Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel mutation in arginine-vasopressin gene in a Brazilian family / Diabetes insípido neuro-hipofisário familial causado por uma nova mutação no gene da arginina-vasopressina em uma família brasileira

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare autosomal dominant disorder characterized by polyuria and polydipsia due to deficiency of arginine vasopressin (AVP). More than 50 mutations causing adFNDI have been already reported in the AVP gene. The aim of the present study is to analyze the AVP gene in four generations of one Brazilian kindred with adFNDI. The proband was a 31-year old female with huge hypotonic polyuria (10 L/day) dated from childhood. Molecular analysis included amplification of all exons and exon-intron regions of the AVP gene by PCR and direct sequencing. Sequencing analysis showed a novel point mutation in heterozygous: G88V (GGC>GTC). All affected patients presented the same mutation also in heterozygous, while it was absent in four normal members. We expand the repertoire of mutations in AVP describing the novel G88V mutation in one Brazilian kindred with adFNDI.

Diabetes insípido neuro-hipofisário com herança autossômica dominante (adFNDI) é uma doença autossômica dominante rara, caracterizada por poliúria e polidipsia devido à deficiência de arginina-vasopressina (AVP). Mais de 50 mutações causando adFNDI foram descritas no gene AVP. O objetivo deste estudo foi analisar o gene AVP em quatro gerações de uma família brasileira com DINF. O caso-índice é de uma paciente de 31 anos, com volumosa poliúria hipotônica desde a infância (10 L/dia). A análise molecular incluiu amplificação por PCR e seqüenciamento automático dos éxons e regiões éxon-íntron do gene AVP. A análise do seqüenciamento mostrou uma nova mutação de ponto em heterozigose: G88V (GGC>GTC). Todos os pacientes afetados apresentaram a mesma mutação, que não foi encontrada em quatro indivíduos normais da família. Expandimos a lista de mutações no gene AVP, descrevendo a nova mutação G88V em uma família brasileira com adFNDI.

Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel mutation in arginine-vasopressin gene in a Brazilian family.

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare autosomal dominant disorder characterized by polyuria and polydipsia due to deficiency of arginine vasopressin (AVP). More than 50 mutations causing adFNDI have been already reported in the AVP gene. The aim of the present study is to analyze the AVP gene in four generations of one Brazilian kindred with adFNDI. The proband was a 31-year old female with huge hypotonic polyuria (10 L/day) dated from childhood. Molecular analysis included amplification of all exons and exon-intron regions of the AVP gene by PCR and direct sequencing. Sequencing analysis showed a novel point mutation in heterozygous: G88V (GGC>GTC). All affected patients presented the same mutation also in heterozygous, while it was absent in four normal members. We expand the repertoire of mutations in AVP describing the novel G88V mutation in one Brazilian kindred with adFNDI.

Hormonal, pituitary magnetic resonance, LHX4 and HESX1 evaluation in patients with hypopituitarism and ectopic posterior pituitary lobe.

OBJECTIVE: LHX4 and HESX1 are important in early stages of pituitary development and their mutations can be associated with an ectopic posterior lobe (EPL) in the pituitary of patients with hypopituitarism. The EPL can be located at the median eminence or at the path of the pituitary stalk. The aim of this study was to analyse LHX4 and HESX1 and characterize the hormonal deficiency profiles, establishing relationships with magnetic resonance imaging (MRI) findings in these patients. PATIENTS AND DESIGN: Sixty-two patients with hypopituitarism associated with EPL were submitted to evaluation of pituitary function, analysis of MRI with EPL location and molecular analysis of LHX4 and HESX1 using polymerase chain reaction (PCR), digestion with restriction enzyme and automatic sequencing. RESULTS: Forty-two patients had a nonvisualized pituitary stalk (NPS), and 20 a visualized pituitary stalk (VPS). Most patients (95%) with NPS had combined pituitary hormone deficiency (CPHD), with ACTH deficiency in 85%. In patients with VPS, CPHD was found in 50% and ACTH deficiency occurred in only 20%. The frequency of the location of EPL was similar in patients with VPS and NPS: 35% at median eminence and 65% at the path of the stalk. No mutations in LHX4 and HESX1 were identified. Three new polymorphisms in LHX4 were found. CONCLUSIONS: ACTH deficiency is frequent in patients with hypopituitarism and NPS (85%), the location of EPL at the median eminence was not predictive of the hormonal profile [isolated GH deficiency (IGHD) or CPHD], and LHX4 and HESX1 genes mutations remain rare causes of hypopituitarism associated with EPL.

