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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.

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.

ObjectiveNut 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 methodsThis 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.ResultsWe 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.ConclusionModerate nut consumption may be beneficial to kidney health among women with prior GDM.

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. Patients with CNC were monitored prospectively between 1995 and 2020 for the development of cardiac myxomas. 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

In the general population renal cysts appear most commonly in patients >50 y and in men. Among published studies, the prevalence of renal cysts detected by MRI was 27%, detected by CT was 20-41%, and detected by US was 4-17% (Mensel, et al., 2018; Choi, et al., 2016). In these studies, the male to female ratio in patients with renal cysts ranged from 1.4:1 to 2.93:1. Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia and lentiginosis syndrome predominantly caused by aberrant cAMP-protein kinase A (PKA) signaling mostly (but not always) due to germline inactivating defects in PRKAR1A which encodes the regulatory subunit type 1α of PKA. In a small retrospective study, 5 of 9 subjects with CNC had renal cysts on MRI or CT (Ye, et al., 2017). This same study evaluated the development of renal cysts in kidney-specific Prkar1a knockout mice, where all mice developed a renal cystic phenotype. To determine the prevalence of renal cysts, we performed a retrospective cohort study of patients with CNC evaluated at our institution between 1984 and 2019 who underwent renal imaging with MRI, CT, and/or US. We hypothesized that CNC leads to renal formation of cysts in humans, with increased number of renal cysts and earlier age at detection. 117 patients with CNC (69 female [59%], 48 male [41%]) were evaluated with renal imaging (56% MRI, 41% CT, 3% US). Of these, 39 (33%) patients had renal cysts that were first detected on imaging between the ages of 13 and 58 y (mean age at diagnosis 37.1 ±12.7 y; 5 [13%] 12-19 y, 5 [13%] 20-29 y, 10 [26%] 30-39 y, 11 [28%] 40-49 y, and 8 [21%] 50-59 y). The mean number of cysts was 1.3 ±0.7, and mean dominant cyst size was 1.2 ±0.9 cm. Average creatinine at diagnosis was 0.8 ±0.2 mg/dl. Of the patients with renal cysts, 22 were female (56% of patients with renal cysts, 32% of females with CNC that underwent renal imaging) and 17 were male (44% of patients with renal cysts, 35% of males with CNC that underwent renal imaging). There was no difference in the prevalence of renal cysts between males and females (35% vs 32%, p=.70, for a 1.1:1 ratio). Age, number, and dominant cyst size were also not different between sexes (p=.51, p=.84, and p=.26, respectively). However, creatinine levels were higher in males (0.9 ±0.1 vs 0.7 ±0.1, p

Simple Summary In 2021 it is estimated that there will be 44,280 new cases of thyroid cancer in the United States and the incidence rate is higher in women than in men by almost 3 times. Well-differentiated thyroid cancer is the most common subtype of thyroid cancer and includes follicular (FTC) and papillary (PTC) carcinomas. Over the last decade, researchers have been able to better understand the molecular mechanisms involved in thyroid carcinogenesis, identifying genes including but not limited to RAS, BRAF, PAX8/PPARγ chromosomal rearrangements and others, as well as several tumor genes involved in major signaling pathways regulating cell cycle, differentiation, growth, or proliferation. Patients with Carney complex (CNC) have increased incidence of thyroid tumors, including cancer, yet little is known about this association. CNC is a familial multiple neoplasia and lentiginosis syndrome cause by inactivating mutations in the PRKAR1A gene which encodes the regulatory subunit type 1α of protein kinase A. This work summarizes what we know today about PRKAR1A defects in humans and mice and their role in thyroid tumor development, as the first such review on this issue. Abstract 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.

OBJECTIVES: Women with gestational diabetes (GDM) are at increased risk for renal complications later in life. Nut intake has been associated with reduced cardiometabolic risk, but few studies have examined its association with renal function. We examined associations of nut intake and renal function among women with prior GDM. METHODS: We studied 330 women from the Danish National Birth Cohort (1996–2002) with a GDM pregnancy who participated in a clinical exam 9 to 16 years after the index pregnancy as part of the Diabetes & Women's Health Study (2012–2014) and were free of major chronic diseases at follow-up. Habitual past year intake of nine types of nuts was ascertained at follow-up using a food frequency questionnaire. Total nut intake was classified as none (1 serving/d). Estimated glomerular filtration rate (eGFR) via CKD-EPI equation and urine albumin-to-creatinine ratio (UACR) were calculated based on serum creatinine (mg/dL) and urine albumin (mg/L), and creatinine (mg/dL) measurements respectively. We estimated % differences with 95% confidence intervals (CI) in these outcomes by nut intake adjusted for current body mass index, age, physical activity, energy intake, and dietary variables. We explored possible non-linear relations using restricted cubic splines. RESULTS: A significant non-linear U-shaped association was detected between total nut consumption and UACR (P = 0.001) with lowest UACR levels among women with weekly consumption. Compared to women with weekly intake (n = 222), adjusted UACR levels were 86% [95% CI: 15%, 200%] and 23% [−1%, 54%] higher among women with no or monthly nut intake, respectively, while UACR levels were 118% [22%, 286%] higher among women with daily intake. Compared to weekly consumers, adjusted eGFR levels were 9% [0%, 19%] higher among daily consumers. CONCLUSIONS: Moderate nut consumption may be beneficial to kidney health among women with prior GDM. FUNDING SOURCES: Intramural Research Program of the NICHD, March of Dimes Birth Defects Foundation, Innovation Fund Denmark, Health Foundation, Heart Foundation, EU, Danish Diabetes Academy supported by Novo Nordisk Foundation, and NIH Building Interdisciplinary Research Careers in Women's Health Program.

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.