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1.
BMC Med Educ ; 24(1): 186, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38395875

RESUMO

BACKGROUND: Digital health has surged during the Covid health crisis, and the use of social media, already prevalent in medicine, has significantly increased. There are Social Networks groups dedicated to physicians with an educational purpose. These groups also facilitate peer discussions on medical questions and the sharing of training materials. OBJECTIVES: The aim of our study was to assess the value of these new tools and their contribution to medical education. METHODS: An anonymous questionnaire was conducted among members of a Social Networks community group for physicians. The survey received responses from 1451 participants. RESULTS: The majority of participants believed they had enriched their medical knowledge and accessed documents they would not have accessed without the group. Subgroup analysis showed that the contribution of this tool is more pronounced for general practitioners and doctors practicing in limited healthcare access. CONCLUSION: It is essential to develop digital tools that enhance physician training, and social networks represent a valuable educational tool.


Assuntos
Clínicos Gerais , Medicina , Humanos , Educação Médica Continuada , Satisfação Pessoal , Inquéritos e Questionários
2.
Cardiovasc Diabetol ; 22(1): 31, 2023 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-36782164

RESUMO

BACKGROUND: The aim of this study was to assess the prevalence of prediabetes and unknown diabetes and its long-term change in a large middle-aged urban population. METHODS: We conducted a screening campaign between 2007 and 2018 for cardiovascular risk factors in the western suburbs of Paris including subjects aged 40-70 (CARVAR 92). Among subjects who reported no previous diabetes, prediabetes and undiagnosed diabetes were defined as follows: fasting plasma glucose (FPG) ≥ 6.1 mmol/l (110 mg/dl) and < 7 mmol/l (126 mg/dl) for prediabetes according to WHO criteria (FPG between 5.6 and 6.9 mmol/l according to ADA criteria) and FPG ≥ 7.0 mmol/l for undiagnosed diabetes. RESULTS: Of the 32,721 subjects in the CARVAR 92 cohort, 32,675 were included in this analysis. The median age of the patients was 56 years [30, 94], 45.4% were male, 5.9% had known diabetes, 36.4% were overweight and 18.7% obese. Among patients without previously known diabetes (n = 30,759), 8.1% had prediabetes according to WHO criteria (27.2% according to ADA criteria) and 2.3% had diabetes. Subjects with prediabetes and unknown diabetes were more likely to be male, older, and overweight or obese than non-diabetic subjects. From 2007 to 2018, the prevalence of prediabetes, unknown diabetes, and known diabetes decreased, except for prediabetes which remained stable for people aged 55-64. CONCLUSION: The prevalence of prediabetes and unknown diabetes remains high but decreased during a 12-year period. About one-quarter of diabetes cases remain undiagnosed. Our results highlight that there is still a room for screening and cardiovascular prevention campaigns. TRIAL REGISTRATION: IRB00012437.


Assuntos
Diabetes Mellitus , Estado Pré-Diabético , Pessoa de Meia-Idade , Humanos , Masculino , Feminino , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/epidemiologia , Sobrepeso , Prevalência , População Urbana , Glicemia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Obesidade , Jejum , Fatores de Risco
3.
Andrologia ; 53(1): e13865, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33108824

RESUMO

Androgen receptor gene (AR) mutations are responsible for androgen insensitivity syndrome (AIS) presenting with a clinical phenotype that ranges from gynaecomastia and/ or infertility in mild AIS (MAIS) to complete testicular feminisation in complete AIS. We report a novel AR gene mutation in two unrelated adult patients with MAIS and we studied its functional impact using 3D modelling. Patient 1, referred for infertility, presented with gynaecomastia, mild hypospadias and bilateral testicular hypotrophy contrasting with high testosterone levels, an elevated FSH, an elevated androgen sensitivity index (ASI) and oligoasthenoteratospermia. In vitro fertilisation and intracytoplasmic sperm injection resulted in a successful twin pregnancy. Patient 2 referred for a decrease in athletic performance had surgically treated gynaecomastia, oligoasthenospermia, high testosterone levels and an elevated ASI. Despite his impaired spermogram, he fathered two children without assisted reproductive technology. AR gene sequencing in the two patients revealed a common novel missense mutation, Ala699Thr, in exon 4 within the ligand-binding domain. 3D modelling studies showed that this mutation may impact dimer stability upon ligand binding or may affect allosteric changes upon dimerisation. This study illustrates the value of structural analysis for the functional study of mutations and expands the database of AR gene mutations.


