The Study of Carotid Artery Intima-Media Thickness in Children With Epilepsy on Anti-Epileptic Drugs.

Objectives. To evaluate carotid artery intima-media thickness (CIMT) and lipid profile in children with epilepsy on long-term antiepileptic drug (AED) monotherapy. Methods. We included 60 children with epilepsy receiving valproate, carbamazepine, or levetiracetam monotherapy and 60 controls. A high-resolution B-mode ultrasound was used to measure (CIMT). Measurement of serum lipids was done. Results. Patients on valproate (0.44 ± 0.03, P ≤ .001), carbamazepine (0.43 ± 0.03with P ≤ .001), and levetiracetam (0.44 ± 0.02 with P ≤ .001) monotherapy showed significantly higher CIMT compared to controls. CIMT was correlated with age (P = .041, r = .112) AEDs{valproate (P = .005, r = .731), carbamazepine (P = .038, r = .365), and levetiracetam (P = .036, r = .155)}, duration of treatment (P = .001, r = .313), TC(P = .001, r = .192), TG (P = .014, r = .018), and LDL (P = .001, r = .219). HDL (P = .003, r = -.126). Seizure severity and Apo A1 were insignificantly involved. Conclusion. Long-term monotherapy with valproate, carbamazepine, and levetiracetam in epileptic children was associated with significant abnormalities in CIMT.

Congenital hyperinsulinism and panhypopituitarism: a rare combination.

Summary: Neonatal hypoglycemia is a serious condition that can have a major impact on the growing neonatal brain. The differential diagnosis of neonatal hypoglycemia is broad and includes hyperinsulinism as well as panhypopituitarism. The FOXA2 gene has been involved in the development of the pancreas as well as the pituitary gland. Six cases have been reported thus far with FOXA2 mutations presenting with variable degrees of hypopituitarism, and only two patients had permanent hyperinsulinism; other cases have been reported with microdeletions in 20p11, the location that encompasses FOXA2, and those patients presented with a wider phenotype. A full-term female infant presented with severe hypoglycemia. Critical sampling showed an insulin of 1 mIU/mL, suppressed beta-hydroxybutyric acids, and suppressed free fatty acids. Blood glucose responded to glucagon administration. Growth hormone (GH) stimulation test later showed undetectable GH in all samples, and cortisol failed to respond appropriately to stimulation. Gonadotropins were undetectable at 1 month of life, and MRI showed ectopic posterior pituitary, interrupted stalk, hypoplastic anterior pituitary, cavum septum pellucidum, and diminutive appearance of optic nerves. Whole-exome sequencing revealed a likely pathogenic de novo c.604 T>C, p.Tyr202His FOXA2 mutation. We expand the known phenotype on FOXA2 mutations and report a likely pathogenic, novel mutation associated with hyperinsulinism and panhypopituitarism. Learning points: FOXA2 has been shown to play an important role in the neuroectodermal and endodermal development. FOXA2 mutation may lead to the rare combination of hyperinsulinism and panhypopituitarism. Patients reported so far all responded well to diazoxide. Dysmorphology may be subtle, and liver functions should be monitored.

Redo aortic valve replacement versus valve-in-valve trans-catheter aortic valve implantation: a UK propensity-matched analysis.

This study sought to compare the morbidity and mortality of redo aortic valve replacement (redo-AVR) versus valve-in-valve trans-catheter aortic valve implantation (valve-in-valve TAVI) for patients with a failing bioprosthetic valve. A multicenter UK retrospective study of redo-AVR or valve-in-valve TAVI for patients referred for redo aortic valve intervention due to a degenerated aortic bioprosthesis. Propensity score matching was performed for confounding factors. From July 2005 to April 2021, 911 patients underwent redo-AVR and 411 patients underwent valve-in-valve TAVI. There were 125 pairs for analysis after propensity score matching. The mean age was 75.2±8.5 years. In-hospital mortality was 7.2% (n=9) for redo-AVR versus 0 for valve-in-valve TAVI, p=0.002. Surgical patients suffered more post-operative complications, including intra-aortic balloon pump support (p=0.02), early re-operation (p<0.001), arrhythmias (p<0.001), respiratory and neurological complications (p=0.02 and p=0.03) and multi-organ failure (p=0.01). The valve-in-valve TAVI group had a shorter intensive care unit and hospital stay (p<0.001 for both). However, moderate aortic regurgitation at discharge and higher post-procedural gradients were more common after valve-in-valve TAVI (p<0.001 for both). Survival probabilities in patients who were successfully discharged from the hospital were similar after valve-in-valve TAVI and redo-AVR over the 6-year follow-up (log-rank p=0.26). In elderly patients with a degenerated aortic bioprosthesis, valve-in-valve TAVI provides better early outcomes as opposed to redo-AVR, although there was no difference in mid-term survival in patients successfully discharged from the hospital.

