Publications by authors named "Constantine A Stratakis"

537 Publications

Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome.

PLoS Negl Trop Dis 2021 Jun 14;15(6):e0009507. Epub 2021 Jun 14.

Laboratório de Bioinformática, Laboratório Nacional de Computação Científica LNCC/MCTIC Petrópolis, Brazil.

Congenital Zika Syndrome (CZS) is a critical illness with a wide range of severity caused by Zika virus (ZIKV) infection during pregnancy. Life-threatening neurodevelopmental dysfunctions are among the most common phenotypes observed in affected newborns. Risk factors that contribute to susceptibility and response to ZIKV infection may be related to the virus itself, the environment, and maternal genetic background. Nevertheless, the newborn's genetic contribution to the critical illness is still not elucidated. Here, we aimed to identify possible genetic variants as well as relevant biological pathways that might be associated with CZS phenotypes. For this purpose, we performed a whole-exome sequencing in 40 children born to women with confirmed exposure to ZIKV during pregnancy. We investigated the occurrence of rare harmful single-nucleotide variants (SNVs) possibly associated with inborn errors in genes ontologically related to CZS phenotypes. Moreover, an exome-wide association analysis was also performed using a case-control design (29 CZS cases and 11 controls), for both common and rare variants. Five out of the 29 CZS patients harbored known pathogenic variants likely to contribute to mild to severe manifestations observed. Approximately, 30% of affected individuals carried at least one pathogenic or likely pathogenic SNV in genes candidates to play a role in CZS. Our common variant association analysis detected a suggestive protective effect of the rs2076469 in DISP3 gene (p-value: 1.39 x 10-5). The IL12RB2 gene (p-value: 2.18x10-11) also showed an unusual distribution of nonsynonymous rare SNVs in control samples. Finally, genes harboring harmful variants are involved in processes related to CZS phenotypes such as neurological development and immunity. Therefore, both rare and common variations may be likely to contribute as the underlying genetic cause of CZS susceptibility. The variations and pathways identified in this study may also have implications for the development of therapeutic strategies in the future.
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http://dx.doi.org/10.1371/journal.pntd.0009507DOI Listing
June 2021

Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis and rescue by IL-21.

J Allergy Clin Immunol 2021 Jun 2. Epub 2021 Jun 2.

Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, MD, USA, 20892. Electronic address:

Background: Pediatric endogenous Cushing syndrome is mainly caused by pituitary corticotropin-producing adenomas and most glucocorticoid-dependent effects progressively regress upon tumor removal. Endogenous Cushing syndrome reproduces long-term high-dose glucocorticoid therapy, representing a clean, natural and unbiased model in which to study glucocorticoid bona-fide effects on immunity.

Objectives: To perform extensive immunologic studies in otherwise healthy pediatric patients with endogenous Cushing syndrome before and 6-13 months after tumor resection, as well as in in-vitro glucocorticoid-treated control cells.

Methods: Flow cytometry, immunoblotting, ELISA, qRT-PCR and RNA-seq techniques were used to characterize patients' and in-vitro glucocorticoid treated cells.

Results: Reduced thymic output, decreased naïve T cells, diminished proliferation, and increased T-cell apoptosis were detected before surgery, and all these defects eventually normalized after tumor removal in patients. In-vitro studies also showed increased T-cell apoptosis, with correspondingly diminished NF-κB signaling and IL-21 levels. In this setting, IL-21 addition upregulated anti-apoptotic BCL2 expression and rescued T-cell apoptosis in a PI3K pathway- dependent manner. Similar and reproducible findings were confirmed in endogenous Cushing syndrome patient cells as well.

Conclusions: We identified decreased thymic output and lymphocyte proliferation, together with increased apoptosis, as the underlying causes to T-cell lymphopenia in endogenous Cushing syndrome patients. IL-21 was decreased in both natural and in-vitro long-term high-dose glucocorticoid environments, and in-vitro addition of IL-21 counteracted the pro-apoptotic effects of glucocorticoid therapy. Thus, our results suggest that administration of IL-21 in patients receiving long-term high-dose glucocorticoid therapy may contribute to ameliorate lymphopenia and the complications associated to it.
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http://dx.doi.org/10.1016/j.jaci.2021.05.031DOI Listing
June 2021

Loss of PKA regulatory subunit 1α aggravates cardiomyocyte necrosis and myocardial ischemia/reperfusion injury.

J Biol Chem 2021 Jun 1:100850. Epub 2021 Jun 1.

