The effect of therapeutic education program on quality of life among type 2 diabetic North-African patients: a randomized controlled trial.

INTRODUCTION: Type 2 Diabetes Mellitus (T2DM) is a chronic non-communicable disease with major impact on health in general and quality of life (QoL) in particular. The ultimate goal of all health interventions is to reduce the burden of this disease. AIM: To evaluate the effect of therapeutic education program on the QoL among patients with T2DM. METHODS: Between May 2021 and July 2022, 320 outpatients were enrolled in a randomized controlled trial in Sfax, Tunisia. The experimental group received the therapeutic education program, whereas the control group received only standard care. For data collection, the Arabic version of the Diabetes Quality of Life (DQoL-Arabic) questionnaire was used. RESULTS: In total, 263 patients completed the intervention, 132 in the experimental group and 131 in the control group. In terms of the main baseline characteristics, the two groups were comparable. After the intervention, there was a significant difference in all domains of QoL scores (median [interquartile]) between the experimental and control groups: satisfaction (3.14 [2.64-3.36] vs. 3.57 [3.43-3.71], p<0.001, respectively), impact (2.09 [1.91-2.36] vs. 2.45 [2.27 2.64], p<0.001, respectively) and worries (2.50 [2.25-2.75] vs. 3.00 [2.75 3.14], p<0.001, respectively). The QoL improves over time in the experimental group (3.01 [2.79-3.17] vs. 2.59 [2.21-2.80], p<0.001, respectively) and remains comparable in the control group (2.99 [2.81-3.14] vs. 3.01 [2.81-3.15], p=0.724, respectively). CONCLUSIONS: The benefits of implementing an educational program among patients with T2DM are observed in terms of all QoL domains.

Metabolic Disorders During Prolactinomas.

The metabolic profile during prolactinoma may be subject to significant changes. We aimed to describe the different metabolic aspects in patients monitored for prolactinoma and to study the correlations between the size of the prolactinoma and the metabolic parameters. We conducted a retrospective, descriptive, and analytical study of 77 cases of prolactinomas collected and monitored at the endocrinology and diabetology department of the Hedi Chaker Hospital in Sfax between 2000 and 2017. Our patients were divided into three groups according to the size of their prolactinomas. Statistical correlations were sought between tumor size and clinical and biological parameters. The mean age of our patients was 38.3 ± 14.2 years. They were divided into 51 women (66.2%) and 26 men (33.7%). Pituitary tumor syndrome was the most common circumstance of discovery in our population (62.3%). The clinical examination revealed an average waist circumference of 95.71 cm. Android fat distribution was observed in 25 women (49%) and 12 men (46.1%). A statistically significant positive correlation was objectified between waist circumference and tumor size (r = 0.29 and P = 0.019). The average body mass index was 28.08 kg/m2. Obesity was noted in 56 cases (72.7%). Glucose tolerance disorders and hypertriglyceridemia were also more evident each time prolactinoma size increased in contrast to the level of high-density lipoprotein cholesterol which decreased with adenoma size. Our study highlighted the metabolic and hormonal repercussions of prolactinomas. Metabolic syndrome was more common in patients with larger prolactinoma. These results should guide the initial assessment and therapeutic management of prolactin adenomas.

Diabetes Distress and Illness Perceptions in Tunisian Type 2 Diabetes Patients.

