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Abstract Introduction We report the case of a patient with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency who presented with unusual anatomical and biochemical features, namely massively enlarged adrenal glands, adrenogenital rest tissue and an unexpected endocrine profile. The contribution of the adrenocortical cells in the adrenals and testicles was determined by a cosyntropin stimulation test before and after adrenalectomy. To the best of our knowledge this is the first report of such a case in the literature. Case presentation A 35-year-old Caucasian man was admitted to the emergency room with an Addisonian crisis. He had been diagnosed with congenital adrenal hyperplasia in the neonatal period. He acknowledged poor adherence to treatment and irregular medical assistance. Physical examination revealed marked cutaneous and gingival hyperpigmentation, hypotension, and hard nodules in the upper pole of both testicles. Blood analysis showed mild anemia and hyponatremia and no evidence of acute infection. Endocrine evaluation showed very low cortisol levels, low dehydroepiandrosterone-sulfate and elevated corticotropin, 11-deoxycortisol and delta-4-androstenedione. The concentration of 17-hydroxyprogesterone was 20,400ng/dL. After the cosyntropin stimulation test the pattern was similar and there was no significant increase in cortisol or 17-hydroxyprogesterone. The abdominal computed tomography scan revealed grossly enlarged and heterogeneous adrenal glands (left, 12cm; and right, six cm). A bilateral adrenalectomy was performed and pathologic examination revealed adrenal myelolipomas with nodular cortical hyperplasia. The sonogram showed bilateral heterogeneous masses on the upper pole of both testes which corresponded to the nodular hyperplasia of adrenal rest tissues. The genetic study revealed compound heterozigoty (mutations R124H and R356W), suggestive of a phenotypically moderate disease. We performed a cosyntropin stimulation test after adrenalectomy. The steroidogenic profile displayed the same unusual features, indicating an important contribution from the adrenogenital cells. Conclusion This case illustrates that congenital adrenal hyperplasia due to 21-hydroxylase deficiency can progress to severe acute and chronic complications. The masses in the patient’s adrenal glands and testicles resulted from chronically elevated adrenocorticotropic hormone and growth of adrenocortical cells. The basal and stimulated steroid profile, before and after adrenalectomy, revealed an unexpected pattern, suggesting significant contribution of the testicular adrenal cells to the steroidogenesis.

Background and Purpose: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder affecting particularly the nervous tissue and adrenal cortex. Adrenomyeloneuropathy (AMN) is the most frequent phenotype, although adrenal insufficiency is usually the first manifestation in male patients. We set out to describe the clinical and biochemical features, together with the clinical course of X-ALD patients, focusing particularly on endocrine dysfunction., Patients and Methods: A retrospective study of 10 male X-ALD patients followed up at the Endocrinology Department. Epidemiologic data, phenotype evolution, endocrine and neurological findings and family history were analysed., Results: All the patients presented with adrenal insufficiency, 4 of them during adulthood, with a mean age of 19.6±17.1 years (6-64 years). Six patients had mineralocorticoid deficiency. At diagnosis, 8 patients had Addison-only phenotype and 2 AMN phenotype. In the course of follow-up (24.9±16.1 years), 4 patients developed AMN about 25.0±7.4 years after the initial diagnosis and 2 patients presented the cerebral adult form 11 and 17 years after the initial diagnosis. Testosterone levels were within the normal range in all patients. There were 7 families, and age of onset and clinical course were similar in 3 of them., Conclusions: The presentation of X-ALD varied widely, 40% of the patients presented with adrenal insufficiency in adulthood, 60% had mineralocorticoid deficiency, and the onset and progression of neurological manifestations showed no pattern. Nevertheless, some similarities in the clinical course were found in some families. Our findings reinforce the need for screening for X-ALD at any age when approaching adrenal insufficiency and the importance of a multidisciplinary approach between endocrinologists and neurologists., (Copyright © 2022 SEEN and SED. Published by Elsevier España, S.L.U. All rights reserved.)

