M. Mnif

Analysis of skewed X-chromosome inactivation in females with rheumatoid arthritis and autoimmune thyroid diseases

IntroductionThe majority of autoimmune diseases such as rheumatoid arthritis (RA) and autoimmune thyroid diseases (AITDs) are characterized by a striking female predominance superimposed on a predisposing genetic background. The role of extremely skewed X-chromosome inactivation (XCI) has been questioned in the pathogenesis of several autoimmune diseases.MethodsWe examined XCI profiles of females affected with RA (n = 106), AITDs (n = 145) and age-matched healthy women (n = 257). XCI analysis was performed by enzymatic digestion of DNA with a methylation sensitive enzyme (HpaII) followed by PCR of a polymorphic CAG repeat in the androgen receptor (AR) gene. The XCI pattern was classified as skewed when 80% or more of the cells preferentially inactivated the same X-chromosome.ResultsSkewed XCI was observed in 26 of the 76 informative RA patients (34.2%), 26 of the 100 informative AITDs patients (26%), and 19 of the 170 informative controls (11.2%) (P < 0.0001; P = 0.0015, respectively). More importantly, extremely skewed XCI, defined as > 90% inactivation of one allele, was present in 17 RA patients (22.4%), 14 AITDs patients (14.0%), and in only seven controls (4.1%, P < 0.0001; P = 0.0034, respectively). Stratifying RA patients according to laboratory profiles (rheumatoid factor and anti-citrullinated protein antibodies), clinical manifestations (erosive disease and nodules) and the presence of others autoimmune diseases did not reveal any statistical significance (P > 0.05).ConclusionsThese results suggest a possible role for XCI mosaicism in the pathogenesis of RA and AITDs and may in part explain the female preponderance of these diseases.

Adrenal Diseases During Pregnancy: Pathophysiology, Diagnosis and Management Strategies

Abstract:Adrenal diseases—including disorders such as Cushing’s syndrome, Addison’s disease, pheochromocytoma, primary hyperaldosteronism and congenital adrenal hyperplasia—are relatively rare in pregnancy, but a timely diagnosis and proper treatment are critical because these disorders can cause maternal and fetal morbidity and mortality. Making the diagnosis of adrenal disorders in pregnancy is challenging as symptoms associated with pregnancy are also seen in adrenal diseases. In addition, pregnancy is marked by several endocrine changes, including activation of the renin-angiotensin-aldosterone system and the hypothalamic-pituitary-adrenal axis. The aim of this article was to review the pathophysiology, clinical manifestation, diagnosis and management of various adrenal disorders during pregnancy.

Complicated urinary tract infections associated with diabetes mellitus: Pathogenesis, diagnosis and management

Diabetes mellitus has a number of long-term effects on the genitourinary system. These effects predispose to bacterial urinary tract infections (UTIs) in the patient with diabetes mellitus. Complicated UTIs are also common and potentially life-threatening conditions. They include emphysematous pyelonephritis, emphysematous pyelitis/cystitis, xanthogranulomatous pyelonephritis, renal/perirenal abscess, and renal papillary necrosis. Improved outcomes of these entities may be achieved by early diagnosis, knowledge of common predisposing factors, appropriate clinical and radiological assessment, and prompt management. Herein we review complicated UTIs associated with diabetes mellitus in terms of pathogenesis, clinical manifestations, radiological features, and current management options.

The heteroplasmic m.14709T>C mutation in the tRNAGlu gene in two Tunisian families with mitochondrial diabetes

UNLABELLED Diabetes mellitus (DM) is a heterogeneous disorder characterized by the presence of chronic hyperglycemia. Genetic factors play an important role in the development of this disorder, and several studies reported mutations in nuclear genes implicated in the insulin function. Besides, DM can be maternally transmitted in some families, possibly due to the maternal mitochondrial inheritance. In fact, mitochondrial genes may be plausible causative agents for diabetes, since mitochondrial oxidative phosphorylation plays an important role in glucose-stimulated insulin secretion from beta cells. MATERIALS AND METHODS In this report, we screened two Tunisian families with mitochondrial diabetes for the m.3243A>G and the m.14709T>C mutations, respectively, in the tRNA(Leu(UUR)) and the tRNA(Glu) genes. RESULTS The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the sequence-specific primers by polymerase chain reaction (SSP-PCR) analysis in the leucocytes and the buccal mucosa in the members of the two families showed the absence of the m.3243A>G mutation and the presence of the heteroplasmic m.14709T>C mutation in the tRNA(Glu) gene in the two tested tissues. CONCLUSIONS We conclude that the m.14709T>C mutation in the tRNA(Glu) gene could be a cause of mitochondrial diabetes in Tunisian affected families. In addition, the heteroplasmic loads correlated with the severity and the onset of mitochondrial diabetes in one family but not in the other, suggesting the presence of environmental factors or nuclear modifier genes.

