Publications by authors named "Fady Hannah-Shmouni"

77 Publications

A case of Carney triad complicated by renal cell carcinoma and a germline SDHA pathogenic variant.

Endocrinol Diabetes Metab Case Rep 2021 Mar 28;2021. Epub 2021 Mar 28.

Section on Endocrinology and Genetics, National Institutes of Health, Bethesda, Maryland, USA.

Summary: Succinate dehydrogenase deficiency has been associated with several neoplasias, including renal cell carcinoma (RCC) and those associated with hereditary paraganglioma (PGL)/ pheochromocytoma (PHEO) syndromes, Carney dyad, and Carney triad. Carney triad is a rare multitumoral syndrome characterized by co-existing PGL, gastrointestinal stromal tumor (GIST), and pulmonary chondroma (CHO). We report a case of a 57-year-old male who presented with para-aortic and gastroesophogeal masses, and a right renal superior pole lesion, which were classified as multiple PGLs, a GIST, and a clear cell renal carcinoma, respectively, on pathology following surgical resection. Additionally, a CHO was diagnosed radiologically, although no biopsy was performed. A diagnosis of Carney triad was made. SDHB immunohistochemical staining was negative for the PGL and the GIST, indicating SDH-deficiency. Interestingly, the renal cell carcinoma (RCC) stained positive for both SDHB and SDHA. Subsequent genetic screening of SDH subunit genes revealed a germline inactivating heterozygous SDHA pathogenic variant (c.91 C>T, p.R31X). Loss of heterozygosity was not detected at the tumor level for the RCC, which likely indicated the SDHA variant would not be causative of the RCC, but could still predispose to the development of neoplasias. To the knowledge of the authors this is the first reported case of an SDHA pathogenic variant in a patient with Carney triad complicated by RCC.

Learning Points: The succinate dehydrogenase enzyme is encoded by four subunit genes (SDHA, SDHB, SDHC, and SDHD; collectively referred to as SDHx), which have been implicated in several neoplasias and are classified as tumor suppressor genes. Carney triad is a rare multiple-neoplasia syndrome presenting as an association of PGLs, GISTs, and CHOs. Carney triad is most commonly associated with hypermethylation of SDHC as demonstrated in tumor tissue, but approximately 10% of cases are due to pathogenic SDHx variants. Although SDHB pathogenic variants are most commonly reported in SDH-deficient renal cell carcinoma, SDHA disease-causing variants have been reported in rare cases.
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http://dx.doi.org/10.1530/EDM-20-0170DOI Listing
March 2021

Molecular Genetic and Genomic Alterations in Cushing's Syndrome and Primary Aldosteronism.

Front Endocrinol (Lausanne) 2021 12;12:632543. Epub 2021 Mar 12.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States.

The genetic alterations that cause the development of glucocorticoid and/or mineralocorticoid producing benign adrenocortical tumors and hyperplasias have largely been elucidated over the past two decades through advances in genomics. In benign aldosterone-producing adrenocortical tumors and hyperplasias, alteration of intracellular calcium signaling has been found to be significant in aldosterone hypersecretion, with causative defects including those in , and In benign cortisol-producing adrenocortical tumors and hyperplasias abnormal cyclic adenosine monophosphate-protein kinase A signaling has been found to play a central role in tumorigenesis, with pathogenic variants in , and being implicated. The role of this signaling pathway in the development of Cushing's syndrome and adrenocortical tumors was initially discovered through the study of the underlying genetic defects causing the rare multiple endocrine neoplasia syndromes McCune-Albright syndrome and Carney complex with subsequent identification of defects in genes affecting the cyclic adenosine monophosphate-protein kinase A pathway in sporadic tumors. Additionally, germline pathogenic variants in , a putative tumor suppressor, were found to be a cause of cortisol-producing primary bilateral macronodular adrenal hyperplasia. This review describes the genetic causes of benign cortisol- and aldosterone-producing adrenocortical tumors.
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http://dx.doi.org/10.3389/fendo.2021.632543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994620PMC
March 2021

First Somatic Defect Associated With Mosaicism for Another Mutation in a Patient With Cushing Syndrome.

J Endocr Soc 2021 Apr 25;5(4):bvab007. Epub 2021 Jan 25.

Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.

Context: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome (CS) associated mostly with Carney complex (CNC), a rare autosomal dominant multiple neoplasia syndrome. More than two-thirds of familial cases and approximately one-third of sporadic cases of CNC harbor germline inactivating defects. Increasingly sensitive technologies for the detection of genetic defects such as next-generation sequencing (NGS) have further highlighted the importance of mosaicism in human disease.

Case Description: A 33-year-old woman was diagnosed with ACTH-independent CS with abdominal computed tomography showing bilateral micronodular adrenal hyperplasia with a left adrenal adenoma. She underwent left adrenalectomy with pathology demonstrating PPNAD with a 1.5-cm pigmented adenoma. DNA analysis by Sanger sequencing revealed 2 different variants in the adenoma that were absent from DNA extracted from blood and saliva: c.682C > T and c.974-2A > G. "Deep" NGS revealed that 0.31% of DNA copies extracted from blood and saliva did in fact carry the c.682C > T variant, suggesting low-level mosaicism for this defect.

Conclusions: We present a case of PPNAD due to low-level mosaicism for a defect which led to the formation of an adenoma due to a second, adrenal-specific, somatic mutation. The identification of mosaicism for , depending on the number and distribution of cells affected has implications for genetic counseling and tumor surveillance. This is the first recorded case of a patient with mosaicism, PPNAD, and an adenoma forming due to complete inactivation of in adrenal tissue from a second, somatic-only, coding sequence mutation.
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http://dx.doi.org/10.1210/jendso/bvab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885549PMC
April 2021

Scoping review of COVID-19-related systematic reviews and meta-analyses: can we really have confidence in their results?

