Genetics of Cushing's disease: an update.

INTRODUCTION: Cushing's disease (CD) results from uncontrolled hypercortisolism induced by ACTH-secreting corticotroph adenomas; accordingly, patients diagnosed with CD usually present several comorbidities and an increased risk of mortality. Hypothesis-driven screenings have led to identification of rare alterations in a low number of patients, although the genetic basis underlying CD has remained unclear until recently. Using whole-exome sequencing, recurrent mutations have been reported in the gene coding for the ubiquitin-specific protease 8 (USP8), a protein with deubiquitinase (DUB) activity that modulates the lysosomal turnover of the EGF receptor (EGFR) and other membrane proteins. METHODS: In this review, we summarize the recent genetic findings and discuss the clinical and pathological implications of USP8 deregulation in corticotroph adenomas. CONCLUSIONS: Mutations in USP8 have been identified in 35-62 % of functional sporadic corticotroph adenomas causing Cushing's disease, but not in any other type of pituitary tumor. These mutations are found mostly in adult female patients and lead to an aberrant DUB activation by impairing the regulation of USP8 by members of the 14-3-3 family of proteins. The consequence of this hyperactivation is a longer retention of EGFR at the plasma membrane which promotes an enhanced production of ACTH.

Genetic characterization of a mouse line with primary aldosteronism.

In an attempt to define novel genetic loci involved in the pathophysiology of primary aldosteronism, a mutagenesis screen after treatment with the alkylating agent N-ethyl-N-nitrosourea was established for the parameter aldosterone. One of the generated mouse lines with hyperaldosteronism was phenotypically and genetically characterized. This mouse line had high aldosterone levels but normal creatinine and urea values. The steroidogenic enzyme expression levels in the adrenal gland did not differ significantly among phenotypically affected and unaffected mice. Upon exome sequencing, point mutations were identified in seven candidate genes (Sspo, Dguok, Hoxaas2, Clstn3, Atm, Tipin and Mapk6). Subsequently, animals were stratified into wild-type and mutated groups according to their genotype for each of these candidate genes. A correlation of their genotypes with the respective aldosterone, aldosterone-to-renin ratio (ARR), urea and creatinine values as well as steroidogenic enzyme expression levels was performed. Aldosterone values were significantly higher in animals carrying mutations in four different genes (Sspo, Dguok, Hoxaas2 and Clstn3) and associated statistically significant adrenal Cyp11b2 overexpression as well as increased ARR was present only in mice with Sspo mutation. In contrast, mutations of the remaining candidate genes (Atm, Tipin and Mapk6) were associated with lower aldosterone values and lower Hsd3b6 expression levels. In summary, these data demonstrate association between the genes Sspo, Dguok, Hoxaas2 and Clstn3 and hyperaldosteronism. Final proofs for the causative nature of the mutations have to come from knock-out and knock-in experiments.

[A comparative study of the incidence of sudden death from Chagas' disease in Uberaba in the years 1980 and 1990]. / Estudo comparativo da freqüência da morte súbita inesperada por doença de Chagas, em Uberaba, nos anos de 1980 e 1990.

A comparison was made between the years 1980 and 1990 for the frequency and causes of sudden death occurring in the urban and rural areas of the city of Uberaba in individuals older than 15 years. It aims mainly to analyse the current frequency of sudden death in that region and to evaluate the impact, it any, of prophylaxis and therapy on sudden death due to Chagas' disease. For the 1226 deaths cases studied from our 1980, 54 (4.4%) were sudden ones; out of these, 13 (24.1%) were supposedly due to Chagas' disease. For the 1740 death cases studied form our 1990 series, 44 (2.5%) were sudden ones; out of these, only 3 (6.8%) were considered to be due to Chagas' disease. The results indicate a significant decrease in the frequency both for sudden death in general and for sudden death due to Chagas' disease when the year 1990 is compared with 1980. Probable explanations for the findings are discussed.

[Extraskeletal primary osteosarcoma of the frontal region]. / Osteossarcoma extra-esquelético primário da região frontal.

BACKGROUND: Extraskeletal osteosarcoma (ESOS) in the head as a primary site has seldom been reported and none in the frontal region. METHODS: A 78-year-old Italian man presented with one month history of a frontal soft tissue mass. A CT scan showed a mass of uneven density occupying the subcutaneous soft tissue and involving fascial planes. No primary bone tumor was found. The entire mass was excised. The mass was solid measuring 0.8 x 0.6 x 0.5 cm. Extraskeletal osteoblastic osteosarcoma was diagnosed by light microscopy. The tumor recurred four months after the diagnosis. The tumor was again ressected. The patient was also submitted to low penetration radiation therapy. Nine months after the first biopsy the patient had symptoms due to infiltration to the base of the cranium. He died 10 months after the first biopsy. CONCLUSIONS: The first case with ESOS of the frontal region without a pre-existing condition or a history of irradiation is described.

Osteossarcoma extra-esquelético primário da regiäo frontal / Extraskeletal primary osteosarcoma of the frontal region

Objetivo. Osteossarcoma extra-esquelético (OSEE) primário de partes moles da cabeça é raro e näo há, ao que nos parece, relato dele originando na regiäo frontal. Métodos. Homem de 78 anos, italiano, com história de tumoraçäo em partes moles de regiao frontal há um mês. Tomografia computadorizada mostrou massa de densidade irregular ocupando tecido celular subcutâneo e fáscia. Nenhum tumor ósseo foi encontrado. A tumoraçäo foi completamente ressecada, media 0,8x0,6x0,5cm, e a superfície de corte era sólida. Diagnosticou-se osteossarcoma osteoblástico extra-esquelético. A neoplasia recorreu quatro meses após o diagnóstico e foi novamente ressecado. O paciente foi submetido também a radioterapia de baixa penetraçao, e nove meses depois da primeira biópsia tinha sintomas em decorrência da infiltraçäo neoplásica na base do crânio. O óbito ocorreu dez meses após a primeira biópsia. Conclusäo. Os autores descrevem o primeiro caso de OSEE da regiäo frontal sem uma condiçäo preexistente ou história de irradiaçäo.