[Venous thrombosis, unrecognized complication of DRESS]. / Thrombose veineuse, complication méconnue du DRESS.

BACKGROUND: DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) is a rare syndrome triggered by an immunological reaction to certain drugs and which may be life-threatening as a result of the onset of severe organ involvement. It is characterised by a long period from the time of drug therapy to the onset of actual signs. Herein, we report the case of 42-year-old female patient who developed DRESS one month after beginning allopurinol treatment. PATIENTS AND METHODS: A 42-year-old woman was hospitalised for febrile exanthema with facial oedema, polyadenopathy, mononucleosis syndrome, major hypereosinophilia and hepatic cytolysis. A diagnosis was made of DRESS with a RegiSCAR score of 5. The implicated drug was allopurinol, which had been initiated one month earlier. HHV-6 IgM serology was positive. Two days after the start of systemic corticosteroids, the patient developed thrombosis of the internal jugular vein. Other than major hypereosinophilia, no other factors favouring thrombosis were detected. A favourable outcome was achieved under effective anticoagulants and corticosteroids. DISCUSSION: They have been rare reports of venous thrombosis during DRESS. Hypereosinophilia can be involved in the onset of this condition. Prophylaxis with systemic anticoagulants may be necessary in DRESS involving major hypereosinophilia.

Unusual association of turner syndrome and hypopituitarism in a Tunisian family.

PURPOSE OF THE STUDY: Familial occurrence of either Turner syndrome or hypopituitarism is very rare. Particularly, their association is an uncommon finding. In this context, we describe for the first time 4 sisters with Turner syndrome, hypopituitarism was reported in three among them. PATIENTS AND METHODS: Our cohort consists of four Tunisian adult sisters belonging to a consanguineous family. Biochemical analysis, resonance magnetic imaging and cytogenetic analyses were performed. RESULTS: Turner syndrome was diagnosed at the ages of 14, 17, 31 and 43 years in cases 1, 2, 3 and 4 respectively. They suffered from short stature, dysmorphic syndrome and/or delayed puberty. Interestingly, 3 among them showed also hypopituitarism, hypogonadotrophic hypogonadism and central hypothyroidism. Somatotropic insufficiency was proven in one case. Pituitary MRI has shown an empty sella turcica with hypoplastic pituitary gland in three cases. Their karyotypes were compatible with 45X in one case, 45X/46XX in the second and 45X/46XX/47XXY with x label in two cases. CONCLUSION: Hence, the presence of these familial cases of TS must evoke new etiopathogenetic arguments. Coincidence of hypopituitarism in this family, might suggest common genetic background for the two diseases. This particular family would be a precious tool for an extensive molecular analysis. More attention should be given to other family's members mainly in the presence of delayed puberty and sterility in other members.

A mitochondrial implication in a Tunisian patient with Friedreich's ataxia-like.

Genes encoding the DNA helicase TWINKLE (C10orf2) or the two subunits of mtDNA polymerase γ (POLγ) (POLG1 and POLG2) have a direct effect on the mitochondrial DNA replication machinery and were reported in many mitochondrial disorders. Friedreich's ataxia (FRDA) is the common cause of ataxia often associated with the expansion of a GAA repeat in intron 1 of the frataxin gene (FXN). Mitochondrial DNA could be considered as a candidate modifier factor for FRDA disease, since mitochondrial oxidative stress is thought to be involved in the pathogenesis of this disease. We screened the FXN, POLG1 and C10orf2 genes in a Tunisian patient with clinical features of Friedreich's ataxia-like. The results showed the absence of the expansion of a GAA triplet repeat in intron 1 of the FXN gene. Besides, the sequencing of all the exons and their flanking regions of the FXN, POLG1 and C10orf2 genes revealed the presence of intronic polymorphisms. In addition, screening of the mtDNA revealed the presence of several mitochondrial known variations and the absence of mitochondrial deletions in this patient. The detected m.16187C>T and the m.16189T>C change the order of the homopolymeric tract of cytosines between 16184 and 16193 in the mitochondrial D-loop and could lead to a mitochondrial dysfunction by inhibiting replication and affecting protein involved in the replication process of the mtDNA which could be responsible for the clinical features of Friedreich ataxia observed in the studied patient.

Screening of SLC26A4 gene in autoimmune thyroid diseases.