Postgrad Med J 2021 Feb 26. Epub 2021 Feb 26.

NICHD, National Institutes of Health, Bethesda, Maryland, USA

Aim: The aim of this study was to systematically appraise the quality of a sample of COVID-19-related systematic reviews (SRs) and discuss internal validity threats affecting the COVID-19 body of evidence.

Design: We conducted a scoping review of the literature. SRs with or without meta-analysis (MA) that evaluated clinical data, outcomes or treatments for patients with COVID-19 were included.

Main Outcome Measures: We extracted quality characteristics guided by A Measurement Tool to Assess Systematic Reviews-2 to calculate a qualitative score. Complementary evaluation of the most prominent published limitations affecting the COVID-19 body of evidence was performed.

Results: A total of 63 SRs were included. The majority were judged as a critically low methodological quality. Most of the studies were not guided by a pre-established protocol (39, 62%). More than half (39, 62%) failed to address risk of bias when interpreting their results. A comprehensive literature search strategy was reported in most SRs (54, 86%). Appropriate use of statistical methods was evident in nearly all SRs with MAs (39, 95%). Only 16 (33%) studies recognised heterogeneity in the definition of severe COVID-19 as a limitation of the study, and 15 (24%) recognised repeated patient populations as a limitation.

Conclusion: The methodological and reporting quality of current COVID-19 SR is far from optimal. In addition, most of the current SRs fail to address relevant threats to their internal validity, including repeated patients and heterogeneity in the definition of severe COVID-19. Adherence to proper study design and peer-review practices must remain to mitigate current limitations.
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http://dx.doi.org/10.1136/postgradmedj-2020-139392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918809PMC
February 2021

Cushing syndrome in a pediatric patient with a KCNJ5 variant and successful treatment with low dose ketoconazole.

J Clin Endocrinol Metab 2021 Feb 25. Epub 2021 Feb 25.

Section on Endocrinology & Genetics (SEGEN), Bethesda, MD, USA.

Context: Pathogenic variants in KCNJ5, encoding the GIRK4 (Kir3.4) potassium channel, have been implicated in the pahogenesis of familial hyperaldosteronism (FH) type-III (FH-III) and sporadic primary hyperaldosteronism (PA). In addition to aldosterone, glucocorticoids (GCs) are often found in PA in association with KCNJ5 pathogenic variants, albeit at subclinical levels. However, to date no GIRK4 defects have been linked to Cushing syndrome (CS).

Patient: We present the case of a 10-year-old child who presented with CS at an early age due to bilateral adrenocortical hyperplasia (BAH). The patient was placed on low-dose ketoconazole (KZL), which controlled hypercortisolemia and CS-related signs. Discontinuation of KZL for even 6 weeks led to recurrent CS.

Results: Screening for known genes causing cortisol-producing BAHs (PRKAR1A, PRKACA, PRKACB, PDE11A, PDE8B, ARMC5) failed to identify any gene defects. Whole-exome sequencing (WES) showed a novel KCNJ5 pathogenic variant (c.506T>C, p.L169S) inherited from her father. In vitro studies showed that the p.L169S variant affects conductance of the Kir3.4 channel without affecting its expression or membrane localization. Although there were no effects on steroidogenesis in vitro, there were modest changes in protein kinase A activity. In silico analysis of the mutant channel proposed mechanisms for the altered conductance.

Conclusions: We present a pediatric patient with CS due to BAH and a germline defect in KCNJ5. Molecular investigations of this KCNJ5 variant failed to show a definite cause of her CS. However, this KCNJ5 variant differed in its function from KCNJ5 defects leading to PA. We speculate that GIRK4 (Kir3.4) may play a role in early human adrenocortical development and zonation and participate in the pathogenesis of pediatric BAH.
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http://dx.doi.org/10.1210/clinem/dgab118DOI Listing
February 2021

Dual molecular diagnoses in a neurometabolic specialty clinic.

Am J Med Genet A 2021 03 24;185(3):766-773. Epub 2020 Dec 24.

Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.

Reports of patients with concomitant diagnoses of two inherited genetic disorders, sometimes referred to as "double trouble," have appeared intermittently in the medical literature. We report eight additional cases with dual diagnoses of two genetic conditions. All cases had a phenotype atypical for their primary diagnosis, leading to the search for a second genetic diagnosis. These cases highlight the importance of the history, physical examination and continued work-up if the phenotype of the patient falls drastically outside what has been reported with their primary diagnosis. Some of the diagnoses of the patients presented here (e.g., Myotonic Dystrophy Type 1, fascioscapulohumeral muscular dystrophy) would not have been identified by genetic testing done on a next generation sequencing backbone (e.g., panel or exome sequencing). When the clinical picture is atypical or more severe than expected the possibility of a dual diagnosis (double trouble) should be considered. Identification of a second genetic condition can impact management and genetic counseling.
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http://dx.doi.org/10.1002/ajmg.a.62034DOI Listing
March 2021

Volumetric Modeling of Adrenal Gland Size in Primary Bilateral Macronodular Adrenocortical Hyperplasia.

J Endocr Soc 2021 Jan 29;5(1):bvaa162. Epub 2020 Oct 29.

Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.

Context: Radiological characterization of adrenal size in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) has not been previously investigated.

Objective: We hypothesized that volumetric modeling of adrenal gland size may correlate with biochemical disease severity in patients with PBMAH. Secondary analysis of patients with concurrent primary aldosteronism (PA) was performed.

Design: A retrospective cross-sectional analysis of 44 patients with PBMAH was conducted from 2000 to 2019.

Setting: Tertiary care clinical research center.

