Publications by authors named "Constantine A Stratakis"

557 Publications

Subclinical Hemorrhage of ACTH-secreting Pituitary Adenomas in Children and Adolescents Changes Their Biochemical Profile.

J Endocr Soc 2022 Jul 17;6(7):bvac080. Epub 2022 May 17.

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

Context: Subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration (SPH) presents mainly in large tumors and prolactinomas. The characteristics of patients with Cushing disease (CD) and SPH are not known.

Objective: To determine if SPH affects the presentation and biochemical profile of young patients with CD.

Methods: Pediatric and adolescent patients who were diagnosed with CD between 2005 and 2021 and available magnetic resonance imaging images were evaluated for SPH. The clinical and biochemical characteristics of patients with and without SPH were compared.

Results: Evidence of possible SPH was present in 12 out of 170 imaging studies (7.1%). Patients with and without SPH had similar age at diagnosis and sex distribution but differed in disease duration (median duration: 1.0 year [1.0-2.0] in the SPH group vs 2.5 years [1.5-3.0] in the non-SPH group,  = .014). When comparing their biochemical evaluation, patients with SPH had higher levels of morning adrenocorticotropin (ACTH) (60.8 pg/mL [43.5-80.3]) compared to patients without SPH (39.4 pg/mL [28.2-53.2],  = .016) and the degree of cortisol reduction after overnight high dose (8 mg or weight-based equivalent) dexamethasone was lower (-58.0% [-85.4 to -49.7]) compared to patients without SPH (85.8 [-90.5 to -76.8],  = .035). The presence of SPH did not affect the odds of remission after surgery or the risk of recurrence after initial remission.

Conclusion: SPH in ACTH-secreting pituitary adenomas may affect their biochemical response during endocrine evaluations. They may, for example, fail to suppress to dexamethasone which can complicate diagnosis. Thus, SPH should be mentioned on imaging and taken into consideration in the work up of pediatric patients with CD.
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http://dx.doi.org/10.1210/jendso/bvac080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9183198PMC
July 2022

Genetic Alterations in Benign Adrenal Tumors.

Biomedicines 2022 Apr 30;10(5). Epub 2022 Apr 30.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

The genetic basis of most types of adrenal adenomas has been elucidated over the past decade, leading to the association of adrenal gland pathologies with specific molecular defects. Various genetic studies have established links between variants affecting the protein kinase A (PKA) signaling pathway and benign cortisol-producing adrenal lesions. Specifically, genetic alterations in , , , , , and have been identified. The PKA signaling pathway was initially implicated in the pathogenesis of Cushing syndrome in studies aiming to understand the underlying genetic defects of the rare tumor predisposition syndromes, Carney complex, and McCune-Albright syndrome, both affected by the same pathway. In addition, germline variants in have been identified as a cause of primary bilateral macronodular adrenal hyperplasia. On the other hand, primary aldosteronism can be subclassified into aldosterone-producing adenomas and bilateral idiopathic hyperaldosteronism. Various genes have been reported as causative for benign aldosterone-producing adrenal lesions, including , , , , and . The majority of them encode ion channels or pumps, and genetic alterations lead to ion transport impairment and cell membrane depolarization which further increase aldosterone synthase transcription and aldosterone overproduction though activation of voltage-gated calcium channels and intracellular calcium signaling. In this work, we provide an overview of the genetic causes of benign adrenal tumors.
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http://dx.doi.org/10.3390/biomedicines10051041DOI Listing
April 2022

USP13 genetics and expression in a family with thyroid cancer.

Endocrine 2022 May 18. Epub 2022 May 18.

Group for Advanced Molecular Investigation (NIMA), Graduate Program in Health Sciences (PPGCS), School of Medicine (EM), Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, Brazil.

Purpose: Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma and its incidence has greatly increased in the last 30 years. Ubiquitin-specific protease 13 (USP13) is a class of deubiquitinating enzymes (DUBs) and plays an important role in cellular functions such as cell cycle regulation, DNA damage repair, and different cell signaling pathways. Studies regarding the role of USP13 in cancer development and progression are divergent and there are no previous data regarding the role of USP13 gene in PTCs. In this study, we investigated the genetic cause of PTC diagnosed in multiple members of a Brazilian family.

