A novel mutation in PRKAR1A gene in a patient with Carney complex presenting with pituitary macroadenoma, acromegaly, Cushing's syndrome and recurrent atrial myxoma

SUMMARY Carney complex (CNC) is a rare syndrome of multiple endocrine and non-endocrine tumors. In this paper we present a 23-year-old Iranian woman with CNC who harbored a novel mutation (c.642dupT) in PRKAR1A gene. This patient presented with pituitary macroadenoma, acromegaly, recurrent atrial myxoma, Cushing's syndrome secondary to primary pigmented nodular adrenocortical disease and pigmented schwanoma of the skin. PRKAR1A gene was PCR amplified using genomic DNA and analyzed for sequence variants which revealed the novel mutation resulting in substitution of amino acid cysteine instead of the naturally occurring valine in the peptide chain and a premature stop codon at position 18 (V215CfsX18). This change leads to development of tumors in different organs due to lack of tumor suppressive activity secondary to failure of synthesis of the related protein.

Inflammatory myopathy in the context of an unusual overlapping laminopathy

Summary Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.

Etiopatogênese molecular dos tumores corticotróficos / Molecular etiopathogenesis of corticotrophic tumors

Os corticotrofinomas representam aproximadamente 80 por cento dos casos de síndrome de Cushing de origem endógena em adultos. Na última década, foram feitos avanços consideráveis na compreensäo do desenvolvimento da hipófise anterior, na patogênese dos tumores hipofisários e nos fatores envolvidos na progressäo tumoral. A aplicaçäo do conceito geral de tumorigênese é adequada aos tumores corticotróficos, sendo este um processo que envolve várias etapas, resultantes da interaçäo de eventos iniciadores e subseqüentemente de fatores promotores, sendo portanto multifatorial. De modo geral, oncogenes e genes de supressäo tumoral freqüentemente relacionados a outros tipos de tumores näo parecem contribuir neste processo, embora alteraçäo na expressäo de alguns destes genes, como p53, plb e PTTG, possa estar relacionada a um comportamento fenotípico mais agressivo. A investigaçäo das vias regulatórias específicas dos corticotrofos, principalmente a estrutura e a expressäo dos genes dos receptores do CRH, AVP e GR também näo evidenciou a presença de mutações. Entretanto, é possível que alterações em regiões promotoras ou em co-fatores que regulam estes genes possam estar presentes. Estudos futuros sobres os mecanismos de regulaçäo da célula corticotrófica normal e tumoral deveräo contribuir na definiçäo de marcadores prognósticos e no desenvolvimento de novas modalidades de tratamento.

Absence of mutations in the P53 tumor suppressor gene in non-invasive Cushing adenomas

A lot of evidence supports the existence of a monoclonal origin for pituitary tumors, and several genetic alterations have already been confirmed as necessary or sufficient for unrestrained cellular growth and pituitary function. The p53 gene, a known tumor-suppressor gene (TSG), encodes a protein that exerts antiproliferative effects such as cell-growth arrest and apoptosis in response to several types of stimuli. In fact, several human cancers are believed to be caused by p53 mutations. In the case of pituitary tumors, p53 protein accumulation has been described in ACTH-secreting pituitary adenomas. Since increased amounts of the p53 protein are often related to mutations of its gene, we decided to explore the existence of p53 mutations in the tumor tissues of 9 patients bearing non-invasive corticotropinomas, excised by the transphenoidal route. We screened mutations in exons 5 to 8 of the p53 gene by the PCR-SSCP analysis. We were not able to find any mutation in the exons investigated. Our results are in close accordance with those obtained previously for other types of pituitary tumors.