Department of Pharmaceutical Sciences, Washington State University, PBS 423, 412 E. Spokane Falls Blvd., Spokane, WA 99202-2131, USA. Electronic address:

Reperfusion therapy, the standard treatment for acute myocardial infarction, can trigger necrotic death of cardiomyocytes and provoke ischemia/reperfusion (I/R) injury. However, signaling pathways that regulate cardiomyocyte necrosis remain largely unknown. Our recent genome-wide RNAi screen has identified a potential necrosis suppressor gene PRKAR1A, which encodes PKA regulatory subunit 1α (R1α). R1α is primarily known for regulating PKA activity by sequestering PKA catalytic subunits in the absence of cAMP. Here, we showed that depletion of R1α augmented cardiomyocyte necrosis in vitro and in vivo, resulting in exaggerated myocardial I/R injury and contractile dysfunction. Mechanistically, R1α loss downregulated the Nrf2 antioxidant transcription factor and aggravated oxidative stress following I/R. Degradation of the endogenous Nrf2 inhibitor Keap1 through p62-dependent selective autophagy was blocked by R1α depletion. Phosphorylation of p62 at Ser349 by mammalian target of rapamycin complex 1 (mTORC1), a critical step in p62-Keap1 interaction, was induced by I/R, but diminished by R1α loss. Activation of PKA by forskolin or isoproterenol almost completely abolished hydrogen peroxide-induced p62 phosphorylation. In conclusion, R1α loss induces unrestrained PKA activation and impairs the mTORC1-p62-Keap1-Nrf2 antioxidant defense system, leading to aggravated oxidative stress, necrosis and myocardial I/R injury. Our findings uncover a novel role of PKA in oxidative stress and necrosis, which may be exploited to develop new cardioprotective therapies.
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http://dx.doi.org/10.1016/j.jbc.2021.100850DOI Listing
June 2021

Lower hair cortisol among patients with sickle cell disease may indicate decreased adrenal reserves.

Am J Blood Res 2021 15;11(2):140-148. Epub 2021 Apr 15.

Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health Bethesda, Maryland, USA.

Introduction: Sickle cell disease (SCD) is a chronic illness that presents with a wide range of phenotypic variation. Stress may be a contributing factor to differences that are found in this population.

Objectives: Our objective is to determine the relationship between hair cortisol content (HCC), a biomarker of stress, and other clinical measures in individuals with SCD.

Methods: We collected hair samples and other clinical measures from 73 subjects with SCD (mean age: 39 ± 12 years, 63% female).

Results: HCC was lower among individuals who had greater than 30% hemoglobin S, compared with those who had less than 30% hemoglobin S (W=272.5, P=0.01). Lower HCC was also associated with report of not being on a chronic transfusion program (β=48.34, SE=14.09, P=0.001) and higher ferritin levels (β=-0.006, SE=0.002, P=0.02). Furthermore, HCC was significantly correlated with serum cortisol (r=0.26, P=0.03) and corticosterone (r=0.29, P=0.01). We also observed a consistent pattern of low steroid values among our population.

Conclusion: Our findings suggest that individuals with higher hemoglobin S and ferritin, both markers of severe SCD, may have decreased cortisol levels. This is consistent with the relationship we observed between higher HCC among individuals who are on a chronic blood transfusion program, which typically increases quality of life. Our results suggest that hair cortisol may be an indicator in patients with SCD who could be at risk for developing adrenal insufficiency. We recommend that clinicians treating patients with SCD follow the Endocrine Society guidelines for testing for adrenal insufficiency and treat accordingly.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165714PMC
April 2021

Family environment and development in children adopted from institutionalized care.

Pediatr Res 2021 May 26. Epub 2021 May 26.

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

Background: After adoption, children exposed to institutionalized care show significant improvement, but incomplete recovery of growth and developmental milestones. There is a paucity of data regarding risk and protective factors in children adopted from institutionalized care. This prospective study followed children recently adopted from institutionalized care to investigate the relationship between family environment, executive function, and behavioral outcomes.

Methods: Anthropometric measurements, physical examination, endocrine and bone age evaluations, neurocognitive testing, and behavioral questionnaires were evaluated over a 2-year period with children adopted from institutionalized care and non-adopted controls.

Results: Adopted children had significant deficits in growth, cognitive, and developmental measurements compared to controls that improved; however, residual deficits remained. Family cohesiveness and expressiveness were protective influences, associated with less behavioral problems, while family conflict and greater emphasis on rules were associated with greater risk for executive dysfunction.