Methods: Whole exome sequencing (WES) was performed to identify the genetic cause of PTC. Cycloheximide chase assay and clonogenic assay were performed to study USP13 stability and function in vitro.

Results: WES analysis identified a heterozygous missense variant c.1483G > A (p.V495M) in the USP13 gene that fully segregates with the disease. In silico modeling suggests that this variant may cause protein structural perturbations. USP13 overexpression increased the potential of a single cell to form colonies. The USP13 c.1483G > A variant enhanced the effects seen in USP13 overexpression and preserved protein stability for longer hours compared to the non-mutated USP13 protein.

Conclusion: Our study suggests that USP13 overexpression may play a role in tumorigenesis of PTCs; and that the USP13 p.V495M (c.1483G > A) variant enhances USP13 estability.
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http://dx.doi.org/10.1007/s12020-022-03068-xDOI Listing
May 2022

Steroidogenic Factor-1 Lineage Origin of Skin Lesions in Carney Complex Syndrome.

J Invest Dermatol 2022 May 12. Epub 2022 May 12.

Institut Genetics, Reproduction & Development (iGReD), CNRS, Inserm, University of Clermont-Auvergne, France. Electronic address:

Carney complex is a rare familial multineoplastic syndrome predisposing to endocrine and nonendocrine tumors due to inactivating mutations of PRKAR1A, leading to perturbations of the cAMP‒protein kinase A signaling pathway. Skin lesions are the most common manifestation of Carney complex, including lentigines, blue nevi, and cutaneous myxomas in unusual locations such as oral and genital mucosa. Unlike endocrine disorders, the pathogenesis of skin lesions remains unexplained. In this study, we show that embryonic invalidation of the Prkar1a gene in steroidogenic factor-1‒expressing cells leads to the development of familial skin pigmentation alterations, reminiscent of those in patients with Carney complex. Immunohistological and molecular analyses, coupled with genetic monitoring of recombinant cell lineages in mouse skin, suggest that familial lentiginosis and myxomas occur in skin areas specifically enriched in dermal melanocytes. In lentigines- and blue nevi‒prone areas from mutant mice and patients, Prkar1a/PRKAR1A invalidation occurs in a subset of dermal fibroblasts capable of inducing, under the influence of protein kinase A signaling, the production of promelanogenic EDN3 and hepatocyte GF signals. Our model strongly suggests that the origin of the typical Carney complex cutaneous lesions is the result of noncell-autonomous promelanogenic activity of a dermal fibroblast population sharing a community of origin with steroidogenic factor-1 lineage.
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http://dx.doi.org/10.1016/j.jid.2022.04.019DOI Listing
May 2022

Copeptin Levels Before and After Transsphenoidal Surgery for Cushing Disease: A Potential Early Marker of Remission.

J Endocr Soc 2022 Jun 6;6(6):bvac053. Epub 2022 Apr 6.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD 20892, USA.

Context: Arginine-vasopressin and CRH act synergistically to stimulate secretion of ACTH. There is evidence that glucocorticoids act via negative feedback to suppress arginine-vasopressin secretion.

Objective: Our hypothesis was that a postoperative increase in plasma copeptin may serve as a marker of remission of Cushing disease (CD).

Design: Plasma copeptin was obtained in patients with CD before and daily on postoperative days 1 through 8 after transsphenoidal surgery. Peak postoperative copeptin levels and Δcopeptin values were compared among those in remission vs no remission.