Patients: Patients were diagnosed with PBMAH based upon clinical, genetic, radiographic and biochemical characteristics.

Intervention: Clinical, biochemical, and genetic data were obtained. Computed tomography scans were used to create volumetric models by manually contouring both adrenal glands in each slice using Vitrea Core Fx v6.3 software (Vital Images, Minnetonka, Minnesota).

Main Outcome And Measures: 17-hydroxycorticosteroids (17-OHS), genetics, and aldosterone-to-renin ratio (ARR) were retrospectively obtained. Pearson test was used for correlation analysis of biochemical data with adrenal volume.

Results: A cohort of 44 patients with PBMAH was evaluated, with a mean age (±SD) of 53 ± 11.53. Eight patients met the diagnostic criteria for PA, of whom 6 (75%) were Black. In the Black cohort, total adrenal volumes positively correlated with midnight cortisol (R = 0.76,  = 0.028), urinary free cortisol (R = 0.70,  = 0.035), and 17-OHS (R = 0.87,  = 0.0045), with a more pronounced correlation with left adrenal volume alone. 17-OHS concentration positively correlated with total, left, and right adrenal volume in patients harboring pathogenic variants in (R = 0.72,  = 0.018; R = 0.65,  = 0.042; and R = 0.73,  = 0.016, respectively).

Conclusions: Volumetric modeling of adrenal gland size may associate with biochemical severity in patients with PBMAH, with particular utility in Black patients.
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http://dx.doi.org/10.1210/jendso/bvaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716656PMC
January 2021

Commentary on A Rare Cause of Virilization, Short Stature, and Hypertension.

Clin Chem 2020 Dec;66(12):1493-1494

LifeLabs, Toronto, ON, Canada.

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http://dx.doi.org/10.1093/clinchem/hvaa243DOI Listing
December 2020

Prevalence of Hypothyroidism in Patients With Erdheim-Chester Disease.

JAMA Netw Open 2020 10 1;3(10):e2019169. Epub 2020 Oct 1.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Importance: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis affecting multiple organs and commonly caused by somatic pathogenic variants in BRAF V600E and mitogen-activated protein kinase genes. Clinical features of ECD result from histiocytic involvement of various tissues; while endocrine involvement in ECD occurs frequently, the prevalence of central or primary hypothyroidism has not been thoroughly investigated.

Objective: To assess hypothalamus-pituitary-thyroid (HPT) dysfunction in patients with ECD.

Design, Setting, And Participants: This cross-sectional study included 61 patients with ECD who were enrolled in a natural history study at a tertiary care center between January 2011 and December 2018. ECD was diagnosed on the basis of clinical, genetic, and histopathological features. Data were analyzed in March 2020.

Exposure: Diagnosis of ECD.

Main Outcomes And Measures: Main outcome was the prevalence of thyroid dysfunction in adults with ECD compared with community estimates. Patients underwent baseline evaluation with a thyroid function test, including thyrotropin, free thyroxine (fT4), and total thyroxine (T4), and sellar imaging with magnetic resonance imaging or computed tomography scan. The association of HPT dysfunction was assessed for differences in age, sex, body mass index, BRAF V600E status, high sensitivity C-reactive protein level, sellar imaging, and pituitary hormonal dysfunction.

Results: A total of 61 patients with ECD (46 [75%] men; mean [SD] age, 54.3 [10.9] years) were evaluated. Seventeen patients (28%) had hypothyroidism requiring levothyroxine therapy. The prevalence of both central and primary hypothyroidism were higher than community estimates (central hypothyroidism: 9.8% vs 0.1%; odds ratio, 109.0; 95% CI, 37.4-260.6; P < .001; primary hypothyroidism: 18.0% vs 4.7%; OR, 4.4; 95% CI, 2.1-8.7; P < .001). Patients with hypothyroidism (both primary and central), compared with patients with euthyroidism, had higher body mass index (median [interquartile range] 31.4 [28.3-38.3] vs 26.7 [24.4-31.9]; P = .004) and a higher prevalence of panhypopituitarism (7 [47%] vs 3 [7%]; P < .001). Among patients with hypothyroidism, those with central hypothyroidism, compared with patients with primary hypothyroidism, had a lower mean (SD) body mass index (28.3 [2.6] vs 36.3 [5.9]; P = .007) and higher frequencies of abnormal sellar imaging (5 [83%] vs 3 [27%]; P = .050) and panhypopituitarism (5 [83%] vs 3 [27%]; P = .050).

Conclusions And Relevance: In this cohort study, a higher prevalence of central and primary hypothyroidism was identified in patients with ECD compared with the community. There should be a low threshold for testing for hypothyroidism in patients with ECD, and treatment should follow standard guidelines.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.19169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596581PMC
October 2020

Insights into the Immunopathophysiology of Severe COVID-19 in Metabolic Disorders.

Ann Natl Acad Med Sci 2020 Apr;56(2):112-115

Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.

COVID-19 has affected millions of people across the world but disproportionately and severely affects persons with metabolic disorders such as obesity, diabetes mellitus and hypertension. In this brief review, we discuss the pathways of immune dysregulation that may lead to severe COVID-19 in persons with metabolic conditions.
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http://dx.doi.org/10.1055/s-0040-1713346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571615PMC
April 2020

Oxidative phosphorylation in creatine transporter deficiency.

NMR Biomed 2021 01 29;34(1):e4419. Epub 2020 Sep 29.

Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland.

