Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort.

STUDY QUESTION: What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. WHAT IS KNOWN ALREADY: CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. STUDY DESIGN SIZE DURATION: Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. PARTICIPANTS/MATERIALS SETTING METHODS: The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). MAIN RESULTS AND THE ROLE OF CHANCE: A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH. STUDY FUNDING/COMPETING INTERESTS: This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests.

Preventive strategies for hypercoagulation in Cushing's syndrome: when and how.

PURPOSE: The endogenous hypercortisolism that characterizes Cushing's syndrome (CS) is associated with a state of hypercoagulability that significantly increases the risk of thromboembolic disease, especially, venous events. Despite this certainty, there is no consensus on the best thromboprophylaxis strategy (TPS) for these patients. Our aim was to summarize the published data about different thromboprophylaxis strategies, and to review available clinical tools assisting thromboprophylaxis decision making. METHODS: Narrative review of thromboprophylaxis strategies in patients with Cushing's syndrome. A search was carried out on PubMed, Scopus and EBSCO until November 14th, 2022, and articles were selected based on their relevance and excluded in case of redundant content. RESULTS: Literature is scarce regarding thromboprophylaxis strategies to be adopted in the context of endogenous hypercortisolism, most often being a case-by-case decision according to the centre expertise. Only three retrospective studies, with a small number of patients enrolled, evaluated the use of hypocoagulation for the thromboprophylaxis of patients with CS in the post-operative period of transsphenoidal surgery and/or adrenalectomy, but all of them with favourable results. The use of low molecular weight heparin is the most frequent option as TPS in CS context. There are numerous venous thromboembolism risk assessment scores validated for different medical purposes, but just one specifically developed for CS, that must be validated to ensure solid recommendations in this context. The use of preoperative medical therapy is not routinely recommended to decrease the risk of postoperative venous thromboembolic events. The peak of venous thromboembolic events occurs in the first three months post-surgery. CONCLUSION: The need to hypocoagulate CS patients, mainly in the post-operative period of a transsphenoidal surgery or an adrenalectomy, is undoubtable, especially in patients with an elevated risk of venous thromboembolic events, but the precise duration and the hypocoagulation regimen to institute is yet to be determined with prospective studies.

A Common Variant in the CDK8 Gene Is Associated with Sporadic Pituitary Adenomas in the Portuguese Population: A Case-Control Study.

The majority of pituitary adenomas occur in a sporadic context, and in the absence of known genetic predisposition. Three common variants at the NEBL (rs2359536), PCDH15 (rs10763170) and CDK8 (rs17083838) loci were previously associated with sporadic pituitary adenomas in the Han Chinese population, but these findings have not yet been replicated in any other population. The aim of this case-control study was to assess if these variants are associated with susceptibility to sporadic pituitary adenomas in the Portuguese population. Genotype and allele frequencies were determined in 570 cases and in 546 controls. The CDK8 rs17083838 minor allele (A allele) was significantly associated with sporadic pituitary adenomas, under an additive (odds ratio (OR) 1.73, 95% confidence interval (CI) 1.19-2.50, p = 0.004) and dominant (OR 1.82, 95% CI 1.24-2.68, p = 0.002) inheritance model. The NEBL rs2359536 and PCDH15 rs10763170 variants were not associated with the overall risk for the disease, although a borderline significant association was observed between the PCDH15 rs10763170 minor allele (T allele) and somatotrophinomas (dominant model, OR 1.55, 95% CI 1.02-2.35, p = 0.035). These findings suggest that the CDK8 rs17083838 variant, and possibly the PCDH15 rs10763170 variant, may increase susceptibility to sporadic pituitary adenomas in the Portuguese population.

A case of severe systemic type 1 pseudohypoaldosteronism with 10 years of evolution.

Type 1 pseudohypoaldosteronism (PHA-1) is a rare genetic syndrome of unresponsiveness to aldosterone and presents in the neonatal period with hyperkalemia, hyponatremia and metabolic acidosis. The mortality rate can be high and multidisciplinary team is needed for optimal management and adequate growth and development of these patients. Many genotype-phenotype correlations remain uncertain, and the description of the evolution of cases can increase scientific knowledge about the psychomotor development and severity of the different mutations. We report the follow-up for the last 10 years of a patient, with previously unrecognized genetic findings identified. In addition, we reviewed the literature and compared it with other pediatric cases.

