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.

Expression of E-cadherin, Slug and NCAM and its relationship to tumor invasiveness in patients with acromegaly

Pituitary adenomas account for 10-15% of primary intracranial tumors. Growth hormone (GH)-secreting adenomas account for 13% of all pituitary adenomas and cause acromegaly. These tumors can be aggressive, invade surrounding structures and are highly recurrent. The objective of this study was to evaluate E-cadherin, Slug and neural cell adhesion molecule (NCAM) expression in GH-secreting pituitary adenomas and its relationship to tumor invasiveness. A cross-sectional study of patients who underwent hypophysectomy due to GH-secreting pituitary adenoma from April 2007 to December 2014 was carried out. The medical records were reviewed to collect clinical data. Immediately after surgery, tumor samples were frozen in liquid nitrogen and stored in a biofreezer at -80°C for assessment of E-cadherin 1 (CDH1), SLUG (SNAI2), and NCAM (NCAM1) by real-time PCR. The samples were fixed in formalin and embedded in paraffin for immunohistochemical analysis of E-cadherin and NCAM. Thirty-five patients with acromegaly were included in the study. Of these, 65.7% had invasive tumors. Immunohistochemically, E-cadherin was expressed in 96.7% of patients, and NCAM in 80% of patients. There was no statistically significant relationship between tumor grade or invasiveness and immunohistochemical expression of these markers. Regarding gene expression, 50% of cases expressed CDH1, none expressed SNAI2, and 53.3% expressed NCAM1. There was no statistically significant relationship between tumor grade or invasiveness and gene expression of CDH1, SNAI2, and NCAM1. The absence of Slug overexpression and of E-cadherin and NCAM suppression suggests that expression of these markers is not associated with tumor invasiveness in GH-secreting pituitary adenomas.

Genetic studies in a coexistence of acromegaly, pheochromocytoma, gastrointestinal stromal tumor (GIST) and thyroid follicular adenoma / Estudos genéticos na coexistência de acromegalia, feocromocitoma, tumor do estroma gastrointestinal (GIST) e adenoma folicular de tireoide

We report on an adult woman with rare coexistence of acromegaly, pheochromocytoma (PHEO), gastrointestinal stromal tumor (GIST), intestinal polyposis, and thyroid follicular adenoma. At the age of 56, she was diagnosed with acromegaly caused by a pituitary macroadenoma, treated by transsphenoidal surgery, radiotherapy, and octreotide. During routine colonoscopy, multiple polyps were identified as tubular adenomas with high-grade dysplasia on histology. Years later, an abdominal mass of 8.0 x 6.2 cm was detected by routine ultrasound. Surgical exploration revealed an adrenal mass and another tumor adhered to the lesser gastric curvature, which were removed. Pathology confirmed the diagnosis of PHEO and GIST. PHEO immunohistochemistry was negative for GHRH. During follow-up, nodular goiter was found with normal levels of calcitonin and inconclusive cytology. Near-total thyroidectomy was performed, revealing a follicular adenoma. Her family history was negative for all of these tumor types. Genetic analysis for PHEO/paraganglioma genes (SDH A-D, SDHAF2, RET, VHL, TMEM127, and MAX), and pituitary-related genes (AIP, MEN1, and p27) were negative. Though the finding of PHEO and acromegaly with multiple other tumors could be a fortuitous coexistence, we suggest that this case may represent a new variant of MEN syndrome with a de novo germline mutation in a not yet identified gene. Arq Bras Endocrinol Metab. 2012;56(8):507-12.

Relatamos o caso de uma mulher com rara coexistência de acromegalia, feocromocitoma (FEO), tumor do estroma gastrointestinal (GIST), polipose intestinal e adenoma folicular de tireoide. Aos 56 anos, ela foi diagnosticada com acromegalia por um macroadenoma hipofisário, tratado com cirurgia transesfenoidal, radioterapia e octreotide. Uma colonoscopia de rotina detectou múltiplos pólipos, que à histologia eram adenomas tubulares com alto grau de displasia. Anos mais tarde, uma ecografia detectou uma massa abdominal de 8.0 x 6.2 cm, que na exploração cirúrgica era uma lesão adrenal e outro tumor aderido à pequena curvatura gástrica. A patologia confirmou os diagnósticos de FEO e GIST. A imuno-histoquímica do FEO foi negativa para GHRH. No seguimento, encontrou-se um bócio nodular com níveis normais de calcitonina e citologia inconclusiva. Após tireoidectomia total o diagnóstico histológico foi de adenoma folicular. A história familiar era negativa para todos esses tumores. As análises genéticas para genes de síndromes de FEO/paragangliomas (SDH A-D, SDHAF2, RET, VHL, TMEM127 e MAX) e para hipofisárias (AIP, MEN1 e p27) foram todas negativas. Embora a presença de FEO e acromegalia com múltiplos outros tumores possa ser uma coexistência fortuita, acreditamos na possibilidade de uma nova variante de NEM com uma mutação germinativa de novo em um gene ainda não identificado Arq Bras Endocrinol Metab. 2012;56(8):507-12.

