Major circadian variations of glucose homeostasis in a patient with Rabson-Mendenhall syndrome and primary insulin resistance due to a mutation (Cys284-->Tyr) in the insulin receptor alpha-subunit.

We have performed clinical, in vitro biochemical, and genetic studies of a patient with severe insulin resistance, considerable growth restriction, and Rabson-Mendenhall syndrome (patient RM-3). The blood IGF-I level was undetectable in this patient, although the GH level was moderately decreased. During the postprandial period, glycemia, ketonuria, and plasma glucagon were very elevated despite high doses of exogenous insulin (glucose levels up to 30 mmol/L). In the postabsorptive state, blood glucose was normalized with small amounts of insulin; ketonuria, and glucagon levels were reduced but remained supranormal. Erythrocytes and cultured skin fibroblasts from the patient displayed a decrease in cell surface insulin receptors (IRs). The ability of physiologic concentrations of insulin to stimulate metabolic processes was altered in patient fibroblasts. Analysis of the IR gene by denaturing gradient gel electrophoresis and direct sequencing showed a homozygous missense mutation in exon 3, replacing Cys284 by Tyr in the alpha-subunit. In conclusion, marked primary insulin resistance was evidenced in patient cells as a result of a structural alteration in the IR alpha-subunit. The in vitro studies could not account alone for the in vivo metabolic alterations because glucose homeostasis varied considerably during the day in the patient.

[Presence of ophthalmopathy in all cases of Basedow disease?]. / Présence d'une ophtalmopathie dans tous les cas de maladie de Basedow?

In order to evaluate the frequency of ophthalmopathy in Graves' disease, we used a progression criterion, the variation of the eyeball protrusion, in a group of 145 patients initially examined at the time when thyrotoxicosis was diagnosed, before any treatment. By the means of a systematic measure of the protrusion with the Hertel's exophthalmometer at every consultation, we calculated for each patient the variation of protrusion (delta PO) between each annual mean value and the initial value. The mean survey was 6.4 years (range 1-18 years). For the whole group, we observed, after a slight increase (0.3 mm) during the first year, a progressive decrease, which reached about 4 mm at the 12th year and kept an afterwards (p < 0.01 at 3 years; p < 0.001 afterwards). The percentage of cases in which the decrease was significant related to the initial value (> or = 2 mm) rose regularly to reach 100% at the 16th year. These results seem to give evidence of the constant nature of ophthalmopathy at the initial stage of Graves' hyperthyroidism.

[Reliability of needle biopsy of solitary thyroid nodules in view of surgical indications]. / Fiabilité de la cytoponction des nodules thyroïdiens solitaires en vue des indications opératoires.

To evaluate the accuracy of fine-needle biopsy in the management of the solitary thyroid nodules, 320 biopsies without aspiration were performed in 212 patients, iteratively in 91 cases. Among the 212 initial biopsies, 93 smears were found presumably benign (43.9%), 6 malignant (2.8%), 49 benign implying cytologic control (23.1%), 24 suspicious with decision to operate (11.3%), 40 inadequate (18.9%). On 67 surgical indications (malignant or suspicious cytology, or clinical data), 59 operations were performed. The 11 diagnosed cancers (5.2% of the patients; 18.6% of the operations) correspond to six malignant and five suspicious cytologies at the first or second biopsy. On 145 cases without decision to operate, 125 were clinically surveyed, with sometimes another biopsy (mean survey: 27.6 months; range: 6-80 months), and it was never necessary to modify the initial expectancy attitude. Our results, rather similar to those related by most of the previous publications, confirm that the fine-needle biopsy is a reliable and effective means for the etiologic diagnosis of thyroid nodules and the indications for operative intervention. It spares many patients from a useless operation and is worthy to take a leading place in exploring these nodules.

[Late onset hyperandrogenism caused by 3-beta-hydroxysteroid dehydrogenase deficiency]. / Hyperandrogénie par déficit en 3 beta-hydroxystéroïde déshydrogénase à révélation tardive.