Ectopic ACTH syndrome: our experience with 25 cases.

OBJECTIVE: Ectopic ACTH syndrome (EAS) occurs in about 5-10% of all patients with ACTH-dependent hypercortisolism with most of them caused by intrathoracic neoplasms. It may be associated with overt malignancies or with occult and indolent tumors. We assessed the accuracy of dynamic tests, inferior petrosal sinus sampling (IPSS) using desmopressin, and imaging in the work-up diagnosis of EAS. DESIGN AND SUBJECTS: Tumor markers, imaging, and outcome data from 25 patients (13F/12M) aged 18-72 years. High dexamethasone suppression test (HDDST), desmopressin test, GHRP-6 test, corticotropin-releasing hormone (CRH) test, IPSS, computed tomography (CT), magnetic resonance imaging (MRI), and (111)In-pentetreotide scintigraphy were revised. RESULTS: In 5 out of 20 patients HDDST was positive. In 13 patients who underwent desmopressin test, ACTH- and cortisol-positive responses were seen in six and five patients respectively. GHRP-6 test was positive in two out of three cases. Two patients underwent CRH test with negative response. In the seven patients submitted to IPSS using desmopressin in six of them, none had ACTH gradients. CT was positive in 15 out of 21 patients and MRI in 8 out of 17 cases. (111)In-pentetreotide scintigraphy was positive in three out of five patients. Fourteen patients had intrathoracic tumors, five had pheochromocytomas, three had pancreatic tumors, one had a glomic tumor, and had three occult tumors. Six out of 11 patients with metastasis died and 3 others without metastasis died. CONCLUSIONS: IPSS with desmopressin was helpful for differential diagnosis. Patients initially harboring occult carcinoids may also exhibit severe hypercortisolism and those harboring tymic carcinoids had poor prognoses when compared with bronchial carcinoids and pheocromocytomas.

Effectiveness of treating ovarian hyperstimulation syndrome with cabergoline in two patients with gonadotropin-producing pituitary adenomas.

OBJECTIVE: To report the effect of cabergoline on ovarian hyperstimulation syndrome associated with gonadotropin-secreting pituitary adenomas. DESIGN: Case report. SETTING: Outpatient practice. PATIENT(S): Two women with menstrual irregularity, enlarged ovaries, high E(2), and normal gonadotropin levels. INTERVENTION(S): Cabergoline treatment and transsphenoidal surgery. MAIN OUTCOME MEASURE(S): Estradiol levels, transvaginal ultrasonography, and pituitary magnetic resonance imaging. Transsphenoidal surgery showed pituitary adenoma staining for LH in both patients. RESULT(S): Cabergoline was effective in reducing E(2) levels and decreasing ovarian size but ineffective in shrinking the pituitary adenomas. CONCLUSION(S): This is the first description of the effectiveness of cabergoline as the primary treatment of spontaneous ovarian hyperstimulation syndrome in patients with gonadotropin-producing pituitary adenomas.

Pituitary apoplexy during therapy with cabergoline in an adolescent male with prolactin-secreting macroadenoma.

Pituitary adenomas are rare in young patients. Prolactinomas are the most common type of pituitary adenomas in children older than 12 years, occurring more often in girls, at a 4.5:1 female-to-male ratio. The clinical presentation may vary according to the age and sex of the patient. Pituitary apoplexy is a rare life-threatening condition caused by a sudden infarction or hemorrhagic necrosis of the pituitary containing an adenoma. A wide variety of conditions can trigger apoplexy such as pituitary irradiation, general anesthesia, traumatic head injury, pituitary stimulatory tests and a wide variety of medications including bromocriptine. We report a case of a 16-year-old male patient with puberty arrest harboring a macroprolactinoma, who developed a sudden clinical picture of pituitary apoplexy during the 12th month of treatment with cabergoline.

Absence of effects of long-term growth hormone replacement therapy on insulin sensitivity in adults with growth hormone deficiency of childhood-onset (GHDA-CO).

In order to assess long-term efficacy and safety of GH therapy in GHDA-CO, we studied 20 patients (8 female, 12 male; mean age 24.6+/-6.2 years) treated with GH for up to 24 months. The assessment (IGF-1, IGFBP3, lipid profile, body composition, glycated hemoglobin, oral glucose tolerance test, ISI-HOMA and ISI-composite derived from OGTT) was carried out before GH and every 3 months during the first year of treatment, and then every 6 months. We observed a significant increase of IGF-1, lean mass and HDL levels and a decrease in LDL levels. Fasting glucose presented a significant increase, within the normal range, after 6 months, returning to pre-treatment levels at 9 months with no further alteration. Fasting insulin, the areas under the glucose and insulin curves, ISI-HOMA and ISI-composite did not vary significantly. We conclude that long-term GH therapy improved body composition and lipid profile, without altering ISI in this cohort of patients with GHDA-CO.

