The spectrum of growth hormone excess in Carney complex and genotype-phenotype correlations.

CONTEXT: Carney complex (CNC) is a familial neoplasia syndrome associated with growth hormone (GH) excess (GHE). OBJECTIVE: To describe the frequency of GHE in a large cohort of patients with CNC, and to identify genotype-phenotype correlations. METHODS: Patients with CNC with at least one biochemical evaluation of GH secretion at our center from 1995-2021 (n=140) were included in the study. Diagnosis of GHE was based on levels of insulin-like growth factor-1 (IGF-1), GH suppression during oral glucose tolerance test (OGTT), GH stimulation after thyrotropin (TRH) administration and overnight GH secretion. RESULTS: Fifty patients (35.7%) had GHE and 28 subjects (20%) had symptomatic acromegaly, with median age at diagnosis of 25.3 and 26.1 years respectively. Most of the patients (99.3%) had a PRKAR1A gene defect. There was a higher risk of GHE in patients harboring a variant that led to no expression of the affected allele [Hazard risk (HR): 3.06, 95% Confidence Intervals (CI): 1.2-7.8] and for patients harboring the hotspot variant c.491_492delTG (HR: 2.10, 95%CI: 1.1-4.1). Almost half of patients with CNC had an abnormal finding on pituitary imaging. CNC patients with an abnormal pituitary imaging had higher risk of GHE (HR: 2.94, 95%CI: 1.5-5.8), especially when single or multiple adenoma-like lesions were identified. Management of patients with symptomatic acromegaly involved surgical and medical approaches. CONCLUSION: Dysregulation of GH secretion is a common finding in CNC. The clinical spectrum of this disorder and its association with genetic and imaging characteristics of the patient make prompt diagnosis and management more successful.

Using a chat-based informed consent tool in large-scale genomic research.

OBJECTIVE: We implemented a chatbot consent tool to shift the time burden from study staff in support of a national genomics research study. MATERIALS AND METHODS: We created an Institutional Review Board-approved script for automated chat-based consent. We compared data from prospective participants who used the tool or had traditional consent conversations with study staff. RESULTS: Chat-based consent, completed on a user's schedule, was shorter than the traditional conversation. This did not lead to a significant change in affirmative consents. Within affirmative consents and declines, more prospective participants completed the chat-based process. A quiz to assess chat-based consent user understanding had a high pass rate with no reported negative experiences. CONCLUSION: Our report shows that a structured script can convey important information while realizing the benefits of automation and burden shifting. Analysis suggests that it may be advantageous to use chatbots to scale this rate-limiting step in large research projects.

Exome sequencing findings in children with annular pancreas.

BACKGROUND: Annular pancreas (AP) is a congenital defect of unknown cause in which the pancreas encircles the duodenum. Theories include abnormal migration and rotation of the ventral bud, persistence of ectopic pancreatic tissue, and inappropriate fusion of the ventral and dorsal buds before rotation. The few reported familial cases suggest a genetic contribution. METHODS: We conducted exome sequencing in 115 affected infants from the California birth defects registry. RESULTS: Seven cases had a single heterozygous missense variant in IQGAP1, five of them with CADD scores >20; seven other infants had a single heterozygous missense variant in NRCAM, five of them with CADD scores >20. We also looked at genes previously associated with AP and found two rare heterozygous missense variants, one each in PDX1 and FOXF1. CONCLUSION: IQGAP1 and NRCAM are crucial in cell polarization and migration. Mutations result in decreased motility which could possibly cause the ventral bud to not migrate normally. To our knowledge, this is the first study reporting a possible association for IQGAP1 and NRCAM with AP. Our findings of rare genetic variants involved in cell migration in 15% of our population raise the possibility that AP may be related to abnormal cell migration.

Increased diagnostic yield from negative whole genome-slice panels using automated reanalysis.