Aims/hypothesis: Intensive insulin therapy in the treatment of type 1 diabetes can, in place of multiple daily injections of subcutaneous insulin (MDI), be performed with continuous subcutaneous insulin infusion (CSII) systems. This method allows for better glycemic control and thus reduces the risk of complications of the disease. The aim of this study was to evaluate the results of treatment with CSII in Portugal., Methods: A retrospective analysis of the records on the national CSII platform was carried out between January 2010 and August 2021. All the registered patients are followed in certified CSII treatment centers in Portugal. Of the 7135 registered patients, 3807 were excluded due to absence of monitoring data. The reasons for treatment were analyzed and a comparison was made between patients with and without CSII. The statistical significance considered was α < 0.05., Results: A total of 3328 patients were included in the study, 1136 under MDI and 2192 under CSII. The main reasons for CSII use were marked glycemic variability (25%) and HbA1c greater than 7% (23%). Patients under CSII had a lower HbA1c (7.7 ± 1.0% vs. 8.0 ± 1.5%, p < 0.001), as well as a lower frequency of episodes of severe hypoglycemia (1.4 vs. 3.3 per 100 patient-years, p < 0.001), and ketoacidosis (1 vs. 2.4 per 100 patient-years, p < 0.001)., Conclusions: The present analysis validates the advantage of using CSII in metabolic control and reduction of acute complications of type 1 diabetes, both severe hypoglycemia and ketoacidosis, in the Portuguese population. CSII therapy is classically associated with an increased risk of ketoacidosis; however, in experienced centers and adequate patient education, the opposite is found., (© 2022. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

A 22-year-old woman with type Ia glycogen storage disease was referred to the endocrinology department with new-onset diabetes mellitus-glycated haemoglobin (HbA1c) of 8.2%. She had suffered from repeated bouts of hypoglycaemia since the first days of her life. The diagnosis was made at 5 months old, after clinical investigations revealed mixed dyslipidaemia, lactic acidosis and hepatomegaly. Compound heterozygosity was documented at the age of 4. The basis of her initial treatment was starch and reinforced soy milk, ingested multiple times a day and night. The patient suffered from obesity since childhood. This case shows a rare association between glycogen storage disease type Ia and diabetes mellitus. A multidisciplinary approach was implemented. Through diet and use of flash continuous glucose monitoring, we were able to improve patient's adherence and metabolic profile. Hypoglycaemia and hyperglycaemia risk significantly decreased; 86% time in range (70-180 mg/dL), 6% hypoglycaemia and 6.3% HbA1c in recent evaluations., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

IgG4-thyroid-related disease (TRD) represents an uncommon spectrum of diseases, with four subcategories established so far, IgG4-related Hashimoto's thyroiditis, fibrosing variant of Hashimoto's thyroiditis, Riedel's thyroiditis and Graves disease with elevated IgG4 levels. We report the case of a 59-year-old woman presenting with painless cervical swelling and hypothyroidism. Thyroid gland was enlarged and distinctively very hard, with reduced mobility. Neck ultrasonography showed multiple nodularity and diffuse thyroid enlargement, which on CT scan conditioned slight deviation of the airway. Fine-needle aspiration of the biggest nodule was suggestive of lymphocytic thyroiditis. She developed compressive symptoms and was submitted to total thyroidectomy. Histology of the thyroid revealed extensive areas of fibrosis, oncocytic cells and lymphoplasmacytic infiltrates. Immunohistochemistry confirmed the predominance of IgG4-secreting plasma cells. IgG4-TRD is characterised by a rapidly progressive and destructive thyroiditis process. Typical presentation can often mimic malignancy; hence, an opportune recognition of IgG4-TRD may avoid unnecessary burdens., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: We hypothesize that patients with type 1 diabetes (T1D) may have abnormal retinal vascular responses before diabetic retinopathy (DR) is clinically evident. Optical coherence tomography angiography (OCTA) was used to dynamically assess the retinal microvasculature of diabetic patients with no clinically visible retinopathy., Methods: Controlled nonrandomized interventional study. The studied population included 48 eyes of 24 T1D patients and 24 demographically similar healthy volunteers. A commercial OCTA device (AngioVue) was used, and two tests were applied: (1) the hypoxia challenge test (HCT) and (2) the handgrip test to induce a vasodilatory or vasoconstrictive response, respectively. The HCT is a standardized test that creates a mild hypoxic environment equivalent to a flight cabin. The handgrip test (i.e., isometric exercise) induces a sympathetic autonomic response. Changes in the parafoveal superficial and deep capillary plexuses in both tests were compared in each group. Systemic cardiovascular responses were also comparatively evaluated., Results: In the control cohort, the vessel density of the median parafoveal superficial and deep plexuses increased during hypoxia (F1,23 = 15.69, P < 0.001 and F1,23 = 16.26, P < 0.001, respectively). In the T1D group, this physiological response was not observed in either the superficial or the deep retinal plexuses. Isometric exercise elicited a significant decrease in vessel density in both superficial and deep plexuses in the control group (F1,23 = 27.37, P < 0.0001 and F1,23 = 27.90, P < 0.0001, respectively). In the T1D group, this response was noted only in the deep plexus (F1,23 = 11.04, P < 0.01)., Conclusions: Our work suggests there is an early impairment of the physiological retinal vascular response in patients with T1D without clinical diabetic retinopathy.