Purpose: Diabetes distress (DD) refers to the negative emotions and burden of living with diabetes. Illness perceptions are among the factors that can influence self-management and psychological distress in diabetics. This study aimed to determine the prevalence and the associated factors of DD in Tunisian patients with type 2 diabetes mellitus. We also studied the relationship between DD and illness perceptions in diabetics. Patients and Methods: This was a cross-sectional study conducted among individuals with type 2 diabetes, followed up at the outpatient endocrinology unit at the Hedi Chaker University Hospital, Tunisia. DD was assessed using the Diabetes Distress Scale (DDS-17). The Brief Illness Perception Questionnaire (Brief-IPQ) was used to assess diabetes illness perceptions. Multivariate logistic regression was used to determine independent factors associated with the presence of DD. Results: A total of 103 patients were recruited. The mean age was 59.31 (±10.83) years; 54.4% were female. In total, 70.9% had DD. Using regression analysis, we demonstrated that the illness perceptions of personal control, HbA1C, absence of comorbidities, lower age at diabetes diagnosis, and socioeconomic status were significantly associated with DD. Conclusion: This study sheds light on the high prevalence of DD among patients with type 2 diabetes in Tunisia. Illness perception-focused psychological intervention would be efficacious in reducing diabetes distress in patients with type 2 diabetes mellitus.

Diagnosis and management of pituitary apoplexy: a Tunisian data.

BACKGROUND: Pituitary apoplexy (PA) is defined as the hemorrhage or the infraction of a pituitary adenoma. Aiming to determine the epidemiological, clinical, paraclinical characteristics as well as management and outcomes of PA in our population, we conducted this cross-sectional study. METHODS: This cross-sectional study was conducted at the Department of Endocrinology of Hedi chaker university hospital, Sfax. Data was collected from medical charts of patients with pituitary apoplexy admitted in our department between 2000 and 2017. RESULTS: We included 44 patients with PA. Their mean age was 50 ± 12.6 years. Among them, 31.8% had a known pituitary adenoma, and it was in all cases a macroadenoma, predominantly a prolactin secreting tumor (42.8%). A triggering factor of PA was encountered in 31.8% of cases and it was mainly: head trauma, dopamine antagonists, and hypertension. The clinical presentation of PA encompassed headaches (84.1%), visual disturbances (75%), and neurological signs (40.9%). Gonadotropin deficiency was the most frequent form of hypopituitarism noted (59.1%), followed by corticotropin deficiency (52.3%), thyrotropin deficiency (47.7%), and somatotropin deficiency (2.3%). Hormonal assessment at PA onset, concluded that 23 had a secreting adenoma: 18 prolactinomas, 3 ACTH-secreting adenomas, and 2 GH-secreting adenomas. In the 21 remaining cases, the tumor was non-functioning (47.7%). Pituitary MRI was performed in 42 cases (95.5%), revealing infraction and or hemorrhage in the pituitary gland in 33 cases; a heterogenous signal or a fluid level within the adenoma, in nine cases. Urgent administration of intra venous hydrocortisone was required in 19 cases. Mannitol administration was mandatory in a patient who had severe intracranial hypertension. Surgical management of the PA was imperative in 24 patients (54.5%): 15 suffered from severe visual impairment, 4 had an intracranial hypertension, 2 cases demonstrated an impaired consciousness, 2 patients experienced a tumor enlargement and one case had a severe Cushing's disease. Operative complications found were rhinorrhea attributable to cerebral spinal fluid leakage, insipidus diabetes associated with rhinorrhea, isolated insipidus diabetes, and hydrocephalus in one case each. Long-term follow-up concluded that headaches persisted in five cases, owing to the tenacity of a macroprolactinoma regardless of cabergoline treatment in one case, the recurrence of an adenoma in two cases and its persistence despite the medical and the surgical treatment in two patients. Concerning the visual acuity defects, only two patients had persistent diminished visual acuity at long-term follow-up. Among 25 patients, 13 were diagnosed with definitive thyrotropin deficiency. Similarly, 14 patients had persistent corticotropin deficiency (CD). Additionally, CD was de novo diagnosed in two patients. Otherwise, gonadotropin deficiency prevailed in all cases. Persistent prolactin deficiency was seen in two patients. Disappearance of the pituitary tumor was encountered in 11 out of 24 cases at long-term follow-up. Overall, surgery was associated with better outcome than conservative management. Pituitary apoplexy is a challenging condition due to its variable course, its diagnosis difficulty and management, as gaps remain to determine the best approach to treat this condition. CONCLUSIONS: To conclude, pituitary apoplexy is a challenging condition due to its variable course, its diagnosis difficulty and management, as gaps remain to determine the best approach to treat this condition. Further studies are thus needed.