We evaluated the diagnostic yield using genome-slice panel reanalysis in the clinical setting using an automated phenotype/gene ranking system. We analyzed whole genome sequencing (WGS) data produced from clinically ordered panels built as bioinformatic slices for 16 clinically diverse, undiagnosed cases referred to the Pediatric Mendelian Genomics Research Center, an NHGRI-funded GREGoR Consortium site. Genome-wide reanalysis was performed using Moon™, a machine-learning-based tool for variant prioritization. In five out of 16 cases, we discovered a potentially clinically significant variant. In four of these cases, the variant was found in a gene not included in the original panel due to phenotypic expansion of a disorder or incomplete initial phenotyping of the patient. In the fifth case, the gene containing the variant was included in the original panel, but being a complex structural rearrangement with intronic breakpoints outside the clinically analyzed regions, it was not initially identified. Automated genome-wide reanalysis of clinical WGS data generated during targeted panels testing yielded a 25% increase in diagnostic findings and a possibly clinically relevant finding in one additional case, underscoring the added value of analyses versus those routinely performed in the clinical setting.

"Development and Implementation of Novel Chatbot-based Genomic Research Consent".

Objective: To conduct a retrospective analysis comparing traditional human-based consenting to an automated chat-based consenting process. Materials and Methods: We developed a new chat-based consent using our IRB-approved consent forms. We leveraged a previously developed platform (GiaⓇ, or "Genetic Information Assistant") to deliver the chat content to candidate participants. The content included information about the study, educational information, and a quiz to assess understanding. We analyzed 144 families referred to our study during a 6-month time period. A total of 37 families completed consent using the traditional process, while 35 families completed consent using Gia. Results: Engagement rates were similar between both consenting methods. The median length of the consent conversation was shorter for Gia users compared to traditional (44 vs. 76 minutes). Additionally, the total time from referral to consent completion was faster with Gia (5 vs. 16 days). Within Gia, understanding was assessed with a 10-question quiz that most participants (96%) passed. Feedback about the chat consent indicated that 86% of participants had a positive experience. Discussion: Using Gia resulted in time savings for both the participant and study staff. The chatbot enables studies to reach more potential candidates. We identified five key features related to human-centered design for developing a consent chat. Conclusion: This analysis suggests that it is feasible to use an automated chatbot to scale obtaining informed consent for a genomics research study. We further identify a number of advantages when using a chatbot.

Disorders of the adrenal cortex: Genetic and molecular aspects.

Adrenal cortex produces glucocorticoids, mineralocorticoids and adrenal androgens which are essential for life, supporting balance, immune response and sexual maturation. Adrenocortical tumors and hyperplasias are a heterogenous group of adrenal disorders and they can be either sporadic or familial. Adrenocortical cancer is a rare and aggressive malignancy, and it is associated with poor prognosis. With the advance of next-generation sequencing technologies and improvement of genomic data analysis over the past decade, various genetic defects, either from germline or somatic origin, have been unraveled, improving diagnosis and treatment of numerous genetic disorders, including adrenocortical diseases. This review gives an overview of disorders associated with the adrenal cortex, the genetic factors of these disorders and their molecular implications.

Adrenal hyperplasias in childhood: An update.

Pediatric adrenocortical hyperplasias are rare; they usually present with Cushing syndrome (CS); of them, isolated micronodular adrenal disease and its variant, primary pigmented adrenocortical disease are the most commonly encountered. Most cases are due to defects in the cyclic AMP/protein kinase A (cAMP/PKA) pathway, although a few cases remain without an identified genetic defect. Another cause of adrenal hyperplasia in childhood is congenital adrenal hyperplasia, a group of autosomal recessive disorders that affect steroidogenic enzymes in the adrenal cortex. Clinical presentation varies and depends on the extent of the underlying enzymatic defect. The most common form is due to 21-hydroxylase deficiency; it accounts for more than 90% of the cases. In this article, we discuss the genetic etiology of adrenal hyperplasias in childhood.

Update on the Genetics of Primary Aldosteronism and Aldosterone-Producing Adenomas.

PURPOSE OF THE REVIEW: Primary aldosteronism (PA) is the leading cause of secondary hypertension, accounting for over 10% of patients with high blood pressure. It is characterized by autonomous production of aldosterone from the adrenal glands leading to low-renin levels. The two most common forms arise from bilateral adrenocortical hyperplasia (BAH) and aldosterone-producing adenoma (APA). We discuss recent discoveries in the genetics of PA. RECENT FINDINGS: Most APAs harbor variants in the KCNJ5, CACNA1D, ATP1A1, ATP2B3, and CTNNB1 genes. With the exception of ß-catenin (CTNNB1), all other causative genes encode ion channels; pathogenic variants found in PA lead to altered ion transportation, cell membrane depolarization, and consequently aldosterone overproduction. Some of these genes are found mutated in the germline state (CYP11B2, CLCN2, KCNJ5, CACNA1H, and CACNA1D), leading then to familial hyperaldosteronism, and often BAH rather than single APAs. Several genetic defects in the germline or somatic state have been identified in PA. Understanding how these molecular abnormalities lead to excess aldosterone contributes significantly to the elucidation of the pathophysiology of low-renin hypertension. It may also lead to new and more effective therapies for this disease acting at the molecular level.