Follow-up of infants born to mothers with Graves' disease.

INTRODUCTION: The prevalence of neonatal hyperthyroidism (HN) due to maternal Graves Disease (GD) ranges from 0.1 to 2.7%. It may occur in pregnant women with the following: active DG, after treatment with radioactive iodine, anti-thyroid or thyroidectomy or with a previous child with hyperthyroidism. The aim of our observational study was to evaluate the follow-up of infants born to mothers with GD at a Tertiary Hospital prior to the implementation of a follow-up protocol. METHODS: This was a retrospective observational study using data from the medical records of mothers with a diagnosis of GD and their newborns from January 2013 until May 2018. Newborns were divided into two groups: high and low risk for NH according to maternal TRAb, third trimester treatment and signs of fetal hyperthyroidism. RESULTS: We identified 31 newborns, 58% female; 87% high risk. In none of the newborns was umbilical cord blood collected. In the high risk group, 22% had thyroid function evaluation at day-1, one patient presented with hyperthyroidism and 82% were asymptomatic. Considering the cases with an insufficient blood sample for analysis, 9 consultations would have been spared. We found a significant delay in obtaining the high-risk group results which would have spared 10 appointments. A positive correlation was found between age at outpatient clinic discharge and the number of appointments and the maternal TRAb titer. CONCLUSION: The correct surveillance of pregnancy and newborns with identification of those at high risk is essential to avoid unnecessary consultations and blood analyses that increase parental anxiety and hospital costs. Consequently, a multidisciplinary protocol was created to standardize the approach.

Primary pituitary abscess: case report and suggested management algorithm.

PURPOSE: To describe a case of successful treatment of a patient with a rare primary pituitary abscess (PA) and propose a management algorithm. SUMMARY OF BACKGROUND DATA: PA is an infrequent entity that can be life-threatening if not promptly diagnosed and treated. PAs can be primary or secondary, the latter in the presence of sellar anomalies, risk factors or a systemic or local infection. Symptoms are nonspecific, making clinical suspicion imperative. Magnetic Resonance Imaging (MRI) is the radiological tool of choice. Despite some characteristic radiographic signs, oftentimes the diagnosis is not suspected until surgical exploration. Treatment includes transsphenoidal decompression surgery with sampling of purulent material and abscess wall for appropriate microbiological staining and cultures (bacteria, mycobacteria and fungus) and prolonged antibiotic treatment. Pituitary hormonal deficiencies must be addressed as well. METHODS AND RESULTS: We describe a case of a female patient who presented with headaches, anorexia and bitemporal hemianopsia. MRI revealed a peripherally enhancing sellar mass. Transsphenoidal surgery was performed, with intra-operative finding of purulent material. Cytology confirmed the presence of abundant leucocytes, but no pathogen was isolated. Patient completed three weeks of antibiotic therapy, with good clinical and radiological response. Headaches and visual deficits resolved. Hormonal substitution therapy was needed for six months after surgery. CONCLUSION: This report highlights the importance of early recognition and treatment of PAs. The diagnosis is commonly very difficult before surgery, due to overlapping clinical, radiological and laboratorial findings with various other pathologies. Prompt management, with surgical decompression and appropriate antibiotic treatment, typically results in a low mortality rate and higher chance of full recovery of pituitary function. We propose a management algorithm for sellar masses suspected of being PAs.

Pituitary apoplexy induced by gonadotropin-releasing hormone agonist administration: a rare complication of prostate cancer treatment.