Insulinoma with equivocal imaging.

Summary: A 55-year-old patient was admitted to our department for the management of a repetitive alteration of consciousness. Biological investigation results were consistent with endogenous hyperinsulinemic hypoglycemia. Insulinoma was therefore suspected. Abdominal computed tomography and endoscopic ultrasound showed no obvious pancreatic mass.Somatostatin receptor scintigraphy showed abnormal radioactive uptake in both the pancreatic tail and the uncinate process. Contrariwise, abdominal magnetic resonance imaging showed a unique lesion in the pancreas tail. The patient was then proposed for pancreatic surgery. Both intraoperative manual palpation and intraoperative ultrasonography of the pancreas showed a single corporal lesion of 1.5 cm. No lesion was found in the uncinate process. After a left pancreatectomy, the lesion was histopathologically confirmed to be a well-differentiated neuroendocrine tumor. The symptoms of the patient resolved almost immediately following the surgery. The follow-up is one and a half years to date. Learning points: The exact preoperative localization of the pancreatic mass remains the most challenging part of insulinoma diagnostic workup. The radiologist's experience is the best warrantor to a precise localization of the tumor. 111In-DTPA-octreotide uptake in the pancreatic uncinate process may be physiological and its interpretation must, therefore, be vigilant. Manual palpation along with intraoperative ultrasonography is considered as the most effective method for the localization of insulinomas during open surgery.

Characteristics of adult-onset auto-immune type 1 diabetes.

BACKGROUND: Classically described as a disease of childhood and adolescence, diabetes mellitus type 1 (T1DM) can occur in adulthood. Adult-onset T1DM is poorly documented and is often misdiagnosed. This study aims to describe the epidemiological aspect of T1DM with adult-onset and detail its clinical, paraclinical, and therapeutic characteristics. MATERIALS AND METHODS: A 9-year retrospective longitudinal study (2011-2019) was conducted including adult patients (age >20 years) with confirmed diabetes and at least one of the auto-antibodies (auto-Abs) to glutamic-acid-decarboxylase (GAD), to islet-tyrosine-phosphatase 2 (IA2) or islet-cell-antibodies (ICA) positive. RESULTS: A total of 166 patients were included (sex-ratio M/F: 1.34; mean age: 28.6 years [20-56 years]). At the onset, 50.6% of patients presented with diabetic ketosis and 13.3% with diabetic ketoacidosis. Cardinal symptoms of diabetes were present in 30.7% of patients only at diagnosis, while the discovery was fortuitous in 5.4% of cases. 27.7% of patients developed an additional auto-immune disease mainly autoimmune thyroid disease. The risk of developing another AUTO-IMMUNE DISEASE was highest in females (p = 0.010) and increased with age (p = 0.011). GAD-Abs, IA2-Abs, and ICA were positive in 98.2%, 13.3%, and 17.4% of cases respectively. Only GAD-Abs were found positive in 73.1%. Upon diagnosis, 75.9% of patients were treated with insulin, while 24.1% of patients were initially put on oral anti-diabetic drugs before requiring insulin within an average of 7.42 months. CONCLUSIONS: Adult-onset T1DM has a different clinical course (slower onset, less abrupt symptoms, more insidious presentation, and more prolonged progression to insulin) that has to be known. Misdiagnosis of adult-onset T1DM can have serious consequences.

Case report: Management challenges of late diagnosed 17-alpha hydroxylase deficiency.

Herein we report the intriguing case of a 42-year-old woman presenting with grade three hypertension, severe hypokalemia and primary amenorrhea, which revealed to be the complete form of 17 alphahydroxylase deficiency. We also discuss the challenging therapeutic approach as well as the outcomes and the follow-up of this patient.