The Pendred syndrome (PS) gene, SLC26A4, was involved in the genetic susceptibility of autoimmune thyroid disease (AITD) in Tunisian population. Recently, functional assays have shown a differential expression of SLC26A4 gene between Graves' disease (GD) and Hashimoto's thyroiditis (HT). Here, by the mean of DHPLC and HRM, we explored the 21 exons and their flanking intronic sequences of 128 patients affected with GD (n = 64) or HT (n = 64). The pathogenic effect of identified variations on splice was investigated using the web server HSF. Eighteen allelic variations were identified and ranged on missense, sens and splice variations. Nine identified variations (c.-66C>G, c.898A>C, c.1002-9A>C, c.1061T>C, c.1544 + 9G>T, c.1545-5T>G, c.1790T>C, c.1826T>G, c.2139T>G) were previously reported in hearing impairment studies. Forty-seven per cent (30/64) of GD patients and 37,5% (24/64) of HT patients present at least one variant in the explored sequences. Moreover, the analysis of the variant distribution between HT (9 (5'UTR), 12 exonic and 13 intronic) and GD (18 (5'UTR), 13 exonic and 5 intronic) patients showed a significant difference (χ² = 6.54, 2df, P = 0.03). Interestingly, missense changes (I300L, p.M283I, F354S and p.L597S) affected conserved residues of pendrin. On the other hand, the HSF analyses ascertain that some variants identified in HT disease are predicted to have a pathogenic effect on splice. In conclusion, our analysis of SLC26A4 sequence variations suggested a distinct genetics basis between HT and GD patients, which should be confirmed on a large cohort.

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

Mutations in the SLC26A4 gene encoding pendrin, an anion transporter, are responsible for non-syndromic hearing loss (HL) (DFNB4) and Pendred syndrome (PS). PS is a genetic disorder that causes early HL and affects the thyroid gland. Here, we report eight Tunisian families affected with profound HL. Clinical investigations revealed goiter in few patients. Genotyping using microsatellite makers showed linkage to SLC26A4, and missense mutations p.L445W and p.M147T were identified by sequencing and polymerase chain reaction-restriction fragment length polymorphism. The p.L445W mutation segregated in seven families and haplotype analysis suggested its founder effect. In order to understand the molecular pathogenic mechanisms of p.L445W and p.M147T mutations, SLC26A4 wild-type and mutant cDNA constructs were transiently expressed in COS7 cells and several human cell lines including Thyroid 8305C cells. Reverse transcription-PCR, western blot and immunofluorescence demonstrated that these two mutations abolished complex glycosylation of pendrin and prevented its targeting to the plasma membrane.

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.

[Papillary carcinoma arising from dyshormonogenetic goiter]. / Cancer papillaire sur goitre dyshormonogénétique.

INTRODUCTION: Dyshormonogenetic goiter is a genetically determined thyroid hyperplasia due to an enzyme defect in thyroid-hormone synthesis. Malignant transformation is one of the most serious complications, rarely reported in the literature. OBSERVATION: We report a new case of a 13-year-old boy with goitrous hypothyroidism who consulted for a voluminous goiter. Total thyroidectomy was performed. Histopathological examination revealed multiple foci of papillary carcinoma with a lymph node metastasis. CONCLUSION: Dyshormonogenetic goiter is a rare entity, representing one of the causes of congenital hypothyroidism. It is morphologically characterized by architectural and cellular pleomorphism that may mimic thyroid malignancy and cause difficulties in differential diagnosis.

[Predisposition to autoimmune thyroid diseases within a Tunisian multiplex family]. / Prédisposition aux maladies auto-immunes thyroïdiennes au sein d'une famille tunisienne multiplexe.

The autoimmune thyroid diseases (AITDs) are multifactorial diseases which result from interplays between predisposing genes and triggering environmental factors. In order to study the genetic susceptibility factors to AITDs, we have followed up 115 control members belonging to a large Tunisian family with a high prevalence of AITDs (Akr family) during 15 years between 1990 to 2005. The follow-up of these control members have showed that 13 subjects (11.3%) developed AITDs (G2). The Hashimoto thyroiditis was the most frequently seen in 77% of the cases, whereas the Graves's disease was present in 23% of the cases. One hundred and two members remained controls (G1). High female predominance was noted in the two groups. The mean age of the G1 subjects group was slightly higher than that of G2. The prevalence of positive antithyroglobulin antibody (TgAb) and antithyroperoxydase antibody (TPOAb) was more frequent in G2 group (P=0.27 and P=0.23) respectively. The HLA haplotypes was realized in 42% of control members. The most frequent HLA haplotypes that were found were B37, DRB11 and A1. HLA B37 and DRB11 were significantly more frequent for the patients of G2 (P=0.0001 and P=0.034) respectively. Our study confirms the contribution of the genetic factors in the development of AITDs in 'Akr' family and suggested that the members of this family share the same genetic inheritance.