Conclusions: Our data suggest that a cohesive and expressive family environment moderated the effect of pre-adoption adversity on cognitive and behavioral development in toddlers, while family conflict and greater emphasis on rules were associated with greater risk for executive dysfunction. Early assessment of child temperament and parenting context may serve to optimize the fit between parenting style, family environment, and the child's development.

Impact: Children who experience institutionalized care are at increased risk for significant deficits in developmental, cognitive, and social functioning associated with a disruption in the development of the prefrontal cortex. Aspects of the family caregiving environment moderate the effect of early life social deprivation in children. Family cohesiveness and expressiveness were protective influences, while family conflict and greater emphasis on rules were associated with a greater risk for executive dysfunction problems. This study should be viewed as preliminary data to be referenced by larger studies investigating developmental and behavioral outcomes of children adopted from institutional care.
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http://dx.doi.org/10.1038/s41390-020-01325-1DOI Listing
May 2021

Carney Triad, Carney-Stratakis Syndrome, 3PAS and Other Tumors Due to SDH Deficiency.

Front Endocrinol (Lausanne) 2021 3;12:680609. Epub 2021 May 3.

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

Succinate dehydrogenase (SDH) is a key respiratory enzyme that links Krebs cycle and electron transport chain and is comprised of four subunits SDHA, SDHB, SDHC and SDHD. All -deficient tumors are caused by or secondary to loss of SDH activity. As many as half of the familial cases of paragangliomas (PGLs) and pheochromocytomas (PHEOs) are due to mutations of the subunits. Gastrointestinal stromal tumors (GISTs) associated with deficiency are negative for mutations and present with distinctive clinical features such as early onset (usually childhood or adolescence) and almost exclusively gastric location. -deficient GISTs may be part of distinct clinical syndromes, Carney-Stratakis syndrome (CSS) or dyad and Carney triad (CT). CSS is also known as the dyad of GIST and PGL; it affects both genders equally and is inherited in an autosomal dominant manner with incomplete penetrance. CT is a very rare disease; PGL, GIST and pulmonary chondromas constitute CT which shows female predilection and may be a mosaic disorder. Even though there is some overlap between CT and CSS, as both are due to deficiency, CSS is caused by inactivating germline mutations in genes encoding for the SDH subunits, while CT is mostly caused by a specific pattern of methylation of the gene and may be due to germline mosaicism of the responsible genetic defect.
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http://dx.doi.org/10.3389/fendo.2021.680609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126684PMC
May 2021

Contralateral Suppression Index Does Not Predict Clinical Cure in Patients Undergoing Surgery for Primary Aldosteronism.

Ann Surg Oncol 2021 May 3. Epub 2021 May 3.

Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Adrenal venous sampling (AVS) is recommended before adrenalectomy for patients with primary aldosteronism (PA) over 35 years old. The literature examining contralateral suppression (CoS) on AVS in predicting surgical outcomes is conflicting. We examined the presence of CoS in patients who underwent adrenalectomy while adjusting for clinical and biochemical factors associated with a clinical cure of hypertension (ccHTN).

Methods: We performed a retrospective review of patients with successful AVS who underwent unilateral adrenalectomy for PA at a quaternary referral center. Patients were excluded if they had overt cortisol co-secretion, or inadequate follow-up. We first evaluated the aldosterone resolution score (ARS) in predicting ccHTN in our cohort. Next, the receiver-operator characteristic analysis (ROC) was used to determine the optimal contralateral suppression index (CSI) cutoff to define CoS. We performed univariable and multivariable analyses of factors associated with ccHTN. The primary outcome was ccHTN defined as blood pressure less than 140/90 mmHg, and off blood pressure medications.

Results: Of the 102 patients on bivariable analysis, age, sex, duration of HTN, number of medications, preoperative systolic blood pressure, and creatinine level were associated with ccHTN. ROC analysis of ARS had an AUC of 0.850 (p < 0.001). On multivariable analysis, only ARS remained associated with ccHTN (OR 3.40, 95% CI 1.20-9.61, p = 0.021). CSI was not significantly associated with ccHTN on ROC, bivariable, or multivariable analyses.

Conclusion: The presence of CoS was not useful in predicting ccHTN following unilateral adrenalectomy for PA in our cohort. After adjusting for clinical and biochemical factors, ARS remains a useful predictor for ccHTN.
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http://dx.doi.org/10.1245/s10434-021-09692-7DOI Listing
May 2021

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052566PMC
March 2021

Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain.

Genet Med 2021 Apr 8. Epub 2021 Apr 8.

Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.

Purpose: We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA).

Methods: Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development.

Results: Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs.