Results: Forty-four patients (64% female, aged 7-55 years) were included, and 19 developed neither diabetes insipidus (DI) or syndrome of inappropriate anti-diuresis (SIADH). Thirty-three had follow-up at least 3 months postoperatively. There was no difference in peak postoperative copeptin in remission (6.1 pmol/L [4.3-12.1]) vs no remission (7.3 pmol/L [5.4-8.4],  = 0.88). Excluding those who developed DI or SIADH, there was no difference in peak postoperative copeptin in remission (10.2 pmol/L [6.9-21.0]) vs no remission (5.4 pmol/L [4.6-7.3],  = 0.20). However, a higher peak postoperative copeptin level was found in those in remission (14.6 pmol/L [±10.9] vs 5.8 (±1.4),  = 0.03]) with parametric testing. There was no difference in the Δcopeptin by remission status.

Conclusions: A difference in peak postoperative plasma copeptin as an early marker to predict remission of CD was not consistently present, although the data point to the need for a larger sample size to further evaluate this. However, the utility of this test may be limited to those who develop neither DI nor SIADH postoperatively.
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http://dx.doi.org/10.1210/jendso/bvac053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9070476PMC
June 2022

Neurofibromatosis Type 1 Has a Wide Spectrum of Growth Hormone Excess.

J Clin Med 2022 Apr 13;11(8). Epub 2022 Apr 13.

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

Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3-5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29-52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH (<1 ng/mL) on oral glucose tolerance test (OGTT, = 9) and frequent overnight sampling of GH levels ( = 6). Genetic testing was ascertained through targeted or whole-exome sequencing ( = 9). Five patients (all children) had an OPG without any pituitary abnormality, three patients (one adolescent and two adults) had a pituitary lesion (two tumors, one suggestive hyperplasia) without an OPG, and two patients (one child and one adult) had a pituitary lesion (a pituitary tumor and suggestive hyperplasia, respectively) with a concomitant OPG. The serial overnight sampling of GH levels in six patients revealed abnormal overnight GH profiling. Two adult patients had a voluminous pituitary gland on pituitary imaging. One pituitary tumor from an adolescent patient who harbored a germline heterozygous p.Gln514Pro variant stained positive for GH and prolactin. One child who harbored a heterozygous truncating variant in exon 46 of had an OPG that, when compared to normal optic nerves, stained strongly for GPR101, an orphan G protein-coupled receptor causing GH excess in X-linked acrogigantism. We describe a series of patients with GH excess and NF1. Our findings show the variability in patterns of serial overnight GH secretion, somatotroph tumor or hyperplasia in some cases of NF1 and GH excess. Further studies are required to ascertain the link between NF1, GH excess and GPR101, which may aid in the characterization of the molecular underpinning of GH excess in NF1.
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http://dx.doi.org/10.3390/jcm11082168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029762PMC
April 2022

Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism.

Am J Hum Genet 2022 04 23;109(4):553-570. Epub 2022 Feb 23.

Laboratory of Cellular and Molecular Endocrinology and Laboratory of Pharmacology and Brain Pathology, Humanitas Research Hospital - IRCCS, 20089 Rozzano (Mi), Italy. Electronic address:

X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes VGLL1, CD40LG, ARHGEF6, RBMX, and GPR101) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. The mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone was previously unclear. Using Hi-C and 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. We showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Next, using 4C-seq with GPR101, RBMX, and VGLL1 viewpoints, we showed that the duplications in multiple X-LAG-affected individuals led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. We then identified several pituitary active cis-regulatory elements (CREs) within the neo-TAD and demonstrated in vitro that one of them significantly enhanced reporter gene expression. At the same time, we showed that the GPR101 promoter permits the incorporation of new regulatory information. Our results indicate that X-LAG is a TADopathy of the endocrine system in which Xq26.3 duplications disrupt the local chromatin architecture forming a neo-TAD. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in pituitary tumors caused by X-LAG.
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http://dx.doi.org/10.1016/j.ajhg.2022.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9069129PMC
April 2022

Inflammatory biomarkers in the evaluation of pediatric endogenous Cushing syndrome.

Eur J Endocrinol 2022 Mar 5;186(4):503-510. Epub 2022 Mar 5.