X-linked creatine transporter deficiency (CTD) is one of the three types of cerebral creatine deficiency disorders. CTD arises from pathogenic variants in the X-linked gene SLC6A8. We report the first phosphorus ( P) MRS study of patients with CTD, where both phosphocreatine and total creatine concentrations were found to be markedly reduced. Despite the diminished role of creatine and phosphocreatine in oxidative phosphorylation in CTD, we found no elevation of lactate or lowered pH, indicating that the brain energy supply still largely relied on oxidative metabolism. Our results suggest that mitochondrial function is a potential therapeutic target for CTD.
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http://dx.doi.org/10.1002/nbm.4419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722185PMC
January 2021

Prevalence of Diabetes and Hypertension and Their Associated Risks for Poor Outcomes in Covid-19 Patients.

J Endocr Soc 2020 Sep 21;4(9):bvaa102. Epub 2020 Jul 21.

Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland.

Coronavirus disease 2019 (Covid-19) has affected millions of people and may disproportionately affect those with hypertension and diabetes. Because of inadequate methods in published systematic reviews, the prevalence of diabetes and hypertension and associated risks of poor outcomes in Covid-19 patients are unknown. We searched databases from December 1, 2019, to April 6, 2020, and selected observational peer-reviewed studies in English of patients with Covid-19. Independent reviewers extracted data on study participants, interventions, and outcomes and assessed risk of bias, and the certainty of evidence. We included 65 (15 794 participants) observational studies at moderate to high risk of bias. Overall prevalence of diabetes and hypertension was 12% (95% confidence interval [CI], 10-15; n = 12 870; : 89%), and 17% (95% CI, 13-22; n = 12 709; : 95%), respectively. In severe Covid-19, the prevalence of diabetes and hypertension were 18% (95% CI, 16-20; n = 1099; : 0%) and 32% (95% CI, 16-54; n = 1078; : 63%), respectively. Unadjusted relative risk for intensive care unit admission and mortality were 1.96 (95% CI, 1.19-3.22; n = 8890; : 80%;  = .008) and 2.78 (95% CI, 1.39-5.58; n = 2058; : 75%;  = .0004) for diabetics; and 2.95 (95% CI, 2.18-3.99; n = 1737; : 0%;  < .001) and 2.39 (95% CI, 1.54-3.73; n = 3107; : 66%;  < .001) for hypertensives. Neither diabetes (1.50; 95% CI, 0.90-2.50; n = 1991; : 74%;  = .119) nor hypertension (1.48; 95% CI, 0.99-2.23; n = 2023; : 69%;  = .058) was associated with severe Covid-19. In conclusion, the risk of intensive care unit admission and mortality for patients with diabetes or hypertension who developed Covid-19 is increased compared with those without these comorbidities.

Prospero Registration Number: CRD42020176582.
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http://dx.doi.org/10.1210/jendso/bvaa102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454711PMC
September 2020

Targeting vulnerable atherosclerotic plaque via PET-tracers aiming at cell-surface overexpression of somatostatin receptors.

Biomed Rep 2020 Sep 16;13(3). Epub 2020 Jun 16.

Department of Radiology, Medical School, University of Crete, 71003 Heraklion, Greece.

Cardiovascular disease (CD) is the leading cause of death in the developed world, with major atherothrombotic events, being mainly attributed to the rupture of unstable, vulnerable atherosclerotic lesions, leading to blood flow obstruction. Since unstable atherosclerotic plaques frequently do not cause hemodynamically significant blood flow restriction, conventional stress imaging tests cannot depict the vulnerable, high-risk for rupture atherosclerotic lesions. Therefore, molecular imaging techniques targeting specific pathophysiologic features related to atherosclerotic plaque rupture mechanism, hold promise for precise and individualized treatment strategies of CD. In the current report, we describe in a patient diagnosed with pancreatic neuroendocrine tumor, the selective uptake of Ga-DOATATE by an atherosclerotic lesion in the thoracic aorta. This data indicates that Ga-DOTATATE, which is a positron emitting tomography tracer, targeting the recruitment of macrophages taking place in the vulnerable plaque, could potentially serve as an imaging probe for the detection of high-risk, prone to rupture plaques.
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http://dx.doi.org/10.3892/br.2020.1316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391298PMC
September 2020

Curative resection of an aldosteronoma causing primary aldosteronism in the second trimester of pregnancy.

Endocrinol Diabetes Metab Case Rep 2020 Aug 4;2020. Epub 2020 Aug 4.

Section on Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.

Summary: A 29-year-old primigravida woman with a known history of primary aldosteronism due to a right aldosteronoma presented with uncontrolled hypertension at 5 weeks of estimated gestation of a spontaneous pregnancy. Her hypertension was inadequately controlled with pharmacotherapy which lead to the consideration of surgical management for her primary aldosteronism. She underwent curative right unilateral adrenalectomy at 19 weeks of estimated gestational age. The procedure was uncomplicated, and her blood pressure normalized post-operatively. She did, however, have a preterm delivery by cesarean section due to intrauterine growth retardation with good neonatal outcome. She is normotensive to date.

Learning Points: Primary aldosteronism is the most common etiology of secondary hypertension with an estimated prevalence of 5-10% in the hypertensive population. It is important to recognize the subtypes of primary aldosteronism given that certain forms can be treated surgically. Hypertension in pregnancy is associated with significantly higher maternal and fetal complications. Data regarding the treatment of primary aldosteronism in pregnancy are limited. Adrenalectomy can be considered during the second trimester of pregnancy if medical therapy fails to adequately control hypertension from primary aldosteronism.
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http://dx.doi.org/10.1530/EDM-20-0043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424322PMC
August 2020

ARMC5 variants in PRKAR1A-mutated patients modify cortisol levels and Cushing's syndrome.

Endocr Relat Cancer 2020 09;27(9):509-517

Section on Endocrinology & Genetics (SEGEN), National Institutes of Health (NIH), Bethesda, Maryland, USA.