SUMMARY: Gonadotropin-releasing hormone (GnRH) agonists, currently used in the treatment of advanced prostate cancer, have been described as a rare cause of pituitary apoplexy, a potentially life-threatening clinical condition. We report the case of a 69-year-old man with a known pituitary macroadenoma who was diagnosed with prostate cancer and started treatment with GnRH agonist leuprorelin (other hormones were not tested before treatment). Few minutes after drug administration, the patient presented with acute-onset severe headache, followed by left eye ptosis, diplopia and vomiting. Pituitary MRI revealed tumor enlargement and T1-hyperintense signal, compatible with recent bleeding sellar content. Laboratory endocrine workup was significant for low total testosterone. The patient was managed conservatively with high-dose steroids, and symptoms significantly improved. This case describes a rare phenomenon, pituitary apoplexy induced by GnRH agonist. We review the literature regarding this condition: the pathophysiological mechanism involved is not clearly established and several hypotheses have been proposed. Although uncommon, healthcare professionals and patients should be aware of this complication and recognize the signs, preventing a delay in diagnosis and treatment. LEARNING POINTS: Pituitary apoplexy (PA) is a potentially life-threatening complication that can be caused by gonadotropin-releasing hormone agonist (GnRHa) administration for the treatment of advanced prostate cancer. This complication is rare but should be taken into account when using GnRHa, particularly in the setting of a known pre-existing pituitary adenoma. PA presents with classic clinical signs and symptoms that should be promptly recognized. Patients should be instructed to seek medical care if suspicious symptoms occur. Healthcare professionals should be aware of this complication, enabling its early recognition, adequate treatment and favorable outcome.

Clinical Performance of Flash Glucose Monitoring System in Patients with Liver Cirrhosis and Diabetes Mellitus.

Flash glucose monitoring system (FGMS) is an improved subset of continuous glucose monitoring with a recognized effectiveness on glycemic control, though validation in patients with Liver Cirrhosis (LC) is lacking. To evaluate the accuracy of FGMS in patients with Type 2 Diabetes Mellitus (DM) and LC, a prospective, case-control study was performed in 61 ambulatory patients with LC and DM (LC group, n = 31) or DM (Control group, n = 30). During 14 days, patients performed 4 assessments per day of self-monitoring of blood glucose (SMBG, reference value) followed by FGMS scanning. There were 2567 paired SMBG and FGMS values used in the accuracy analysis, with an overall mean absolute relative difference (MARD) of 12.68% in the LC group and 10.55% in the control group (p < 0,001). In patients with LC, the percentage of readings within Consensus Consensus Error Grid analysis Zone A and A + B were 80.36% and 99,26%, respectively. Sensor clinical accuracy was not affected by factors such as body mass index, age, gender, Child-Pugh score or edematoascitic decompensation. This is the first study to approach FGMS clinical accuracy in LC, revealing a potential usability of this system to monitor glycemic control in this population.

Lipoprotein(a) Change After Sleeve Gastrectomy Is Affected by the Presence of Metabolic Syndrome.

BACKGROUND: Patients with metabolic syndrome (MetS) are at high risk of developing cardiovascular disease (CVD) and lipoprotein(a) (Lp(a)) is an independent risk factor for CVD. This study aimed to determine the effect of vertical sleeve gastrectomy (VSG)-induced weight loss on Lp(a) levels in obese individuals. METHODS: Patients submitted to VSG from January 2011 to July 2015 were included. Anthropometric and metabolic parameters were recorded before and 12 months after surgery. Univariate analysis identified associations between Lp(a) and anthropometry and metabolic parameters, and the logistic regression predictors of Lp(a) decrease after VSG. RESULTS: MetS was present in 47% of the 330 patients involved. Patients with MetS had higher body mass index (BMI) and triglyceride levels and were more insulin-resistant. No differences were found between groups respecting Lp(a) levels prior to surgery (15.2 mg/dL vs. 15.0 mg/dL, p = 0.795). After surgery, patients without MetS had a decrease in Lp(a) levels (14.7 mg/dL vs. 12.3 mg/dL, p = 0.006), while MetS patients showed no differences (13.9 mg/dL vs. 14.6 mg/dL, p = 0.302). The regression model evidenced that older age and Δ HDL-c were predictors of Lp(a) decrease, whereas the greater the number of MetS components and lower estimated BF% loss, the lesser odds of decreasing Lp(a) after surgery. CONCLUSIONS: Despite a global improvement of conventional CVD risk factors, only individuals without MetS showed a decrease of Lp(a) levels after VSG. Further studies should explore not only the pathophysiological mechanisms underlying the absence of decrease of Lp(a) levels in MetS patients, but also its impact on the metabolic beneficial changes usually observed after VSG.