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

Objective: Inflammatory biomarkers, such as absolute neutrophil and lymphocyte counts, neutrophil-to-lymphocyte ratio (NLR), platelet (PLT)-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR), are associated with the progression and development of several disorders. Although patients with Cushing syndrome (CS) have immunosuppression with altered leucocyte counts, the profile of the inflammatory biomarkers in these patients has not been extensively studied.

Design: We compared a panel of inflammatory biomarkers in patients with active endogenous CS (n of complete blood count (CBC) reports = 319) and eucortisolemic subjects of similar age, gender and BMI (n of CBC reports = 93). Patients were divided into two age groups (6-12 years at the time of CBC and >12 years at the time of CBC) based on age differences in normal reference ranges.

Results: Patients with CS had higher NLR vs controls (6-12 years: 2.47 (1.86, 3.32) vs 1.35 (1.11, 2.27), P < 0.0001; >12 years: 3.00 (2.23-4.17) vs 1.80 (1.23-2.31), P < 0.0001). Similarly, absolute neutrophil and lymphocyte counts, MLR and PLR differed between patients with CS and controls. The inflammatory biomarkers correlated with indices of cortisol secretion, such as midnight serum cortisol, 24-h urinary free cortisol and morning cortisol. On receiver operating characteristic analysis, NLR showed high area under the curve (AUC) (6-12 years: cutoff of 1.72 had AUC: 0.77, >12 years: cutoff of 2.35 had AUC: 0.81).

Conclusions: We conclude that multiple inflammatory biomarkers differed between patients with CS and controls suggesting substantial effects of hypercortisolemia on the immune system.
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http://dx.doi.org/10.1530/EJE-21-1199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9059943PMC
March 2022

The regulation of PKA signaling in obesity and in the maintenance of metabolic health.

Pharmacol Ther 2022 Jan 17;237:108113. Epub 2022 Jan 17.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA; Human Genetics & Precision Medicine, IMBB, Foundation for Research & Technology Hellas, Greece; Research Institute, ELPEN, SA, Athens, Greece.

The cAMP-dependent protein kinase (PKA) system represents a primary cell-signaling pathway throughout systems and across species. PKA facilitates the actions of hormones, neurotransmitters and other signaling molecules that bind G-protein coupled receptors (GPCR) to modulate cAMP levels. Through its control of synaptic events, exocytosis, transcriptional regulation, and more, PKA signaling regulates cellular metabolism and emotional and stress responses making it integral in the maintenance and dysregulation of energy homeostasis. Neural PKA signaling is regulated by afferent and peripheral efferent signals that link specific neural cell populations to the regulation of metabolic processes in adipose tissue, liver, pancreas, adrenal, skeletal muscle, and gut. Mouse models have provided invaluable information on the roles for PKA subunits in brain and key metabolic organs. While limited, human studies infer differential regulation of the PKA system in obese compared to lean individuals. Variants identified in PKA subunit genes cause Cushing syndrome that is characterized by metabolic dysregulation associated with endogenous glucocorticoid excess. Under healthy physiologic conditions, the PKA system is exquisitely regulated by stimuli that activate GPCRs to alter intracellular cAMP concentrations, and by PKA cellular localization and holoenzyme stability. Adenylate cyclase activity generates cAMP while phosphodiesterase-mediated cAMP degradation to AMP decreases cAMP levels downstream of GPCRs. Chronic perturbations in PKA signaling appear to be capable of resetting PKA regulation at several levels; in addition, sex differences in PKA signaling regulation, while not well understood, impact the physiologic consequences of metabolic dysregulation and obesity. This review explores the roles for PKA signaling in the pathogenesis of metabolic diseases including obesity, type 2 diabetes mellitus and associated co-morbidities through neural-peripheral crosstalk and cAMP/PKA signaling pathway targets that hold therapeutic potential.
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http://dx.doi.org/10.1016/j.pharmthera.2022.108113DOI Listing
January 2022

KDM1A inactivation causes hereditary food-dependent Cushing syndrome.

Genet Med 2022 02 30;24(2):374-383. Epub 2021 Nov 30.

Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France.

Purpose: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS.

Methods: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing).

Results: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS.

Conclusion: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.
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http://dx.doi.org/10.1016/j.gim.2021.09.018DOI Listing
February 2022

Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex.

J Clin Invest 2021 12;131(23)

iGReD, Université Clermont-Auvergne, CNRS6293, INSERM U1103, Clermont-Ferrand, France.

Large-cell calcifying Sertoli cell tumors (LCCSCTs) are among the most frequent lesions occurring in male Carney complex (CNC) patients. Although they constitute a key diagnostic criterion for this rare multiple neoplasia syndrome resulting from inactivating mutations of the tumor suppressor PRKAR1A, leading to unrepressed PKA activity, LCCSCT pathogenesis and origin remain elusive. Mouse models targeting Prkar1a inactivation in all somatic populations or separately in each cell type were generated to decipher the molecular and paracrine networks involved in the induction of CNC testis lesions. We demonstrate that the Prkar1a mutation was required in both stromal and Sertoli cells for the occurrence of LCCSCTs. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to the understanding of human LCCSCT pathogenesis and demonstrated PKA-induced paracrine molecular circuits in which the aberrant WNT4 signal production is a limiting step in shaping intratubular lesions and tumor expansion both in a mouse model and in human CNC testes.
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http://dx.doi.org/10.1172/JCI146910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631603PMC
December 2021

Association between Maternal Non-Coding Interferon-λ Polymorphisms and Congenital Zika Syndrome in a Cohort from Brazilian Northeast.

Viruses 2021 11 10;13(11). Epub 2021 Nov 10.

Laboratório de Virologia Molecular, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.

Congenital Zika syndrome (CZS) is characterized by a diverse group of congenital malformations induced by ZIKV infection during pregnancy. Type III interferons have been associated with placental immunity against ZIKV and restriction of vertical transmission in mice, and non-coding single-nucleotide polymorphisms (SNPs) on these genes are well known to influence susceptibility to other viral infections. However, their effect on ZIKV pathogenesis has not yet been explored. To investigate whether maternal non-coding SNPs at genes are associated with CZS, 52 women infected with ZIKV during pregnancy were enrolled in a case-control association study. A total of 28 women were classified as cases and 24 as controls based on the presence or absence of CZS in their infants, and seven Interferon-λ non-coding SNPs (rs12980275, rs8099917, rs4803217, rs4803219, rs8119886, rs368234815, rs12979860) were genotyped. The results of logistic regression analyses show an association between the G allele at rs8099917 and increased susceptibility to CZS under a log-additive model (OR = 2.80; CI = 1.14-6.91; = 0.02), after adjustment for trimester of infection and genetic ancestry. These results provide evidence of an association between Interferon-λ SNPs and CZS, suggesting rs8099917 as a promising candidate for further studies on larger cohorts.
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http://dx.doi.org/10.3390/v13112253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622836PMC
November 2021

CYP11B1 variants influence skeletal maturation via alternative splicing.

Commun Biol 2021 11 9;4(1):1274. Epub 2021 Nov 9.

Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Dr Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.

We performed genome-wide association study meta-analysis to identify genetic determinants of skeletal age (SA) deviating in multiple growth disorders. The joint meta-analysis (N = 4557) in two multiethnic cohorts of school-aged children identified one locus, CYP11B1 (expression confined to the adrenal gland), robustly associated with SA (rs6471570-A; β = 0.14; P = 6.2 × 10). rs6410 (a synonymous variant in the first exon of CYP11B1 in high LD with rs6471570), was prioritized for functional follow-up being second most significant and the one closest to the first intron-exon boundary. In 208 adrenal RNA-seq samples from GTEx, C-allele of rs6410 was associated with intron 3 retention (P = 8.11 × 10), exon 4 inclusion (P = 4.29 × 10), and decreased exon 3 and 5 splicing (P = 7.85 × 10), replicated using RT-PCR in 15 adrenal samples. As CYP11B1 encodes 11-β-hydroxylase, involved in adrenal glucocorticoid and mineralocorticoid biosynthesis, our findings highlight the role of adrenal steroidogenesis in SA in healthy children, suggesting alternative splicing as a likely underlying mechanism.
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http://dx.doi.org/10.1038/s42003-021-02774-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578655PMC
November 2021

Consensus on diagnosis and management of Cushing's disease: a guideline update.

