Apresentação clínica e análise molecular do gene da arginina-vasopressina neurofisina II de pacientes com diabetes insípido central idiopático com longo seguimento

INTRODUCTION: Central diabetes insipidus (DI) characterized by polyuria, polydipsia and inability to concentrate urine, has different etiologies including genetic, autoimmune, post-traumatic, among other causes. Autosomal dominant central DI presents the clinical feature of a progressive decline of arginine-vasopressin (AVP) secretion. OBJECTIVE: In this study, we characterized the clinical features and sequenced the AVP-NPII gene of seven long-term follow-up patients with idiopathic central DI in an attempt to determine whether a genetic cause would be involved. METHODS: The diagnosis of central DI was established by fluid deprivation test and hyper-tonic saline infusion. For molecular analysis, genomic DNA was extracted and the AVP-NPII gene was amplified by polymerase chain reaction and sequenced. RESULTS: Sequencing analysis revealed a homozygous guanine insertion in the intron 2 (IVS2 +28 InsG) of the AVP-NPII gene in four patients, which represents an alternative gene assembly. No mutation in the code region of the AVP-NPII gene was found. CONCLUSIONS: The homozygous guanine insertion in intron 2 (IVS2 +28 InsG) is unlikely to contribute to the AVP-NPII gene modulation in DI. In addition, the etiology of idiopathic central DI in children may not be apparent even after long-term follow-up, and requires continuous etiological surveillance.INTRODUÇÃO: O diabetes insípido (DI) central, caracterizado por poliúria, polidipsia e inabilidade em concentrar a urina, apresenta diferentes etiologias, incluindo causas genética, autoimune, pós-traumática, entre outras. O DI central autossômico dominante apresenta a característica clínica de falência progressiva da secreção da arginina-vasopressina (AVP). OBJETIVO: No presente estudo, caracterizou-se a apresentação clínica e sequenciou-se o gene AVP-NPII de sete pacientes com DI central idiopático seguidos de longa data na tentativa de determinar se uma causa genética estava envolvida na etiologia. MÉTODOS: O diagnóstico do DI central foi estabelecido por meio do teste de jejum hídrico e infusão de salina hipertônica. Para a realização da análise molecular, o DNA genômico foi extraído e o gene AVP-NPII foi amplificado pela reação em cadeia da polimerase e, posteriormente, sequenciado. RESULTADOS: A análise do sequenciamento do gene AVP-NPII revelou uma inserção em homozigose de uma guanina no íntron 2 (IVS2 +28 InsG) em quatro pacientes, correspondendo a um arranjo alternativo do gene. Nenhuma mutação da região codificadora do gene AVP-NPII foi encontrada. CONCLUSÕES: A inserção em homozigose de uma guanina no íntron 2 (IVS2 +28 InsG) provavelmente não contribui na modulação do gene AVP-NPII no DI. Adicionalmente, a etiologia do DI central idiopático em crianças pode não se tornar evidente mesmo após um longo período de seguimento, necessitando de contínua vigilância da etiologia

Mielolipoma adrenal gigante associado à deficiência da 21-hidroxilase: associação não usual simulando um carcinoma adrenocortical secretor de androgênios

The objective of this study was to describe a case of giant myelolipoma associated with undiagnosed congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21OH) deficiency. Five seven year-old male patient referred with abdominal ultrasound revealing a left adrenal mass. Biochemical investigation revealed hyperandrogenism and imaging exams characterized a large heterogeneous left adrenal mass with interweaving free fat tissue, compatible with the diagnosis of myelolipoma, and a 1.5 cm nodule in the right adrenal gland. Biochemical correlation has brought concerns about differential diagnosis with adrenocortical carcinoma, and surgical excision of the left adrenal mass was indicated. Anatomopathologic findings revealed a myelolipoma and multinodular hyperplasic adrenocortex. Further investigation resulted in the diagnosis of CAH due to 21OH deficiency. Concluded that CAH has been shown to be associated with adrenocortical tumors. Although rare, myelolipoma associated with CAH should be included in the differential diagnosis of adrenal gland masses. Moreover, CAH should always be ruled out in incidentally detected adrenal masses to avoid unnecessary surgical procedures.O objetivo deste trabalho foi descrever um caso de mielolipoma gigante associado à hiperplasia adrenal congênita (HAC) por deficiência da 21-hidroxilase (21OH). Paciente do sexo masculino, 57 anos de idade, encaminhado por achado ultrassonográfico de massa adrenal esquerda. Investigação bioquímica revelou hiperandrogenismo e exames de imagem revelaram grande lesão sólida em adrenal esquerda de aspecto heterogêneo, entremeada de tecido gorduroso, compatível com diagnóstico de mielolipoma, e um nódulo de 1,5 cm na adrenal direita. Os achados bioquímicos sugeriam o diagnóstico de carcinoma adrenocortical, indicando cirurgia para retirada da massa adrenal esquerda. O anatomopatológico confirmou mielolipoma e hiperplasia multinodular do córtex adrenal. A investigação subsequente diagnosticou HAC por deficiência da 21OH. Concluiu-se que a HAC tem sido descrita em associação com tumores adrenocorticais. Apesar de raro, o mielolipoma associado à HAC deve ser incluído nas possibilidades diagnósticas de massa adrenal. Adicionalmente, a HAC deve ser sempre afastada nos casos de massa adrenal de achado incidental, evitando cirurgias desnecessárias.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Efeito da evolução temporal da adrenalectomia na secreção de prolactina