Assuntos
Síndrome de Resistência a Andrógenos , Adulto , Síndrome de Resistência a Andrógenos/genética , Criança , Éxons , Feminino , Humanos , Masculino , Mutação , Fenótipo , Gravidez , Receptores Androgênicos/genética
4.
Clin Endocrinol (Oxf) ; 89(6): 805-812, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30222204

RESUMO

OBJECTIVE: Mitotane/Op'DDD is used in the treatment of adrenocortical carcinoma and for other causes of hypercortisolism. Mitotane inhibits cortisol secretion and displays adrenolytic and antitumor actions. This compound is a metabolite of the pesticide and endocrine disruptor DDT (dichlorodiphenyltrichloroethane) and is classified among teratogenic compounds worldwide. However, little is known about its effects on human development. DESIGN: The outcome of four children exposed to mitotane during their intrauterine life was examined. PATIENTS: Patients having conceived while taking mitotane, or with detectable mitotane plasma levels, were retrospectively recruited via the French COMETE and FIRENDO networks. MEASUREMENTS: Mitotane in maternal plasma, adrenocortical hormones in children. RESULTS: Three women treated with mitotane gave birth to four children. During early pregnancy, all patients had detectable mitotane plasma levels (0.9, 2.4 and 6.7 mg/L, respectively). During pregnancy, no foetal malformations were detected. The four exposed newborns presented at birth with apparently normal adrenal function and genitalia. One twin female had a low birthweight. Evaluation at birth and after 3 months, 2 years and 7 years of follow-up showed no significant neurological abnormality. Evaluation of adrenocortical functions showed no cortisol deficiency. CONCLUSIONS: Unexpectedly, exposure of these four children to mitotane during foetal life seemed to have no clear teratogenic effect. However, considering the sub-therapeutic mitotane concentrations used here, the small number of cases, and because long-term follow-up is unknown, we strongly advise not to take mitotane during pregnancy and still recommend avoiding pregnancy, at least as long as mitotane plasma levels remain detectable.


Assuntos
Diclorodifenildicloroetano/toxicidade , Feto/efeitos dos fármacos , Mitotano/toxicidade , Adulto , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Estudos Retrospectivos , Adulto Jovem
5.
Hum Mol Genet ; 23(5): 1163-74, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24122441

RESUMO

Carney complex (CNC) is a hereditary disease associating cardiac myxoma, spotty skin pigmentation and endocrine overactivity. CNC is caused by inactivating mutations in the PRKAR1A gene encoding PKA type I alpha regulatory subunit (RIα). Although PKA activity is enhanced in CNC, the mechanisms linking PKA dysregulation to endocrine tumorigenesis are poorly understood. In this study, we used Förster resonance energy transfer (FRET)-based sensors for cAMP and PKA activity to define the role of RIα in the spatiotemporal organization of the cAMP/PKA pathway. RIα knockdown in HEK293 cells increased basal as well as forskolin or prostaglandin E1 (PGE1)-stimulated total cellular PKA activity as reported by western blots of endogenous PKA targets and the FRET-based global PKA activity reporter, AKAR3. Using variants of AKAR3 targeted to subcellular compartments, we identified similar increases in the response to PGE1 in the cytoplasm and at the outer mitochondrial membrane. In contrast, at the plasma membrane, the response to PGE1 was decreased along with an increase in basal FRET ratio. These results were confirmed by western blot analysis of basal and PGE1-induced phosphorylation of membrane-associated vasodilator-stimulated phosphoprotein. Similar differences were observed between the cytoplasm and the plasma membrane in human adrenal cells carrying a RIα inactivating mutation. RIα inactivation also increased cAMP in the cytoplasm, at the outer mitochondrial membrane and at the plasma membrane, as reported by targeted versions of the cAMP indicator Epac1-camps. These results show that RIα inactivation leads to multiple, compartment-specific alterations of the cAMP/PKA pathway revealing new aspects of signaling dysregulation in tumorigenesis.