Lancet Diabetes Endocrinol 2021 12 20;9(12):847-875. Epub 2021 Oct 20.

San Raffaele Vita-Salute University, Milan, Italy.

Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified.
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http://dx.doi.org/10.1016/S2213-8587(21)00235-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743006PMC
December 2021

Younger age and early puberty are associated with cognitive function decline in children with Cushing disease.

Clin Endocrinol (Oxf) 2022 04 19;96(4):569-577. Epub 2021 Oct 19.

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

Objective: To investigate the effect of hypercortisolism on the developing brain we performed clinical, cognitive, and psychological evaluation of children with Cushing disease (CD) at diagnosis and 1 year after remission.

Study Design: Prospective study of 41 children with CD. Children completed diverse sets of cognitive measures before and 1 year after remission. Neuropsychological evaluation included the Wechsler Intelligence Scale, California Verbal Learning Test, Trail Making Test, the combined subset scores of Wide Range Achievement Test and Woodcock-Johnson Psychoeducational Battery Test of Achievement, and the Behavioral Assessment System for Children.

Results: Comprehensive cognitive evaluations at baseline and 1 year following cure revealed significant decline mostly in nonverbal skills. Decrements occurred in most of the various indices that measure all aspects of cognitive function and younger age and early pubertal stage largely contributed to most of this decline. Results indicated that age at baseline was associated with positive regression weights for changes in scores for verbal, performance, and full intelligence quotient (IQ) scores and for subtests arithmetic, picture completion, coding, block design, scores; indicating that older age at baseline was associated with less of a deterioration in cognitive scores from pre- to posttreatment.

Conclusion: Our findings suggest that chronic glucocorticoid excess and accompanying secondary hormonal imbalances followed by eucortisolemia have detrimental effects on cognitive function in the developing brain; younger age and pubertal stage are risk factors for increased vulnerability, while older adolescents have cognitive vulnerabilities like that of adult patients affected with CD.
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http://dx.doi.org/10.1111/cen.14611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8897227PMC
April 2022

Pituitary Imaging Abnormalities and Related Endocrine Disorders in Erdheim-Chester Disease.

Cancers (Basel) 2021 Aug 17;13(16). Epub 2021 Aug 17.

Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.

Purpose: We examined abnormal pituitary imaging (API) and associated endocrine dysfunction in subjects with ECD.

Methods: A cross-sectional descriptive examination of a natural history cohort study diagnosed with ECD was conducted at a clinical research center. Subjects underwent baseline endocrine tests of anterior and posterior pituitary function and dedicated pituitary gland MRI scans. We determined the frequency of various pituitary imaging abnormalities in ECD and assessed its relationships with age, sex, body mass index (BMI), V600E status, high sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), pituitary hormone deficits and number, diabetes insipidus (DI), and panhypopituitarism.

Results: Our cohort included 61 subjects with ECD [age (SD): 54.3 (10.9) y, 46 males/15 females]. API was present in 47.5% (29/61) of ECD subjects. Loss of the posterior pituitary bright spot (36.1%) followed by thickened pituitary stalk (24.6%), abnormal enhancement (18.0%), and pituitary atrophy (14.8%) were the most common abnormalities. DI and panhypopituitarism were more frequent in subjects with API without differences in age, sex distribution, hsCRP, ESR, and V600E status compared to normal pituitary imaging.

Conclusions: We noted a high burden of API and endocrinopathies in ECD. API was highly associated with the presence of panhypopituitarism and DI. Therefore, a thorough assessment of hypothalamic-pituitary integrity should be considered in subjects with ECD.
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http://dx.doi.org/10.3390/cancers13164126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392147PMC
August 2021

Paediatric patients with Cushing disease and negative pituitary MRI have a higher risk of nonremission after transsphenoidal surgery.