Mutations in the protein kinase A (PKA) regulatory subunit type 1A (PRKAR1A) and armadillo repeat-containing 5 (ARMC5) genes cause Cushing's syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD) and primary bilateral macronodular adrenocortical hyperplasia (PBMAH), respectively. Between the two genes, ARMC5 is highly polymorphic with several variants in the population, whereas PRKAR1A has very little, if any, non-pathogenic variation in its coding sequence. We tested the hypothesis that ARMC5 variants may affect the clinical presentation of PPNAD and CS among patients with PRKAR1A mutations. In this study, 91 patients with PPNAD due to PRKAR1A mutations were tested for abnormal cortisol secretion or CS and for ARMC5 sequence variants. Abnormal cortisol secretion was present in 71 of 74 patients with ARMC5 variants, whereas 11 of 17 patients negative for ARMC5 variants did not have hypercortisolemia. The presence of ARMC5 variants was a statistically strong predictor of CS among patients with PRKAR1A mutations (P < 0.001). Among patients with CS due to PPNAD, ARMC5 variants were associated with lower cortisol levels at baseline (P = 0.04) and after high dose dexamethasone administration (P = 0.02). The ARMC5 p.I170V variant increased ARMC5 protein accumulation in vitro and decreased viability of NCI-H295 cells (but not HEK 293T cells). PPNAD tissues with ARMC5 variants showed stronger ARMC5 protein expression than those that carried a normal ARMC5 sequence. Taken together, our results suggest that ARMC5 variants among patients with PPNAD due to PRKAR1A defects may play the role of a genetic modifier for the presence and severity of hypercortisolemia.
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http://dx.doi.org/10.1530/ERC-20-0273DOI Listing
September 2020

Endocrine Conditions and COVID-19.

Horm Metab Res 2020 Jul 8;52(7):471-484. Epub 2020 Jun 8.

Section on Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland, USA.

COVID-19 was declared a global pandemic by the WHO and has affected millions of patients around the world. COVID-19 disproportionately affects persons with endocrine conditions, thus putting them at an increased risk for severe disease. We discuss the mechanisms that place persons with endocrine conditions at an additional risk for severe COVID-19 and review the evidence. We also suggest precautions and management of endocrine conditions in the setting of global curfews being imposed and offer practical tips for uninterrupted endocrine care.
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http://dx.doi.org/10.1055/a-1172-1352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417289PMC
July 2020

Adrenocortical tumorigenesis: Lessons from genetics.

Best Pract Res Clin Endocrinol Metab 2020 05 23;34(3):101428. Epub 2020 May 23.

Section on Endocrinology and Genetics & Inter-Institute Endocrinology Fellowship Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA. Electronic address:

Advances in genomics over the past two decades have allowed for elucidation of the genetic alterations leading to the development of adrenocortical tumors and/or hyperplasias. These molecular changes were initially discovered through the study of rare familial tumor syndromes such as McCune-Albright Syndrome, Carney complex, Li-Fraumeni syndrome, and Beckwith-Wiedemann syndrome, with the identification of alterations in genes and molecular pathways that subsequently led to the discovery of aberrations in these or related genes and pathways in sporadic tumors. Genetic alterations in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B, that lead to aberrant cyclic adenosine monophosphate-protein (cAMP) kinase A signaling, were found to play a major role in the development of benign cortisol-producing adrenocortical tumors and/or hyperplasias, whereas genetic defects in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2 were implicated in the development of benign aldosterone-producing tumors and/or hyperplasias through modification of intracellular calcium signaling. Germline ARMC5 defects were found to cause the development of primary bilateral macronodular adrenocortical hyperplasia with glucocorticoid and/or mineralocorticoid oversecretion. Adrenocortical carcinoma was linked primarily to aberrant p53 signaling and/or Wnt-β-catenin signaling, as well as IGF2 overexpression, with frequent genetic alterations in TP53, ZNRF3, CTNNB1, and 11p15. This review focuses on the genetic underpinnings of benign cortisol- and aldosterone-producing adrenocortical tumors/hyperplasias and adrenocortical carcinoma.
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http://dx.doi.org/10.1016/j.beem.2020.101428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427505PMC
May 2020

Inhibin A as a tumor marker for primary bilateral macronodular adrenal hyperplasia.

Endocrinol Diabetes Metab Case Rep 2020 Apr 29;2020. Epub 2020 Apr 29.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Summary: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing syndrome (CS). This condition is characterized by glucocorticoid and/or mineralocorticoid excess, and is commonly regulated by aberrant G-protein coupled receptor expression may be subclinical, allowing the disease to progress for years undetected. Inhibin A is a glycoprotein hormone and tumor marker produced by certain endocrine glands including the adrenal cortex, which has not been previously investigated as a potential tumor marker for PBMAH. In the present report, serum inhibin A levels were evaluated in three patients with PBMAH before and after adrenalectomy. In all cases, serum inhibin A was elevated preoperatively and subsequently fell within the normal range after adrenalectomy. Additionally, adrenal tissues stained positive for inhibin A. We conclude that serum inhibin A levels may be a potential tumor marker for PBMAH.

Learning Points: PBMAH is a rare cause of CS. PBMAH may have an insidious presentation, allowing the disease to progress for years prior to diagnosis. Inhibin A is a heterodimeric glycoprotein hormone expressed in the gonads and adrenal cortex. Inhibin A serum concentrations are elevated in some patients with PBMAH, suggesting the potential use of this hormone as a tumor marker. Further exploration of serum inhibin A concentration, as it relates to PBMAH disease progression, is warranted to determine if this hormone could serve as an early detection marker and/or predictor of successful surgical treatment.
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http://dx.doi.org/10.1530/EDM-20-0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219132PMC
April 2020

Hookah smoking and COVID-19: call for action.