Familial gigantism

Familial GH-secreting tumors are seen in association with three separate hereditary clinical syndromes: multiple endocrine neoplasia type 1, Carney complex, and familial isolated pituitary adenomas.

Clinical and genetic aspects of familial isolated pituitary adenomas

Pituitary adenomas represent a group of functionally diverse neoplasms with relatively high prevalence in the general population. Most occur sporadically, but inherited genetic predisposing factors are increasingly recognized. Familial isolated pituitary adenoma is a recently defined clinical entity, and is characterized by hereditary presentation of pituitary adenomas in the absence of clinical and genetic features of syndromic disease such as multiple endocrine neoplasia type 1 and Carney complex. Familial isolated pituitary adenoma is inherited in an autosomal dominant manner and accounted for approximately 2-3% of pituitary tumors in some series. Germline mutations in the aryl-hydrocarbon interacting protein gene are identified in around 25% of familial isolated pituitary adenoma kindreds. Pituitary adenomas with mutations of the aryl-hydrocarbon interacting protein gene are predominantly somatotropinomas and prolactinomas, but non-functioning adenomas, Cushing disease, and thyrotropinoma may also occur. These tumors may present as macroadenomas in young patients and are often relatively difficult to control. Furthermore, recent evidence indicates that aryl-hydrocarbon interacting protein gene mutations occur in >10% of patients with sporadic macroadenomas that occur before 30 years of age, and in >20% of children with macroadenomas. Genetic screening for aryl-hydrocarbon interacting protein gene mutations is warranted in selected high-risk patients who may benefit from early recognition and follow-up.

Análise do gene AIP na acromegalia familial isolada / Analysis of the AIP gene in familial isolated acromegaly

A acromegalia é doença insidiosa e desfigurante caracterizada por um crescimento desproporcional dos ossos das mãos, pés e do crânio devido à exposição crônica a altos níveis de hormônio de crescimento (GH) e de seu efetor insuline growth factor 1 (IGF-1). Trata-se de uma doença rara, com incidência estimada de 3-4 casos por milhão, com prevalência de aproximadamente 50 casos por milhão de pessoas. A principal causa da acromegalia é a presença de um tumor hipofisário secretor de GH (somatotropinoma). Caso o somatotropinoma ocorra durante a infância ou adolescência, antes do fechamento das epífises dos ossos longos, a criança crescerá longitudinalmente de forma descontrolada, caracterizando a forma clínica gigantismo. Na grande maioria dos casos a acromegalia se apresenta na forma esporádica, entretanto casos familiais da doença podem ocorrer associados à Neoplasia Endócrina Múltipla tipo 1 (NEM-1), ao complexo de Carney (CNC) e à acromegalia familial isolada (IFS). Os genes responsáveis pela NEM-1 (MEN1) e CNC (PRKAR1A) foram clonados há mais 10 anos, entretanto etiologia molecular da IFS permaneceu desconhecida até recentemente. Vierimaa et al. (2006) combinaram estudos de ligação por análise de polimorfismos e estudos de expressão gênica e identificaram mutações no gene AIP em famílias com acromegalia não-NEM-1 e não-CNC; além de perda de heterozigose (LOH) nos somatotropinomas dos pacientes com mutação AIP. No presente estudo, investigamos o gene AIP em três famílias brasileiras com IFS e em seus tumores (hipofisários e não-hipofisários). Descrevemos uma nova mutação AIP (Y268X) em uma família brasileira com IFS, confirmando o papel desse novo gene na predisposição a tumores hipofisários. A partir de dados gerados em uma extensa revisão da literatura, sugerimos que os tumores hipofisários familiais isolados são doenças multigênicas que possuiriam um gene principal, mas que sofreriam influência de outros genes/loci ainda pouco caracterizados...