Assuntos
Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Alprostadil/farmacologia , Complexo de Carney/genética , Complexo de Carney/metabolismo , Membrana Celular/metabolismo , Colforsina/farmacologia , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Inativação Gênica , Células HEK293 , Humanos , Espaço Intracelular/metabolismo , Transporte Proteico , Interferência de RNA , Transdução de Sinais
6.
Clin Endocrinol (Oxf) ; 81(4): 566-72, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24601912

RESUMO

OBJECTIVE: Silent corticotroph adenomas (SCAs) present as nonfunctional pituitary tumours in routine pre-operative evaluation. The objective of this study was to evaluate the diagnostic accuracy of MRI T2-weighted sequences for detecting the corticotroph subtype pre-operatively. DESIGN: The pre-operative T2-weighted MRI sequences were retrospectively evaluated in patients with SCA and two control groups: clinically manifest corticotroph macroadenomas (CSMs) and nonfunctional gonadotroph macroadenomas (NFGMs). All were selected from a registry of 1096 patients in whom transsphenoidal surgery was performed in the same tertiary reference centre. T2-weighted MRI sequences were independently classified by one senior endocrinologist and one senior radiologist who were blinded to the clinical and histological features. PATIENTS: Seventeen patients with SCA, 14 with CSM and 60 with NFGM were included in this study. MEASUREMENTS: Pituitary MRI with T2-weighted sequences. Two aspects were retained: multiple microcysts (MMs) and the absence of microcysts. Hormonal data included plasma prolactin, IGF-1, testosterone or oestradiol, LH, FT4, TSH, morning plasma cortisol and an ACTH-stimulation test, when available. RESULTS: Multiple microcysts were present in 76% (13/17) of SCAs, 21% (3/14) of CSMs and 5% (3/60) of NFGMs. The presence of MMs in clinically nonfunctioning macroadenomas had a sensitivity of 76% and a specificity of 95% for predicting SCA. CONCLUSION: The presence of MMs in T2-weighted MRI is a good diagnostic tool to suggest the corticotroph subtype in an apparently nonfunctional pituitary tumour.


Assuntos
Adenoma Hipofisário Secretor de ACT/diagnóstico , Adenoma Hipofisário Secretor de ACT/patologia , Imageamento por Ressonância Magnética/métodos , Adenoma Hipofisário Secretor de ACT/sangue , Hormônio Adrenocorticotrópico/sangue , Adulto , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
7.
Eur J Endocrinol ; 190(6): 501-508, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38857190

RESUMO

OBJECTIVE: Pituitary stalk interruption syndrome (PSIS) is a rare cause of congenital hypopituitarism. Limited data exist on the gonadotropic status and fertility of adult women with PSIS. Our study aims to describe pubertal development and the evolution of gonadotropic function and fertility in adult women with PSIS. DESIGN: A retrospective multicentric French study. METHODS: We described gonadotropic function in 56 adult women with PSIS from puberty onward. We compared live birth rates per woman with PSIS with age-matched controls from the large French epidemiological cohort (CONSTANCES). Additionally, we assessed height, body mass index (BMI), blood pressure, other metabolic parameters, and socioeconomic status. RESULTS AND CONCLUSIONS: Among 56 women with PSIS, 36 did not experience spontaneous puberty. Of these, 13 underwent ovarian stimulation, resulting in 7 women having a total of 11 children. In the subgroup with spontaneous puberty (n = 20), 4 had a total of 8 pregnancies, while 6 developed secondary gonadotropic deficiency. Women with PSIS had fewer children than controls (0.33 vs 0.63, P = .04). Median height was also lower (160.5 vs 165.0 cm, P < .0001). Although mean blood pressure was lower in women with PSIS compared with controls (111.3/65.9 ± 11.2/8.1 vs 118.7/72.1 ± 10.1/7.7 mmHg, P < .001), there were no significant differences in other metabolic parameters, notably BMI and lipid profile. Employment/academic status was not different in the 2 groups, but fewer women with PSIS were in relationships (42% vs 57.6% in controls, P = .02). The fertility prognosis in patients with PSIS needs optimization. Patients should be informed about the likelihood of declining gonadotropic function over time.