CMAJ 2020 04;192(17):E462

Director, Graduate Medical Education, National Institute of Child Health and Human Development, NIH, Bethesda, Md.

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http://dx.doi.org/10.1503/cmaj.75332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207196PMC
April 2020

Hypertension Canada's 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children.

Can J Cardiol 2020 05;36(5):596-624

Division of Internal Medicine, Department of Medicine, McGill University, and Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.

Hypertension Canada's 2020 guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children provide comprehensive, evidence-based guidance for health care professionals and patients. Hypertension Canada develops the guidelines using rigourous methodology, carefully mitigating the risk of bias in our process. All draft recommendations undergo critical review by expert methodologists without conflict to ensure quality. Our guideline panel is diverse, including multiple health professional groups (nurses, pharmacy, academics, and physicians), and worked in concert with experts in primary care and implementation to ensure optimal usability. The 2020 guidelines include new guidance on the management of resistant hypertension and the management of hypertension in women planning pregnancy.
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http://dx.doi.org/10.1016/j.cjca.2020.02.086DOI Listing
May 2020

Mass spectrometry-based steroid profiling in primary bilateral macronodular adrenocortical hyperplasia.

Endocr Relat Cancer 2020 07;27(7):403-413

Section on Endocrinology and Genetics, TheEunice Kennedy ShriverInstitute of Child Health and Human Development National Institutes of Health, Bethesda, Maryland, USA.

Biochemical characterization of primary bilateral macronodular adrenocortical hyperplasia (PBMAH) by distinct plasma steroid profiles and its putative correlation to disease has not been previously studied. LC-MS/MS-based steroid profiling of 16 plasma steroids was applied to 36 subjects (22 females, 14 males) with PBMAH, 19 subjects (16 females, 3 males) with other forms of adrenal Cushing's syndrome (ACS), and an age and sex-matched control group. Germline ARMC5 sequencing was performed in all PBMAH cases. Compared to controls, PBMAH showed increased plasma 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, 18-hydroxycortisol, and aldosterone, but lower progesterone, DHEA, and DHEA-S with distinct differences in subjects with and without pathogenic variants in ARMC5. Steroids that showed isolated differences included cortisol and 18-oxocortisol with higher (P < 0.05) concentrations in ACS than in controls and aldosterone with higher concentrations in PBMAH when compared to controls. Larger differences in PBMAH than with ACS were most clear for corticosterone, but there were also trends in this direction for 18-hydroxycortisol and aldosterone. Logistic regression analysis indicated four steroids - DHEA, 11-deoxycortisol, 18-oxocortisol, and corticosterone - with the most power for distinguishing the groups. Discriminant analyses with step-wise variable selection indicated correct classification of 95.2% of all subjects of the four groups using a panel of nine steroids; correct classification of subjects with and without germline variants in ARMC5 was achieved in 91.7% of subjects with PBMAH. Subjects with PBMAH show distinctive plasma steroid profiles that may offer a supplementary single-test alternative for screening purposes.
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http://dx.doi.org/10.1530/ERC-20-0102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354003PMC
July 2020

Management of mitochondrial diabetes in the era of novel therapies.

J Diabetes Complications 2021 Jan 13;35(1):107584. Epub 2020 Apr 13.

Section on Endocrinology & Genetics (SEGEN), National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.

Mitochondrial disorders refer to the complex group of conditions affecting energy metabolism. A number of mitochondrial disorders can lead to the development of diabetes mellitus, and mitochondrial diabetes is thought to account for up to 3% of all diabetes mellitus cases. Depending on the degree of preservation of beta cell secretory capacity and peripheral muscle insulin sensitivity, the phenotype of mitochondrial diabetes may resemble that of type 1 or type 2 diabetes. Additionally, mitochondrial diabetes may rarely present with diabetic ketoacidosis, and can be distinguished from other forms of monogenic diabetes including maturity onset diabetes of the young by the presence of multi-organ involvement, particularly pre-senile sensorineural hearing loss, maternal transmission, and later-onset diagnosis, typically affecting adults over 35 years. Various guidelines on diabetes care do not address this important subset of cases, and this diagnosis is easily missed. Additionally, there is paucity of data on tailored diabetes therapies for mitochondrial diabetes, particularly in the era of novel therapies including glucagon-like peptide-1 receptor agonist and sodium glucose co-transporter-2 inhibitors. Here, we report three patients with mitochondrial diabetes who responded well to the addition of these novel agents and propose a new treatment algorithm for this condition.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554068PMC
January 2021

Neurological manifestations of Erdheim-Chester Disease.

Ann Clin Transl Neurol 2020 04 29;7(4):497-506. Epub 2020 Mar 29.

NINDS, NIH, Bethesda, Maryland.

Objective: To characterize the spectrum of neurologic involvement in Erdheim-Chester Disease (ECD), a treatable inflammatory neoplasm of histiocytes.

Methods: Sixty-two patients with ECD were prospectively enrolled in a natural history study that facilitated collection of clinical, imaging, laboratory, neurophysiologic, and pathologic data.

Results: Ninety-four percent of the patients had neurologic abnormalities on examination or imaging, and 22% had neurologic symptoms as the initial presentation of ECD. The most common neurologic findings were cognitive impairment, peripheral neuropathy, pyramidal tract signs, cranial nerve involvement, and cerebellar ataxia. Imaging revealed atrophy and demyelination along with focal lesions that were located throughout the nervous system, dura, and extra-axial structures. The BRAF V600E variant correlated with cerebral atrophy. Brain pathology revealed lipid-laden, phagocytic macrophages (histiocytes) accompanied by demyelination and axonal degeneration.