Cardiovascular Disease Risk Factors and Metabolic Morbidity in a Longitudinal Study of Congenital Adrenal Hyperplasia.

CONTEXT: Patients with congenital adrenal hyperplasia (CAH) are exposed to hyperandrogenism and supraphysiologic glucocorticoids, both of which can increase risk of metabolic morbidity. OBJECTIVE: Our aim was to evaluate cardiovascular and metabolic morbidity risk in a longitudinal study of patients with CAH spanning both childhood and adulthood. DESIGN AND SETTING: Patients with classic CAH followed for a minimum of 5 years during both childhood and adulthood (n = 57) at the National Institutes of Health were included and compared with the US general population using NHANES data. MAIN OUTCOME MEASURES: Obesity, hypertension, insulin resistance, fasting hyperglycemia, and dyslipidemia. RESULTS: Compared to the US population, patients with CAH had higher (P < 0.001) prevalence of obesity, hypertension, insulin resistance, fasting hyperglycemia, and low high-density lipoprotein (HDL) during childhood and obesity (P = 0.024), hypertension (P<0.001), and insulin resistance (P < 0.001) during adulthood. In our cohort, obesity, hypertension, fasting hyperglycemia, and hypertriglyceridemia began prior to age 10. During childhood, increased mineralocorticoid dose was associated with hypertension (P = 0.0015) and low HDL (P = 0.0021). During adulthood, suppressed androstenedione was associated with hypertension (P = 0.002), and high low-density lipoprotein (P = 0.0039) whereas suppressed testosterone (P = 0.003) was associated with insulin resistance. Elevated 17-hydroxyprogesterone, possibly reflecting poor disease control, was protective against high cholesterol (P = 0.0049) in children. Children whose mothers were obese (maternal obesity) had increased risk of obesity during adulthood (P = 0.0021). Obesity, in turn, contributed to the development of hypertension, insulin resistance, and hypertriglyceridemia in adulthood. CONCLUSION: Patients with CAH develop metabolic morbidity at a young age associated with treatment-related and familial factors. Judicious use of glucocorticoid and mineralocorticoid is warranted.

Advances in genomic diagnosis of a large cohort of Egyptian patients with disorders of sex development.

Disorders/differences of sex development (DSD) comprise a group of congenital disorders that affect the genitourinary tract and usually involve the endocrine and reproductive system. The aim of this work was to identify genetic variants responsible for disorders of human urogenital development in a cohort of Egyptian patients. This three-year study included 225 patients with various DSD forms, referred to the genetic DSD and endocrinology clinic, National Research Centre, Egypt. The patients underwent thorough clinical examination, hormonal and imaging studies, detailed cytogenetic and fluorescence in situ hybridization analysis, and molecular sequencing of genes known to commonly cause DSD including AR, SRD5A2, 17BHSD3, NR5A1, SRY, and WT1. Whole exome sequencing (WES) was carried out for 18 selected patients. The study revealed a high rate of sex chromosomal DSD (33%) with a wide array of cytogenetic abnormalities. Sanger sequencing identified pathogenic variants in 33.7% of 46,XY patients, while the detection rate of WES reached 66.7%. Our patients showed a different mutational profile compared with that reported in other populations with a predominance of heritable DSD causes. WES identified rare and novel pathogenic variants in NR5A1, WT1, HHAT, CYP19A1, AMH, AMHR2, and FANCA and in the X-linked genes ARX and KDM6A. In addition, digenic inheritance was observed in two of our patients and was suggested to be a cause of the phenotypic variability observed in DSD.

Plasma cystatin C versus renal resistive index as early predictors of acute kidney injury in critically ill neonates.

INTRODUCTION: Acute kidney injury (AKI) independently predicts morbidity and mortality of critically ill neonates. Serum cystatin C is a promising early biomarker for AKI. Evaluating the renal resistive index (RRI) by Doppler ultrasound demonstrates abnormal intrarenal vascular impendence. OBJECTIVE: The objective of this study was to compare the ability of plasma cystatin C and the RRI to predict AKI early in critically ill neonates. STUDY DESIGN: Sixty critically ill neonates in neonatal intensive care units were assigned to three groups: group 1 (cases) of thirty participants fulfilling the AKI diagnostic criteria of neonatal Kidney Disease Improving Global Outcome, group 2 of thirty participants not fulfilling the criteria, as well as the 3rd group of thirty age- and sex-matching healthy participants. RESULTS: Group 1 demonstrated a significantly high mean cystatin C level during the 1st day of incubation compared with the other two groups [group 1 (3.18 ± 1.25), group 2 (1.68 ± 0.66), and group 3 (0.80 ± 0.26)]. Serum creatinine and RRI were insignificantly different among all groups. At a cutoff value of 2.68 (mg/l), cystatin C level had significantly higher area under the curve (AUC) (0.804) than both serum creatinine (0.453) and RRI (0.551) and had 53.3% sensitivity and 100% specificity in the early prediction of neonates with AKI. The RRI had a lower non-significant AUC (0.551) at a cutoff value of 0.53 and had 100% sensitivity and 40% specificity, while serum creatinine had a low non-significant AUC (0.453) at a cutoff value of 0.49 (mg/dl) and had 33.3% sensitivity and 86.7% specificity. Applying regression analysis to predict AKI in critically ill neonates as early as possible, higher plasma cystatin C and lower estimated glomerular filtration rate cystatin were the only independent risk factors within critically ill neonates. CONCLUSIONS: The level of plasma cystatin C increased 48 h before both RRI and serum creatinine did in critically ill neonates who developed AKI, so it is more reliable in predicting AKI in critically ill neonates than serum creatinine and RRI.