Long-Term Outcome of Patients With Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

Introduction:Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder affecting adrenal steroid synthesis. In this study, the authors aim to evaluate the impact of CAH due to 21-hydroxylase deficiency on final height (FH), bone health, cardiometabolic risk, fertility, neurocognition and quality of life in a hospital-based sample from Tunisia. Methods:Twenty-six patients (11 males and 15 females; mean age: 27.4 ± 8.2 years) were recruited. Results:Mean FH was 159.5 ± 9.7 cm. Twenty-one patients (80.7%) had a FH below the target height. Ten patients (38.4%) exhibited bone demineralization. Eight patients (30.7%) had obesity. Lipid profile alterations and carbohydrate metabolism disorders were detected in 10 (38.4%) and 5 (19.2%) patients, respectively. Seven patients (27%) had insulin resistance. Ambulatory blood pressure monitoring showed abnormalities in 6 patients (23%). Increased carotid intima-media thickness was found in 14 patients (53.8%). Inhibin B level was decreased in 4 male patients. Semen analysis showed abnormalities in 4 of 10 patients. Testicular tumors were detected in 6 of 11 patients. Anti-Müllerian hormone level was reduced in 4 female patients. Six patients showed poly-cystic ovary syndrome. Brain magnetic resonance imaging showed abnormalities in 11 patients (42.3%). Quality of life was reduced in 14 of 22 patients (63.6%). Many of the suboptimal outcomes appeared to be related to poor adherence to medication schedules, some to overtreatment. Conclusion:CAH patients have a number of issues due to the disease or its treatment. Regular follow-up, early lifestyle interventions, bone health assessment, testicular ultrasound and psychological management are needed.

The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy

Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patients skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions.

Two missense mutations in SLC26A4 gene: a molecular and functional study.

Ben Rebeh I, Yoshimi N, Hadj‐Kacem H, Yanohco S, Hammami B, Mnif M, Araki M, Ghorbel A, Ayadi H, Masmoudi S and Miyazaki H. Two missense mutations in SLC26A4 gene: a molecular and functional study.

A maternally inherited diabetes and deafness patient with the 12S rRNA m.1555A>G and the ND1 m.3308T>C mutations associated with multiple mitochondrial deletions

Maternally inherited diabetes and deafness (MIDD) is a mitochondrial syndrome characterized by the onset of sensorineural hearing loss and diabetes in adults. Some patients may have other additional clinical features common in mitochondrial disorders such as pigmentary retinopathy, ptosis, cardiomyopathy, myopathy and renal affections. We report a 40-year-old Tunisian patient presenting maternally inherited type 2 diabetes and deafness (MIDD). A molecular genetic analysis was conducted in the patient and his twin sister, but no reported mutations in the tRNA(Leu(UUR)) and tRNA(Glu) genes were found, especially the two mitochondrial m.3243A>G and the m.14709T>C mutations in muscle and blood leukocytes. The results showed the presence of the mitochondrial NADH deshydrogenase 1 (ND1) homoplasmic m.3308T>C mutation the 2 tested tissues (blood leukocytes and skeletal muscle) of the proband and in the patients sister blood leukocytes. In addition, we identified the mitochondrial 12S rRNA m.1555A>G mutation in muscle and blood leukocytes. The Long-range PCR amplification revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patients skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of MIDD in whom we detected the 12S rRNA m.1555A>G and the ND1 m.3308T>C mutations with mitochondrial multiple deletions.

Hyperparathyroidism-jaw tumor syndrome: a case report.

We report the clinical and genetic findings in a 23-year-old woman with hyperparathyroidism-jaw tumor syndrome (HPT-JT). The patient had a family history of primary hyperparathyroidism (PHPT) and uterine fibroma in her mother. The patient presented muscle weakness. The diagnosis of PHPT was confirmed by an elevated parathyroid hormone level above 1450 pg/ml with hypercalcemia and hypercalciuria. X-ray radiographies showed a radiolucent lesion in the right body of the mandible. Bilateral neck exploration was performed. An inferior right parathyroidectomy, a left thyroid lobectomy with isthmectomy and thymectomy were carried out. Histopathological examination of the specimen showed a diffuse hyperplasia of the parathyroid principal cells. The association of PHPT with a right jaw tumor and uterine fibroma suggested the diagnosis of HPT-JT syndrome. Mutation screening of HRPT2 gene was carried out and identified a germline mutation, consisting in a base deletion in exon 1, 85delG, inducing a frameshift. The diagnosis of HPT-JT syndrome is clinically important because of its hereditary component and its high risk of parathyroid malignancy, making a genetic inquiry necessary.

A Novel Nonsense Mutation in HSD17B3 Gene in a Tunisian Patient with Sexual Ambiguity

INTRODUCTION 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) isoenzyme is present almost exclusively in the testes and converts delta 4 androstenedione to testosterone. Mutations in the HSD17B3 gene cause HSD17B3 deficiency and result in 46,XY Disorders of Sex Development (46,XY DSD). AIM This study aimed to present the clinical and biochemical features of a Tunisian patient who presented a sexual ambiguity orienting to HSD17B3 deficiency and to search for a mutation in the HSD17B3 gene by DNA sequencing. METHODS Polymerase chain reaction (PCR) amplification and subsequent sequencing of all the coding exons of HSD17B3 gene were performed on genomic DNA from the patient, her family, and 50 controls. RESULTS Genetic mutation analysis of the HSD17B3 gene revealed the presence of a novel homozygous nonsense mutation in the exon 9 (c.618 C>A) leading to the substitution p.C206X. The mutation p.C206X in the coding exons supports the hypothesis of HSD17B3 deficiency in our patient. CONCLUSION The patient described in this study represented a new case of a rare form of 46,XY DSD, associated to a novel gene mutation of HSD17B3 gene. The screening of this mutation is useful for confirming the diagnosis of HSD17B3 deficiency and for prenatal diagnosis.