Conclusion: Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
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http://dx.doi.org/10.1038/s41436-021-01152-7DOI Listing
April 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

Inhibition of Aurora kinase A activity enhances the antitumor response of beta-catenin blockade in human adrenocortical cancer cells.

Mol Cell Endocrinol 2021 05 11;528:111243. Epub 2021 Mar 11.

Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA; Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD20892, USA.

Adrenocortical cancer (ACC) is a rare and aggressive type of endocrine tumor with high risk of recurrence and metastasis. The overall survival of patients diagnosed with ACC is low and treatment for metastatic stages remain limited to mitotane, which has low efficiency in advanced stages of the disease and is associated with high toxicity. Therefore, identification of new biological targets to improve ACC treatment is crucial. Blockade of the Wnt/beta-catenin pathway decreased adrenal steroidogenesis and increased apoptosis of NCI-H295 human ACC cells, in vitro and in a xenograft mouse model. Aurora kinases play important roles in cell division during the G1-M phase and their aberrant expression is correlated with a poor prognosis in different types of tumors. Hence, we hypothesized that inhibition of aurora kinases activity combined with the beta-catenin pathway blockade would improve the impairment of ACC cell growth in vitro. We studied the combinatorial effects of AMG 900, an aurora kinase inhibitor and PNU-74654, a beta-catenin pathway blocker, on proliferation, survival and tumor progression in multiple ACC cell lines: NCI-H295, CU-ACC1 and CU-ACC2. Exposure of ACC cells to the combination of AMG 900 with PNU-74654 decreased cell proliferation and viability compared to either treatment alone. In addition, AMG 900 inhibited cell invasion and clonogenesis compared to PNU-74654, and the combination showed no greater effects. In contrast, PNU-74654 was more effective in decreasing cortisol secretion. These data suggest that inhibition of aurora kinases activity combined with blockade of the beta-catenin pathway may provide a combinatorial approach for targeting ACC tumors.
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http://dx.doi.org/10.1016/j.mce.2021.111243DOI Listing
May 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 May;106(6):1606-1616

Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892,USA.

Context: Pathogenic variants in KCNJ5, encoding the GIRK4 (Kir3.4) potassium channel, have been implicated in the pathogenesis of familial hyperaldosteronism type-III (FH-III) and sporadic primary aldosteronism (PA). In addition to aldosterone, glucocorticoids are often found elevated 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 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.

Conclusion: 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118581PMC
May 2021

Insulin sensitivity and pancreatic β-cell function in patients with primary aldosteronism.

Endocrine 2021 Apr 18;72(1):96-103. Epub 2021 Jan 18.

Clinical Endocrine Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

Background: Primary aldosteronism (PA) is associated with an increased risk for dysglycemia. However, the effects of hyperaldosteronism on insulin sensitivity and β-cell function are unclear.

Methods: Using a cross-sectional study design, we assessed insulin sensitivity and pancreatic β-cell function from an oral glucose tolerance test (OGTT) in patients from two cohorts: subjects with PA (n = 21) and essential hypertension control (EHC) subjects (n = 22). Age, sex, BMI, and mean arterial pressure adjusted measures of insulin sensitivity and β-cell function were compared between the groups.

Results: PA individuals were less insulin sensitive compared to EHC subjects (Quantitative insulin sensitivity check index [QUICKI]: 0.340 ± 0.006 vs. 0.374 ± 0.013, p < 0.001; Matsuda index: 4.14 ± 0.49 vs. 7.87 ± 1.42, p < 0.001; S: 11.45 ± 4.85 vs. 21.23 ± 6.11 dL/kg/min per μU/mL, p = 0.02). The hepatic insulin resistance index (HIRI) was higher in PA subjects (PA: 5.61 ± 1.01 vs. EHC: 4.13 ± 0.61, p = 0.002). The insulinogenic index (IGI), an index of β-cell function was higher in the PA cohort (PA: 1.49 ± 0.27 vs. 1.11 ± 0.21 μU/mL/mg/dL, p = 0.03). However, the oral disposition index (DI) was similar between the groups (PA: 4.77 ± 0.73 vs. EHC: 5.46 ± 0.85, p = 0.42), which likely accounts for the similar glucose tolerance between the two cohorts, despite lower sensitivity.

Conclusions: In summary, insulin sensitivity is significantly lower in PA with an appropriately compensated β-cell function. These results suggest that excess aldosterone and/or other steroids in the context of PA may negatively affect insulin action without adversely impacting β-cell function.
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http://dx.doi.org/10.1007/s12020-020-02576-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087621PMC
April 2021

Corticotroph tumor progression after bilateral adrenalectomy (Nelson's syndrome): systematic review and expert consensus recommendations.