Acromegaly is a rare disfigurating and insidious disease characterized by enlargement of hands, feet and skull bones due to excess of growth hormone (GH) secreted by a pituitary tumor (somatotropinoma). The majority of the cases with acromegaly is sporadic, however it may occur in association with inherited disorders as Multiple Endocrine Neoplasia type 1 (MEN1), Carney complex (CNC) and Isolated Familial Somatotropinoma (IFS). The genes associated with MEN1 syndrome (MEN1) and CNC (PRKAR1A) have been described more than a decade ago, however until very recently the molecular etiology of IFS remained unknown. Using a combined strategy of single nucleotide polymorphism (SNP) analysis and gene expression analysis, Vierimaa et al. (2006) described mutations in the AIP gene occurring in families with acromegaly not associated with MEN1 and CNC. In the current study, we investigated three Brazilian families with IFS and were able to describe two germline mutations in the AIP gene, confirming the role of this new gene in the predisposition to familial somatotropinoma. We revised the literature of genetic studies of isolated pituitary adenoma syndromes, which indicated a genetic heterogeneity as well as possible multigenic inheritance for these diseases. Thus, we investigated the role of several genes/loci (SSTR2, SSTR5, CDKN1B, AHR, PRKAR1A, PTTG, PROP1, MEG3, RB1 and 2p16) selected as potentially acting as phenotypic modulators in IFS. Our data indicate that AIP-mutated patients are prone to pituitary disease, however it is necessary the co-segregation of markers located at oncogenic regions to the development of the pituitary tumors and manifestation of the disease. Herein, we also present the first somatic analysis of non-pituitary tumors of AIP-mutated patients. A potential role of AIP, which is implicated in the cAMP pathway, could not be excluded in the development of an adrenocortical carcinoma.

Isolated familial somatotropinoma: 11Q13-LOH and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis

OBJECTIVE: Non-pituitary tumors have been reported in a subset of patients harboring germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. However, no detailed investigations of non-pituitary tumors of AIP-mutated patients have been reported so far. PATIENTS: We examined a MEN1- and p53-negative mother-daughter pair with acromegaly due to somatotropinoma. Subsequently, the mother developed a large virilizing adrenocortical carcinoma and a grade II B-cell non-Hodgkin's lymphoma. DESIGN: Mutational analysis was performed by automated sequencing. Loss-of-heterozygosity (LOH) analysis was carried out by sequencing and microsatellite analysis. AIP expression was assessed through quantitative PCR (qPCR) and immunohistochemistry. RESULTS: The functional inactivating mutation c.241C>T (R81X), which blocks the AIP protein from interacting with phosphodiesterase 4A (PDE4A), was identified in the heterozygous state in the leukocyte DNA of both patients. Analyzing the tumoral DNA revealed that the AIP wild-type allele was lost in the daughter's somatotropinoma and the mother's adrenocortical carcinoma. Both tumors displayed low AIP protein expression levels. Low AIP gene expression was confirmed by qPCR in the adrenocortical carcinoma. No evidence of LOH was observed in the DNA sample from the mother's B-cell lymphoma, and this tumor displayed normal AIP immunostaining. CONCLUSIONS: Our study presents the first molecular analysis of non-pituitary tumors in AIP-mutated patients. The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.

Lipodistrofia generalizada congênita / Congenital generalized lipodystrophy

OBJETIVO: Apresentar as principais características clínicas e bioquímicas da lipodistrofia generalizada congênita, desordem rara e pouco conhecida dos pediatras. DESCRIÇAO: Nos ambulatórios de Doenças Nutricionais e de Endocrinologia do Serviço de Pediatria do Hospital das Clínicas da UFMG, foram identificados oito pacientes com lipodistrofia generalizada congênita. As características clínicas comuns a todos os casos foram hipertrofia muscular, lipoatrofia generalizada e aparência acromegálica. Manifestações clínico-laboratoriais associadas incluíram acantose nigricans em cinco pacientes, hepatoesplenomegalia em seis, hipertrigliceridemia com baixas concentrações de HDL em sete, hipertrofia cardíaca em um e diabetes melito secundário em dois pacientes. Todos os pacientes estão em controle clínico e dietético, visando à correção ou prevenção dos distúrbios metabólicos. COMENTARIOS: As características fenotípicas da lipodistrofia generalizada congênita são bem identificadas, possibilitando o diagnóstico clínico na maioria dos casos. Trata-se de uma síndrome rara que ilustra a importância do funcionamento normal do tecido adiposo para a maioria dos processos metabólicos vitais do organismo. O seu melhor conhecimento poderá abrir novos horizontes em estudos de doenças mais prevalentes como o diabetes melito e a obesidade.

Acromegalia familiar: Caso 05/96 (Serviço de Endocrinologia, Hospital Universitário Clementino Fraga Filho e Departamento de Clínica Médica, Faculdade de Medicina da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ) / Familial acromegaly: Case 05/96 (Serviço de Endocrinologia, Hospital Universitário Clementino Fraga Filho e Departamento de Clínica Médica, Faculdade de Medicina da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ)

Apresentamos o estudo de uma família na qual comprovadamente três membros têm acromegalia/gigantismo. A confirmaçäo diagnóstica foi obtida pela análise histopatológica e imunohistoquímica do tumor hipofisário, além das características clínicas, dosagens hormonais (basais e testes dinâmicos) e achados de imagem (radiografias convencionais do crâneo e esqueleto e tomografia computadorizada da sela turca). Foi descartada em todos os pacientes a síndrome de adenomatose endócrina do tipo I (MEA I), ficando rotulados como acromegalia familiar isolada.