ABSTRACT Objective: The aim of this study is to investigate the molecular genetic causes of non-syndromic primary ovarian insufficiency (POI) cases with the gene panel based on next generation sequencing analysis and to establish the relationship between genotype and phenotype. Subjects and methods: Twenty three cases aged 14-40 years followed up with POI were included. Patients with a karyotype of 46, XX, primary or secondary amenorrhea before the age of 40, with elevated FSH (>40 IU/mL) and low AMH levels (<0.03 ng/mL) were included in the study. Molecular genetic analyzes were performed by the next generation sequencing analysis method targeted with the TruSightTM Exome panel. Results: Median age of the cases was 17.8 (14.0-24.3) years, and 12 (52%) cases admitted before the age of 18. Fifteen (65%) patients had consanguineous parents. In 2 (8.6%) cases, variants detected were in genes that have been previously proven to cause POI. One was homozygous variant in FIGLA gene and the other was homozygous variant in PSMC3IP gene. Heterozygous variants were detected in PROK2, WDR11 and CHD7 associated with hypogonadotropic hypogonadism, but these variants are insufficient to contribute to the POI phenotype. Conclusion: Genetic panels based on next generation sequencing analysis technologies can be used to determine the molecular genetic diagnosis of POI, which has a highly heterogeneous genetic basis.

ABSTRACT Objective: This research aimed to evaluate retrospectively the effect of anastrozole on height gain and sex hormone levels in pubertal boys receiving growth hormone (GH). Materials and methods: Pubertal boys who received both GH and anastrozole (GH+A) were one-to-one matched with boys who received only GH (GH-Only) for chronological and bone age, pubertal stage and height before the GH initiation, treatment duration and midparental height. Anthropometric measurements throughout treatment and adult heights were compared between the groups. Sex hormone levels were evaluated longitudinally in the GH+A group. Results: Forty-eight cases (24 in each group) were included. There was no statistical difference in adult height between the GH+A and GH-Only (p = 0.071). However, when the analysis was limited to those receiving anastrozole for at least 2 years, mean adult height was higher in the GH+A than in the GH-Only group (173.1 ± 6.2/169.8 ± 5.6 cm, p = 0.044). Despite similar growth rates between the two groups, bone age advancement was slower in the GH+A than in the GH-Only in a mean anastrozole treatment period of 1.59 years (1.37 ± 0.80/1.81 ± 0.98 years, p = 0.001). The greatest increase for FSH, LH, total and free testosterone and decrease for estradiol levels were observed in the third month after anastrozole was started, albeit remaining within the normal ranges according to the actual pubertal stages. Conclusions: Using anastrozole with GH for at least 2 years decelerates the bone age advancement resulting in adult height gain with no abnormality in sex hormone levels. These results suggest anastrozole can be used as an additional treatment to GH for further height gain in pubertal boys.

ABSTRACT Objective: To assess the association between leptin/adiponectin ratio (LAR) and insulin resistance surrogates in prepubertal children. Subjects and methods: Study based on data from the Growth and Obesity Chilean Cohort Study (GOCS) involving 968 Chilean prepubertal children. Plasma insulin, leptin, and adiponectin were determined by immunoassays. Several common insulin resistance surrogates were calculated, including the homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride/HDL cholesterol index, triglyceride-glucose (TyG) index, and the TyG index corrected for body mass index (BMI; TyG-BMI) and waist circumference (WC; TyG-WC). Associations among variables were assessed using multiple linear and logistic regression analysis. Results: There was a significant direct association between plasma leptin and LAR with BMI z-score but no association between plasma adiponectin and adiposity. After adjustments for sex and age, LAR was significantly associated with all insulin resistance surrogates (which were categorized using the 75th percentile as the cutoff point), with the TyG-WC index emerging as the surrogate with the highest magnitude of association (odds ratio [OR] 2.44, 95% confidence interval [CI] 2.05-2.9). After additional adjustment for BMI z-score, only the association between LAR and TyG-WC remained significant (OR 1.64, 95% CI 1.27-2.12). Conclusion: Plasma leptin and LAR were strongly associated with several common insulin resistance surrogates in prepubertal children, most notably with the TyG-WC index. Associations between LAR and insulin resistance indexes were mainly driven by the effect of plasma leptin, which is also directly associated with increased adiposity.