Eur J Endocrinol 2021 Mar;184(3):P1-P16

Section on Genetics & Endocrinology Eunice Kennedy Shriver National Insitute of Child Health & Human Development (NICHD) National Institute of Health (NIH), NIH Clinical Research Center, Bethesda, Maryland, USA.

Background: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing.

Methods: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018.

Results: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients).

Conclusions: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.
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http://dx.doi.org/10.1530/EJE-20-1088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060870PMC
March 2021

A SOX5 gene variant as a possible contributor to short stature.

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

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

Summary: SOX5 plays an important role in chondrogenesis and chondrocyte differentiation. SOX5 defects in humans (often deletions) result in a Lamb-Shaffer syndrome (LSS), presenting with speech delay, behavioral problems and minor dysmorphic features. We present a patient with idiopathic short stature (ISS) who carried a heterozygous novel variant in SOX5. The patient had no dysmorphic features, but a skeletal survey revealed minor skeletal abnormalities. Laboratory and endocrine evaluation for known causes of growth disorders was negative. The missense variant in SOX5 gene (c.1783A>G, p.K595E) was de novo and was predicted to be deleterious by in silico programs. In summary, we present a patient whose presentation may provide evidence that gene defects in SOX5 may contribute to the etiology of short stature and/or mild skeletal defects beyond LSS.

Learning Points: We report a girl with idiopathic short stature and mild skeletal defects presenting with a de novo variant in SOX5 gene, predicted in silico to be deleterious. Although SOX5 has not been previously specifically associated with short stature, several evidences support its contributing effect on dyschondrogenesis. Missense variants in SOX5 gene may lead to mild phenotypes, differing from typical presentation of patients with Lamb-Shaffer syndrome.
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http://dx.doi.org/10.1530/EDM-20-0133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774745PMC
December 2020

Insulin-like growth factor 2 (IGF2) expression in adrenocortical disease due to PRKAR1A mutations compared to other benign adrenal tumors.

Endocrine 2021 Jun 9;72(3):823-834. Epub 2021 Jan 9.

Section on Genetics & Endocrinology (SEGEN), Intramural Research Program (IRP), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD, USA.

Purpose: Insulin-like growth factor-II (IGF2), a key regulator of cell growth and development, is tightly regulated in its expression by epigenetic control that maintains its monoallelic expression in most tissues. Biallelic expression of IGF2 resulting from loss of imprinting (LOI) has been reported in adrenocortical tumors. In this study, we wanted to check whether adrenocortical lesions due to PRKAR1A mutations lead to increased IGF2 expression from LOI and compare these findings to those in other benign adrenal lesions.

Methods: We compared the expression of IGF2 by RNA and protein studies in primary pigmented nodular adrenocortical disease (PPNAD) caused by PRKAR1A gene mutations to that in primary macronodular adrenocortical hyperplasia (PMAH) and cortisol-producing adenomas (CPA) that did not have any mutations in known genes. We also checked LOI in all lesions by DNA allelic studies and the expression of other components of IGF2 signaling at the RNA and protein level.

Results: We identified cell clusters overexpressing IGF2 in PPNAD; although immunostaining was patchy, overall, by RNA and immunoblotting PPNAD expressed high IGF2 message and protein. However, this was not due to LOI, as there was no correlation between IGF2 expression and the presence of LOI.

Conclusions: Our data pointed to over-expression of IGF2 protein in PPNAD compared to other benign adrenocortical lesions, such as PMAH and CPA. However, there was no correlation of IGF2 mRNA levels with LOI of IGF2/H19. The discrepancy between mRNA and protein levels with regards to LOI points, perhaps, to different control of IGF2 gene expression in PPNAD.
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http://dx.doi.org/10.1007/s12020-020-02583-zDOI Listing
June 2021

Pde8b haploinsufficiency in mice is associated with modest adrenal defects, impaired steroidogenesis, and male infertility, unaltered by concurrent PKA or Wnt activation.

Mol Cell Endocrinol 2021 02 15;522:111117. Epub 2020 Dec 15.

