clinical diagnosis of either familial glucocorticoid deficiency (FGD) or triple A syndrome. Patients lacked mutations in other genes known to cause ACTH resistance, including AAAS for patients diagnosed with triple A syndrome and MC2R and MRAP for patients diagnosed with familial glucocorticoid deficiency. Thirty-five additional patients with adrenal disease phenotypes were added to form an expanded cohort of 60 patients. Measurements  Identification of DNA sequence changes in the ACD gene in the primary cohort and analysis of putative ACD haplotypes in the expanded cohort. Results  No disease-causing mutations were found, but several novel single nucleotide polymorphisms (SNPs) and two putative haplotypes were identified. The overall frequency of SNPs in ACD is low compared to other gene families. Conclusions  No mutations were identified in ACD in this collection of patients with ACTH resistance phenotypes. However, the newly identified SNPs in ACD should be more closely examined for possible links to disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73948/1/j.1365-2265.2007.02855.x.pd

Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease.

The CABLES1 cell cycle regulator participates in the adrenal-pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing's disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene

Is there a common cause for paediatric Cushing’s disease?

Introduction: According to recent literature, somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are the most common changes in patients with Cushing’s disease (CD). Data on the frequency of these mutations in the paediatric population are limited. The aim of the presented study was to determine the frequency of the USP8 gene mutations in a group of paediatric patients with CD treated at the Children’s Memorial Health Institute (CMHI). Material and methods: Eighteen patients (nine females) with CD were treated at CMHI, Warsaw, Poland between 1993 and 2019. All patients underwent transsphenoidal surgery (TSS) as a primary treatment for CD. The average age of all patients at TSS was 13.10 years (5.42–17.25). DNA was extracted from formalin-fixed paraffin-embedded resected tumour tissue. Sanger sequencing was performed on DNA sequence corresponding to the exon 14 of USP8 gene. Results: The mean age at diagnosis of CD was 13.08 years, and the average duration of symptoms before diagnosis was 2.96 years. All patients were operated at CMHI by the same neurosurgeon. Fifteen out of 18 patients (83.33%) had initial biochemical remission after a single TSS procedure (post-operative serum cortisol < 1.8 μg/dL). The result of genetic testing was negative for all samples at the hotspot area of the USP8 gene. Conclusion: The current retrospective study demonstrates that mutations in the USP8 gene may not be as common a cause of paediatric Cushing’s disease, as previously reported