Deficiência de GH em adultos: resultados do estudo multicêntrico brasileiro / GH deficiency in adults: results of the Brazilian multicenter study

Avaliamos 70 pacientes com deficiência de GH, 39 mulheres e 31 homens, com idades entre 18 e 69 anos (média de 38,3±13,5), provenientes de 3 centros no Brasil. A dose de reposiçäo variou entre os centros, bem como a resposta do IGF-1, que mostrou maior aumento nos centros com maior dose de GH. Reposiçäo de GH levou a um aumento significativo nos níveis de IGF-1 e HDL colesterol, bem como da densidade mineral óssea (DMO), e a uma reduçäo significativa nos níveis de colesterol total e LDL colesterol, semelhante nos 3 centros. Encontramos aumento mais significativo de HDL colesterol nas mulheres e aumento mais acentuado da DMO nos pacientes do sexo masculino. Concluimos que reposiçäo de GH leva à melhora do perfil lipídico e da DMO, e que doses menores apresentam o mesmo benefício, provavelmente com menor incidência de efeitos colaterais

Effects of growth hormone replacement therapy on metabolic and cardiac parameters, in adult patients with childhood-onset growth hormone deficiency.

OBJECTIVE: We evaluated metabolic and cardiac parameter changes with GH-therapy. DESIGN: Sixteen adults with childhood-onset hypopituitarism receiving pituitary hormone replacement, except GH-replacement, were assessed at baseline and after 6 and 12 months of GH-replacement. Sixteen healthy adults matched for sex, age, weight, height, body mass index, and body surface area served as the control group to compare cardiac function in both groups. RESULTS: All patients had GH-deficiency. After 12 months, serum insulin-like growth factor-1 levels normalized. Basal glucose or insulin levels had no alterations. The low/high density lipoprotein-cholesterol ratio decreased (3.18+/-1.32 x 2.17+/-0.8, p<0.001). Percent lean body mass increased (69.9+/-5.5 x 78.4+/-8.1%), and percent fat body mass decreased (30.1+/-5.5 x 21.6+/-8.1%) (both, p<0.001). Before treatment, patients had decreased left ventricular (LV) echocardiographic morphologic indexes, which were corrected (initial versus 12 months): interventricular septal thickness (0.68+/-0.06 x 0.78+/-0.06 cm), LV posterior wall thickness (0.69+/-0.07 x 0.78+/-0.05 cm), and LV mass index (58.9+/-11.0 x 71.1+/-9.4 g/m(2)) (all, p<0.001). Exercise capacity improved, as assessed by oxygen consumption (7.84+/-1.44 x 9.67+/-1.74 METS, p<0.001). CONCLUSIONS: GH-replacement seems to reduce cardiovascular risks in adults with childhood-onset GH-deficiency.

Treatment of acromegaly improves myocardial abnormalities.

BACKGROUND: Treatment for acromegaly decreases left ventricular (LV) mass, but it is not clear whether diastolic dysfunction is also reversible. With Doppler echocardiography, before and after effective therapy, we assessed the LV morphology and function of patients with acromegaly who were free of complications. METHODS: In 15 patients with active acromegaly (age range, 33.4 +/- 9.3 years), we compared LV Doppler echocardiographic indices, before and after transsphenoidal surgery or radiotherapy or before and after both procedures, noting a significant drop in plasma levels of growth hormone (<2.0 ng/mL after oral glucose tolerance testing). Patients did not have arterial hypertension, diabetes mellitus, thyroid dysfunction, or coronary artery disease. Occasionally, in this series, patients had no symptoms of heart failure, and patients who underwent treatment with somatostatin analog drugs were not included because they did not have a significant hormonal drop. The follow-up period after hormonal control was 2.7 +/- 1.7 years. We also studied 15 healthy control subjects matched for age, sex, and body surface area. RESULTS: Patients with acromegaly compared with healthy control subjects had increased LV mass index, relative wall thickness, and deteriorated diastolic function. After therapy, most of the abnormalities improved: LV mass index (104 +/- 21 g/m(2) x 87 +/- 21 g/m(2); P <.01), LV relative wall thickness (0.40 +/- 0.06 x 0.35 +/- 0.04; P <.01), proto/telediastolic transmitral peak flow velocity ratio (1.17 +/- 0.33 x 1.49 +/- 0.34; P <.001), and isovolumetric relaxation period (126 +/- 18 ms x 113 +/- 13 ms; P <.05). CONCLUSION: Treatment of acromegaly in patients without clinical heart failure improves both LV morphology and diastolic function. Avoidance of progression to more advanced forms of acromegalic cardiomyopathy should be possible.