[Paradoxal growth hormone and cortisol response to hypoglycemia caused by endogenous hyperinsulinemia: a case report]. / Inhibition paradoxale de la réponse somatotrope et corticotrope à l'hypoglycémie par hyperinsulinisme endogène: à propos d'une observation.

Growth hormone (GH) together with cortisol are two important counter-regulatory hormones maintaining normal glycemia. Hyperinsulinemic hypoglycemia is a disorder of this counter-regulation described in neonates. We report here a rare case of reversible dissociated hypopituitarism secondary to an insulinoma in a 38-year-old man referred for investigation of hypoglycemic episodes. Hormonal investigations were in favour of dissociated anterior pituitary failure, with growth hormone and corticotroph deficiency. The hypothalamic-pituitary MRI was normal. The fasting test argued in favour of a hyperinsulinemic hypoglycemia. The abdominal scan and the endoscopic ultrasound showed a mass within the tail of the pancreas. Distal pancreatectomy was performed. Histology disclosed an insulinoma. On follow-up, no hypoglycemic episodes recurred and cortisol and GH response to induced hypoglycemia was normal. Our clinical case shows that hyperinsulinemia and hypoglycemia in patients with insulinoma can give rise to functional growth hormone and corticotrophin deficiency. The pathophysiological mechanism of this defective counter-regulation remains to be clarified; some studies suggest it could be related to hyperinsulinemia-induced decreased in CRF secretion and GHRH pulse.

[Rare complication of diabetic acidoketosis: the pneumomediastinum]. / Complication rare de l'acidocétose diabétique: le pneumomédiastin.

Pneumomediastinum is a rare condition with an incidence of 1/33,000. It can be a rare complication of diabetic acidoketosis. We present the cases of two diabetic patients and review the literature, focusing our analysis on the interrelationships between these two diseases. Both patients were young subjects, a 21-year-old woman and an 18-year-old man with type 1 diabetes who were admitted for acidoketosis. Clinically, the patients presented the cardinal signs of diabetes and a flu-like syndrome associated with dyspnea and chest pain. Physical examination revealed a poor general health status, tachycardia and polymnea, as well as a painful diffuse tumefaction of the neck with subcutaneous emphysema. Blood tests disclosed elevated glycemia and urine was positive for acetone. The diagnosis of severe metabolic acidosis was retained. The chest x-ray demonstrated the subcutaneous emphysema and air in the anterior mediastinum. On the computed tomography scan obtained in the second patient, the heart was silhouetted with a hyperlucent zone laterally. Treatment consisted in strict bed rest with oxygen therapy, fluid replacement, insulin and heparin. The pneumomediastinum resolved in both patients within three days on average. The causal effect of diabetic acidoketosis in the development of pneumomediastinum in our two patients was retained after ruling out all other potential causes, including chest trauma and asthma.

[Epidemiologic study of autoimmune thyroid disease in south Tunisia]. / Etude épidémiologique des maladies autoimmunes thyroïdiennes dans le sud tunisien.

In order to study incidence and prevalence of autoimmune thyroid diseases (AITDs), we studied a retrospective cohort of 1,079 patients explored in the department of Endocrinology of Sfax (south of Tunisia). The overall incidence of AITDs was 9.9%. Mean age was 39.6+15 years; sex ratio 5 F/1M. Graves' disease was the most frequent (45%). Atrophic thyroiditis was present in 32.2% of patients and Hashimoto's thyroiditis in 22.8%. The incidence of AITDs increased from 1990 to 2000 and by 2003 it had fallen to 67 cases per year. TPO antibody was present in two-thirds of patients with Hashimoto thyroiditis, and half of those with atrophic thyroiditis. TG antibodies were less frequent (one-third of patients). Association with other autoimmune diseases was noted in 6.3% of patients: type I diabetes mellitus, adrenal insufficiency and vitiligo. Statistic analysis did not disclose any association between autoantibody levels and thyroid dysfunction. There was an association between TG antibody and TSH levels among patients with Graves' disease and between TG antibody level and age in atrophic thyroiditis patients (p<0.05); a correlation was also noted between these antibodies and other autoimmune diseases (p=0.05). It is difficult to assess the frequency of ATD in the clinical setting. Characteristic features of AITDs in patients seen in south Tunisia were found to be similar to those described in the literature. Other more large-scale representative studies would be useful to establish the epidemiology of AITDs in Tunisia.