Assuntos
Hipopituitarismo , Hipófise , Humanos , Feminino , Adulto , Estudos Retrospectivos , Hipopituitarismo/sangue , Hipopituitarismo/epidemiologia , Gravidez , Adulto Jovem , Puberdade/fisiologia , França/epidemiologia , Adolescente , Estudos de Casos e Controles
8.
Artigo em Inglês | MEDLINE | ID: mdl-38452869

RESUMO

Pituitary deficiency, or hypopituitarism, is a rare chronic disease. It is defined by insufficient synthesis of one or more pituitary hormones (growth hormone, TSH, ACTH, LH-FSH, prolactin), whether or not associated with arginine vasopressin deficiency (formerly known as diabetes insipidus). In adult patients, it is usually acquired (notably during childhood), but can also be congenital, due to abnormal pituitary development. The present study focuses on congenital pituitary deficiency in adults, from diagnosis to follow-up, including special situations such as pregnancy or the elderly. The clinical presentation is highly variable, ranging from isolated deficit to multiple deficits, which may be part of a syndromic form or not. Diagnosis is based on a combination of clinical, biological (assessment of all hormonal axes), radiological (brain and hypothalamic-pituitary MRI) and genetic factors. Treatment consists in hormonal replacement therapy, adapted according to the period of life and the deficits, which may be progressive. Comorbidities, risk of complications and acute decompensation, and the impact on fertility and quality of life all require adaptative multidisciplinary care and long-term monitoring.

9.
Ann Endocrinol (Paris) ; 84(6): 697-710, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37579837

RESUMO

Acromegaly is a rare disease with prevalence of approximately 60 cases per million, slight female predominance and peak onset in adults in the fourth decade. Clinical diagnosis is often delayed by several years due to the slowly progressive onset of symptoms. There are multiple clinical criteria that define acromegaly: dysmorphic syndrome of insidious onset, symptoms related to the pituitary tumor (headaches, visual disorders), general signs (sweating, carpal tunnel syndrome, joint pain, etc.), complications of the disease (musculoskeletal, cardiovascular, pneumological, dental, metabolic comorbidities, thyroid nodules, colonic polyps, etc.) or sometimes clinical signs of associated prolactin hypersecretion (erectile dysfunction in men or cycle disorder in women) or concomitant mass-induced hypopituitarism (fatigue and other symptoms related to pituitary hormone deficiencies). Biological confirmation is based initially on elevated IGF-I and lack of GH suppression on oral glucose tolerance test or an elevated mean GH on repeated measurements. In confirmed cases, imaging by pituitary MRI identifies the causal tumor, to best determine management. In a minority of cases, acromegaly can be linked to a genetic predisposition, especially when it occurs at a young age or in a familial context. The first-line treatment is most often surgical removal of the somatotroph pituitary tumor, either immediately or after transient medical treatment. Medical treatments are most often proposed in patients not controlled by surgical removal. Conformal or stereotactic radiotherapy may be discussed on a case-by-case basis, especially in case of drug inefficacy or poor tolerance. Acromegaly should be managed by a multidisciplinary team, preferably within an expert center such as a reference or skill center for rare pituitary diseases.


Assuntos
Acromegalia , Hormônio do Crescimento Humano , Neoplasias Hipofisárias , Masculino , Adulto , Humanos , Feminino , Acromegalia/diagnóstico , Acromegalia/etiologia , Acromegalia/terapia , Hormônio do Crescimento Humano/uso terapêutico , Hormônio do Crescimento Humano/metabolismo , Neoplasias Hipofisárias/cirurgia , Teste de Tolerância a Glucose , Protocolos Clínicos
10.
Eur J Endocrinol ; 185(6): 783-791, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34605772

RESUMO

OBJECTIVE: Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment. DESIGN: Follow-up of a cohort of consecutive patients treated by surgery. METHODS: Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients presented with a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan-Meier representation. A cox regression model was used to predict remission. RESULTS: Median follow-up was 18.2 months (range: 2.8-155). In this cohort, 14/114 (12%) patients were not cured by surgery, including ten early surgical failures and four late relapses occurring 37.4 months (33-41.8) after surgery. From Kaplan-Meier estimates, 1-year and 5-year disease free survival was 90.9% (95% CI: 85.6-96.4%) and 81% (95% CI: 71.2-92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P < 0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty. CONCLUSIONS: In well-selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.