Molecular mechanisms underlying the defects of two novel mutations in the HSD17B3 gene found in the Tunisian population.

17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3) converts Δ4-androstene-3,17-dione (androstenedione) to testosterone. It is expressed almost exclusively in the testes and is essential for appropriate male sexual development. More than 70 mutations in the HSD17B3 gene that cause 17ß-HSD3 deficiency and result in 46,XY Disorders of Sex Development (46,XY DSD) have been reported. This study describes three novel Tunisian cases with mutations in HSD17B3. The first patient is homozygous for the previously reported mutation p.C206X. The inheritance of this mutation seemed to be independent of consanguineous marriage, which can be explained by its high frequency in the Tunisian population. The second patient has a novel splice site mutation in intron 6 at position c.490 -6 T > C. A splicing assay revealed a complete omission of exon 7 in the resulting HSD17B3 mRNA transcript. Skipping of exon 7 in HSD17B3 is predicted to cause a frame shift in exon 8 that affects the catalytic site and results in a truncation in exon 9, leading to an inactive enzyme. The third patient is homozygous for the novel missense mutation p.K202M, representing the first mutation identified in the catalytic tetrad of 17ß-HSD3. Site-directed mutagenesis and enzyme activity measurements revealed a completely abolished 17ß-HSD3 activity of the p.K202M mutant, despite unaffected protein expression, compared to the wild-type enzyme. Furthermore, the present study emphasizes the importance of genetic counselling, detabooization of 46,XY DSD, and a sensitization of the Tunisian population for the risks of consanguineous marriage.

The Impact of Exercise Training Intensity on Physiological Adaptations and Insulin Resistance in Women with Abdominal Obesity.

Abdominal obesity has emerged globally as a major public health issue due to its high prevalence and morbidity. The benefits of physical exercise among the obese population are well documented. However, the optimal exercise intensity for reducing body fat and preventing insulin resistance and metabolic disorders is still under debate. This study aimed to examine the effects of three different intensities of combined endurance and strength training programs on anthropometric variables, physiological and muscular adaptations, and insulin sensitivity. Forty-three obese young women (age 26.4 ± 4.7 years, BMI 33.1 ± 2.5 kg/m2) were randomly assigned to one of four groups: a control group (G0), a moderate-intensity training group (G50, exercising brisk walking at 50% heart rate reserve HRR), a high-intensity training group (G75, exercise jogging at 75% HRR), and an alternated-intensity training group (G50/75, exercise brisk-walking/jogging at 50−75% HRR) with additional strength training once a week for each group. Body composition, waist circumference (WC), fasting blood glucose, insulin sensitivity and resistance (Homa-IR), resting heart rate (RHR), 6-min walk distance (6MWD), 1-repetition maximum (1-RM), and time to exhaustion (TTE) at 45% and 75% maximal voluntary contraction (MVC) for both the flexor and extensor muscle groups of the knees, were recorded before and after three months of exercise training. All training groups showed significant decreases in body mass, BMI, total body fat, body fat percentage, WC, abdominal and visceral mass (p < 0.001), with a greater reduction of body mass and BMI in G75 (p < 0.05). Lean mass increased significantly only in G50/75 (p < 0.05). The insulin sensitivity and Homa-IR decreased in the three training groups (p < 0.01), with greater enhanced resistance in G50 compared to G75 and G50/75 (p < 0.05). In contrast, there were no pre-post changes in all groups for fasting blood glucose (p > 0.05). 1-RM and TTE of the knee flexor and extensor muscles were improved in the three groups (p < 0.01), with greater improvement in G50/75 for 1RM and G75 in most of the TTE parameters (p < 0.05). RHR decreased and 6MWD increased significantly in the three training groups (p < 0.01), with greater 6MWD improvement in G75 (p < 0.05). In conclusion, the three training intensities seem to generate benefits in terms of body composition, physiological and muscular adaptations, and insulin resistance. High training intensity resulted in greater improvements in body mass, BMI, and endurance and strength, whereas moderate training intensity resulted in greater improvements of insulin resistance and homo-IR. Following alternate-intensity training, greater improvements were observed in lean mass and maximal strength performance.