OBJECTIVE: To evaluate the modulation of the hypothalamus-pituitary-adrenal axis (HPA) on prolactin secretion in rats after adrenalectomy (ADX). MATERIALS AND METHODS: Plasma corticosterone, ACTH, and prolactin concentrations were measured by radioimmunoassay in rats after bilateral ADX in the short- (3 hours and 1day) and long-term (3, 7, and 14 days). RESULTS: Animals that underwent ADX showed undetectable corticosterone levels and a triphasic ACTH response with a transient increase (3h), a decrease (1d), and further increase in the long-term after ADX. Sham animals showed a marked increase in corticosterone and ACTH levels three hours after surgery, with a decrease to basal levels thereafter. Plasma prolactin levels were not changed after ADX. CONCLUSION: There are different points of equilibrium in the HPA axis after the glucocorticoid negative feedback is removed. Prolactin plasma secretion is not altered in the short or long- term after ADX, suggesting that the peptidergic neurons essential for prolactin release are not activated after ADX

Gonadotropin-dependent pubertal disorders are common in patients with virilizing adrenocortical tumors in childhood

Objective: To investigate the impact of early exposure to androgen excess on gonadotropin-dependent puberty (GDP) and final height (FH) of patients with androgen-secreting adrenocortical tumors (ACT) in childhood. Methods: Retrospective cohort study. Occurrence of GDP and achievement of FH were evaluated. Central precocious puberty (CPP) and early fast puberty (EFP) were considered pubertal disorders. Patients with normal puberty and pubertal disorders were compared. Results: The study included 63 patients (44F), followed in a single institution from 1975 until 2017. At diagnosis of ACT, median age was 25.8 month s; duration of signs, 6 months; stature SDS, 0.5 (−3.6 to 3.9) and bone age advancement, 14.7 months (−27.9 to 85.4). To date, 37 patients developed GDP: 26 had normal puberty; one, precocious thelarche; seven, CPP and three, EFP. GnRHa effectively treated CPP/EFP. Tall stature and older age at diagnosis of ACT were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.04–8.65)). Recurrence/metastasis during follow-up were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.12–8.02)). Among the 19 patients that reached FH, stature SDS dropped from 1.4 to −0.02 since diagnosis of ACT (P = 0.01). Seventeen achieved normal FH. There was no difference in FH SDS between patients with norm al puberty and pubertal disorders (P = 0.75). Conclusions: Gonadotropin-dependent pubertal disorders are common in patients with androgen-secreting ACT in childhood. FH is usually not impaired. The study reinforces the importance of close follow-up after surgery to identify and treat consequences of early exposure to androgen excess

A review of Cushing’s disease treatment by the Department of Neuroendocrinology of the Brazilian Society of Endocrinology and Metabolism

The treatment objectives for a patient with Cushing’s disease (CD) are remission of hypercortisolism, adequate management of co-morbidities, restoration of the hypothalamic-pituitary-adrenal axis, preservation of fertility and pituitary function, and improvement of visual defects in cases of macroadenomas with suprasellar extension. Transsphenoidal pituitary surgery is the main treatment option for the majority of cases, even in macroadenomas with low probability of remission. In cases of surgical failure, another subsequent pituitary surgery might be indicated in cases with persistent tumor imaging at post surgical magnetic resonance imaging (MRI) and/or pathology analysis of adrenocorticotropic hormone-positive (ACTH+) positive pituitary adenoma in the first procedure. Medical treatment, radiotherapy and adrenalectomy are the other options when transsphenoidal pituitary surgery fails.There are several options of medical treatment, although cabergoline and ketoconazole are the most commonly used alone or in combination. Novel treatments are also addressed in this review. Different therapeutic approaches are frequently needed on an individual basis, both before and, particularly, after surgery, and they should be individualized. The objective of the present review is to provide the necessary information to achieve a more effective treatment for CD. It is recommended that patients with CD be followed at tertiary care centers with experience in treating this condition

Análise dos critérios diagnósticos dos distúrbios do metabolismo de glicose e variáveis associadas à resistência insulínica Diagnostic criteria of the glucose metabolism disorders and variables associated to insulin resistence