Clin Endocrinol (Oxf) 2021 12 25;95(6):856-862. Epub 2021 Aug 25.

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

Objective: Diagnostic workup of Cushing disease (CD) involves imaging evaluation of the pituitary gland, but in many patients no tumour is visualised. The aim of this study is to describe the association of magnetic resonance imaging (MRI) findings with the postoperative course of paediatric and adolescent patients with CD.

Patients: Patients with a diagnosis of CD at less than 21 years of age with MRI evaluation of the pituitary before first transsphenoidal surgery were included.

Measurements: Clinical, imaging and biochemical data were analysed.

Results: One hundred and eighty-six patients with paediatric or adolescent-onset CD were included in the study. Of all patients, 127 (68.3%) had MRI findings consistent with pituitary adenoma, while the remaining had negative or inconclusive MRI. Patients with negative MRI were younger in age and had lower morning cortisol and adrenocorticotropin levels. Of 181 patients with data on postoperative course, patients with negative MRI had higher odds of not achieving remission after the first surgery (odds ratio = 2.6, 95% confidence intervals [CIs] = 1.1-6.0) compared to those with positive MRI. In patients with remission after first transsphenoidal surgery, long-term recurrence risk was not associated with the detection of a pituitary adenoma in the preoperative MRI (hazard risk = 2.1, 95% CI = 0.7-5.8).

Conclusions: Up to one-third of paediatric and adolescent patients with CD do not have a pituitary tumour visualised in MRI. A negative MRI is associated with higher odds of nonremission after surgery; however, if remission is achieved, long-term risk for recurrence is not associated with the preoperative MRI findings.
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http://dx.doi.org/10.1111/cen.14560DOI Listing
December 2021

Homozygous Variant () Linked to Gonadotropin-Independent Precocious Puberty in a Young Girl.

J Endocr Soc 2021 Oct 19;5(10):bvab125. Epub 2021 Jul 19.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1109, USA.

Sex hormone-binding globulin (SHBG) in the blood is a major determinant of bioactivity for key sex steroids such as testosterone and estradiol. Low serum levels of SHBG have been associated with obesity, polycystic ovaries, and metabolic syndrome, and other states associated with hyperandrogenemia. A 9-year, 6-month-old girl presented with a history of peripheral precocious puberty and aggressive behavior. The patient's SHBG level was remarkably low for her age, at less than 5 nmol/L (reference range for a girl with a bone age of 10 years, 73 nmol/L [SEM = 10]) [1]. On genetic and protein analysis, the patient was found to have a homozygous missense potentially pathogenic variant in the gene (c.554C>T, p.P185L); her parents were asymptomatic heterozygote carriers. Laboratory investigations supported the possible involvement of this genetic alteration in the patient's phenotype. Various analyses of this variant support its pathogenicity, although the exact mechanism remains unclear. In conclusion, we present a genetic variant in the homozygote state that may have been associated with gonadotropin-independent precocious puberty in a young girl.
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http://dx.doi.org/10.1210/jendso/bvab125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364343PMC
October 2021

and Thyroid Tumors.

Cancers (Basel) 2021 Jul 30;13(15). Epub 2021 Jul 30.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Thyroid cancer is the most common type of endocrine malignancy and the incidence is rapidly increasing. Follicular (FTC) and papillary thyroid (PTC) carcinomas comprise the well-differentiated subtype and they are the two most common thyroid carcinomas. Multiple molecular genetic and epigenetic alterations have been identified in various types of thyroid tumors over the years. Point mutations in , as well as and chromosomal rearrangements are common. Thyroid cancer, including both FTC and PTC, has been observed in patients with Carney Complex (CNC), a syndrome that is inherited in an autosomal dominant manner and predisposes to various tumors. CNC is caused by inactivating mutations in the tumor-suppressor gene encoding the cyclic AMP (cAMP)-dependent protein kinase A (PKA) type 1α regulatory subunit () mapped in chromosome 17 (17q22-24). Growth of the thyroid is driven by the TSH/cAMP/PKA signaling pathway and it has been shown in mouse models that PKA activation through genetic ablation of the regulatory subunit can cause FTC. In this review, we provide an overview of the molecular mechanisms contributing to thyroid tumorigenesis associated with inactivation of the gene.
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http://dx.doi.org/10.3390/cancers13153834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345073PMC
July 2021