Partial deficiency of 17α-hydroxylase: a rare cause of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) due to 17α-hydroxylase deficiency, a rare CAH syndrome, is characterised by failure to synthetise cortisol, adrenal androgens and gonadal steroids. The partial deficiency is much rarer, presenting with subtler symptoms. Failure to reach a proper diagnosis causes inappropriate hypertension treatment and impairs the development of secondary sexual characteristics. We report a case of a 30-year-old woman transferred to an endocrinology clinic for evaluation of autoimmune thyroiditis. She was started on oral contraceptives at the age of 13 due to oligomenorrhea and presented underdeveloped pubic and axillar hair and Tanner stage 3 breast development. Biochemical tests evidenced very low androgens levels and genetic analysis confirmed a CAH due to 17α-hydroxylase deficiency. Partial 17α-hydroxylase deficiency is a rare clinical entity, nevertheless, it should be included in the differential diagnosis of menstrual disorders.

High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is characterized by lack of normal pubertal development due to deficient gonadotropin-releasing hormone (GnRH) secretion or action, and is caused by genetic defects in several genes. Mutations in the CHD7 gene cause CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital hypoplasia and Ear abnormalities), but have also been found in patients with isolated CHH. The aim of this study was to identify CHD7 mutations in patients with CHH. Fifty Portuguese patients with CHH were screened for mutations in the CHD7 gene by DNA sequencing. Eight (16%) patients had CHD7 rare sequence variants that consisted of six missense (p.Gly388Glu, p.His903Pro, p.Thr1082Ile, p.Val1452Leu, p.Asp1854Gly, and p.Arg2065His) and two synonymous (p.Ser559Ser, and p.Ala2785Ala) mutations. Five of these mutations have never been reported before. Three CHD7 mutations occurred in patients that had mutations in additional CHH-genes. This study uncovered novel genetic variants that expand the known spectrum of mutations associated with CHH. The frequency of CHD7 mutations in this cohort was higher than that of other major CHH-genes and confirms the importance of including CHD7 in the genetic testing of CHH, even in the absence of additional CHARGE features.

Iron Deficiency and Obesity - Are we Diagnosing with Appropriate Indicators?

INTRODUCTION: We aim to define the iron deficiency prevalence and eventual differences between obese patients with and without metabolic syndrome. MATERIAL AND METHODS: Analysis of patients evaluated at multidisciplinary consultation of obesity in our institution between 2013 and 2015 (n = 260). Iron deficiency: ferritin levels < 15 ng/mL. EXCLUSION CRITERIA: prior bariatric surgery; lack of ferritin or hemoglobin determinations. RESULTS: We analyzed data from 215 patients (84.2% female) with a mean age of 42.0 ± 10.3 years. The median body mass index was 42.5 (40.0 - 46.8) kg/m2 and 52.1% had metabolic syndrome. Iron deficiency was present in 7.0%, with no differences between genders or between patients with or without metabolic syndrome. Hypertension was associated with lower prevalence of iron deficiency. Type 2 diabetes and hypertension patients had higher levels of ferritin. The multivariate analysis showed that metabolic syndrome and increasing body mass index were predictive of higher risk of iron deficiency while hypertension predicted lower odds of iron deficiency. DISCUSSION: The prevalence of iron deficiency was similar in other published studies. Iron deficiency may be underdiagnosed if based only on ferritin concentrations. In our study, diabetes and hypertension appear to contribute to the increase in ferritin levels described in obesity. CONCLUSION: Ferritin may not be a reliable index for evaluating iron stores in obese patients, particularly when associated with comorbidities such as type 2 diabetes and hypertension. Further studies are needed to guide the diagnosis and iron supplementation in these patients.