SUMMARY Primary pigmented nodular adrenocortical disease (PPNAD) is a rare adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS). Pediatric patients with PPNAD typically have unusual skin lesions and slow growth with unknown causes. We present a case of a female Chinese patient with PPNAD caused by the germline PRKACA gene copy number gain of chromosome 19. The patient initially presented with kidney stones, short stature, and obesity. After further testing, it was discovered that the patient had diabetes, mild hypertension, low bone mass, a low ACTH level, and hypercortisolemia, and neither the low-dose or high-dose dexamethasone suppression test was able to inhibit hematuric cortisol, which paradoxically increased. PPNAD was pathologically diagnosed after unilateral adrenalectomy. Chromosome microarrays and whole exon sequencing analyses of the peripheral blood, as well as testing of sectioned adrenal tissue, showed a rise in the copy number of the duplication-containing PRKACA gene on chromosome 19p13.13p13.12, a de novo but not heritable gene defect that causes disease. The clinical signs and symptoms supported the diagnosis of Carney complex (CNC). One significant mechanism of CNC pathogenesis may be the rise in germline PRKACA copy number of chromosome 19. When assessing PPNAD patients for CNC, the possibility of PRKACA gene amplification should be considered. The effect of PRKACA gene amplification on the clinical manifestations of CNC needs to be confirmed by more cases.

SUMMARY Brugada syndrome (BrS) is an inherited disorder that can cause ventricular fibrillation and sudden cardiac death in individuals with otherwise structurally normal hearts. Several provoking factors are known to potentially unmask or exacerbate a typical Brugada ECG pattern in predisposed subjects. Hypothyroidism has been suggested as one of these triggers, but the exact mechanisms underlying this relationship remain poorly understood. Moreover, the severity of thyroid dysfunction beyond which a Brugada-type ECG alteration might be triggered is still unclear. We report the case of a 33-year-old male who displayed a Brugada type 1 ECG pattern and was diagnosed with severe hypothyroidism (TSH > 100 mU/L with undetectable levels of fT4 and fT3). Hormonal replacement therapy with levothyroxine was initiated at increasing doses; serial biochemical and ECG controls were performed, initially every 3 weeks up to 15 weeks and afterward every 3 months. The regression of typical Brugada ECG waveforms could be seen at an early stage, when the patient was still taking a low dose of levothyroxine (37.5 µg/day, i.e., one-fourth of his final requirements of 150 µg/day), and laboratory tests still showed a marked alteration of thyroid hormonal parameters. Hypothyroidism may act as a trigger for Brugada-type ECG abnormalities, but a very severe alteration of the hormonal parameters is necessary to prompt these alterations. In our case, the initiation of replacement therapy with levothyroxine rapidly reversed the ECG modifications, even at a low subtherapeutic dose.

ABSTRACT Objective: To evaluate the effects of medical education on hospital hyperglycemia on physician's technical knowledge and the quality of medical prescriptions, patient care, and clinical outcomes. Subjects and methods: The intervention included online classes and practical consultations provided by an endocrinologist to medical preceptors and residents of the Department of Internal Medicine. A pretest and a post-test (0 to 10 points) were applied before and after the intervention and patients medical records were reviewed before and after the intervention. The outcomes were improvement in medical knowledge, in the quality of prescriptions for patients in the clinical area, and clinical outcomes. Results: The global mean of correct answers improved with the intervention [before: 6.9 points (±1.7) versus after the intervention: 8.8 points (±1.5) (p < 0.001)]. The number of patients who did not have at least one blood glucose assessment during the entire hospitalization for acute illness decreased from 12.6% before to 2.6% (p < 0.001) after the intervention. There was also a significant reduction in hospital hypoglycemia rates (p < 0.026). The use of sliding-scale insulin as the main treatment was quite low before and after the intervention (2.2% and 0%). After 6 months, medical knowledge did not show significant reduction. Conclusion: Medical education on hospital hyperglycemia can improve medical knowledge and clinical outcomes for patients. The improvement in medical knowledge was maintained after 6 months.