Interpretation: In patients with ECD, neurologic morbidity is common and contributes significantly to disability. Since neurologic symptoms can be the presenting feature of ECD and, given the mean delay in ECD diagnosis is 4.2 years, it is critical that neurologists consider of ECD and other histiocytosis in patients with inflammatory, infectious, or neoplastic-appearing white matter. Furthermore, given the broad spectrum of neurologic involvement, neurologists have an important role in a team of specialists treating ECD patients.
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http://dx.doi.org/10.1002/acn3.51014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187721PMC
April 2020

A Gene-Based Classification of Primary Adrenocortical Hyperplasias.

Horm Metab Res 2020 Mar 25;52(3):133-141. Epub 2020 Mar 25.

Section on Endocrinology & Genetics (SEGEN), NICHD, Bethesda, MD, USA.

Primary or adrenocorticotropin-independent adrenocortical tumors and hyperplasias represent a heterogeneous group of adrenocortical neoplasms that arise from various genetic defects, either in isolation or familial. The traditional classification as adenomas, hyperplasias, and carcinomas is non-specific. The recent identification of various germline and somatic genes in the development of primary adrenocortical hyperplasias has provided important new insights into the molecular pathogenesis of adrenal diseases. In this new era of personalized care and genetics, a gene-based classification that is more specific is required to assist in the understanding of their disease processes, hormonal functionality and signaling pathways. Additionally, a gene-based classification carries implications for treatment, genetic counseling and screening of asymptomatic family members. In this review, we discuss the genetics of benign adrenocorticotropin-independent adrenocortical hyperplasias, and propose a new gene-based classification system and diagnostic algorithm that may aid the clinician in prioritizing genetic testing, screening and counseling of affected, at risk individuals and their relatives.
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http://dx.doi.org/10.1055/a-1107-2972DOI Listing
March 2020

Assessment of Thyroid Function in Patients With Alkaptonuria.

JAMA Netw Open 2020 03 2;3(3):e201357. Epub 2020 Mar 2.

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

Importance: Alkaptonuria is an autosomal recessive disorder caused by pathogenic variants in the HGD gene. Deficiency of the HGD enzyme leads to tissue deposition of homogentisic acid (HGA), causing severe osteoarthropathies and cardiac valve degeneration. Although HGD is vital for the catabolism of tyrosine, which provides the basis for thyroid hormone synthesis, the prevalence of thyroid dysfunction in alkaptonuria is unknown.

Objective: To assess thyroid structure and function in patients with alkaptonuria.

Design, Setting, And Participants: A single-center cohort study was conducted in a tertiary referral center including patients with alkaptonuria followed up for a median of 93 (interquartile range, 48-150) months between February 1, 2000, and December 31, 2018. The alkaptonuria diagnosis was based on clinical presentation and elevated urine HGA levels. A total of 130 patients were considered for participation.

Main Outcomes And Measures: Prevalence of thyroid dysfunction in adults with alkaptonuria compared with the general population. Thyrotropin and free thyroxine levels were measured by immunoassay and repeated in each patient a median of 3 (interquartile range, 2-22) times. Neck ultrasonographic scans were analyzed in a subset of participants. Logistic regression was used to test the association of thyroid dysfunction with age, sex, thyroid peroxidase (TPO) antibodies, serum tyrosine levels, and urine HGA levels.

Results: Of the 130 patients, 5 were excluded owing to thyroidectomy as the cause of hypothyroidism. The study cohort consisted of 125 patients; the median age was 45 (interquartile range, 35-51) years. Most of the patients were men (72 [57.6%]). The prevalence of primary hyperthyroidism was 0.8% (1 of 125 patients), similar to 0.5% observed in the general population (difference, 0.003; 95% CI, -0.001 to 0.04; P = .88). The prevalence of primary hypothyroidism was 16.0% (20 of 125 patients), which is significantly higher than 3.7% reported in the general population (difference, 0.12; 95% CI, 0.10-0.24; P < .001). Women were more likely to have primary hypothyroidism than men (odds ratio, 10.99; 95% CI, 3.13-38.66; P < .001). Patients with TPO antibodies had a higher likelihood of primary hypothyroidism than those without TPO antibodies (odds ratio, 7.36; 95% CI, 1.89-28.62; P = .004). There was no significant difference in the prevalence of thyroid nodules between patients in this study (29 of 49 [59.2%]) vs the general population (68%) (difference, 0.088; 95% CI, -0.44 to 0.73; P = .20) or of cancer (7% vs 5%; difference, 0.01; 95% CI, -0.01 to 0.17; P = .86).

Conclusions And Relevance: The high prevalence of primary hypothyroidism noted in patients with alkaptonuria in this study suggests that serial screening in this population should be considered and prioritized.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.1357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090965PMC
March 2020

Hypophysitis: An update on the novel forms, diagnosis and management of disorders of pituitary inflammation.

Best Pract Res Clin Endocrinol Metab 2019 12 12;33(6):101371. Epub 2019 Dec 12.