An unusual familial Xp22.12 microduplication including EIF1AX: A novel candidate dosage-sensitive gene for premature ovarian insufficiency.

We report on the results of array-CGH and Whole exome sequencing (WES) studies carried out in a Tunisian family with 46,XX premature ovarian insufficiency (POI). This study has led to the identification of a familial Xp22.12 tandem duplication with a size of 559.4 kb, encompassing only three OMIM genes (RPS6KA3, SH3KBP1and EIF1AX), and a new heterozygous variant in SPIDR gene: NM_001080394.3:c.1845_1853delTATAATTGA (p.Ile616_Asp618del) segregating with POI. Increased mRNA expression levels were detected for SH3KBP1 and EIF1AX, while a normal transcript level for RPS6KA3 was detected in the three affected family members, explaining the absence of intellectual disability (ID). To the best of our knowledge, this is the first duplication involving the Xp22.12 region, reported in a family without ID, but rather with secondary amenorrhea (SA) and female infertility. As EIF1AX is a regulatory gene escaping X-inactivation, which has an extreme dosage sensitivity and highly expressed in the ovary, we suggest that this gene might be a candidate gene for ovarian function. Homozygous nonsense pathogenic variants of SPIDR gene have been reported in familial cases in POI. It has been suggested that chromosomal instability associated with SPIDR molecular defects supports the role of SPIDR protein in double-stranded DNA damage repair in vivo in humans and its causal role in POI. In this family, the variant (p.Ile616_Asp618del), present in a heterozygous state, is located in the domain that interacts with BLM and might disrupt the BLM binding ability of SPIDR protein. These findings strengthen the hypothesis that the additional effect of this variant could lead to POI in this family. Although the work represents the first evidence that EIF1AX duplication might be responsible for POI through its over-expression, further functional studies are needed to clarify and prove EIF1AX involvement in POI phenotype.

Diagnostic value of miR-199a and miR-21 in the plasma of infertile women with dysregulated AMH levels.

This work aimed to explore the expression pattern of circulating miR-199a-3p, miR-21-5p and miR-let7i-3p in infertile women with dysregulated AMH levels. Quantitative real-time PCR was used to measure miR-199a-3p, miR-21-5p, and miR-let7i-3p expression levels in 60 plasma samples of infertile women with low or high AMH levels. Bioinformatic analyses for microRNAs predicting target genes and molecular pathways were performed according to gene ontology (GO) analysis and KEGG pathways. Only miR-199a-3p and miR-21-5p were significantly over and under-expressed, respectively, in the plasma samples of all infertile women with low or high AMH levels versus controls (p-value = 0.01). Furthermore, the diagnostic value miR-199a-3p yielded a receiver operating characteristic (ROC) curve with area under the curve (AUC) of 0.82 with a 95% CI [0.72-0.92] and an AUC of 0.81, for miR-21-5p, 95% CI [0.69-0.92]. The combined ROC curve of miR-21 and miR-199a provided an optimal combination with AUC = 0.98, 95% CI [0.96-1], and, a cut-off point (0.42) which provided 98% sensitivity and 87% specificity. In conclusion, circulating miR-199a-3p and miR-21-5p vary significantly whenever AMH levels of infertile women are disturbed and could potentially serve as non-invasive biomarkers in distinguishing infertile from fertile women.

The first concurrent detection of mitochondrial DNA m.3243A>G mutation, deletion, and depletion in a family with mitochondrial diabetes.