Inhaled corticosteroids are generally considered safe and do not usually lead to systemic adverse events since their plasma concentrations are low due to hepatic metabolism by the cytochrome P450 3A4. However, when associated with inhibitors of this cytochrome, such as ritonavir, they may lead to iatrogenic Cushing syndrome by the systemic accumulation of corticosteroids and consequent suppression of the hypothalamic-pituitary-adrenal axis. We present a case of iatrogenic Cushing syndrome complicated by multifocal osteonecrosis in a patient with HIV infection on antiretroviral therapy with protease inhibitors boosted with ritonavir, after the association of inhaled fluticasone. This clinical case highlights a relevant interaction between corticosteroids and inhibitors of the cytochrome P450 and the severe consequences that may occur., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: Previous data suggest the existence of retinal vascular changes and impaired autoregulation in the very early stages of diabetic retinopathy (DR). We compared the retinal plexuses between patients with type 1 diabetes (T1D) without DR and a demographically similar healthy cohort, using optical coherence tomography angiography (OCT-A)., Methods: Patients with T1D and no signs of DR were prospectively recruited from an outpatient clinic. Using OCT-A (AngioVue ® ), the parafoveal superficial (SCP) and deep (DPC) capillary plexus as well as the foveal avascular zone (FAZ) and perimeter were gathered. Mean comparison tests and linear regression analysis were used as statistical tests (STATA v14)., Results: Studied population included 48 subjects (24 T1D). The analysis of SCP revealed an attenuation of the capillary network compared with the control group in both parafoveal (51.8 ± 4.5 vs. 55.8 ± 3.2, p < 0.001) and perifoveal (51.9 ± 3.3 vs. 53.9 ± 1.9, p = 0.01) regions. A similar finding was observed in the DCP for both parafoveal (56.4 ± 4.3 vs. 60.4 ± 2.2, p < 0.001) and perifoveal (54.7 ± 3.9 vs. 60.8 ± 3.4, p = 0.001) sectors. Also, a longer time since T1D diagnosis was associated with a larger FAZ area (p = 0.055) and perimeter (p = 0.03)., Conclusions: Significant differences in the retinal microvasculature were observed between healthy subjects and T1D patients using OCT-A, even before clinically detectable disease on fundus biomicroscopy.

Introduction: Optical coherence tomography angiography (OCT-A) is a novel diagnostic tool with increasing applications in ophthalmology clinics that provides non-invasive high-resolution imaging of the retinal microvasculature. Our aim is to report in detail an experimental protocol for analyzing both vasodilatory and vasoconstriction retinal vascular responses with the available OCT-A technology., Methods: A commercial OCT-A device was used (AngioVue ® , Optovue, CA, United States), and all examinations were performed by an experienced technician using the standard protocol for macular examination. Two standardized tests were applied: (i) the hypoxia challenge test (HCT) and (ii) the handgrip test, in order to induce a vasodilatory and vasoconstriction response, respectively. OCT-A was performed at baseline conditions and during the stress test. Macular parafoveal vessel density of the superficial and deep plexuses was assessed from the en face angiograms. Statistical analysis was performed using STATA v14.1 and p < 0.05 was considered for statistical significance., Results: Twenty-four eyes of 24 healthy subjects (10 male) were studied. Mean age was 31.8 ± 8.2 years (range, 18-57 years). Mean parafoveal vessel density in the superficial plexus increased from 54.7 ± 2.6 in baseline conditions to 56.0 ± 2.0 in hypoxia ( p < 0.01). Mean parafoveal vessel density in the deep plexuses also increased, from 60.4 ± 2.2 at baseline to 61.5 ± 2.1 during hypoxia ( p < 0.01). The OCT-A during the handgrip test revealed a decrease in vessel density in both superficial (55.5 ± 2.6 to 53.7 ± 2.9, p < 0.001) and deep (60.2 ± 1.8 to 56.7 ± 2.8, p < 0.001) parafoveal plexuses., Discussion: In this work, we detail a simple, non-invasive, safe, and non-costly protocol to assess a central nervous system vascular response (i.e., the retinal circulation) using OCT-A technology. A vasodilatory response and a vasoconstriction response were observed in two physiologic conditions-mild hypoxia and isometric exercise, respectively. This protocol constitutes a new way of studying retinal vascular changes that may be applied in health and disease of multiple medical fields.