OBJECTIVES: Clinical manifestations of hyperandrogenism, including hirsutism and acne with or without dysmenorrhoea are well recognized in late onset hyperandrogenism due to deficiency in 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), yet the frequency of this deficiency in patients with post-puberty hirsutism is not well established. We therefore evaluated retrospectively this deficiency state in women who consulted our unit for manifestations suggestive of hyperandrogenism from 1990 to 1992. METHODS: We included 32 women with clinical manifestations of hyperandrogenism for whom a partial deficit in 3 beta-HSD could be searched for on the basis of hormone assays. Their mean age was 27.5 years (range 14 to 46) and the clinical manifestation was hirsutism in 21 cases, acne in 13, alopecia in 5 and dysmenorrhoea in 11. Diagnostic tests included adrenal stimulation with 0.25 mg beta 1-24 corticotrophin and immunoradioassay of plasma levels of 17-hydroxypregnenolone (17-OHPreg), 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHA) and cortisol (F). Pang's criteria for the diagnosis of partial deficiency in 3 beta-HSD were retained. We defined deficiency in 3 beta-HSD as certain when the 4 following criteria were present 60 minutes after stimulation: 17-OHPreg > 17.5 ng/ml; DHA > 20 mg/ml; 17-OHPreg/17-OHP > 9; 17-OHPreg/F.10(-3) > 53. Diagnosis was considered probable when only 3 criteria were met and was excluded in all other cases. RESULTS: Positive diagnosis of deficiency in 3 beta-hydroxysteroid dehydrogenase was made in 4 of the 32 patients and probable in 4 others. CONCLUSION: Based on our series of patients, late onset hyperandrogenism due to 3 beta-hydroxysteroid dehydrogenase deficiency would thus appear to be a relative frequent deficiency state. Since therapeutic measures can be taken, this deficiency should be carefully searched for in all young patients presenting with manifestations suggesting hyperandrogenism.

[Partial 3-beta-hydroxysteroid dehydrogenase deficiencies]. / Les déficits partiels en 3 bêta-hydroxystéroïde déshydrogénase.

An overview of the partial 3 beta-hydroxysteroid dehydrogenase deficiency is presented. The classical, congenital or early postnatal form is characterized by a salt-losing syndrome and/or ambiguous genitalia. The late-onset forms, only recognized for the last ten years and diagnosed with an increasing frequency, are to be systematically suspected in the presence of clinical hyperandrogenism with or without oligomenorrhea. This deficit, involved in both adrenal and gonadal tissues, seems to be transmitted by an autosomal recessive gene. An ovarian 3 beta-hydroxysteroid dehydrogenase deficit can be a primary cause of some cases of polycystic ovary syndrome and the relations with this affection are disputed. The increased ratios of delta 5 steroids/delta 4 steroids ensure the diagnostic conviction while the elevated ratio of 17-hydroxy-pregnenolone/17-hydroxyprogesterone and the normal ratio of 11-desoxycortisol/cortisol allow to eliminate the possibility of a 21-hydroxylase or 11 beta-hydroxylase deficiency, respectively. The treatment is based above all on the glucocorticoid utilization, which can lead to the return of menses and the ovulatory function, but the cutaneous symptoms of hyperandrogenism will be better controlled by cyproterone acetate out of situations of stress.

[Stress and immunity. The role of stress in auto-immunity of Basedow's disease]. / Stress et immunité. Place du stress dans l'auto-immunité de la maladie de Basedow.

The possible influence of stress on the immune system, long since suspected by the clinicians in their daily practice, was confirmed by human and animal studies, some of which being recent. Stress generally exert an immunosuppressive effect, but some of its characteristics (nature, duration, intensity, controllability of the stressing situation) can modulate this response, amplifying or reversing it. The concerned mechanisms are complex, involving the autonomic nervous system, the hypothalamo-pituitary complex and its target-glands through hormonal receptors born on immunocompetent cells. The immune system, conversely, is able to inform the brain about the interference of non cognitive stimuli (viruses, bacteria, tumors) through immunologic cell-derived immunohormones active in the central nervous system. Thus, close immune-neuroendocrine interactions exist, in order to cope with stress of all kinds. The stress can act in Graves' disease by depressing the T suppressive function via the hypothalamo-pituitary-adrenal axis, by eliciting the secretion of catecholamines capable of initiating an hyperthyroidism, by facilitating through its immunosuppressive action a viral infection that can have a part in initiating the auto-immune process.