BACKGROUND: Mitochondrial diabetes (MD) is a rare monogenic form of diabetes and divided into type l and type 2. It is characterized by a strong familial clustering of diabetes with the presence of maternal transmission in conjunction with bilateral hearing impairment in most of the carriers. The most common form of MD is associated with the m.3243A>G mutation in the mitochondrial MT-TL1, but there are also association with a range of other point mutations, deletion, and depletion in mtDNA. METHODS: The mitochondrial genome anomalies were investigated in a family with clinical features of MD, which includes a proband presenting severe MD conditions including cardiomyopathy, retinopathy, and psychomotor retardation. RESULTS: By investigating the patient's blood leukocytes and skeletal muscle, we identified the m.3243A>G mutation in heteroplasmic state. This mutation was absent in the rest of the family members. In addition, our analysis revealed in the proband a large mtDNA heteroplasmic deletion (~1 kb) and a reduction in mtDNA copy number. CONCLUSION: Our study points out, for the first time, a severe phenotypic expression of the m.3243A>G point mutation in association with mtDNA deletion and depletion in MD.

A Rare Cause of Refractory Chronic Diarrhea and Cachexia: A Case Report.

VIPoma is an unusual neuroendocrine neoplasm that autonomously secretes VIP. It is associated with secretory diarrhea and electrolyte disturbances. Herein we report a case of a male patient, who was hospitalized in the Department of Endocrinology in Hedi Chaker Hospital, Sfax, Tunisia. He presented VIPoma syndrome, with hepatic metastases at diagnosis. He had a history of chronic, watery diarrhea. He was dehydrated with many electrolytic disorders as hypokalemia, hyponatremia and metabolic acidosis. Abdominal CT scan showed a heterogeneous mass in the pancreatic head with multiple hepatic lesions. A high VIP hormone level was found. Histological study of a liver biopsy revealed hepatic metastases of neuroendocrine carcinoma. The patient received analogues of somatostatin and systemic chemotherapy, with a transient symptomatic relief. Sadly the patient was lost to follow-up.

High Diagnostic Yield of Targeted Next-Generation Sequencing in a Cohort of Patients With Congenital Hypothyroidism Due to Dyshormonogenesis.

Objective: To elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS). Study design: We studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature. Results: TNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis. Conclusions: In a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.

[Insulinoma associated with adrenocorticotropic insufficiency and hypergonadotropic hypogonadism: a case study]. / Insulinome associé à une insuffisance corticotrope et un hypogonadisme hypergondadotrope: à propos d'une observation.

Pancreatic insulinoma is a rare, often benign, neuroendocrine tumor which may give rise to life-threatening consequences due to hypoglycemia-related accidents. Adrenal deficiency can also cause hypoglycemia. We report the case of a 68-year old patient hospitalized for recurrent hypoglycaemia. Tests were performed that showed endogenous hyperinsulinism, adrenocorticotropin deficiency and hypergonadotropic hypogonadism. The patient received hydrocortisone without improvement. Five years later topography showed insulinoma. This study highlights the clinical, biological, radiological and therapeutic features of insulinoma as well as laboratory test results and shows that insulinoma can cause adrenocorticotropic deficiency and peripheral hypogonadism.

Successful Treatment of Insulin Allergy with Desensitization Therapy: A Case Report and Literature Review.

Insulin therapy is an essential treatment for type 1 and uncontrolled type 2 diabetes mellitus (DM). Hypersensitivity reactions have been described since the first administration of insulin, the same as any other therapy. Despite being a rare situation nowadays, it requires careful intra-hospital monitoring and multidisciplinary management. Here, we present a case of a 57-year-old patient with type 2 DM, an average glycemic control, and both penicillin and insulin allergy. Heunderwent a desensitization protocol which allowed successfully dismiss him with intermediate-acting insulin.

Fahr's syndrome in Southern Tunisia: A broad spectrum of clinical and etiological features.