Complete Ultrasound-guided Percutaneous Nephrolithotomy in Prone and Supine Positions: A Randomized Controlled Study.

OBJECTIVES: To evaluate the safety, efficacy, adverse events, and feasibility of ultrasound guided percutaneous nephrolithotomy (US-PCNL) in the management of large renal stones in supine and prone positions and to point out the practical considerations related to these techniques in comparison with standard PCNL. PATIENTS AND METHODS: This study was conducted between August 2013 to September 2018 as a prospective randomized and controlled study. A total of 392 consecutive patients with nephrolithiasis >2 cm were randomly assigned to undergo ultrasound PCNL in prone (P-US-PCNL) (132 patients); supine position (S-US-PCNL) (129 patients) or conventional PCNL (C-PCNL) (131 patients). The preoperative parameters, the intraoperative findings, operative time, hospital stay, perioperative morbidities, stone free rate, and related data were recorded. RESULTS: The demographic and the baseline characteristics were comparable in all study groups. The mean number of trails and time for successful puncture in P-US-PCNL, S-US-PCNL, and C-PCNL were 1.9 ± 1, 2.3 ± 1.2, and 1.7±1, respectively (P < .001), and 15.8 ± 5.8, 19.3 ± 9.4, and 16.5 ± 8.1 seconds, respectively (P < .001). The operation time was 69 ± 22, 75 ± 23, and 72 ± 27 minutes, respectively, (P > .05). The mean nephrostomy time and length of hospital stay were 3 ± 1.3, 3.4 ± 1.5, 3.2 ± 1.2 hours, respectively, and 3.8 ± 1.5, 4.1 ± 1.5, 3.9 ± 1.3 days, respectively (P > .05). The mean percentage decrease in hemoglobin concentration was 1.65 ± 0.66, 1.77 ± 0.78, and 2.1 ± 0.9, respectively (P < .001), overall stone clearance was 88%, 79%, and 85%, respectively (P > .05). Complications were acceptable and similar between groups. CONCLUSION: US-PCNL either in prone or supine position is as effective, feasible, and safe as C-PCNL with zero radiation exposure.

Characterization of the CYP11A1 Nonsynonymous Variant p.E314K in Children Presenting With Adrenal Insufficiency.

Context: Cholesterol side-chain cleavage enzyme (P450scc), encoded by CYP11A1, catalyzes the first step of steroidogenesis. Complete P450scc deficiency leads to primary adrenal insufficiency (PAI) and 46,XY disordered sexual development. Partial impairment can cause variable adrenal and gonadal dysfunction. Objective: Our aim was to evaluate the effects of the CYP11A1 variant p.E314K, identified in patients with PAI, specifically on P450scc enzyme stability and function. Patients and Methods: We studied four boys from two unrelated families presenting with PAI during childhood (3.6 to 9 years old). All patients were compound heterozygous for c.940G>A (p.E314K), a CYP11A1 nonsynonymous variant likely to be pathogenic by some but not all in silico prediction models, and c.835delA (p.I79Yfs*10), a known pathogenic variant. HEK293T cells were transfected with wild type (WT) and p.E314K mutant vectors, and a cycloheximide chase assay was performed to analyze protein stability. Pregnenolone production was assayed from cells expressing WT and p.E314K-F2 fusion proteins. Results: Two boys experienced spontaneous puberty but then developed evidence of primary gonadal failure at 14 and 18 years old. Two boys had testicular adrenal rest tumor (TART), detected by ultrasound at ages 8.6 and 16 years. Compared with WT, mutant protein synthesis was reduced (P = 0.0006) with increased protein turnover, and mutant P450scc half-life was decreased by ~50%. p.E314K mutant P450scc retained 60% of WT enzymatic activity (P = 0.007). Conclusions: The CYP11A1 p.E314K variant impairs P450scc stability and is a possible cause of PAI in childhood. Pathogenic CYP11A1 variants potentially affect both adrenal and gonadal function, and male patients may develop TART.

