ACTA ENDOCRINOLOGICA (BUC)

Genome Wide Association Studies (GWAS) are excellent opportunities to define culprit genes in complex disorders such as the polycystic ovary syndrome (PCOS). PCOS is a prevalent disorder characterized by anovulation, hyperandrogenism and polycystic ovaries, which benefitted from several GWASs in Asians and Europeans revealing more than 20 potential culprit genes near associated single nucleotide variations (SNV). Translation of these findings into the clinical practice raises difficulties since positive hits are surrogate SNVs linked with causative mutations by linkage disequilibrium (LD). Studies in Mediterranean populations (e.g. Southern Europe and North Africa) raise supplementary problems because of a different LD-pattern, which may disrupt the link with causative mutations. Our experience in MEDIGENE program between Tunisia and France enforces the necessity of genetic anthropology studies before translating GWAS data. Tunisians are a heterogeneous population with ancestral Berbers, European, Arab and Sub-Saharan African components while South Europeans display a high level of genetic diversity, partially explained by gene flow from North Africa. Human diversity studies require sampling from Middle East and North Africa (MENA) region that will help to understand genetic factors in complex diseases.

Context. Gender identity, psychosexual function, psychiatric adjustment and quality of life have been investigated in congenital adrenal hyperplasia(CAH) patients. Objective. We aimed to investigate gender identity problems and the psychiatric disorders and associated factors in children and adolescents with CAH patients. Subjects and methods. Forty-five children and adolescents with CAH were included in the study. Psychiatric comorbidity was assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children – Present and Lifetime Version. Gender identity problems were investigated using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Results. The mean age of the sample was 11.02 years (SD: 3.25, range: 6–18). 51.1% of the patients had at least one lifetime comorbid psychiatric disorder. The most common diagnoses were anxiety disorders, attention deficit hyperactivity disorder(ADHD), tic disorders and enuresis nocturna. Tic disorders and ADHD were higher in males but they were not statistically significant. Two female patients were diagnosed with gender dysphoria and 18.5% of females showed variably masculinized behaviors. The girls with gender identity problems expressed lower satisfaction with their sex than other girls and boys. Conclusions. Children and adolescents with CAH had many psychiatric disorders, especially neurodevelopmental disorders. ADHD and tic disorders should be kept in mind during assessment especially in male patients. Gender dysphoria and masculine behaviors seem to be common in female patients with CAH so they should be carefully investigated.

Background. Thyroid nodules are common; however, the association of two or more different tumors in the thyroid gland is unusual. We present a first case with the association of three histological types of thryroid tumors. To the best of our knowledge, this association has not been reported in the literature before. We aim here to highlight the possible coexistence of many lesions in the thyroid gland and to discuss treatment options. Case presentation. We report the case of a female patient who presented with a multinodular goiter. The final pathology after total thyroidectomy found the association of a multifocal papillary thyroid microcarcinoma arising within a Hurthle cells adenoma in a lobe and a noninvasive follicular thyroid neoplasm with papillary nuclear features in the other lobe. Due to the very low risk of recurrence, the patient was not treated with radioactive iodine. Conclusions. Many controversies remain about the management of Hurthle cells tumors and many variants of papillary thyroid carcinoma. Although the management of our case did not change, more studies are necessary to analyze the evolution of patients with multiple thyroid neoplasms. When discussing therapeutic options, the advantages and disadvantages should be considered case by case based on disease staging.

Objective: Co-existence of Cushing disease and Rathke?s Cleft Cyst (RCC) has been reported in a few cases in the literature so far. We herein describe a rare condition of Cushing disease that might originate from epithelium of RCC. \r\nCase: A 48-year-old woman was admitted to the hospital with complaints of headache, weakness, and weight gain. The patient underwent endoscopic transsphenoidal surgery due to Cushing Disease. Histopathological examination revealed cyst contents and walls compatible with RCC, and normal adenohypophysis and neurohypophysis tissues. Immunhistochemical staining with ACTH, GH, and prolactin were positive on the epithelium of the cyst. \r\nConclusion: In our case Cushing disease might be associated with hormonal activity derived from cyst wall of RCC or disappearance of a small microadenoma during surgical or pathological processing. According to recent data, origin of this lesion and histogenetic link between RCC with Cushing disease could not be explained.

Context. The metabolic effects of primary hyperparathyroidism (PHPT) causing increased cardiovascular morbidity have begun to gain importance in medical science, and the number of studies investigating glucose metabolism disorders in asymptomatic PHPT patients is rare. Objective. To evaluate the relationship between glucose metabolism disorders and calcium, phosphorus and parathyroid hormone concentrations in asymptomatic PHPT patients. Subjects and Methods. Fifty-five asymptomatic PHPT patients were included into the study. Control group consisted of 55 normocalcemic cases. Oral glucose tolerance test (OGTT) of 75 g was performed with patients and controls. Insulin resistance was calculated by HOMA index. Results. No significant difference was present between groups regarding fasting plasma glucose, basal insulin and HOMA levels. Glucose levels measured at minutes 30, 90 and 120 after OGTT were higher in patients than in controls (p=0.041, p=0.025 and p=0.001, respectively). No individuals in both groups were diagnosed with diabetes mellitus. While impaired glucose tolerance was detected in six patients with asymptomatic PHPT, no impaired glucose tolerance was determined in controls. A positive correlation was found between serum calcium levels, and fasting plasma glucose and OGTT glucose levels were measured at minutes 60, 90 and 120. Mean fasting plasma glucose was significantly higher in patients with serum calcium levels ≥ 10.5 mg/dL than those with serum calcium levels <10.5 mg/dL (p=0.008). No significant correlation was detected between serum phosphorus and parathyroid hormone levels, and glucose levels were determined in OGTT and HOMA index. Conclusion. Increased levels of serum calcium affect glucose metabolism, so leading to glucose intolerance.