The University of Tennessee Health Science Center, Memphis, TN, 38163, USA; Fox Chase Cancer Center, Philadelphia, PA, USA. Electronic address:

Hypophysitis is a heterogeneous condition that leads to inflammation of the sella and/or suprasellar region, potentially resulting in hormonal deficiencies and/or mass effects. A preponderance of hypophysitis subtypes have an underlying autoimmune aetiology. The overall incidence and prevalence of hypophysitis has dramatically increased over the past decade, mainly due to increased awareness of the condition in the medical community, improvements in imaging techniques, and a rise in the occurrence of certain forms of hypophysitis such as IgG4 hypophysitis (IgG4Hy) and immune checkpoint inhibitor induced hypophysitis (ICIHy). The clinical presentation varies from an asymptomatic condition to a fatal disease often as a result of electrolyte abnormalities due to glucocorticoid deficiency in the context of adrenal crisis from central adrenal insufficiency. Milder forms of hypophysitis are treated with replacement of deficient hormones while more acute presentations with mass effects require glucocorticoid therapy, immunosuppressive therapy or surgery. Timely diagnosis and interventions are keys to prevention of the lethal complications of this disease. In this review, we provide an update on the recent advances in the field of pituitary autoimmunity, with an emphasis on autoimmune hypophysitis and novel forms of hypophysitis such as anti-PIT1 hypophysitis, IgG4Hy and ICIHy.
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http://dx.doi.org/10.1016/j.beem.2019.101371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078033PMC
December 2019

Whole-exome sequencing identifies a homozygous pathogenic variant in in a girl with palmoplantar keratoderma.

Mol Genet Metab Rep 2019 Dec 22;21:100534. Epub 2019 Nov 22.

Clinical Genetics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Canada.

Palmoplantar keratoderma (PPK) is a defect in cornification that is characterized by progressive hyperkeratosis of palms and soles. Many phenotypes are linked with PPK, making exome-based diagnosis increasingly efficient. In this report, we identified tyrosinemia type II on whole-exome sequencing in a 7-year-old Syrian refugee that presented with PPK. Dietary therapy helped improve her overall symptoms.
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http://dx.doi.org/10.1016/j.ymgmr.2019.100534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881597PMC
December 2019

Adrenocortical carcinoma and pulmonary embolism from tumoral extension.

Endocrinol Diabetes Metab Case Rep 2019 Nov 25;2019. Epub 2019 Nov 25.

Section on Endocrinology & Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.

Summary: Adrenococortical carcinoma (ACC) is a rare cancer, occurring at the rate of one case in two million person years. Cushing syndrome or a mixed picture of excess androgen and glucocorticoid production are the most common presentations of ACC. Other uncommon presentations include abdominal pain and adrenal incidentalomas. In the present report, a 71-year-old male presented with abdominal pain and was eventually diagnosed with ACC. He was found to have pulmonary thromboembolism following an investigation for hypoxemia, with the tumor thrombus extending upto the right atrium. This interesting case represents the unique presentation of a rare tumor, which if detected late or left untreated is associated with poor outcomes, highlighting the need for a low index of suspicion for ACC when similar presentations are encountered in clinical practice.

Learning Points: ACC is a rare but aggressive tumor. ACC commonly presents with rapid onset of hypercortisolism, combined hyperandrogenism and hypercortisolism, or uncommonly with compressive symptoms. Clinicians should have a low index of suspicion for ACC in patients presenting with rapid onset of symptoms related to hypercortisolism and/or hyperandrogenism. Venous thromboembolism and extension of the tumor thrombus to the right side of the heart is a very rare but serious complication of ACC that clinicans should be wary of. The increased risk of venous thromboembolism in ACC could be explained by direct tumor invasion, tumor thrombi or hypercoagulability secondary to hypercortisolism. Early diagnosis and prompt treatment can improve the long-term survival of patients with ACC.
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http://dx.doi.org/10.1530/EDM-19-0095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893304PMC
November 2019

Resistant Hypertension: A Clinical Perspective.

Endocrinol Metab Clin North Am 2019 12;48(4):811-828

The University of Tennessee Health Science Center, 910 Madison Avenue, Memphis, TN 38163, USA.

Resistant hypertension is a common clinical entity, defined as suboptimal blood pressure response to multiple therapies after excluding medication nonadherence and secondary forms of hypertension. Patients with resistant hypertension generally share several comorbidities. Resistant hypertension is more common in individuals of African descent. Blood pressure should be optimized using multiple strategies, including lifestyle changes and single-pill combination therapies, with the aim of reducing cardiovascular events while reducing side effects from using antihypertensive therapy. A renin/aldosterone-based diagnostic and treatment approach will help tailor therapy. The use of mineralocorticoid receptor antagonists or amiloride as appropriate is favored.
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http://dx.doi.org/10.1016/j.ecl.2019.08.010DOI Listing
December 2019

Mosaicism for KCNJ5 Causing Early-Onset Primary Aldosteronism due to Bilateral Adrenocortical Hyperplasia.

Am J Hypertens 2020 02;33(2):124-130

Section on Genetics & Endocrinology, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA.

Background: Somatic variants in KCNJ5 are the most common cause of primary aldosteronism (PA). There are few patients with PA in whom the disease is caused by germline variants in the KCNJ5 potassium channel gene (familial hyperaldosteronism type III-FH-III).

Methods: A 5-year-old patient who developed hypertension due to bilateral adrenocortical hyperplasia (BAH) causing PA had negative peripheral DNA testing for any known genetic causes of PA. He was treated medically with adequate control of his PA but by the third decade of his life, due to worsening renal function, he underwent bilateral adrenalectomy.

Results: Focused exome sequencing in multiple nodules of his BAH uncovered a "hot-spot" pathogenic KCNJ5 variant, while repeated Sanger sequencing showed no detectable DNA defects in peripheral blood and other tissues. However, whole exome, "deep" sequencing revealed that 0.23% of copies of germline DNA did in fact carry the same KCNJ5 variant that was present in the adrenocortical nodules, suggesting low level germline mosaicism for this PA-causing KCNJ5 defect.

Conclusions: Thus, this patient represents a unique case of BAH due to a mosaic KCNJ5 defect. Undoubtedly, his milder PA compared with other known cases of FH-III, was due to his mosaicism. This case has a number of implications for the prognosis, treatment, and counseling of the many patients with PA due to BAH that are seen in hypertension clinics.
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http://dx.doi.org/10.1093/ajh/hpz172DOI Listing
February 2020