Hypercalcemia is a known cause of heart rhythm disorders, however its association with ventricular arrhythmias is rare. The authors present a case of a fifty-three years old male patient with a ischemic and ethanolic dilated cardiomyopathy, and severely reduced ejection fraction, carrier of cardiac resynchronization therapy (CRT) with cardioverter defibrillator (ICD), admitted in the emergency department with an electrical storm, with multiple appropriated ICD shocks, refractory to antiarrhythmic therapy. In the etiological investigation was documented severe hypercalcemia secondary to primary hyperparathyroidism undiagnosed until then. Only after the serum calcium level reduction ventricular tachycardia was stopped., (Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Adverse reactions associated to anti-thyroid drugs include fever, rash, arthralgia, agranulocytosis and hepatitis that are thought to be hypersensitivity reactions. Five cases of pleural effusion associated to thionamides have also been reported, two with propylthiouracil and three with carbimazole., Case Presentation: We report here a case of a 75-year-old man admitted because of unilateral pleural effusion. The patient had a recent diagnosis of hyperthyroidism and 6 days after starting methimazole complained of pleuritic chest pain. He had elevated C-reactive protein and erythrocyte sedimentation rate and normal white blood cell count and liver enzymes. Chest radiography showed a moderate right pleural effusion and the ultrasound revealed a loculated effusion that was shown to be an eosinophilic exudate., Conclusions: The temporal relationship between methimazole intake and the development of pleural effusion combined with the extensive exclusion of alternative causes, namely infectious, neoplastic and primary auto-immune diseases, led to the diagnosis of hypersensitivity reaction to methimazole. The thionamide was stopped and corticosteroid was started with complete resolution of the pleural effusion in 3 months. Awareness of this rare adverse reaction of anti-thyroid drugs is important and methimazole can be added to the list of possible etiologies of drug-induced eosinophilic pleural effusion.

Background and Objective: Multiple Endocrine Neoplasia type 2 (MEN2) is a rare genetic disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary hyperparathyroidism. MEN2 is an autosomal dominant syndrome caused by mutations in the RET proto-oncogene. In the vast majority of patients, the mutations are localized in exons 10, 11 and 13-15 of the RET gene. Rare variants located in exon 8 were recently identified but their clinical significance remains unclear., Design and Methods: We studied two sisters presenting with pheochromocytoma as the first tumor. One of the sisters was diagnosed with a right pheochromocytoma at the age of 44 and at age 53 she developed an invasive left pheochromocytoma with no other endocrine neoplasia. The other sister was diagnosed with a left pheochromocytoma at age 50 and at age 64 she had a right phemochromocytoma and MTC. Neither of the two sisters presented evidence of primary hyperparathyroidism. Mutations of the RET proto-oncogene were investigated by DNA sequencing., Results: We detected a germline missense variant in RET exon 8 (p.Cys531Arg) in both sisters. The p.Cys531Arg variant was not present in a third 50-year-old sister who has remained to date clinically unaffected., Conclusion: This is the first case showing the p.Cys531Arg variant in RET exon 8 co-segregating with family members affected by a syndrome reminiscent of MEN2A. Our results suggest that this variant has a specific genotype-phenotype correlation as it is associated with the development of pheochromocytoma before the onset of MTC.

Takotsubo cardiomyopathy (TTC) is characterized by reversible left ventricular apical and/or midventricular hypokinesia with unknown etiology. The clinical presentation is similar to acute myocardial infarction in the absence of significant obstructive coronary artery disease. Various predisposing factors have been related to TTC, such as acute neurological illnesses, endocrine diseases, pain, and emotional stress. We present the first description of an association between TTC cardiomyopathy and panhypopituitarism. This case reinforces the connection between the hormonal and cardiovascular systems. Furthermore, it supports the importance of a comprehensive and integrated medical history in the approach of a patient with cardiac disease, towards clinical decision-making.