Introdução: Os objetivos foram a determinação da prevalência de défice de ferro e de eventuais diferenças entre os doentes obesos com e sem síndrome metabólica. Material e Métodos: Análise dos doentes observados na consulta multidisciplinar de obesidade na nossa instituição entre 2013 e 2015 (n = 260). Défice de ferro: ferritina < 15 ng/mL. Critérios de exclusão: cirurgia bariátrica prévia, ausência de doseamentos de ferritina e de hemoglobina. Resultados: Avaliaram-se 215 doentes (84,2% mulheres) com uma idade média de 42,0 ± 10,3 anos. O índice de massa corporal mediano foi 42,5 (40,0 - 46,8) kg/m2 e 52,1% apresentavam síndrome metabólica. O défice de ferro estava presente em 7,0% sem diferenças entre os géneros e entre os doentes com e sem síndrome metabólica. A hipertensão associou-se a menor prevalência de défice de ferro. Doentes com diabetes tipo 2 e hipertensão apresentaram valores mais elevados de ferritina. Na análise multivariada, a síndrome metabólica e o índice de massa corporal constituíram fatores preditivos de défice de ferro, enquanto a hipertensão se associou a um menor risco. Discussão: A prevalência de défice de ferro foi similar a estudos previamente publicados. O défice de ferro pode ser subdiagnosticado se baseado apenas nas concentrações de ferritina. No nosso estudo, a diabetes e a hipertensão parecem contribuir para os níveis elevados de ferritina descritos na obesidade. Conclusão: A ferritina poderá não ser um índice fiável para avaliação de reservas de ferro na obesidade, particularmente quando associada a diabetes tipo 2 e hipertensão. São necessários mais estudos de forma a orientar o diagnóstico e a suplementação com ferro nestes doentes.

Macroprolactinomas: longitudinal assessment of biochemical and imaging therapeutic responses.

PURPOSE: To assess biochemical and imaging therapeutic response rates, when these occur and their predictive factors in patients with macroprolactinomas treated with dopamine agonists (DA). METHODS: Retrospective, longitudinal study of patients with macroprolactinomas treated with DA for ≥12 months. OUTCOMES: prolactin normalization, reduction in maximum tumor diameter ≥50% and time until therapeutic responses. RESULTS: We included 67 patients; 49.3% females, with median age at diagnosis of 43 years, 61.2% only treated with bromocriptine, 10.4% only with cabergoline, and 28.4% with both DA. Median follow-up time was 73 months. Prolactin levels normalized in 87%, mostly during the first 2 years. Prolactin levels after 6 months (HR 0.994, p = 0.012), 1 year (HR 0.970, p = 0.003), and 2 years (HR 0.970, p = 0.015) predicted its normalization time. Only 62% of the patients achieved a ≥50% reduction in maximum tumor diameter. Percent tumor diameter reduction after 1 year (OR 1.098, p = 0.022) and 2 years (OR 1.102, p = 0.008) predicted a ≥50% size reduction. Size reduction occurred later than prolactin normalization. Initial tumor diameter (HR 1.050, p = 0.032) and its percent reduction at 6 months (HR 1.110, p = 0.002), 1 (HR 1.060, p < 0.001), 2 (HR 1.045, p < 0.001), 3 (HR 1.048, p = 0.002), and 4 years (HR 1.074, p = 0.042) predicted the time until imaging response. CONCLUSION: A significant number of patients did not obtain an imaging response. Biochemical and imaging responses were asynchronous and occurred mainly in the first 4 years of treatment. This may allow an earlier identification of partially resistant and resistant macroprolactinomas, with consequent change in the therapeutic approach.

Treatment of Graves' disease in children: The Portuguese experience / Tratamiento de la enfermedad de Graves en niños: la experiencia portuguesa

Introduction: Graves' disease (GD) is an autoimmune thyroid disease, common in adults but rare in children. The best therapeutic approach remains controversial. Objectives: To ascertain the current treatment of pediatric GD in Portugal and to assess the clinical and biochemical factors that determine definitive/long-term remission after treatment with antithyroid drugs (ATDs). Patients and methods: A retrospective analysis of data about pediatric GD treatment collected from a nationwide survey conducted by the Portuguese Society of Pediatric Endocrinology and Diabetology from May to August 2013. Population was categorized based on sex, age, use of ATDs, dosage, treatment duration, adverse reactions, thyrotropin receptor-stimulating antibody (TRAB) titer, remission and remission/relapse rates, and definitive treatment, and divided into group A (with ongoing treatment) and group B (with treatment stopped). Group B was subdivided into 'Remission', 'Remission+relapse' and 'No remission' subgroups based on the course of disease. The same parameters were compared between both groups. Results: Survey response rate was 77%; 152 subjects, 116 female, mean age at diagnosis 11.23±3.46 years. They all started treatment with ATDs, 70.4% with thiamazole, with a mean treatment duration of 32.38±28.29 months, and 5.9% had adverse effects. Remission rate was 32.6%. Lower age at diagnosis correlated with higher remission rates. Treatment duration was longer when propylthiouracil was used. Initial TRAB titer was significantly higher in the 'No remission' group. Surgery and radioiodine were used as second-line treatments. Conclusion: Our study results were similar to those reported in the literature. Age and TRAB titer were identified as potential clinical and laboratory determinants of remission. Based on risk/benefit analysis, it was concluded that treatment should be individualized based on age, accessibility to treatments, and physician's experience (AU)