Assuntos
Agonistas de Dopamina/uso terapêutico , Neuroendoscopia/tendências , Neoplasias Hipofisárias/terapia , Prolactinoma/terapia , Adolescente , Adulto , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neuroendoscopia/métodos , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/diagnóstico , Prolactina/sangue , Prolactinoma/sangue , Prolactinoma/diagnóstico , Resultado do Tratamento , Adulto Jovem
11.
Hum Mutat ; 31(4): 369-79, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20358582

RESUMO

PRKAR1A encodes the regulatory subunit type 1-alpha (RIalpha) of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA). Inactivating PRKAR1A mutations are known to be responsible for the multiple neoplasia and lentiginosis syndrome Carney complex (CNC). To date, at least 117 pathogenic variants in PRKAR1A have been identified (online database: http://prkar1a.nichd.nih.gov). The majority are subject to nonsense mediated mRNA decay (NMD), leading to RIalpha haploinsufficiency and, as a result, activated cAMP signaling. Recently, it became apparent that CNC may be caused not only by RIalpha haploinsufficiency, but also by the expression of altered RIalpha protein, as proven by analysis of expressed mutations in the gene, consisting of amino acid substitutions and in-frame genetic alterations. In addition, a new subgroup of mutations that potentially escape NMD and result in CNC through altered (rather than missing) protein has been analyzed-these are frame-shifts in the 3' end of the coding sequence that shift the stop codon downstream of the normal one. The mutation detection rate in CNC patients is recently estimated at above 60%; PRKAR1A mutation-negative CNC patients are characterized by significant phenotypic heterogeneity. In this report, we present a comprehensive analysis of all presently known PRKAR1A sequence variations and discuss their molecular context and clinical phenotype.


Assuntos
Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Processamento Alternativo/genética , Complexo de Carney/diagnóstico , Complexo de Carney/enzimologia , Complexo de Carney/genética , Mutação da Fase de Leitura/genética , Estudos de Associação Genética , Humanos , Penetrância , Deleção de Sequência/genética
12.
Eur Thyroid J ; 9(5): 263-268, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33088795

RESUMO

INTRODUCTION: Resistance to thyroid hormone beta (RTHß) is a rare disease with an autosomal dominant transmission. Diagnosis may be challenging especially in patients with hyper- or hypothyroidism. CASE PRESENTATION: A 31-year-old male patient with suppressed thyroid-stimulating hormone (TSH), elevated free thyroxine and free triiodothyronine, along with high thyroid receptor antibodies was diagnosed with Graves' disease. Benzylthiouracil was started. One month later, reduced sensitivity to thyroid hormones was suspected because of persistently high thyroid hormone levels contrasting with high TSH level. Molecular analysis highlighted a 10c.1357C>T p.P453S mutation in the thyroid hormone receptor beta gene (THRB). RTHß was diagnosed. Several relatives also had RTHß (the mother, the young son, and 2 out of 3 siblings). Autoimmune hypothyroidism was present in the mother, whereas 2 out of 3 siblings had asymptomatic autoimmunity. DISCUSSION/CONCLUSION: Both Graves' disease and autoimmune hypothyroidism were described in patients with RTHß. We show here for the first time that autoimmune hypo- and hyperthyroidism may coexist in kindred with RTHß. Seven previously published cases of Graves' disease and RTHß were retrieved and analyzed. Treatments and thyroid hormone level targets are discussed as well as the possible link between RTHß and autoimmune thyroid diseases.

