Context: Acromegaly is usually sporadic, but familial cases occur in association with several familial pituitary tumor syndromes. Recently mutations in the aryl hydrocarbon receptor interacting ...protein (AIP) gene were associated with familial pituitary adenoma predisposition.
Objective: The objective of the study was to investigate the status of AIP in a pituitary tumor predisposition family.
Settings: The study was conducted at a nonprofit academic center and medical centers.
Patients: Eighteen members of a Brazilian family with acromegaly were studied.
Results: A novel germline mutation in the AIP gene, Y268X, predicted to generate a protein lacking two conserved domains, was identified in four members of this family: two siblings with early-onset acromegaly; a third, 41-yr-old sibling with a microadenoma but no clinical features of disease, and his 3-yr-old son. No changes were found in 14 unaffected at-risk relatives or 92 healthy controls.
Conclusions: We confirm the role of the AIP gene in familial acromegaly. This finding increases the spectrum of molecular defects that can give rise to pituitary adenoma susceptibility. Establishment of genotype-phenotype correlations in AIP mutant tumors will determine whether AIP screening can be used as a tool for clinical surveillance and genetic counseling of families with pituitary tumor predisposition. The underlying basis for the phenotypic variation within AIP-mutant families and the mechanism of AIP-mediated tumorigenesis remain to be defined.
We assessed the ability of desmopressin to stimulate the pituitary-adrenal axis in patients with Cushing's syndrome.
The cortisol response to 5 ot 10 micrograms of intravenous desmopressin was ...evaluated in 31 patients with Cushing's syndrome of several aetiologies and in 15 normal subjects.
Cortisol responses were observed in 15 out of 16 patients with pituitary dependence and in two patients with adrenal nodular hyperplasia, the increase above baseline ranging from 61 to 379% in the responders. Eight patients with adrenal tumours and one with the ectopic ACTH syndrome did not respond to desmopressin, having shown changes in their cortisol levels from -5 to 42% above baseline. Responses occurred in two out of the 15 normal individuals, whose cortisol increased 58 and 69% above baseline, respectively. Stimulation tests with standard agents as lysine vasopressin or ovine corticotrophin-releasing hormone were performed in the same patients and there was a high degree of concordance. No serious adverse reactions were observed in the tests with desmopressin.
Desmopressin was able to stimulate the pituitary-adrenal axis in patients with Cushing's disease and, like corticotrophin releasing hormone, it may prove useful in the differential diagnosis of Cushing's syndrome.
The clinical features and natural history of adrenocortical carcinoma are highly dependent on the type of center reporting their experience. Observations from oncology services suggest a high ...incidence of nonfunctioning tumors, whereas reports from endocrine clinics emphasize excessive corticoid and androgen production in the majority of tumors. The incidence rate and natural history of childhood adrenal carcinoma generally has been under emphasized.
Over the past 17 years, the authors have evaluated and treated 47 patients with adrenocortical carcinoma referred to the University of Sao Paulo, 22 of whom were children.
There is a bimodal age incidence of adrenal carcinoma, with the disease peaking in the first and fourth decades of life. Childhood adrenal carcinoma is characterized by a high rate of incidence of virilization, marked overproduction of androgens, and a less aggressive clinical course, and appears to be more amenable to surgical and other therapeutic modalities. By contrast, adrenocortical carcinoma occurring in adults presents more commonly as a mixed Cushing and virilizing syndrome, with overproduction of corticoids and androgens and a far more aggressive clinical course, leading to rapid death within months or years. Nonfunctioning adrenocortical carcinoma is less common; it generally occurs in older adults and exhibits a rapid downhill course. Modern day imaging methods have improved the diagnosis and staging of adrenal carcinoma greatly. In the authors' experience, the histologic criteria of Weiss appeared to predict tumor prognosis most accurately, whereas immunologic markers, cytoskeletal markers, DNA ploidy, cell phase markers, and oncogenic probes have yielded inconsistent results to date. Surgical removal of a localized tumor remains the best hope for long term survival. Medical therapy with mitotane and its successors in patients with Stage III or IV (MacFarlane system as modified by Sullivan et al.) disease appear to have added little to longevity or quality of life.
When diagnosed in children, adrenal carcinoma is associated with virilism and a less aggressive natural history; however, when it occurs in adults, the disease presents more commonly as a mixed Cushing-virilizing syndrome and has a virulent course. The Weiss histologic criteria appear to correlate best with disease prognosis, but other histochemical, cell cycle, and genetic markers have not, to date, aided in disease management.