AIM: We describe the clinical and etiological profile of patients with Fahr's syndrome (FS). METHODS: Charts of sixteen patients diagnosed with FS between 1999 and 2014 were retrospectively assessed. RESULTS:   The mean age at diagnosis was 44.68 years (11-67 years). The most main presenting neurological features were seizures in 6 cases, headaches in 5 cases and parkinson's syndrome in 3 cases. Psychiatric disorders were observed in 2 patients including memory loss and iritability. Hypocalcemia clinical features were observed in 7 cases. The mean value of hypocalcemia was 1.69 mmol/l. Etiologies included idiopathic hypoparathyroidism in 4 patients, pseudohypoparathyroidism in 5 cases, secondary hypoparathyroidism, isolated hypovitaminosis D and cerebral radiotherapy in one case for each and Fahr's disease in 4 patients.  Oral calcium and vitamin D substitution were started in patients with parathyroid disturbances with favorable outcome. CONCLUSION: In this report, we propose to discuss the clinical manifestations of FS, its etiologies especially parathyroid disturbances and its therapeutic modalities.

Thyroid Hypoplasia in Congenital Hypothyroidism Associated with Thyroid Peroxidase Mutations.

BACKGROUND: Primary congenital hypothyroidism (CH) affects about 1:3000 newborns worldwide and is mainly caused by defects in thyroid gland development (thyroid dysgenesis [TD]) or hormone synthesis. A genetic cause is identified in <10% of TD patients. The aim was to identify novel candidate genes in patients with TD using next-generation sequencing tools. PATIENT FINDINGS: Whole exome sequencing was used to study two families: a consanguineous Tunisian family (one child with severe thyroid hypoplasia) and a French family (two newborn siblings, with a thyroid in situ that was not enlarged on ultrasound at diagnosis). Variants in candidate genes were filtered according to type of variation, frequency in public and in-house databases, in silico prediction tools, and inheritance mode. Unexpectedly, three different variants of the thyroid peroxidase (TPO) gene were identified. A homozygous missense mutation (c.875C>T, p.S292F) was found in the Tunisian patient with severe thyroid hypoplasia. The two French siblings were compound heterozygotes (c.387delC/c.2578G>A, p.N129Kfs*80/p.G860R) for TPO mutations. All three mutations have been previously described in patients with goitrous CH. In these patients, treatment was initiated immediately after diagnosis, and the effect, if any, of thyrotropin stimulation of these thyroids remains unclear. CONCLUSIONS: The first cases are reported of thyroid hypoplasia at diagnosis during the neonatal period in patients with CH and TPO mutations. These cases highlight the importance of screening for TPO mutations not only in goitrous CH, but also in normal or small-size thyroids, and they broaden the clinical spectrum of described phenotypes.

[Cardiovascular and metabolic impact of glucocorticoid substitution therapy in patients with Addison's disease]. / Répercussions métaboliques et cardiovasculaires de la substitution glucocorticoïde au cours de la maladie d'Addison.

Recent studies conducted in patients with Addison's disease (AD) highlighted that this disease, even after treatment, is a significant cause of morbi-mortality. This study aims to determine the cardiovascular and metabolic deleterious impact of long-course glucocorticoid substitution therapy. We conducted a retrospective study of 28 patients with treated Addison's disease evolving for more than 15 years. The average age of patients was 58, 53 years, with a female predominance (65%). The average follow-up period was 17, 87 years. Initial dose of hydrocortisone was 32, 5 mg/day (20.52 mg/m2) and 27, 9 mg/day (16,41mg/m2) at the time of the study. The prevalence of the metabolic syndrome (MS) in patients with AM was 35.71% after a period of treatment longer than 15 years. At the end of the follow-up period, 28.57% of patients were obese; 25% of patients had developed AH (arterial hypertension) and type 2 diabetes. The prevalence of dyslipidemia went from 3.57% to 42.85%. Only one patient had myocardial infarction at 25-year follow-up. Factors favoring the onset of MS in our study were history of disease and weight loss at the moment of diagnosis. Adjustment of substitution therapy is a challenge in patients with Addison's disease due to morbi-mortality associated with overdose. A regular follow-up and a personalized therapeutic approach are necessary to improve patients' prognosis.