The PRKAR1B p.R115K Variant is Associated with Lipoprotein Profile in African American Youth with Metabolic Challenges.

J Endocr Soc 2021 Aug 16;5(8):bvab071. Epub 2021 Apr 16.

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

Context: High childhood obesity rates coincide with increased incidence of nonalcoholic fatty liver disease (NAFLD) and other comorbidities. Understanding the genetics of susceptibility to obesity and its comorbidities could guide intervention. The cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) signaling pathway regulates energy balance, glucose homeostasis, and lipid metabolism.

Objective: We hypothesized that PKA-related gene variants may be associated with obesity or associated metabolic conditions.

Methods: We included 457 youths from the Yale Obesity Clinic into the Pathogenesis of Youth-Onset Diabetes cohort (NCT01967849); a variety of clinical tests were performed to characterize NAFLD. Exon sequencing of 54 PKA pathway genes was performed. Variants were confirmed by Sanger sequencing. Clinical data were analyzed, correcting for NAFLD status and body mass index z-score with adjustments for multiple comparisons. Fluorescence resonance energy transfer (FRET) and PKA enzymatic assays were performed in HEK293 cells transfected with the PRKAR1B p.R115K construct. In silico structural analysis for this variant was done.

Results: We identified the variant PRKAR1B p.R115K in 4 unrelated, African American patients. Analyses compared this variant group to other African American patients in the cohort. PRKAR1B p.R115K was associated with favorable circulating lipoprotein levels. Analysis of FRET and PKA enzymatic assay showed stronger interaction between the R1β mutant and PKA catalytic subunit Cα and decreased basal PKA activity compared with the wildtype ( < .0001). Structural analysis revealed that p.R115K may hinder conformational changes resulting from cAMP binding at cAMP binding domain A.

Conclusion: Data suggest PRKAR1B p.R115K affects cAMP signaling and may favorably modulate lipoprotein profile in African American youth, protecting them from some adverse metabolic outcomes.
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http://dx.doi.org/10.1210/jendso/bvab071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237845PMC
August 2021

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

PLoS Negl Trop Dis 2021 06 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224898PMC
June 2021

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

J Allergy Clin Immunol 2022 01 2;149(1):302-314. Epub 2021 Jun 2.

Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, National Institutes of Health (NIH), Bethesda, Md. Electronic address:

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

Objective: We performed extensive immunologic studies in otherwise healthy pediatric patients with eCs before and 6 to 13 months after tumor resection, as well as in in vitro glucocorticoid-treated control cells.

Methods: Flow cytometry, immunoblotting, enzyme-linked immunosorbent assay, real-time quantitative PCR, and RNA-Seq techniques were used to characterize patients' and in vitro glucocorticoid treated cells.

Results: Reduced thymic output, decreased naive T cells, diminished proliferation, and increased T-cell apoptosis were detected before surgery; 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 antiapoptotic BCL2 expression and rescued T-cell apoptosis in a PI3K pathway-dependent manner. Similar and reproducible findings were confirmed in eCs 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 eCs 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 proapoptotic 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636539PMC
January 2022

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

J Biol Chem 2021 07 1;297(1):100850. Epub 2021 Jun 1.

Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington, 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233231PMC
July 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 2022 May 26;91(6):1562-1570. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617065PMC
May 2022

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
December 2021

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

Ann Surg Oncol 2021 Nov 3;28(12):7487-7495. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530859PMC
November 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 08 8;23(8):1465-1473. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354857PMC
August 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
December 2021
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