[MRI pituitary stalk abnormalities: etiology aspects in 11 patients]. / Anomalies de la tige pituitaire à l'IRM: aspects étiologiques à propos de 11 cas.

Newer techniques of magnetic resonance imaging (MRI) describe more accurately pituitary stalk abnormalities such as infections, infiltrative lesions and tumors. In absence of all the above mentioned etiological factors, genetics defects are suspected, mainly when other malformations are equally present. We attempt to show through 11 observations the variability of pathologies involving the pituitary stalk with their respective clinical and radiological features and associated endocrine abnormalities. This is a retrospective study of 7 men (67%) and 4 women (33%), mean age of 28 year (range: 15 to 53) in whom pituitary MRI was performed for hypopituitarism, diabetes insipidus or hyperprolactinemia. Three patients had brain MRI for an extra-pituitary condition. The pituitary MRI showed a stalk section in 3 cases (27%), atrophy in 1 case and thickening in 7 cases (67%). The pituitary stalk anomaly was associated with hyperprolactinemia in 3 cases (27%), central diabetes insipidus in 4 cases (36%), growth hormone deficiency in 4 cases (36%), adrenal insufficiency in 5 cases (45%), hypogonadism in 5 cases (45%) and hypothyroidism in one case (9%). Established diagnoses were: sellar metastasis in 2 cases (18%), Langerhans' histocytosis, tuberculosis and autoimmune hypophysitis respectively in 3 cases (9%). In 6 cases (54%), no clear etiology was found. Given the multitude of pituitary stalk pathologies, a detailed etiologic inquiry must be performed in order to detect elements able to reclassify an initially idiopathic disorder.

[Myasthenia gravis and hyperthyroidism: two cases]. / Myasthénie et hyperthyroïdie: à propos de deux observations.

It is well known that hyperthyroidism occurs in approximately 2 to 17.5% of patients with myasthenia gravis. Hyperthyroidism may influence the clinical course of myasthenia gravis. We report the cases of two patients, a 53-year-old man and an 18-year-old woman, who had both severe myasthenia gravis and hyperthyroidism due to Graves' disease. Myasthenia gravis affected in particular facio-ocular areas with diffuse myopathy and signs of neuromuscular block on the electromyogram. In one patient, the diagnosis of thyroid disease was made three months before the diagnosis of myasthenia gravis while in the other, thyroid disease was recognized four months after myasthenia gravis. Myasthenia gravis worsened after the development of hyperthyroidism in the second patient. Both patients were given anti-cholinesterase drugs. One underwent thymectomy. Radioiodine used for the treatment of hyperthyroidism improved the symptoms of myasthenia gravis in the first patient. The association of myasthenia gravis and hyperthyroidism is more than a coincidence; our cases illustrate the difficult diagnosis and management of these diseases. Clinicians should look for myasthenia gravis in hyperthyroid patients and vice versa, especially when symptoms of myasthenia gravis or hyperthyroidism worsen.

[Feminizing testicular syndrome with multiple hamartomas and bilateral paratesticular leiomyomas]. / Syndrome du testicule féminisant associé à des hamartomes multiples et à des léiomyomes paratesticulaires bilatéraux.

INTRODUCTION: Complete androgen insensitivity syndrome or testicular feminization syndrome (TF) is the most common form of male pseudohermaphrodism, caused by a failure of androgen receptor binding. Patient with male genotype 46 XY, has a female morphotype with well developed external sexual organs. EXEGESIS: - We report the case of a 29 year-old girl with a TF syndrome discovered during the exploration of a primary amenorrhoea. Bilateral orchidectomy was performed. The testis were immature; they showed bilateral leiomyoma of the tunica albuginea and multiple hamartomas on the right side. CONCLUSION: Benign tumors are developped in 80% of cases of TF and they are generally hamartomatous nodules of testis. Association of paratesticular leiomyoma to synchronous hamartoma has never been described, its histogenesis is discussed.

