ACTA ENDOCRINOLOGICA (BUC)

Familial hypercholesterolemia (FH) is a genetic disease with autosomal dominant transmission, characterised by high blood cholesterol levels. The evolution of this disease leads to primary atherosclerosis and cardiovascular disease. Patients with HF develop atherosclerosis by the age of 20 and usually do not survive past the age of 30. We present the case and oro-dental aspects of a preschooler that was diagnosed at the age of 4 with FH, compound heterozygote (mutation/genotype1 LDLR: C20IX, exon 4; mutation/ genotype2 LDLR: G571E, exon 12) and the experience of our clinic in the management of this patient that received offlabel treatment with statins. When diagnosed, his cholesterol level was 932 mg/dL and his LDL-cholesterol level was 792 mg/dL. Treatment with rosuvastatin and ezetimibe was prescribed. Both substances (rosuvastatin and ezetimibe) are not approved for children under the age of 6 in Europe. Taking into considerations the diagnosis and prognosis for unfavorable evolution, treatment with statins was started at the age of 5 years.

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).

Context. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder, which is characterized by renal phosphate wasting, hypercalciuria, increased 1,25-dihydroxyvitamin D, and decreased parathormone (PTH) levels. Objective. Here we report different clinical features of two siblings with HHRH, confirmed with molecular diagnosis. Subjects and methods. 16.4 years old boy (P1), and 8.7 years old girl (P2) were referred to our outpatient clinic due to clinical suspicion of metabolic bone diseases. Results. P1 had severe hypophosphatemia. Additionally, PTH concentration was near to the lower limit, 1,25-dihydroxyvitamin-D concentration was near to the upper limit. P2 had relatively milder clinical and laboratory findings. Bilateral renal calculi were detected on ultrasound in both of them. HHRH was suspected due to their described biochemistry and the presence of bilateral renal calculi. Molecular analysis of SLC34A3 gene revealed a homozygous variant c.756G>A (p.Gln252=) and a splice donor variant c.1335+2T>A. After oral phosphate treatment, clinical and biochemical improvements were observed. However treatment nonadherence of patients was a barrier to reach treatment goal Conclusion. The clinical phenotype due to the same mutation in the SLC34A3 gene may vary even among the members of the same family. An accurate diagnosis is important for the appropriate treatment.

Context. Thyroid cancer is the most common endocrine malignancy. Within various subtypes of thyroid neoplasms, those with follicular growth pattern usually make diagnostic problems. Objectives. To examine ck19 expression as a diagnostic marker in thyroid neoplasms with follicular growth pattern. Design. In this cross sectional study, 86 patients were enrolled. Subjects and Methods. Totally 22 follicular adenoma (FA), 18 well differentiated tumors with undetermined malignant potential (WT-UMP) and 46 follicular variants of papillary thyroid carcinoma (FV-PTC) were enrolled and examined for Ck19 expression by immunohistochemistry staining. Membranous/cytoplasmic staining patterns were considered as positive. Specimens without staining were considered as 0, < 5% positively stained cells as 1+, 5%-25% as 2+, 25%-75% as 3+ and >75% as 4+. Result. CK19 was negative in most cases of FA while positive in most WDT-UMP and FV-PTCs, p<0.001. Additionally, most cases with 2+ and 3+ staining patterns were FV-PTC (75% and 81%, respectively, p<0.001) and none of FAs showed 3+ positivity (p<0.001). Additionally, most of strongly positive results in patients > 45 y/o were PTC (p<0.001). Conclusion. Ck19 is a useful marker in differentiating FA from FV-PTC. We found diffuse and strong (3+) staining pattern in FV-PTC but none of FAs were so. We concluded that diffuse and strong staining for ck19 in a thyroid lesion with follicular pattern of growth, especially in a patient older than 45 y/o should raise the possibility of malignancy.

Background. Thyroid hormone resistance (RTH) is defined as a decrease in response to thyroid hormones in the target tissue. Most patients present with nonspecific findings. In this article, we aimed to represent a 22-yearold female patient who presented with palpitation, fatigue, and heat intolerance. She was thought to have thyroid hormone resistance and her genetic examination revealed NM_001128177.1 (THRβ): c.1034G > A (p.Gly345Asp) pathogenic variation in the THRβ gene. Case report. A 22-year-old female patient presented with complaints of fatigue, heat intolerance and palpitations. She was taking Propranolol twice daily at admission. Her family history revealed hypothyroidism in her grandmother. Her physical examination results were as follows: height 160 cm, weight 65 kg, body mass index 25.4kg/m2, body temperature 36.5˚C, respiratory rate 18/min, heart rate 86 beats/min, blood pressure 120/80 mmHg. Her palms were sweaty. The heart sounds were normal, and no heart murmur was auscultated. The laboratory results were TSH: 5.31uU/mL, fT3: 6.83 pg/mL, and fT4: 2.43 ng/dL. THRβ gene mutation analysis was requested for our patient whose clinical history and laboratory results were compatible with thyroid hormone resistance. The pathogenic variation NM_001128177.1(THRβ):c.1034G>A (p.Gly345Asp) was detected after analysis. Conclusion. A diagnosis of RTH requires high clinical suspicion and a genetic mutation analysis should be requested in the case of clinical suspicion. In this way, unnecessary anti-thyroid treatment can be prevented.