Linkage analysis of hereditary thyroid carcinoma with and without pheochromocytoma.

The use of polymorphic DNA segments as markers for the gene for the multiple endocrine neoplasia (MEN) syndrome, type 2a, allows the identification of family members at high risk for developing medullary carcinoma of the thyroid and other tumors, especially pheochromocytoma. Several families have also been identified in which medullary thyroid carcinoma is inherited, but pheochromocytoma is not seen. We have analysed 18 families, 9 with MEN 2A and 9 with medullary carcinoma of the thyroid without pheochromocytoma, with probes specific for the pericentromeric region of chromosome 10 and conclude that the mutations for the two presentations are closely situated. Genetic heterogeneity of the susceptibility locus was not seen among this sample of 18 families. The genetic mutation for medullary carcinoma was in disequilibrium with the marker alleles of the two closely linked probes, IRBPH4 and MCK2. These data suggest that different mutant alleles of the same gene or closely linked mutations account for the variation in penetrance of pheochromocytoma in families with hereditary medullary thyroid carcinoma.

[Thorburn's posture. A sign of lesion of the cervical cord]. / La posture de Thorburn. Signe de lésion de la moelle cervicale.

In two infants hypertonia of the scapular muscles (C5-C6 level) associated with flacid palsy in other muscles of the upper limb produced an unusual posture. This one, described in adults by Thorburn, suggests a traumatic or ischaemic lesion of the cervical cord.

[Improvement of the prognosis of Basedow's disease by using high doses of carbimazole]. / Amélioration du pronostic de la maladie de Basedow par utilisation de fortes doses de carbimazole.

The influence of synthetic antithyroid drug dosage on the course of Graves' disease was evaluated by comparing two groups of matched patients treated with carbimazole. Thirty-seven patients received a rapidly degressive treatment (60 mg/day initially rapidly reduced without replacement thyroid hormone therapy), and 36 patients received a prolonged treatment in high doses (60 mg daily for 6 months with progressive reduction of dosage over 5 months and replacement therapy). There was a highly significant difference in the actuarial curves of patients without relapse during 36 months: 82 per cent in patients with high doses, as against 38 per cent in patients with rapidly degressive treatment (log rank: chi 2 = 7.67, P less than 0.01). The anti-TSH receptor antibody titers decreased more rapidly in patients under prolonged treatment with high doses than in those with the rapidly degressive treatment. It is concluded that carbimazole in high doses is more immunosuppressive than in rapidly degressive doses and that it improves the prognosis of Graves' disease.

[Can Acarus siro be considered an allergenic mite in children? Evaluation of 248 cases]. / Acarus siro peut-il être considéré comme un acarien allergisant chez l'enfant? Bilan de 248 explorations.

Among 248 allergic children we noted 44 children (21%) with strongly or moderately positive cutaneous tests (In seven out of these tested children respiratory provocation tests are very positive). They are urban children and their houses are not different from other allergic children. They are mostly boys (72%), more than 5 years old (91%), with an asthma (84%), a radiological sinusitis (45%), an hypereosinophilia (88%) and elevated total IgE (90%). 43/44 children also have positive cutaneous tests to Dermatophagoides pteronyssinus mite. Since respiratory sensitivity is exquisite, we undertook a specific hyposensitization for some patients with encouraging results.

[Does immediate-type respiratory allergy occur regarding Stemphylium? Evaluation of 39 challenge tests]. / L'allergie respiratoire de type immédiat existe-t-elle vis-à-vis de Stemphylium? Bilan de 39 tests de provocation.

Does immediate respiratory allergy with stemphylium exist? About 39 provocation tests. We present 39 children with positive cutaneous and/or RAST tests for stemphylium mold. Provocation tests individualize 19 patients (14 boys and 4 girls, 10 to 16 years old in 17/19) with a respiratory sensitivity: 6/10 by passive anterior rhinomanometry and 13/15 by bronchial tests. Clinical symptoms are asthma and spasmodic rhinitis (14/19), predominantly from june to august. We noted a mite allergy in 11 cases and a grass pollenosis in 13 children. Positive cutaneous and/or RAST tests are found for alternaria mold in 13/19 cases. We undertook a specific hyposensitization in 14 children with a three years experience in 10 cases. Tolerance is excellent. This provocation respiratory exploration shows the important role played by stemphylium mold in the etiology of recurring respiratory incidents in children.