14.
Horm Res ; 71(3): 132-41, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19188737

RESUMO

Heterozygous germline mutations in the gene encoding the aryl hydrocarbon receptor-interacting protein (AIP) were first described in two Finnish families with pituitary adenomas. The gene is involved in about 15% of familial isolated pituitary adenomas (FIPA), in about 50% of cases of familial acromegaly and in a small proportion of acromegalic patients with sporadic presentation. This review describes the genetic and clinical features of published patients with AIP, with either familial or sporadic pituitary tumors. A genotype-phenotype correlation is proposed: patients with AIP mutations resulting in a truncated protein are significantly younger than those bearing a mutation which preserves the structure of the C-terminal end of the protein (22.7 +/- 9.6 vs. 29.8 +/- 10.9 years). Pituitary tumors linked to AIP mutations are almost exclusively somatotropic (87.5%, n = 56/64) or lactotropic (9.4%, n = 6). Patients with AIP mutations are mostly men (70%, 44 M/19 F), suffer macroadenomas (97%) and are younger at diagnosis (24.4 +/- 10.5 years) than unselected patients with pituitary tumors. Thus, AIP is involved in the development of pituitary tumors, especially involving the somatomammotroph lineage. Genetic testing could be discussed for FIPAs and in young acromegalic patients with a sporadic presentation. Functional studies are needed to understand AIP-induced tumorigenesis.


Assuntos
Adenoma/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Neoplasias Hipofisárias/genética , Adenoma/diagnóstico , Adenoma/metabolismo , Linhagem da Célula/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Biológicos , Mutação/fisiologia , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/metabolismo , Somatotrofos/metabolismo , Somatotrofos/fisiologia
15.
J Clin Endocrinol Metab ; 92(5): 1952-5, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17299063

RESUMO

CONTEXT: Limited screening suggests that three germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are not involved in sporadic pituitary tumorigenesis. Multiple novel mutations of this gene have since been identified in familial isolated pituitary adenoma cohorts. OBJECTIVE: The objective of the study was to undertake full AIP coding sequence screening to assess for the presence of germline and somatic mutations in European Union subjects with sporadic pituitary tumors. DESIGN: The study design was the analysis of DNA from peripheral blood lymphocytes and analysis of exons 1-6 and paraexonic intron sequences of AIP. Multiplex ligation-dependent probe amplification was used to screen separate sporadic pituitary tumor tissue samples for discrete and extensive deletions or mutations of the AIP gene. SETTING: The study was conducted in university tertiary referral Clinical Genetics, Molecular Biology, and Endocrinology Departments. RESULTS: In 107 patients [prolactinomas (n =49), nonfunctioning tumors (n = 29), somatotropinomas (n = 26), ACTH-secreting tumors (n = 2), TSH-secreting tumors (n = 1)], no germline mutations of AIP were demonstrated. Among a group of 41 tumor samples from other subjects, a novel AIP mutation (R22X) was found in one sample in which the corresponding allele was deleted; follow-up screening of the patient demonstrated a germline R22X AIP mutation. CONCLUSIONS: AIP mutations do not appear to play a prominent role in sporadic pituitary tumorigenesis in this population of European subjects.


Assuntos
Adenoma/genética , Mutação/genética , Neoplasias Hipofisárias/genética , Proteínas/genética , Adulto , DNA de Neoplasias/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/genética , Mutação/fisiologia , Polimorfismo Genético/genética
16.
Eur J Endocrinol ; 157(1): 1-8, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17609395

RESUMO

OBJECTIVE: Germline mutations of the aryl hydrocarbon receptor-interacting protein gene (AIP) have recently been described in three families with GH or prolactin-secreting tumors, as well as in a few patients with apparently sporadic somatotropinomas. The aim of the study was to determine the prevalence of AIP mutations in a large cohort of patients with apparently sporadic GH-secreting tumors. DESIGN: One hundred and fifty-four patients were included in a prospective cohort designed to study the genetic predisposition to GH-secreting tumors together with 270 controls. METHODS: In all these subjects, the entire coding sequence of the AIP gene was screened for germline mutations. RESULTS: AIP mutations were detected in 5 out of 154 patients (3%): nonsense mutations in exon 4 (p.Lys201X; n = 2) and in exon 6 (p.Arg304X), one deletion in exon 3 (c.404delA; pHis135LeufsX21), and one mutation affecting the splice acceptor site of exon 4 (c.469-2 A > G). The five patients with an AIP mutation were significantly younger (mean age +/- S.D.: 25 +/- 10 vs 43 +/- 14 years, P = 0.005) and three of them presented with gigantism. One missense mutation (p.Arg304Gln) was found in a single patient that was absent in all controls. CONCLUSIONS: Germline mutations of the AIP gene were found in a small proportion of patients with sporadic pituitary somatotropinomas. This study shows that age and gigantism are simple clinical features which can help to select patients for mutation screening. It also supports the role of AIP in pituitary tumorigenesis.