Cavernous sinus invasion by pituitary macroadenomas

The classical imaging gold-standard for this diagnosis is the presence of tumor lateral to the carotid artery. Seventeen patients with pituitary macroadenomas with intraoperative confirmation of cavernous sinus invasion were studied with MRI. Only 8 patients had tumor lateral to the carotid artery; 13 had tumor within the carotid syphon and all lacked the ring enhancement of the medial wall of the cavernous sinus. In 10 patients, widening of the posterior double leaflets of the cavernous sinus could be. All patients were operated by the transephenoidal route. Only one patient was cured by surgery alone. Only 3 patients disclosing the above mentioned MRI features were identified in a series of 250 patients and did not have cavernous sinus invasion. The present criteria proved to be useful in the pre-operative diagnosis of cavenous sinus invasion and patients' counselling. Pre-operative diagnosis of cavernous sinus invasion of pituitary tumors has a great impact in the management of such patients.

Failure of Partial Hypophysectomy as Definitive Treatment in Cushing's Disease Owing to Nodular Corticotrope Hyperplasia: Report of Four Cases.

Nodular corticotrope hyperplasia is a rare pathology causing Cushing's syndrome owing to a primary pituitary disease or ectopic CRH production. In this study, we evaluated the laboratory and pathological findings and results of transsphenoidal pituitary surgery in four patients with Cushing's disease. Dynamic tests of pituitary-adrenal function (dexamethasone suppression, metyrapone, CRH, and DDAVP tests) were done before and after transsphenoidal pituitary surgery. Plasma and total urinary cortisol, serum 11-deoxycortisol, and plasma ACTH were determined by RIA. Hormonal dynamic tests and radiologic studies were compatible with a pituitary ACTH source. The transsphenoidal surgery revealed the presence of corticotrope hyperplasia confirmed by immunoperoxidase stain and a preserved reticulum framework in the removed pituitary tissue of these four patients. The pituitary surgery led to a short period of improvement in two of the patients (1 and 4), a 3-yr remission in one patient (patient 2), and no improvement in one (patient 3). We conclude that although our patients appear to have inadequate suppression with high-dose dexamethasone, there is no way to diagnose this pathology presurgically, and that total hypophysectomy, bilateral adrenalectomy, and irradiation are the only alternatives for definitive treatment. A CRH-secreting ectopic tumor could not be found in our patients either before or after surgery in the follow-up period.

Emprego do cetoconazol em pacientes com doença de Cushing

Com o objetivo de se avaliar a aplicaçäo do efeito antiadrenal do cetoconazol, administramos 600 a 800 mg/dia deste medicamento durante quatro semanas a cinco pacientes com doença de Cushing. Observamos diminuiçäo dos níveis de cortisol plasmático (microng/dl) e urinário (microng/24h) em todos os pacientes (média ñ ero padräo: basal = 26,1 ñ 3,5 e 757,6 ñ216,0; final = 15,6 ñ 2,5 e 219,0 ñ 95,6, respectivamente, p < 0,05) e elevaçäo do ACTH plasmático em quatro destes. Paralelamente ocorreu reduçäo precoce de sulfato de deidroepiandrosterona e delta4 androsterona e de 17 cetoesteróides urinários. A reserva adrenal mostrou-se preservada durante o emprego de cetoconazol, como demonstrado pelo incremento dos níveis de cortisol após administraçäo de ACTH (delta = 11,8 ñ 3,0 microng/dl) em relaçäo a préterapêutica (delta = 18,2 ñ 5,5 microng/dl). Durante a administraçäo de cetoconazol verificou-se perda de peso acompanhada de diminuiçäo da pletora facial e descamaçäo de pele, sinais clínicos sugestivos da diminuiçäo de produçäo de cortisol. Concluímos que o cetoconazol pode ser uma droga útil no manuseio clínico da doença de Cushing em que outras terapêuticas falharam, ou no preparo prévio a tratamento cirúrgico definitivo, ou ainda no aguardo do efeito de radioterapia hipofisária