[Role of rhinomanometry in childhood mite allergy apropos of 76 cases]. / Place de la rhinomanométrie dans l'allergie aux acariens de l'enfant à propos de 76 explorations.

Place for Passive Anterior Rhinomanometry (PAR) in mite allergic children. PAR is a simple method to investigate chronic or recurrent rhinopathies in children. Among 59 investigations with a Dermatophagoides pteronyssinus extract, we found 27 positive responses, 3 doubtful results and 32 negative explorations. Nasal sensitization is usually important: the liminal dose is less than 250 mcg in 17/28 cases. Most children have no bronchial sensitivity. None of 14 children with negative cutaneous and RAST tests have nasal sensitivity. When cutaneous and RAST tests are both positive, 12/16 positive PAR are found. We note a nasal sensitivity in 3/5 cases with only cutaneous test positive and 12/26 cases with only RAST tests positive. For other mites a nasal sensitivity is found in 8 out of 14 explorations (Tyrophagus and Glyciphagus especially). Among all patients when cutaneous tests, RAST tests and history are doubtful for the real part played by mites in the child rhinopathy, nasal exploration allows more explicit diagnostic and therapy.

[Does mugwort pollenosis occur in children in the northern region?]. / La pollinose à l'armoise est-elle fréquente chez l'enfant dans la région nord?

Is Mugwort pollenosis frequent among children in North of France? In North of France where no ragweed grows, mugwort (artemisia) is after grasses and plantago, the third pollenosis in children. Among 184 children with summer clinical signs, positive cutaneous tests with a mugwort extract are noted in 40 patients (21%). RAST are positive only in 23 on 34 children with positive cutaneous test. Among the 40 children only two are less 5 years old and 26 are more 10 years old. Respiratory provocation tests confirm in 13/19 cases a sensitization of upper or lower respiratory tract. No food allergy exists among those children.

[Prognostic value of anti-TSH receptor antibodies in Basedow's disease treated with carbimazole]. / Valeur pronostique des anticorps anti-récepteurs de TSH dans la maladie de Basedow traitée par le carbimazole.

In order to precise their prognostic value, the anti-TSH receptor antibodies (TRAK) have been measured in 70 cases of Graves' disease treated with carbimazole. Results (expressed in percentage of inhibition of labeled TSH binding) were grouped into 7 mean values: before treatment, from 15 days to 3 months, from 3 to 12 months, 2nd, 3rd, 4th and 5th years. For all cases together, a progressive decrease was observed: 40, 37, 29, 19, 14, 10, 7 p. 100. In 16 cases with good outcome, the mean values are significantly lower than those of 29 cases with bad outcome, respectively: 33 vs 46, 29 vs 43, 17 vs 30, 12 vs 27, 11 vs 22, 3 vs 15, 1 vs 11 p. 100. The TRAK titers at whatever t time are correlated to the clinical state at t + 2 years: about 30 p. 100 relapses if the TRAK titer is less than 10 p. 100; about 80 p. 100 relapses if it is 80 p. 100. So, the anti-TSH receptor antibodies have their place among the prognostic parameters of Graves' disease treated with carbimazole.

[Malignant pheochromocytoma. A case]. / Les phéochromocytomes malins. Une observation.

A case of malignant phaeochromocytoma is reported. The primary tumour was removed in 1970. Metastases were diagnosed in 1979 and management of the condition included antihypertensive treatment with alphamethylparatyrosine, antitumoral chemotherapy and surgical reduction of secreting tissue. In these rare tumours malignancy can only be confirmed by metastases, i.e. presence of chromaffin cells in loci where they are not usually found. Histology is of little value. High levels of catecholamine precursors or their metabolites in the urine may be a sign of malignancy, but some asymptomatic tumours are only revealed by metastases. Computerized tomography and radioisotope scanning with I131 metaiodobenzylguanidine are the best available methods to locate the lesions. In view of the small number of cases and of the unpredictable course (sometimes spread over many years) of malignant phaeochromocytomas, the effectiveness of treatments with alphamethylparatyrosine, chemotherapy and radiotherapy is difficult to evaluate.