Introduction. Irisin is a recently discovered novel adipomyokine that induces an increase in total body energy expenditure, improves insulin sensitivity and glucose tolerance. It has been shown that circulating levels of irisin are low in patients with obesity, diabetes mellitus and impaired glucose tolerance. However, the information about the level of circulating irisin in gestational diabetes mellitus (GDM) is controversial. Material and Methods. Serum irisin was measured by an ELISA in a longitudinal prospective cohort study in 221 women. There were 156 healthy pregnant and 65 women with GDM. Results. Circulating irisin levels were significantlly higher in the middle pregnancy compared with early pregnancy levels in healthy pregnant women and in women with GDM. Serum irisin levels were found to be lower in GDM compared to healthy pregnant women during first trimester but the difference was not observed throughout the pregnancy and it was comparable in middle pregnancy. There was a significant inverse correlation of BMI with serum irisin (r = -0.193, p = 0.004) and between HbA1c and mean glucose of OGTT with serum irisin (r =-0.377, p =0.0001) and (r = -0.147, p:0.03) in the early pregnancy of pregnant women repectively. Conclusions. The present study shows that serum irisin level increases throughout the gestational period from early to middle pregnancy in women with GDM, but there is no effect of irisin on the development of GDM.

Context. SARS-CoV-2 infection was declared a pandemic in 2020 and affected millions of people worldwide. Angiotensin-converting enzyme-2 receptors, through which coronavirus enters the cells of different organs, have been detected in the thyroid gland. The most common cause of thyrotoxicosis is Graves’ disease in which thyroid-receptors antibodies (TRAb) stimulate the TSH receptor, increasing thyroid hormone production and release. Case presentation. A 22-year-old woman had symptoms of palpitation, tremor, muscle weakness, anxiety and sleep disturbance. 3 weeks before the onset of these symptoms, the patient suffered from COVID-19, which lasted 14 days and was characterized by a course of moderate severity with fever up to 38˚C, general weakness without shortness of breath. The patient had no pre-existing thyroid problems. Her TSH was <0.01 mU/L, FT4, FT3 and TRAb were increased. Antithyroid drugs, glucocorticosteroids and β-blockers were prescribed. During 3 months of treatment doses of methimazole, methylprednisolone and bisoprolol were gradually reduced due to the improvement of the patient’s condition and thyroid tests normalization. Conclusions. COVID-19 infection can cause Graves’ disease and thyrotoxicosis. The onset of this disease after SARS-CoV-2 does not depend on the presence of preexisting thyroid pathology and requires the appointment of glucocortisteroids.

Background. Retinopathy is a common complication of diabetes and strongly related to the duration of the disease and the quality of its management. Despite this relationship, some studies have reported the prevalence of diabetic retinopathy at diagnosis to be 5-30%.\r\nAim. To investigate the prevalence of retinopathy in patients with newly diagnosed type 2 diabetes and its relation to some association factors in Isfahan, Iran.\r\nMethods. During 2001-2004, all newly diagnosed type 2 diabetics (n= 710) attending Isfahan Endocrine and Metabolism Research Center, were enrolled, by consecutive patient selection. Everybody accepted our invitation. The patients were examined by an internist and then by an ophthalmologist for retinopathy. Fasting plasma glucose, glycosylated hemoglobin, lipid profile, and 24-hour urinary albumin and creatinine concentrations were measured.\r\nResults. Of 710 patients, 286 were male. Mean age of the patients was 48.8(9.8) years (31-72 years) and median of diabetes duration was 6 months (0.5-12 months), respectively. Nine percent of patients (CI95%: 7-11) [(9.8% of men (CI95%: 6-13) and 8.5% of women (CI95%: 6-11)] had retinopathy (Odds ratio= 0.85, CI95%: 0.51-1.43, P= 0.5). In the final analysis using logistic regression test, body mass index (OR= 0.9, CI 95%: 0.8-1, P= 0.01), diastolic hypertension (OR= 3.9, CI 95%: 1.33-11.7, P= 0.01) and 24-hour urinary albumin concentration (OR= 1.005, CI 95%: 1-1.01, P= 0.01) were identified as association factors\r\nfor retinopathy.\r\nConclusions. Retinopathy was moderately prevalent in our patients.