ABSTRACT Objective: Quality of Life (QoL) has been a multifactorial concerning issue in oncology. We aimed to inspect the pre-operative QoL among patients with craniopharyngioma and to explore the potential correlations between parameters of QoL and clinical indices. Subjects and methods: We enrolled a total of 109 patients with craniopharyngioma. We utilized Short Form 36 (SF-36), Symptom Check List-90, Generalized Anxiety Disorder Questionnaire scale (GAD7), Patient Health Questionnaire Depression (PHQ9) and Pittsburgh Sleep Quality Index to prospectively evaluated their QoL. Parameters of QoL along with clinical indices were compared among sub-groups divided according to Puget classification. Correlation analyses and regression analyses were performed to detect influential determinants to self-reported wellness. Results: Patients presented impaired QoL compared with general population ( p < 0.001), as assessed by SF-36. Correlation analyses indicated the detrimental influence resulting from central diabetes insipidus (CDI). Multivariate linear regression unveiled the adverse effect of CDI on Mental Component Summary (coefficient = −13.869, p = 0.007), GAD7 total score (coefficient = 2.072, p = 0.049) as well as PHQ9 total score (coefficient = 3.721, p = 0.001). Multivariate logistic regression verified CDI as a risk factor of developing depressive symptoms (OR = 6.160, p = 0.001). Conclusion: QoL of patients with craniopharyngioma was remarkably compromised before operation. CDI exerted detrimental influences on patients’ QoL and it might serve as a marker for early identification of patients at risk of depression.

ABSTRACT Objective: We aimed to analyze the association of diabetes and subclinical hypothyroidism with subclinical atherosclerosis measured by coronary artery calcium (CAC) in the baseline of the ELSA-Brasil study. Materials and methods: CAC was measured using a 64-detector computed tomographic scanner. The association of CAC > 0 was presented as an odds ratio (OR) and 95% confidence intervals (95%CI) in logistic models and as β (95%CI) in linear models after multivariable adjustment for confounders. Results: We analyzed 3,809 participants (mean-age (SD) 50.5 (8.8); 51.7% women). In the main analysis, we did not find an association of diabetes and subclinical hypothyroidism with CAC. However, in stratified analysis according to age strata, we found no significative interaction terms, an important heterogeneity between the groups, with the younger age strata showing an association of the group with both diseases and CAC > 0 (OR 7.16; 95%CI, 1.14; 44.89) with a wide but significative 95%CI, suggesting that the smaller number of participants in the younger group may influence the results. Our findings also showed an association of CAC > 0 and log (CAC+1) with diabetes in logistic (OR, 1.31; 95%CI, 1.05-1.63) and linear models (β, 0.24, 0.16, 0.40), respectively. Diabetes was independently associated with CAC > 0 in linear models. Discussion: In conclusion, our results showed a great heterogeneity in stratified analysis based on age in the younger age strata. Although we found no significant interaction factors, the smaller sample size for the analysis may influence the negative findings.

SUMMARY Mutations in the insulin receptor (INSR) gene may present with variable clinical phenotypes. We report herein a novel heterozygous INSR mutation in an adolescent girl with type A insulin resistance syndrome and her mother. The index case was a 12-year-old girl without obesity who presented with excessive hair growth, especially in the chest and back area, and hyperpigmentation on the back of the neck (acanthosis nigricans). Acanthosis nigricans was first observed at the age of 11 years. On physical examination, the patient had acanthosis nigricans and hypertrichosis with no acne. Systolic and diastolic blood pressure measurement was within the normal range for age and sex. Laboratory tests revealed fasting hyperglycemia, fasting and postprandial hyperinsulinemia, elevated HbA1c level, and biochemical hyperandrogenemia. Fasting plasma lipids were normal. A diagnosis of type A insulin resistance syndrome was considered, and INSR gene mutation analysis was performed. Next-generation sequence analysis was performed with the use of primers containing exon/exon-intron junctions in the INSR gene, and a novel heterozygous c.3486_3503delGAGAAACTGCATGGTCGC/p. Arg1163_Ala1168del change was detected in exon 19 of the INSR gene. In segregation analysis, the same variant was detected in the patient's mother, who had a milder clinical phenotype. We reported a novel, heterozygous, p. Arg1163_Ala1168del mutation in exon 19 of the INSR gene in a patient with type A insulin resistance syndrome, expanding the mutation database. The same mutation was associated with variable phenotypical severity in two subjects within the same family.

ABSTRACT Objective: Data regarding rare FPAs from India, a resource limited setting, are limited. We describe a case series of rare FPAs from a single center in western India. Materials and methods: This was a retrospective case record review of patients diagnosed between January 2010 and July 2022. The diagnosis was based on biochemical (inappropriately elevated serum FSH/LH) and pathologic (positive immunostaining for FSH/LH) features in patients with FGA, and elevated serum thyroid hormones and normal/elevated TSH in patients with TSHomas. Results: We identified 11 patients with a total of six FGAs (median age 43.5 years, five men, one FGA cosecreting TSH, median largest dimension 40 mm, range 33–60 mm) and six TSHomas (median age 34.5 years, four women, two TSHomas cosecreting GH, median largest dimension 42.5 mm, range 13–60 mm). Symptoms of sellar mass effects led to pituitary imaging in most patients with FGA. Patients with TSHomas had symptoms of excess hormone secretion (GH/TSH) or sellar mass effects. The TSHomas that cosecreted GH/FSH were larger than those secreting only TSH. Transsphenoidal resection was the most common first-line therapy but significant residual disease was frequent (3 out of 6 FGAs and 4 out of 5 TSHomas). Conclusion: This is the first and second case series of FGAs and TSHomas, respectively, from India. In this study, TSHomas presented at younger age, were larger and had low surgical cure rates.