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

PDE8B, PRKAR1A and the Wnt/β-catenin signaling are involved in endocrine disorders. However, how PDEB8B interacts with both Wnt and protein kinase A (PKA) signaling in vivo remains unknown. We created a novel Pde8b knockout mouse line (Pde8b); Pde8b haploinsufficient (Pde8b) mice were then crossed with mice harboring: (1) constitutive beta-catenin activation (Pde8b;ΔCat) and (2) Prkar1a haploinsufficieny (Pde8b;Prkar1a). Adrenals and testes from mice (3-12-mo) were evaluated in addition to plasma corticosterone, aldosterone and Dkk3 concentrations, and the examination of expression of steroidogenesis-, Wnt- and cAMP/PKA-related genes. Pde8b male mice were infertile with down-regulation of the Wnt/β-catenin pathway which did not change significantly in the Pde8b;ΔCat mice. Prkar1a haploinsufficiency also did not change the phenotype significantly. In vitro studies showed that PDE8B knockdown upregulated the Wnt pathway and increased proliferation in CTNNB1-mutant cells, whereas it downregulated the Wnt pathway in PRKAR1A-mutant cells. These data support an overall weak, if any, role for PDE8B in adrenocortical tumorigenesis, even when co-altered with Wnt signaling or PKA upregulation; on the other hand, PDE8B appears to play a significant role in male fertility.
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http://dx.doi.org/10.1016/j.mce.2020.111117DOI Listing
February 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

The X-linked acrogigantism-associated gene gpr101 is a regulator of early embryonic development and growth in zebrafish.

Mol Cell Endocrinol 2021 01 26;520:111091. Epub 2020 Nov 26.

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

We recently described X-linked acrogigantism (X-LAG), a condition of early childhood-onset pituitary gigantism associated with microduplications of the GPR101 receptor. The expression of GPR101 in hyperplastic pituitary regions and tumors in X-LAG patients, and GPR101's normally transient pituitary expression during fetal development, suggest a role in the regulation of growth. Nevertheless, little is still known about GPR101's physiological functions, especially during development. By using zebrafish models, we investigated the role of gpr101 during embryonic development and somatic growth. Transient ectopic gpr101 expression perturbed the embryonic body plan but did not affect growth. Loss of gpr101 led to a significant reduction in body size that was even more pronounced in the absence of maternal transcripts, as well as subfertility. These changes were accompanied by gastrulation and hypothalamic defects. In conclusion, both gpr101 loss- and gain-of-function affect, in different ways, fertility, embryonic patterning, growth and brain development.
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http://dx.doi.org/10.1016/j.mce.2020.111091DOI Listing
January 2021

Genetics, clinical features and outcomes of non-syndromic pituitary gigantism: experience of a single center from Sao Paulo, Brazil.

Pituitary 2021 Apr 6;24(2):252-261. Epub 2020 Nov 6.

Laboratorio de Endocrinologia Celular E Molecular/LIM25, Disciplina de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.

Purpose: Non-syndromic pituitary gigantism (PG) is a very rare disease. Aryl hydrocarbon receptor-interacting protein (AIP) and G protein-coupled receptor 101 (GPR101) genetic abnormalities represent important etiologic causes of PG and may account for up to 40% of these cases. Here, we aimed to characterize the clinical and molecular findings and long-term outcomes in 18 patients (15 males, three females) with PG followed at a single tertiary center in Sao Paulo, Brazil.

Methods: Genetic testing for AIP and GPR101 were performed by DNA sequencing, droplet digital PCR and array comparative genomic hybridization (aCGH).

Results: Pathogenic variants in the AIP gene were detected in 25% of patients, including a novel variant in splicing regulatory sequences which was present in a sporadic male case. X-LAG due to GPR101 microduplication was diagnosed in two female patients (12.5%). Of interest, these patients had symptoms onset by age 5 and 9 years old and diagnosis at 5 and 15 years, respectively. X-LAG, but not AIP, patients had a significantly lower age of symptoms onset and diagnosis and a higher height Z-score when compared to non-X-LAG. No other differences in clinical features and/or treatment outcomes were observed among PG based on their genetic background.

Conclusion: We characterize the clinical and molecular findings and long-term outcome of the largest single-center PG cohort described so far.
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http://dx.doi.org/10.1007/s11102-020-01105-4DOI Listing
April 2021

Loss of habenular Prkar2a reduces hedonic eating and increases exercise motivation.

JCI Insight 2020 12 3;5(23). Epub 2020 Dec 3.

Section on Endocrinology and Genetics and.