Introduction. Adrenal glands play a major role in the control of blood pressure and mild defects of steroidogenesis and/or inappropriate control of mineralocorticoid production have been reported in high blood pressure (HBP). Patients and Methods. We used a specific protocol for the evaluation of 100 consecutive patients with inappropriate or recent onset HBP. Specific methods were used to confirm HBP and to diagnose secondary forms of HBP. In addition we tested adrenal steroidogenesis with the common cosyntropin test, modified to include the simultaneous measurement of renin and aldosterone besides 17-hydroxyprogesterone (17OHP) and 11-deoxycortisol (S). Results. Secondary forms of HBP were diagnosed in 32 patients, including 14 patients with primary hyperaldosteronism (PA) (14%) and 10 patients with pheochromocytoma (10%). Mild defects of the 21-hydroxylase (21OHD) and 11-hydroxylase (11OHD) enzymes were common (42%). ACTH-dependent aldosterone secretion was found in most patients (54%) and characteristically in those with mild defects of adrenal steroidogenesis (>60%), PA (>75%), and otherwise in patients with apparent essential HBP (EHBP) (32%). Discussion. Mild defects of adrenal steroidogenesis are common in patients with HBP, occurring in almost half of the patients. In those patients as well as in patients with apparent EHBP, aldosterone secretion is commonly dependent on ACTH.

The tumor suppressor adenomatous polyposis coli (APC) has recently been implicated in parathyroid development. We here report clinical, histopathological and molecular investigations in parathyroid tumors arising in two patients; one familial adenomatous polyposis (FAP) syndrome patient carrying a constitutional APC mutation, and one Lynch syndrome patient demonstrating a germline MLH1 mutation as well as a non-classified, missense alteration of the APC gene. We sequenced the entire APC gene in tumor and constitutional DNA from both cases, assessed the levels of APC promoter 1A and 1B methylation by bisulfite Pyrosequencing analysis and performed immunohistochemistry for APC and parafibromin. In addition, copy number analysis regarding the APC gene on chromosome 5q21-22 was performed using qRT-PCR. Histopathological workup confirmed both tumors as parathyroid adenomas without signs of malignancy or atypia. No somatic mutations or copy number changes for the APC gene were discovered in the tumors; however, in both cases, the APC promoter 1A was hypermethylated while the APC promoter 1B was unmethylated. APC promoter 1B-specific mRNA and total APC mRNA levels were higher than in normal parathyroid samples. Immunohistochemical analyses revealed strong APC protein immunoreactivity and positive parafibromin expression in both parathyroid tumors. Absence of additional somatic APC mutations and copy number changes in addition to the positive APC immunoreactivity obtained suggest that the tumors arose without biallelic inactivation of the APC tumor suppressor gene. The finding of an unmethylated APC promoter 1B and high APC 1B mRNA levels could explain the maintained APC protein expression. Moreover, the findings of positive parafibromin and APC immunoreactivity as well as a low MIB-1 proliferation index and absence of histopathological features of malignancy/atypical adenoma indicate that the parathyroid adenomas arising in these patients did not harbor malignant potential.

Objectives: Dehydroepiandrosterone-sulphate (DHEAS) physiologic relevance remains controversial. However, several central nervous system and behavioural effects of DHEAS have been described. We explored the relation between DHEAS and both pituitary-adrenal axis reactivity and personality in human subjects., Design: We studied 120 consecutive patients assisted at the out patient endocrine department of a public central hospital before medical treatment. Personality was evaluated with the Minnesota Multiphasic Personality Inventory (MMPI) and the pituitary-adrenal axis reactivity was assessed with the CRH test., Results: Baseline DHEAS was inversely related to peak/basal cortisol (parcial r=-0.454, p<0.05) response to CRH infusion. DHEAS reactivity in the CRH test was directly related to the Deviant Behaviour triad (BD) (r=0.257, p<0.05) and type A personality (AP) (r=0.295, p<0.05). Basal ACTH was directly related to baseline DHEAS (r=0.366, p<0.001) and together with age and gender explained 34% of DHEAS variability., Conclusions: DHEAS may be a protective factor against an excessive cortisol response when people are under stress situations. Personality may be related to DHEAS reactivity.