Genetic Alterations in Benign Adrenal Tumors.

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 GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B 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 ARMC5 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 KCNJ5, CACNA1D, CACNA1H, CLCN2, ATP1A1, and ATP2B3. 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.

Exome sequencing identifies variants in infants with sacral agenesis.

BACKGROUND: Sacral agenesis (SA) consists of partial or complete absence of the caudal end of the spine and often presents with additional birth defects. Several studies have examined gene variants for syndromic forms of SA, but only one has examined exomes of children with non-syndromic SA. METHODS: Using buccal cell specimens from families of children with non-syndromic SA, exomes of 28 child-parent trios (eight with and 20 without a maternal diagnosis of pregestational diabetes) and two child-father duos (neither with diagnosis of maternal pregestational diabetes) were exome sequenced. RESULTS: Three children had heterozygous missense variants in ID1 (Inhibitor of DNA Binding 1), with CADD scores >20 (top 1% of deleterious variants in the genome); two children inherited the variant from their fathers and one from the child's mother. Rare missense variants were also detected in PDZD2 (PDZ Domain Containing 2; N = 1) and SPTBN5 (Spectrin Beta, Non-erythrocytic 5; N = 2), two genes previously suggested to be associated with SA etiology. Examination of variants with autosomal recessive and X-linked recessive inheritance identified five and two missense variants, respectively. Compound heterozygous variants were identified in several genes. In addition, 12 de novo variants were identified, all in different genes in different children. CONCLUSIONS: To our knowledge, this is the first study reporting a possible association between ID1 and non-syndromic SA. Although maternal pregestational diabetes has been strongly associated with SA, the missense variants in ID1 identified in two of three children were paternally inherited. These findings add to the knowledge of gene variants associated with non-syndromic SA and provide data for future studies.

Exome sequencing of child-parent trios with bladder exstrophy: Findings in 26 children.

Bladder exstrophy (BE) is a rare, lower ventral midline defect with the bladder and part of the urethra exposed. The etiology of BE is unknown but thought to be influenced by genetic variation with more recent studies suggesting a role for rare variants. As such, we conducted paired-end exome sequencing in 26 child/mother/father trios. Three children had rare (allele frequency ≤ 0.0001 in several public databases) inherited variants in TSPAN4, one with a loss-of-function variant and two with missense variants. Two children had loss-of-function variants in TUBE1. Four children had rare missense or nonsense variants (one per child) in WNT3, CRKL, MYH9, or LZTR1, genes previously associated with BE. We detected 17 de novo missense variants in 13 children and three de novo loss-of-function variants (AKR1C2, PRRX1, PPM1D) in three children (one per child). We also detected rare compound heterozygous loss-of-function variants in PLCH2 and CLEC4M and rare inherited missense or loss-of-function variants in additional genes applying autosomal recessive (three genes) and X-linked recessive inheritance models (13 genes). Variants in two genes identified may implicate disruption in cell migration (TUBE1) and adhesion (TSPAN4) processes, mechanisms proposed for BE, and provide additional evidence for rare variants in the development of this defect.

PRKAR1A and Thyroid Tumors.

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 BRAF, RAS as well as RET/PTC and PAX8/PPARγ 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 (PRKAR1A) 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 Prkar1a can cause FTC. In this review, we provide an overview of the molecular mechanisms contributing to thyroid tumorigenesis associated with inactivation of the RRKAR1A gene.

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

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 SDH-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 SDHx subunits. Gastrointestinal stromal tumors (GISTs) associated with SDH deficiency are negative for KIT/PDGFRA mutations and present with distinctive clinical features such as early onset (usually childhood or adolescence) and almost exclusively gastric location. SDH-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 SDH 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 SDHC gene and may be due to germline mosaicism of the responsible genetic defect.