The habenula (Hb) is a bilateral, evolutionarily conserved epithalamic structure connecting forebrain and midbrain structures that has gained attention for its roles in depression, addiction, rewards processing, and motivation. Of its 2 major subdivisions, the medial Hb (MHb) and lateral Hb (LHb), MHb circuitry and function are poorly understood relative to those of the LHb. Prkar2a codes for cAMP-dependent protein kinase (PKA) regulatory subunit IIα (RIIα), a component of the PKA holoenzyme at the center of one of the major cell-signaling pathways conserved across systems and species. Type 2 regulatory subunits (RIIα, RIIβ) determine the subcellular localization of PKA, and unlike other PKA subunits, Prkar2a has minimal brain expression except in the MHb. We previously showed that RIIα-knockout (RIIα-KO) mice resist diet-induced obesity. In the present study, we report that RIIα-KO mice have decreased consumption of palatable, "rewarding" foods and increased motivation for voluntary exercise. Prkar2a deficiency led to decreased habenular PKA enzymatic activity and impaired dendritic localization of PKA catalytic subunits in MHb neurons. Reexpression of Prkar2a in the Hb rescued this phenotype, confirming differential roles for Prkar2a in regulating the drives for palatable foods and voluntary exercise. Our findings show that in the MHb decreased PKA signaling and dendritic PKA activity decrease motivation for palatable foods, while enhancing the motivation for exercise, a desirable combination of behaviors.
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http://dx.doi.org/10.1172/jci.insight.141670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714411PMC
December 2020

A phosphodiesterase 11 (Pde11a) knockout mouse expressed functional but reduced Pde11a: Phenotype and impact on adrenocortical function.

Mol Cell Endocrinol 2021 01 27;520:111071. Epub 2020 Oct 27.

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

Phosphodiesterases catalyze the hydrolysis of cyclic nucleotides and maintain physiologic levels of intracellular concentrations of cyclic adenosine and guanosine mono-phosphate (cAMP and cGMP, respectively). Increased cAMP signaling has been associated with adrenocortical tumors and Cushing syndrome. Genetic defects in phosphodiesterase 11A (PDE11A) may lead to increased cAMP signaling and have been found to predispose to the development of adrenocortical, prostate, and testicular tumors. A previously reported Pde11a knockout (Pde11a) mouse line was studied and found to express PDE11A mRNA and protein still, albeit at reduced levels; functional studies in various tissues showed increased cAMP levels and reduced PDE11A activity. Since patients with PDE11A defects and Cushing syndrome have PDE11A haploinsufficiency, it was particularly pertinent to study this hypomorphic mouse line. Indeed, Pde11a mice failed to suppress corticosterone secretion in response to low dose dexamethasone, and in addition exhibited adrenal subcapsular hyperplasia with predominant fetal-like features in the inner adrenal cortex, mimicking other mouse models of increased cAMP signaling in the adrenal cortex. We conclude that a previously reported Pde11a mouse showed continuing expression and function of PDE11A in most tissues. Nevertheless, Pde11a partial inactivation in mice led to an adrenocortical phenotype that was consistent with what we see in patients with PDE11A haploinsufficiency.
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http://dx.doi.org/10.1016/j.mce.2020.111071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771190PMC
January 2021

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

Endokrynol Pol 2021 30;72(2):104-107. Epub 2020 Oct 30.

Department of Neurosurgery, The Children's Memorial Health Institute (CMHI), Warsaw, Poland, Warsaw, Poland.

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.
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http://dx.doi.org/10.5603/EP.a2020.0073DOI Listing
October 2020

Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism.

Endocr Relat Cancer 2021 01;28(1):1-13

Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, 'sporadic' bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of genetic etiologies of PA.
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http://dx.doi.org/10.1530/ERC-20-0384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757641PMC
January 2021

Pediatric Cushing's syndrome: greater risk of being overweight or obese after long-term remission and its predictive factors.

Eur J Endocrinol 2021 Jan;184(1):179-187

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

Objective: Due to the rarity of Cushing's syndrome (CS) in children and adolescents, data are scarce about BMI during active disease and following remission. Therefore, our aim was to analyze BMI after long-term remission and determine predictive factors for promptly identifying patients at risk of being overweight or obese after remission for CS.

Design: Retrospective cohort study.

Patients: 73 patients: 58 (79.4%) had Cushing disease, 40 males (58%), median age of 12 years (IQR: 9-15). The mean follow-up time was 22.4 ± 18.2 months (range: 4-98).

Methods: Main outcome measures: BMI, lipid profile, blood pressure, HOMA-IR.

Results: At diagnosis, only eight (11%) patients had a normal weight. Although the BMI z-score at the last follow-up improved (2.0 ± 0.7 to 1.0 ± 1.2, P < 0.001), 44% remained overweight or obese after 2 years of remission according to the Kaplan-Meier curves. The BMI z-scores at the last follow-up correlated only with HOMA-IR levels (r: 0.49, P = 0.027). We found two independent factors related to reaching a normal weight: BMI z-score at diagnosis (HR: 0.156, 95% CI: 0.038-0.644; P = 0.01) and BMI z-score change at 6 ± 2 months (HR: 2.980, 95% CI:1.473-6.028; P = 0.002), which had high accuracy when a cut-off of 0.5 was used for ROC analysis (AUC = 0.828 (0.67-0.97); P < 0.001).