Low Value of Thyroid Testing in the Pediatric Inpatient Setting.

OBJECTIVES: Our objective was to assess the frequency of pediatric inpatient thyroid testing, frequency of detection of abnormal results, and apparent impact on patient management. METHODS: This is a retrospective study of admissions from July 2015 to June 2016 at a large urban children's hospital. Chart review was conducted on all hospitalized pediatric patients who underwent thyroid testing. We used a normal range of 0.5 to 5.0 µIU/mL for thyroid-stimulating hormone (TSH) and 1.0 to 2.0 ng/dL for free thyroxine (FT4), except for neonates for whom we used the higher reference ranges specified by the hospital laboratory. RESULTS: Thyroid testing occurred in 1202 (5.7%) of 20 907 hospitalizations; 79.3% had combined thyroid function tests (TFTs) with TSH + FT4 being most common, and 20.6% had TSH only. Combined TFTs were ordered routinely by psychiatry and frequently by endocrine, gastrointestinal, cardiology, and neurology services, but many cases had no identified reason for testing. Of the 205 abnormal tests (17.1%), the most common abnormalities in the combined TFTs group were normal FT4 and increased TSH (35.4%) (76% of which were between 5 and 10 µIU/mL), normal FT4 and TSH 0.1 to 0.5 µIU/mL (33.1%), and high FT4 but normal TSH (14.3%). Patients with new-onset type 1 diabetes had borderline low or high TSH in about 20% of cases, but all abnormalities resolved at outpatient follow-up. Overall, 8 patients (0.66%) were started on levothyroxine. CONCLUSIONS: Pediatric inpatient thyroid testing is relatively common at our institution, and although results are often abnormal, they do not point to thyroid disease that has contributed to the reason for hospitalization and do not identify patients in urgent need of starting therapy.

Serum markers for asymptomatic atherosclerosis in Egyptian psoriatic patients: study controlled by Doppler estimation of carotid intima-media thickness.

BACKGROUND: The aim of the study was to measure serum levels of endocan, myeloperoxidase (MPO), pentraxin 3 (PTX3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in psoriatic patients and to study their correlations with carotid intima-media thickness (CIMT) in trial to evaluate predictability of these parameters in diagnosing asymptomatic atherosclerosis (AAS). PATIENTS AND METHODS: Seventy-five psoriasis patients and 75 control subjects underwent complete clinical examination and Doppler estimation of CIMT using thickness of 0.9 mm as cutoff point for diagnosis of AAS. Blood samples were collected for determination of fasting blood glucose, lipid profile and serum C-reactive protein (CRP), endocan, MPO, PTX3 and 1,25(OH)2D3. RESULTS: Estimated blood low-density lipoprotein cholesterol (LDL-c) and serum CRP, PTX3, MPO and endocan levels were significantly higher, while blood high-density lipoprotein cholesterol (HDL-c) and serum 1,25(OH)2D3 levels were significantly lower in patients than in controls. CIMT showed significant positive correlation with disease severity and duration; patients' age; and endocan, MPO, LDL-c, PTX3 and CRP levels, and significant negative correlation with HDL-c and 1,25(OH)2D3 levels. Regression analysis defined high serum endocan and MPO, low serum 1,25(OH)2D3 and increased disease severity as significant predictors of high CIMT. CONCLUSION: Elevated serum levels of endocan and MPO and low 1,25(OH)2D3 levels may underlie the development of psoriasis-related cardiac manifestations. Elevated serum endocan and low 1,25(OH)2D3 levels could be used as early predictors of increased CIMT, which is a pathognomonic feature of AAS.

A novel mutation (c.2735_2736delTC) in the androgen receptor gene in 46,XY females with complete androgen insensitivity syndrome in an Egyptian family.

BACKGROUND: Androgen insensitivity syndrome (AIS) results from resistance of the target tissues to the effect of the androgenic hormones producing a phenotype with varying degrees of feminization ranging from male infertility to completely normal female external genitalia. Androgen receptor (AR) is a transcription factor that interacts with the androgenic steroids that act as ligands activating the AR, and via different cellular mechanisms, the activated AR binds to the DNA of target tissues to induce the desired biological changes. To date, more than 800 different mutations in the AR gene have been identified in patients with AIS and the majority of these mutations are localized in the ligand-binding domain. METHODS: Here we describe an Egyptian family with 7 affected 46,XY females with complete androgen insensitivity. RESULTS: Mutational analysis of the AR gene revealed a novel frameshift mutation in exon 8 of the gene c.2735_2736delTC. CONCLUSION: This study extends the number of AR gene mutations identified so far. Further, it confirms that AR gene mutations are the most frequent cause of 46,XY disorder of sexual development, with higher frequency in the complete phenotype.