SUMMARY Treating hypothyroidism can be challenging in patients with malabsorption, as they require a higher daily dose of oral levothyroxine (L-T4). Oral L-T4 absorption occurs mainly in the jejunum and the ileum and is affected by gastric acidity. As a result, absorption can be impaired by bariatric surgery. This paper presents a case of myxedema in a young man who had previously undergone biliopancreatic diversion. He was referred to the Emergency Department with deteriorated mental state, hypotension, bradycardia and hypothermia. Laboratory tests revealed severe hypothyroidism and hypokalaemia. The clinical and biochemical profile of the patient suggested myxedema coma. The tablet-based L-T4 therapy was replaced with intravenous (iv) L-T4, oral liquid L-T4 and oral liothyronine (L-T3) and inotropic agents and supportive care were also administered, resulting in a gradual improvement in clinical condition. The patient reported taking L-T4 tablets as prescribed before hospitalization. In patients with malabsorption, impaired L-T4 absorption may lead to severe forms of hypothyroidism. This case outlines the need for more frequent monitoring of serum Thyroid Stimulating Hormone in patients submitted to bariatric surgery and suggests the benefit of using liquid L-T4 in the place of tablets in cases of malabsorption.

ABSTRACT Objective: Recent studies have shown a relationship between adipose tissue and coronary artery disease (CAD). The ABCA1 transporter regulates cellular cholesterol content and reverses cholesterol transport. The aim of this study was to determine the relationship between single nucleotide polymorphisms (SNPs) R230C, C-17G, and C-69T and their expression in epicardial and mediastinal adipose tissue in Mexican patients with CAD. Subjects and methods: The study included 71 patients with CAD and a control group consisting of 64 patients who underwent heart valve replacement. SNPs were determined using TaqMan probes. mRNA was extracted using TriPure Isolation from epicardial and mediastinal adipose tissue. Quantification and expression analyses were done using RT-qPCR. Results: R230C showed a higher frequency of the GG genotype in the CAD group (70.4%) than the control group (57.8%) [OR 0.34, 95% CI (0.14-0.82) p = 0.014]. Similarly, C-17G (rs2740483) showed a statistically significant difference in the CC genotype in the CAD group (63.3%) in comparison to the controls (28.1%) [OR 4.42, 95% CI (2.13-9.16), p = 0.001]. mRNA expression in SNP R230C showed statistically significant overexpression in the AA genotype compared to the GG genotype in CAD patients [11.01 (4.31-15.24) vs. 3.86 (2.47-12.50), p = 0.015]. Conclusion: The results suggest that the GG genotype of R230C and CC genotype of C-17G are strongly associated with the development of CAD in Mexican patients. In addition, under-expression of mRNA in the GG genotype in R230C is associated with patients undergoing revascularization.

SUMMARY Calcitonin (CT) is a diagnostic and follow-up marker of medullary thyroid carcinoma. Heterophile antibodies (HAbs) may interfere during immunometric assay measurements and result in falsely high CT levels and different markers. A 50-year-old female patient was referred to our institution for elevated CT levels (3,199 pg/mL [0-11,5]). Physical examination and thyroid ultrasonography show no thyroid nodules. Because of the discrepancy between the clinical picture and the laboratory results, various markers and hormones were examined to determine whether there was any interference in the immunometric assay. Thyroglobulin (Tg) and Adrenocorticotropic hormone (ACTH) levels were also found inaccurately elevated. After precipitation with polyethylene glycol, CT, Tg, and ACTH levels markedly decreased, showing macro-aggregates. Also, serial dilutions showed non-linearity in plasma concentrations. Additionally, CT samples were pretreated with a heterophilic blocking tube before measuring, and the CT level decreased to < 0.1 pg/mL, suggesting a HAb presence. Immunoassay interference should be considered when conflicting laboratory data are observed. This may help reduce the amount of unnecessary laboratory and imaging studies and prevent patients from complex diagnostic procedures.