Introducción: La enfermedad de Graves (EG) es una enfermedad tiroidea autoinmune frecuente en el adulto pero rara en edad pediátrica. La mejor opción terapéutica sigue siendo controvertida. Objetivos: Conocer su tratamiento en Portugal, y evaluar factores clínicos y bioquímicos determinantes de la remisión definitiva/prolongada con fármacos antitiroideos (AT). Pacientes y métodos: Análisis retrospectivo de los datos obtenidos mediante un cuestionario nacional realizado por la Sociedad Portuguesa de Endocrinología Pediátrica y Diabetología entre mayo y agosto de 2013. Caracterizamos la población por sexo, edad, uso de AT, dosis, duración del tratamiento, reacciones adversas, thyrotropin receptor-stimulating antibody (TRABs), tasas de remisión y remisión/recaída, y tratamiento definitivo. Se definieron los siguientes grupos: grupo A (mantiene tratamiento) y grupo B (tratamiento detenido), el cual se subdividió en «remisión», «remisión+recaída» y «no remisión»; se compararon los parámetros entre los diferentes grupos. Resultados: La tasa de respuesta al cuestionario fue del 77%: 152 sujetos, 116 de ellos mujeres, con un promedio de edad al diagnóstico de 11,23±3,46años. Todos iniciaron tratamiento con AT (70,4% con tiamazol), con una duración media del tratamiento de 32,38±28,29meses; un 5,9% presentaron efectos adversos y la tasa de remisión fue del 32,6%. Las edades menores al diagnóstico se correlacionaron con mayor índice de remisión. La duración del tratamiento fue mayor con propiltiouracilo. El título inicial de TRABs fue significativamente mayor en el grupo sin remisión. Cirugía y yodo radioactivo se utilizaron en segunda línea. Conclusión: Se obtuvieron resultados similares a los de la literatura. Como posibles determinantes de la remisión, se identificaron la edad y el título de TRABs. Considerando los riesgos/beneficios, se concluye que la terapéutica debe ser individualizada, teniendo en cuenta la edad, la accesibilidad a las terapias y la experiencia del médico (AU)

Iatrogenic water intoxication in a female adolescent with hypopituitarism.

The authors report a case of a 15-year-old girl with hypopituitarism due to pituitary stalk interruption syndrome diagnosed in the neonatal period. The patient was admitted to the emergency room with impaired consciousness and hypoglycaemia. The day before, she increased her water intake to about 1.5 L to perform a pelvic ultrasound. In the following hours, she developed vomiting and food refusal. Blood analysis revealed hypoglycaemia, hyponatraemia, decreased serum osmolality and normal urinary density. Hyponatraemia and adrenal crisis were managed with a gradual but slow resolution of consciousness and electrolytic balance. This case describes an episode of iatrogenic water intoxication in a patient under desmopressin treatment. Although uncommon, dilutional hyponatraemia is the main complication of desmopressin treatment. We reinforce the importance of patients and caregivers' long-life education for the potential complications of an increase in fluid intake in patients treated with desmopressin.

Treatment of Graves' disease in children: The Portuguese experience.