Os critérios diagnósticos dos distúrbios do metabolismo de glicose foram estabelecidos pela Organização Mundial de Saúde (OMS)/National Diabetes Data Group (NDDG) no início da década de 1980. Em 1997, a American Diabetes Association (ADA) sugeriu novos critérios diagnósticos, baseados na interpretação da glicemia de jejum. Neste estudo, 56 indivíduos foram submetidos ao teste de tolerância à glicose oral (oGTT) (75g) e aplicamos ambos os critérios diagnósticos para estimar a prevalência de distúrbios de metabolismo de glicose. Dos 56 indivíduos, 11 (19,6% - grupo 1) foram considerados intolerantes pelos critérios da OMS/NDDG e seis (10,7% - grupo 2), como glicemia de jejum alterada (GJA) pelos novos critérios da ADA. Comparamos variáveis clínicas e bioquímicas (idade, índice de massa corporal, pico de insulina durante o oGTT, área sob a curva de insulina durante o oGTT e concentrações séricas basais da proteína carreadora dos fatores de crescimento insulina-símiles 1 (IGFBP-1) entre ambos os grupos, não observando diferença significativa em nenhuma das variáveis (43 ± 13 x 46 ± 4,4 anos, 29,5 ± 3,2 x 27,2 ± 2,6kg/m², 153,7 ± 100,7 x 171,3 ± 145,6µUI/ml, 12.040 ± 8.488 x 13.970 ± 12.170 e 14,4 ± 9,3 x 19,4 ± 11,8ng/ml, respectivamente, p = NS). Entretanto, quando comparamos estas mesmas variáveis entre o grupo de indivíduos considerados normais pelos critérios da ADA e intolerantes pelos critérios da OMS/NDDG (n = 8, grupo 3) e o grupo de indivíduos considerados normais por ambos os critérios (n = 42, grupo 4), observamos que não houve também diferença em relação à idade (42 ± 15 x 38 ± 10 anos, respectivamente, NS); entretanto o grupo 3 apresenta índice de massa corporal (IMC) (29,5 ± 3,9 x 24,5 ± 3,5kg/m², respectivamente, p < 0,02), pico de insulina durante o oGTT (115,2 ± 29,1 x 84,4 ± 56,5µUI/ml, respectivamente, p < 0,02) e área sob a curva de insulina durante o oGTT (9.112 ± 2.323 x 6.649 ± 4.438, respectivamente, p < 0,007) com valores médios superiores ao grupo 4. O grupo 3 apresentou ainda concentrações séricas basais de IGFBP-1 com valores em média inferiores ao grupo 4 (14,9 ± 10,1 x 28,9 ± 17,6ng/ml, respectivamente, p < 0,03).<br>The diagnostic criteria of the glucose metabolism disorders had been established by the World Health Organization (WHO)/National Data Group (NDDG) in the beginning of the 1980's. In 1997, the American Diabetes Association (ADA) suggested new criteria, based upon the interpretation of the fasting glucose. In this study, 56 subjects underwent an oral glucose tolerance test (oGTT), and we have applied both criteria to estimate the prevalence of the glucose metabolism disorders. Out of 56 subjects, 11 (19,6% - Group 1) had been considered glucose intolerants by the criteria of the WHO/NDDG and 6 (10,7% - Group 2) as impaired fasting glycemia (IFG) by the ADA new criteria. We have compared clinical and biochemical variables (age, BMI, insulin peak during oGTT, area under the insulin curve during oGTT and serum concentrations of IGFBP-1) between both groups, not observing differences in any of the variables (43 ± 13 x 46 ± 4.4 years, 29.5 ± 3.2 x 27.2 ± 2.6kg/m², 153.7 ± 100.7 x 171.3 ± 145.6µUI/ml, 12,040 ± 8,488 x 13,970 ± 12,170 e 14.4 ± 9.3 x 19.4 ± 11.8ng/ml, respectively, p = NS). However, when we compare these same variables between the subjects considered normal by the ADA criteria and intolerants by the WHO/NDDG (n = 8, Group 3) and the subjects considered normal by both criteria (n = 42, Group 4), we observed that it also did not have difference in relation to age (42 ± 15 x 38 ± 10 years, respectively, NS), however, Group 3 presents BMI (29.5 ± 3.9 x 24.5 ± 3.5kg/m², respectively, p < 0.02), insulin peak (115.2 ± 29.1 x 84.4 ± 56.5µUI/ml, respectively, p < 0.02) and area under the insulin curve (9,112 ± 2,323 x 6,649 ± 4,438, respectively, p < 0.007)with higher values than Group 4. Group 3 still presented serum concentration of IGFBP-1 with lower values than Group 4 (14.9 ± 10.1 x 28.9 ± 17.6ng/ml, respectively, p < 0.03)