Assuntos
Acromegalia/genética , Adenoma/genética , Códon sem Sentido , Mutação em Linhagem Germinativa , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Proteínas/genética , Adolescente , Adulto , Fatores Etários , Idoso , Estudos de Casos e Controles , Códon sem Sentido/análise , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Testes Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade
17.
Pituitary ; 9(3): 211-9, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17036196

RESUMO

Primary Pigmented Nodular Adrenocortical Disease (PPNAD) is a rare primary bilateral adrenal defect causing corticotropin-independent Cushing's syndrome. It occurs mainly in children and young adults. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. PPNAD is most often diagnosed in patients with Carney complex (CNC), but it can also be observed in patients without other manifestations or familial history (isolated PPNAD). The CNC is an autosomal dominant multiple neoplasia syndrome characterized by the association of myxoma, spotty skin pigmentation and endocrine overactivity. One of the putative CNC genes has been identified as the gene of the regulatory R1A subunit of protein kinase A (PRKAR1A), located at 17q22-24. Germline heterozygous inactivating mutations of PRKAR1A have been reported in about 45% of patients with CNC, and up to 80% of CNC patients with Cushing's syndrome due to PPNAD. Interestingly, such inactivating germline PRKAR1A mutations have also been found in patients with isolated PPNAD. The hot spot PRKAR1A mutation termed c.709[-7-2]del6 predisposes mostly to isolated PPNAD, and is the first clear genotype/phenotype correlation described for this gene. Somatic inactivating mutations of PRKAR1A have been observed in macronodules of PPNAD and in sporadic cortisol secreting adrenal adenomas. Isolated PPNAD is a genetic heterogenous disease, and recently inactivating mutations of the gene of the phosphodiesterase 11A4 (PDE11A4) located at 2q31-2q35 have been identified in patients without PRKAR1A mutations. Interestingly, both PRKAR1A and PDE11A gene products control the cAMP signaling pathway, which can be altered at various levels in endocrine tumors.


Assuntos
Doenças do Córtex Suprarrenal/genética , Síndrome de Cushing/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Mutação , Transtornos da Pigmentação/genética , Doenças do Córtex Suprarrenal/complicações , Doenças do Córtex Suprarrenal/enzimologia , Doenças do Córtex Suprarrenal/patologia , Animais , Síndrome de Cushing/enzimologia , Síndrome de Cushing/patologia , AMP Cíclico/metabolismo , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulação Enzimológica da Expressão Gênica , Predisposição Genética para Doença , Hormônios/metabolismo , Humanos , Neoplasia Endócrina Múltipla/enzimologia , Neoplasia Endócrina Múltipla/genética , Transtornos da Pigmentação/complicações , Transtornos da Pigmentação/enzimologia , Transtornos da Pigmentação/patologia , Transdução de Sinais/genética
18.
Eur J Endocrinol ; 174(4): 523-30, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26792934

RESUMO

CONTEXT: Recently, germline and somatic GPR101 p.(E308D) mutation was found in patients with isolated acromegaly. It is not known whether GPR101 point mutations are associated with other histological types of pituitary adenoma. OBJECTIVE: We sought germline GPR101 mutations in patients with sporadic pituitary adenomas, and compared the phenotypes of GPR101 mutation carriers and AIP mutation carriers. DESIGN: An observational cohort study performed between 2007 and 2014 in a single referral center. PARTICIPANTS: This prospective study involved 766 unselected patients (413 women) with sporadic pituitary adenomas of all histotypes. METHODS: Entire GPR101 and AIP coding sequence were screened for germline mutations. RESULTS: Twelve patients (1.6%) were found to carry the GPR101 p.(E308D) mutation or rare GPR101 variants. The minor allele frequency of the GPR101 mutation and variants was higher in patients with pituitary adenomas than in unaffected individuals included in the Exome Aggregation Consortium database. Three of the six patients with the GPR101 p.(E308D) mutation had adult-onset acromegaly, two had adrenocorticotropin-secreting adenomas, and one had a nonfunctioning macroadenoma. Six patients carried rare GPR101 variants. Germline AIP mutations or rare AIP variants were identified in 32 patients (4.2%). AIP mutation carriers were younger at diagnosis than GPR101 mutation carriers and non carriers. None of the patients harbored mutations in both the GPR101 and AIP genes. CONCLUSION: Germline GPR101 mutations are very rare in patients with sporadic pituitary adenomas of various histotypes. No digenism with AIP was identified. Further studies are required to establish whether and how genetic variation in GPR101 gene contributes to pituitary tumorigenesis.