Zygomycosis is a frequently fatal infection in the immunocompromised and diabetic host. A 12 year old girl with type 1 diabetes presented in diabetic ketoacidosis and consolidation of right lung along with thymic abscess causing persistent respiratory symptoms. A diagnosis of\r\nmucormycosis was made on smear examination of the thymic aspirate. Intravenous amphotericin along with surgical excision of the abscess resulted in clinical cure. Thymic involvement as seen in this case is an extremely rare occurrence in a diabetic patient which has not been\r\nreported in literature so far .

Context. Immunoassays are vulnerable to occasional analytical errors despite their sensitivity and specificity. Adrenocorticotropic hormone (ACTH) is among hormones which are vulnerable to assay interference. Objective. In this case report, we aimed to present a case of ACTH interference in a patient with subclinical hypercortisolism. Case report. We present a case of subclinical hypercortisolism with unexpectedly elevated levels of ACTH in whom interference was shown by different biochemical methods. It is important for the clinician to keep in mind the possibility of interference when clinical and laboratory results are discordant. The communication between the clinician and laboratory staff is important while interpreting results. This case report shows that ACTH interference should be considered in patients with subclinical hypercortisolism who have unexpectedly high levels of adrenocorticotropic hormone.

Hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1 gene, and causes fasting as well as protein sensitive symptomatic hypoglycemia, in addition to persistently elevated plasma ammonia levels. First-line treatment is diazoxide, and most patients respond well to this agent, however side effects may be observed. The most frequent side effect of diazoxide is fluid retention and hypertrichosis, while hyperuricemia and hematologic side effects are observed less often. Herein, we report a case who had a heterozygous mutation of GLUD1 gene and who developed diazoxide related neutropenia 8 years after the start of treatment. On follow-up, leucopenia and mild neutropenia persisted and the treatment was changed to somatostatin analogues. However, she developed persistent severe symptomatic hypoglycemia and required diazoxide retreatment. A lower dose of diazoxide (6 mg/kg/day) successfully controlled hypoglycemia and cell counts increased even though they were not normalized. Neutropenia in current case presented after a long period of time of diazoxide use and this period is the longest defined in the literature. Long-term endocrine and hematologic follow-up of this patient up to 18 years old will also be presented.

Triple A syndrome is an autosomal recessive inherited multisystem disorder that was first described in 1978. Triple A syndrome has a high genotypic and phenotypic heterogeneity and has been linked with mutations in the AAAS gene, which has been identified on chromosome 12q13. A 14 years old male patient applied to outpatient clinic complaining of weakness and darkening of skin color since 4 months. On physical examination hyperpigmentation was observed on both the skin and mucosa. The morning cortisol level was 1.8 μg/dL and ACTH was >1250 ng/L. Schirmer test showed absence of tears. In the patient’s esophagoscopy, mucosal paleness and stenosis of the cardia were observed. Molecular genetic analysis of AAAS gene confirmed the diagnosis of triple A syndrome caused by homozygous mutation: c.1368_1372delGCTCA (p.Gln456HisfsTer38). This variant is considered to be a possible pathogenic because it causes a frame shift that changes the protein structure. As a result of the genetic analysis of the patient’s parents, the AAAS gene was detected as heterozygous in both parents for the c.1368_1372delGCTCA mutation. To the best of our knowledge, this is the first report of homozygous mutation: c.1368_1372delGCTCA (p.Gln456HisfsTer38).

A 52-year old women was diagnosed with acromegaly 5 years ago, and transseptal transsphenoidal pituitary microsurgery has been performed. Later the patient did not come to controls and the complaints prior to operation growth of the hands and feet, headache, sweating and resistant hypertension have continued. She was referred to our clinic with the same complaints. Physical examination showed typical acromegalic features without typical Cushingoid features. Magnetic resonance imaging of the brain revealed the presence of a pituitary macroadenoma. Basal plasma levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels were high. GH suppression was not observed in 75 gr oral glucose suppression test. Due to refractory hypertension and central obesity hypothalamo-pituitaryadrenal (HPA) axis was evaluated. HPA showed a lack of circadian rhythm of adrenocorticotropic hormone (ACTH) and cortisol, non-suppressibility to 1 mg overnight and classical 2 day low-dose dexamethasone, but suppressibility to high-dose (8 mg) dexamethasone. The tumour resected by transsphenodial surgery was histopathologically consistent with the diagnosis of adenoma. Immunostaining showed GH and ACTH producing cells. After surgery plasma GH and IGF-1 levels decreased to normal along with normalization of HPA axis. Hypertension disappeared without medical treatment after removal of the pituitary tumour. This is a very rare case of GH-producing pituitary adenoma causing typical acromegaly with concomitant production of ACTH causing subclinical Cushing’s disease.