INTRODUCTION: Graves' disease (GD) is an autoimmune thyroid disease, common in adults but rare in children. The best therapeutic approach remains controversial. OBJECTIVES: To ascertain the current treatment of pediatric GD in Portugal and to assess the clinical and biochemical factors that determine definitive/long-term remission after treatment with antithyroid drugs (ATDs). PATIENTS AND METHODS: A retrospective analysis of data about pediatric GD treatment collected from a nationwide survey conducted by the Portuguese Society of Pediatric Endocrinology and Diabetology from May to August 2013. Population was categorized based on sex, age, use of ATDs, dosage, treatment duration, adverse reactions, thyrotropin receptor-stimulating antibody (TRAB) titer, remission and remission/relapse rates, and definitive treatment, and divided into group A (with ongoing treatment) and group B (with treatment stopped). Group B was subdivided into 'Remission', 'Remission+relapse' and 'No remission' subgroups based on the course of disease. The same parameters were compared between both groups. RESULTS: Survey response rate was 77%; 152 subjects, 116 female, mean age at diagnosis 11.23±3.46 years. They all started treatment with ATDs, 70.4% with thiamazole, with a mean treatment duration of 32.38±28.29 months, and 5.9% had adverse effects. Remission rate was 32.6%. Lower age at diagnosis correlated with higher remission rates. Treatment duration was longer when propylthiouracil was used. Initial TRAB titer was significantly higher in the 'No remission' group. Surgery and radioiodine were used as second-line treatments. CONCLUSION: Our study results were similar to those reported in the literature. Age and TRAB titer were identified as potential clinical and laboratory determinants of remission. Based on risk/benefit analysis, it was concluded that treatment should be individualized based on age, accessibility to treatments, and physician's experience.

Metastasis of a Dorsal Melanoma to a Pituitary Adenoma Mimicking Pituitary Apoplexy

Metastases to pituitary adenomas are very rare. From the 20 cases found in the literature, none originated from a cutaneous melanoma. We present the case of a 67-year-old man with a history of transcranial approach to treat a pituitary macroadenoma followed by adjuvant radiotherapy. Fifteen years later, he presented a dorsal nodular melanoma, and three years after that, he developed symptoms of pituitary apoplexy. He was submitted to transsphenoidal surgery, and the histology result revealed metastasis of the melanoma into a pituitary adenoma. The similarity in the clinical presentation of the two entities­pituitary apoplexy and metastasis of the melanoma into a pituitary adenoma­and the rarity of this type of metastization alert to challenges in the differential diagnosis that may confound the neurosurgeon's decision.

As metástases em adenomas pituitários são muito raras. Dos 20 casos descritos na literatura, nenhum foi originado por um melanoma cutâneo. Apresentamos um caso de um homem de 67 anos de idade, com história de abordagem transcraniana para tratar um macroadenoma pituitário, seguido de radioterapia adjuvante. Quinze anos depois, o paciente apresentou um melanoma nodular dorsal e 3 anos mais tarde desenvolveu sintomas de apoplexia pituitária. Ele foi então submetido a uma cirurgia transfenoidal, e o resultado histológico revelou tratar-se de uma metástase do melanoma em um adenoma hipofisário. A semelhança na apresentação clínica entre as duas entidades­apoplexia pituitária e metástase do melanoma em um adenoma hipofisário ­ e a raridade deste tipo de metastização alertam para desafios no diagnóstico diferencial que podem confundir a decisão do neurocirurgião.

A Pediatric Case of Cowden Syndrome with Graves' Disease.

Cowden syndrome (CS) is a rare dominantly inherited multisystem disorder, characterized by an extraordinary malignant potential. In 80% of cases, the human tumor suppressor gene phosphatase and tensin homolog (PTEN) is mutated. We present a case of a 17-year-old boy with genetically confirmed CS and Graves' disease (GD). At the age of 15, he presented with intention tremor, palpitations, and marked anxiety. On examination, he had macrocephaly, coarse facies, slight prognathism, facial trichilemmomas, abdominal keratoses, leg hemangioma, and a diffusely enlarged thyroid gland. He started antithyroid drug (ATD) therapy with methimazole and, after a 2-year treatment period without achieving a remission status, a total thyroidectomy was performed. Diagnosis and management of CS should be multidisciplinary. Thyroid disease is frequent, but its management has yet to be fully defined. The authors present a case report of a pediatric patient with CS and GD and discuss treatment options.