Assuntos
Adenoma/genética , Mutação em Linhagem Germinativa , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hipofisárias/genética , Receptores Acoplados a Proteínas G/genética , Adenoma/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Feminino , Deleção de Genes , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/epidemiologia , Adulto Jovem
19.
Ann Endocrinol (Paris) ; 77(2): 139-47, 2016 Jun.
Artigo em Francês | MEDLINE | ID: mdl-27172868

RESUMO

Adrenocortical carcinoma is a rare cancer with a poor but heterogeneous prognosis. These tumours are more frequently encountered in women, sometimes very young and may be diagnosed in women in their child bearing years or already pregnant. Several clinical data have indicated that the secretion and or proliferation of adrenocortical tumors may be affected by the hormonal context of pregnancy. In this review, we will examine the link between ACC and pregnancy in two main aspects. We will first consider the situation of a pregnant woman with a clinical suspicion of adrenocortical carcinoma: which diagnostic procedures will be useful and safe for the foetus? What are the therapeutic options? What is the prognosis if the diagnosis is confirmed? In a second part, we will examine the possible risk of mothering a child in a patient previously treated for an ACC. The data shown here were obtained from studies carried out in a tertiary reference medical centre in Paris (Hôpital Cochin) and from the European Network for the Study of Adrenal Tumor (ENS@T) database of adrenocortical carcinoma.


Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Complicações Neoplásicas na Gravidez , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/terapia , Técnicas de Diagnóstico Endócrino/efeitos adversos , Feminino , Humanos , Gravidez , Complicações Neoplásicas na Gravidez/diagnóstico , Complicações Neoplásicas na Gravidez/terapia , Diagnóstico Pré-Natal/efeitos adversos , Diagnóstico Pré-Natal/métodos , Prognóstico
20.
Ann Endocrinol (Paris) ; 76(3): 191-200, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26054868

RESUMO

Prevalence of pituitary incidentaloma is variable: between 1.4% and 27% at autopsy, and between 3.7% and 37% on imaging. Pituitary microincidentalomas (serendipitously discovered adenoma <1cm in diameter) may increase in size, but only 5% exceed 10mm. Pituitary macroincidentalomas (serendipitously discovered adenoma>1cm in diameter) show increased size in 20-24% and 34-40% of cases at respectively 4 and 8years' follow-up. Radiologic differential diagnosis requires MRI centered on the pituitary gland. Initial assessment of nonfunctioning (NF) microincidentaloma is firstly clinical, the endocrinologist looking for signs of hypersecretion (signs of hyperprolactinemia, acromegaly or Cushing's syndrome), followed up by systematic prolactin and IGF-1 assay. Initial assessment of NF macroincidentaloma is clinical, the endocrinologist looking for signs of hormonal hypersecretion or hypopituitarism, followed up by hormonal assay to screen for hypersecretion or hormonal deficiency and by ophthalmologic assessment (visual acuity and visual field) if and only if the lesion is near the optic chiasm (OC). NF microincidentaloma of less than 5mm requires no surveillance; those of≥5mm are not operated on but rather monitored on MRI at 6months and then 2years. Macroincidentaloma remote from the OC is monitored on MRI at 1year, with hormonal exploration (for anterior pituitary deficiency), then every 2years. When macroincidentaloma located near the OC is managed by surveillance rather than surgery, MRI is recommended at 6months, with hormonal and visual exploration, then annual MRI and hormonal and visual assessment every 6months. Surgery is indicated in the following cases: evolutive NF microincidentaloma, NF macroincidentaloma associated with hypopituitarism or showing progression, incidentaloma compressing the OC, possible malignancy, non-compliant patient, pregnancy desired in the short-term, or context at risk of apoplexy.


Assuntos
Neoplasias Hipofisárias/terapia , Consenso , Humanos , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/epidemiologia , Prevalência
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