To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical ...presentation of patients unaccounted for.
As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals.
Genotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression.
There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR=2.55, P=0.019, CI=1.013-5.76). Among patients who are ≥30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; OR=18.33; P=0.002, CI=2.88-16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors.
Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.
Germline mutations in p27(kip1) are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of ...this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, n=252; pheochromocytomas, n=125; medullary thyroid carcinoma, n=51; and parathyroid adenomas, n=19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (P=0.01), particularly for those with ACTH-secreting pituitary adenomas (P=0.005). In contrast, no association was found with GH-secreting pituitary tumors alone or with the sporadic counterpart of MEN2-component neoplasias. Our in vitro analyses revealed increased colony formation and cell growth rate for an AtT20 corticotropin mouse cell line overexpressing the p27-V109G variant compared with cells transfected with the WT p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH-secreting pituitary tissues, the overexpression of p27-V109G in a GH3 somatotropin rat cell line resulted in no difference compared with the WT. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far.
This work presents alterations in the concentrations of alkaline metals sodium, lithium and potassium, in abiotic compartments, at Araçá stream micro-basin, located in Canoas, RS. Its spring is ...located in a low populational density region and crosses an elevated environmental impacted urban area. Its final course crosses an agricultural area. Samples of atmospheric particulates, macrophites, water and sediments were analyzed. High concentrations of alkaline metals, related with draining of rice fields or with the ground type, as well as correlations among its concentrations with regional activities were verified. Tripogandra diurética has shown bioaccumulation compatible with their concentrations on waters.
Summary
Objective To characterize clinical features and identify MEN1 germline mutations in Brazilian families with multiple endocrine neoplasia type 1 (MEN1).
Settings Non‐profit academic centre.
...Patients Fourteen Brazilian families with MEN1 and 141 at‐risk relatives.
Results We identified 12 different MEN1 disease‐causing mutations, seven of them previously unreported: 308delC; 375del21; 549A>T (I147F); 1243delA; 1348T>G (L413R); 1351T>C (L414P) and 1523G>T (W471C). Families with the recurrent mutations 360delTCTA and L413R were shown to be unrelated by mitochondrial‐DNA and Y‐chromosome haplotype analyses. Most of the MEN1 single point mutations involved evolutionarily conserved residues, whereas most of the deletion/frameshift changes occurred in GC‐rich repetitive regions. Genetic screening of 141 at‐risk family members identified 38 MEN1 mutation carriers, 37 (97·4%) of whom had at least one major MEN1‐related tumour upon clinical investigation.
Conclusions High frequencies of MEN1 gene mutations were detected in Brazilian families with MEN1, including seven new genetic mutations that are predicted to cause inactivation of the MEN1 tumour suppressor gene. Our data underscore the need to implement a systematic MEN1 screening programme in Brazil.
Apoplexia subclínica em tumores pituitários PINHEIRO, MARCELO M.; CUKIERT, ARTHUR; SALGADO, LUIS R. ...
Arquivos de neuro-psiquiatria,
1999, Letnik:
57, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Apoplexia pituitária aguda é fenômeno relativamente raro, mesmo em macroadenomas. No entanto, a presença de áreas necro-hemorrágicas intratumorais nestes tumores que não se relacionam a qualquer ...sintomatologia aguda parece ser bem mais frequente do que se imaginava na era da tomografia. Com o advento da ressonância magnética estas áreas podem ser facilmente diagnosticadas pré-operatoriamente. Dentre os 40 últimos macroadenomas operados e examinados com RMN, 10 possuíam áreas apopléticas subclínicas em seu interior. Sete destes tumores eram não secretores, 2 secretores de GH e um de prolactina. O quadro clínico incluiu, além daqueles correspondentes à eventual secreção endócrina, perda visual progressiva (sem história de piora abrupta ou rápida) (n=8) e cefaléia (n=3). Após a remoção cirúrgica destes tumores e descompressão do aparato óptico, obtivemos melhora visual em 6 pacientes e em 2 a visão permaneceu inalterada. A cefaléia desapareceu em 2 casos. A presença de áreas apopléticas nestes macrotumores bem como sua ausência em séries de microtumores relatadas na literatura sugere que se relacionam mais ao tamanho do tumor do que ao seu caráter secretor ou não, o que é compatível com a provável natureza (insuficiência vascular) da apoplexia subclínica nesses casos.
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 transesphenoidal 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 cavernous 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.
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