Predicting the risk of cardiac myxoma in Carney complex.

PURPOSE: Carney complex (CNC), is an autosomal dominant multiple neoplasia and lentiginosis syndrome. We aimed to identify risk factors associated with the occurrence and recurrence of cardiac myxomas, the predominant cause of death in CNC patients. METHODS: Patients with CNC were monitored prospectively between 1995 and 2020 for the development of cardiac myxomas. RESULTS: Of the 319 patients studied, 136 (42.6%) developed myxomas. The mean age at diagnosis was 28.7 ± 16.6 years in females and 25.0 ± 16.4 years in males. By age 30, 35% of females and 45% of males had at least one myxoma. The CNC-related lesions, lentigines, cutaneous, mucosal, or breast myxomas, thyroid nodules, pituitary adenoma, and schwannoma were significantly more frequent (all p < 0.05) among patients with myxomas. Forty-four percent of patients had recurrences; nearly all within the first 8 and 16 years for males and females, respectively. Recurrences were more common in females. CONCLUSION: This is the largest study to date and provides the first-time risk estimates by age and gender for cardiac myxomas in CNC patients. Cardiac myxomas are common by age 30 and often recur, especially in women, but the risk drops in 10 to 20 years. These findings may guide patient counseling, screening intervals, and surgical approaches. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration: Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease and the Carney complex, Registration number: NCT00001452 URL: https://clinicaltrials.gov/ct2/show/NCT00001452.

Nut Consumption and Renal Function Among Women With a History of Gestational Diabetes.

OBJECTIVE: Nut intake has been associated with reduced cardiometabolic risk, but few studies have examined its association with renal function. We examined associations between nut intake and renal function among women with previous gestational diabetes mellitus (GDM), a population with an increased risk for renal dysfunction. DESIGN AND METHODS: This study included 607 women with a history of GDM who participated in the Diabetes & Women's Health Study (2012-2014) follow-up clinical examination in Denmark. At the clinic, biospecimens were collected, and habitual intake of nuts (9 types) in the past year was assessed using a food frequency questionnaire. A total of 330 women free of major chronic diseases were included in the analysis. Total nut intake was classified as none (≤1 serving/month), monthly (2-3 servings/month), weekly (1-6 servings/week), and daily (≥1 serving/day). One serving was defined as 28 g. Renal function markers included estimated glomerular rate (eGFR) and urinary albumin-to-creatinine ratio (UACR), calculated based on plasma creatinine (mg/dL), and urinary albumin (mg/L), and creatinine (mg/dL) measurements, respectively. We estimated percent differences with 95% confidence intervals for each outcome by nut intake, adjusted for current body mass index, age, physical activity, energy intake, alcohol consumption, and vegetables intake. RESULTS: We observed a nonlinear association between total nut intake and UACR with lowest UACR values among women with weekly intake. Compared to women with weekly intake (n = 222), the adjusted UACR values were higher by 86% [95% confidence interval: 15%, 202%], 24% [-1%, 54%], and 117% [22%, 288%] among women with no (n = 13), monthly (n = 86), and daily (n = 9) intake, respectively. Compared to weekly consumers, daily nut consumers also had 9% [0%, 19%] significantly higher eGFR values, but eGFR values were similar among women with no and monthly intake. CONCLUSION: Moderate nut consumption may be beneficial to kidney health among women with prior GDM.

Ventilator-associated pneumonia in neonates and children: a systematic analysis of diagnostic methods and prevention.

AIM: While ventilator-associated pneumonia (VAP) remains frequent in Pediatric ICU, there is no gold standard for diagnosis. METHODOLOGY: We conducted a systematic PUBMED analysis (January 1990-January 2017) searching original, full-length studies addressing only pediatric patients; for VAP diagnosis, only those comparing different diagnostic methods and for VAP prevention those implementing preventive measures. RESULTS: Among 367 articles, 17 and 16 were analyzed for diagnosis and prevention, respectively. For diagnosis, 13 studies used CDC criteria; whereas, 14 assessed algorithms: clinical pulmonary index score, ventilator-associated events and biomarkers. Among five randomized trials assessing preventive strategies one found a role of probiotics. Ventilator-care bundles reduced VAP rates. CONCLUSION: Absence of diagnostic gold standard impedes comparison of current approaches and preventive strategies.