[Association of distal tubular acidosis, Hashimoto's thyroiditis and Gougerot-Sjögren's syndrome]. / Association d'une acidose tubulaire distale, d'une thyroïdite de Hashimoto et d'un syndrome de Gougerot-Sjögren.

INTRODUCTION: Distal tubular acidosis is associated with auto-immune diseases not specific to organ. The coexistence of distal tubular acidosis and auto-immune thyroid affection is very rare. OBSERVATION: A 36-year-old woman exhibiting primary hypothyroidism, Gougerot-Sjögren's syndrome and hypergammaglobulinemia, presented distal tubular acidosis revealed by severe hypokaliemia and complicated by quadriplegia and circulatory arrest. Correcting the thyroid defect did not appear to influence the progression of acidosis. COMMENTS: Based on this observation, one can discuss the pathogenesis of distal tubular acidosis during auto-immune diseases (hypothyroidism, Gougerot-Sjögren's syndrome and monoclonal hypergammaglobulinemia) and its impact on therapy.

[Hypothyroidism after external radiotherapy. Fifteen cases]. / Hypothyroïdie après radiothérapie externe. A propos de 15 cas.

Hypothyroidism frequency is estimated to be between 10 and 45% after radiotherapy alone, and 40 to 67% after radiotherapy associated with thyroidectomy. This hypothyroidism is infraclinical in 60% of the cases. Our study concerned 15 cases of hypothyroidism after external radiotherapy delivered between and 1991 and 1999. An irradiation of the cervical, cerebral and thorax regions was indicated for different types of cancers. Larynx carcinoma epidermoid was the most frequent cancer (seven cases); the radiation treatment used cobalt 60 with conventional fractionation, i.e., 2 Gy per treatment, five treatments a week. In nine cases, the hypothyroidism was discovered during a systematic examination; it was clinically evident in the six remaining cases. Hypothyroidism appeared after an irradiation dose average of 50 Gy (extremes 30-65 Gy). The average duration of the irradiation was about 7 weeks and the hypothyroidism appeared in a mean 22 months. In all cases, the substituting treatment was initiated with a favorable progression. Faced with the risk of hypothyroidism, it is necessary to check patients who have undergone external irradiation of the neck.

[Thyrotoxicosis hepatitis: a case report]. / Hépatite thyrotoxique.

Abnormal liver function in thyroid disorders may be secondary to thyrotoxicosis or to autoimmune injury to the liver. We report the case of a 36-year-old female who developed jaundice and pruritus with mild cholestasis and moderately elevated transaminase levels. The diagnosis of Graves' disease was made shortly thereafter. Laboratory findings were: alanine and aspartate aminotransferase 219 (IU/I (N: 9-50) and 102 IU/I (N: 10-15) respectively, alkaline phosphatase 336 IU/I (N: 40-135), bilirubin 24 micromol/I (N: 2-23), and gamma-glutamyl transpeptidase 232 IU/I (N: 9-43). Abdominal ultrasonography showed normal bile ducts; echocardiography ruled out heart failure; viral and autoimmune markers for hepatitis and cirrhosis were negative. Percutaneous liver biopsy showed moderate intrahepatic steatosis, anisokaryosis, lymphocyte infiltration in the portal areas, and Kupffer cell hyperplasia. Outcome was favorable after seven months of iodine therapy, confirming the diagnosis of thyrotoxicosis hepatitis.

[Post-traumatic hypopituitarism]. / Insuffisance antéhypophysaire post-traumatique.

BACKGROUND: Post-trauma hypopituitarism is a rare disease, accounting for only 3% of all cases of hypopituitarism reported in the literature. CASE REPORT: A 56-year old woman developed central diabetes insipidus immediately after severe cranio-facial trauma. Four years later, she suffered severe asthenia and hypoglycemia faintness. The diagnosis of isolated corticotrope insufficiency was retained. Magnetic resonance imaging evidenced an intrasellar arachnoidoceae with extinction of the posterior pituitary gland's spontaneous hypersignal. DISCUSSION: Most cases of post-trauma hypopituitarism occur after high-energy head trauma. Hypopituitarism exceptionally involves only one hormone, particularly growth hormone. The pathogenesis involves hypothalamic failure more often than pituitary gland failure.