Conclusions: Children and adolescents with CS have a high risk of being overweight or obese after successful treatment for their disease. At risk patients can be identified quickly based on their baseline BMI and initial weight loss after surgery. Efforts should focus on adopting healthy diet and lifestyle in the immediate postoperative period.
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http://dx.doi.org/10.1530/EJE-20-0848DOI Listing
January 2021

Kisspeptin deficiency leads to abnormal adrenal glands and excess steroid hormone secretion.

Hum Mol Genet 2020 12;29(20):3443-3450

Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD 20892, USA.

Knockout mice for the kisspeptin receptor, Kiss1r (Kiss1r-/-) and its ligand kisspeptin, Kiss1 (Kiss1-/-) replicate the phenotype of isolated hypogonadotropic hypogonadism (IHH) associated with variants of these genes in humans. A recent report suggests that kisspeptin may be involved in human fetal adrenocortical development and function. Herein, we characterized the adrenal function and morphology in Kiss1-/- mice that do not go through normal puberty. Two fetal markers were expressed in eosinophilic cells potentially derived from the X-zone that should disappear at puberty in male mice and during the first pregnancy in female animals. Although the hypercorticosteronism observed in Kiss1-/- females corrected overtime, hyperaldosteronism persisted at 14 months and correlated with the overexpression of Star. To determine if KISS1 and KISS1R genes are involved in the development of primary aldosteronism (PA) and hypercortisolism [Cushing's syndrome (CS)] in humans, we sequenced these 2 genes in 65 patients with PA and/or CS. Interestingly, a patient with CS presented with a germline KISS1 variant (p.H90D, rs201073751). We also found three rare variants in the KISS1R gene in three patients with PA: p.C95W (rs141767649), p.A189T (rs73507527) and p.R229R (rs115335009). The two missense variants have been previously associated with IHH. Our findings suggest that KISS1 may play a role in adrenal function in mice and possibly adrenocortical steroid hormone secretion in humans, beyond its recently described role in human fetal adrenocortical development.
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http://dx.doi.org/10.1093/hmg/ddaa215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906779PMC
December 2020

Correction: Genomic and sequence variants of protein kinase A regulatory subunit type 1β (PRKAR1B) in patients with adrenocortical disease and Cushing syndrome.

Genet Med 2021 Jan;23(1):239

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

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http://dx.doi.org/10.1038/s41436-020-01018-4DOI Listing
January 2021

PRKACB variants in skeletal disease or adrenocortical hyperplasia: effects on protein kinase A.

Endocr Relat Cancer 2020 11;27(11):647-656

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

Genetic variants in components of the protein kinase A (PKA) enzyme have been associated with various defects and neoplasms in the context of Carney complex (CNC) and in isolated cases, such as in primary pigmented nodular adrenocortical disease (PPNAD), cortisol-producing adrenal adenomas (CPAs), and various cancers. PRKAR1A mutations have been found in subjects with impaired cAMP-dependent signaling and skeletal defects; bone tumors also develop in both humans and mice with PKA abnormalities. We studied the PRKACB gene in 148 subjects with PPNAD and related disorders, who did not have other PKA-related defects and identified two subjects with possibly pathogenic PRKACB gene variants and unusual bone and endocrine phenotypes. The first presented with bone and other abnormalities and carried a de novo c.858_860GAA (p.K286del) variant. The second subject carried the c.899C>T (p.T300M or p.T347M in another isoform) variant and had a PPNAD-like phenotype. Both variants are highly conserved in the PRKACB gene. In functional studies, the p.K286del variant affected PRKACB protein stability and led to increased PKA signaling. The p.T300M variant did not affect protein stability or response to cAMP and its pathogenicity remains uncertain. We conclude that PRKACB germline variants are uncommon but may be associated with phenotypes that resemble those of other PKA-related defects. However, detailed investigation of each variant is needed as PRKACB appears to be only rarely affected in these conditions, and variants such as p.T300M maybe proven to be clinically insignificant, whereas others (such as p.K286del) are clearly pathogenic and may be responsible for a novel syndrome, associated with endocrine and skeletal abnormalities.
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http://dx.doi.org/10.1530/ERC-20-0309DOI Listing
November 2020