Jérôme Bertherat

Assistance Publique – Hôpitaux de Paris, Lutetia Parisorum, Île-de-France, France

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Publications (296)1484.17 Total impact

  • S Espiard, B Ragazzon, J Bertherat
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    ABSTRACT: Stimulation of the cAMP pathway by adrenocorticotropin (ACTH) is essential for adrenal cortex maintenance, glucocorticoid and adrenal androgens synthesis, and secretion. Various molecular and cellular alterations of the cAMP pathway have been observed in endocrine tumors. Protein kinase A (PKA) is a central key component of the cAMP pathway. Molecular alterations of PKA subunits have been observed in adrenocortical tumors. PKA molecular defects can be germline in hereditary disorders or somatic in sporadic tumors. Heterozygous germline inactivating mutations of the PKA regulatory subunit RIα gene (PRKAR1A) can be observed in patients with ACTH-independent Cushing's syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A is considered as a tumor suppressor gene. Interestingly, these mutations can also be observed as somatic alterations in sporadic cortisol-secreting adrenocortical adenomas. Germline gene duplication of the catalytic subunits Cα (PRKACA) has been observed in patients with PPNAD. Furthermore, exome sequencing revealed recently activating somatic mutations of PRKACA in about 40% of cortisol-secreting adrenocortical adenomas. In vitro and in vivo functional studies help in the progress to understand the mechanisms of adrenocortical tumors development due to PKA regulatory subunits alterations. All these alterations are observed in benign oversecreting tumors and are mimicking in some way cAMP pathway constitutive activation. On the long term, unraveling these alterations will open new strategies of pharmacological treatment targeting the cAMP pathway in adrenal tumors and cortisol-secretion disorders.
    08/2014;
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    ABSTRACT: Illegitimate G-protein coupled receptors are known to control cortisol secretion in adrenal adenomas and bilateral macronodular adrenal hyperplasias (BMAHs) causing Cushing's syndrome. In the present study, we have evaluated the role of glucagon in the regulation of cortisol secretion in 13 patients with BMAH or adrenocortical adenoma causing subclinical or overt Cushing's syndrome. Injection of glucagon provoked an increase in plasma cortisol in 2 patients. After surgery, immunohistochemical studies showed the presence of glucagon receptor-like immunoreactivity in clusters of spongiocytic cells in adrenal tissues from patients who were sensitive in vivo to glucagon. We also observed an in vitro cortisol response to vasoactive intestinal peptide from an adenoma, which was insensitive to glucagon and pituitary adenylate cyclase-activating peptide. Altogether, our data show that ectopic glucagon receptors are expressed in some adrenal cortisol-producing benign lesions. Our results also indicate that circulating glucagon may influence cortisol release under fasting conditions.
    07/2014;
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    ABSTRACT: Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating mutations of the PRKAR1A tumor suppressor gene that encodes the regulatory subunit R1α of the cAMP-dependent protein kinase (PKA). In human and mouse adrenocortical cells, these mutations lead to increased PKA activity, which results in increased resistance to apoptosis that contributes to the tumorigenic process. We used in vitro and in vivo models to investigate the possibility of a crosstalk between PKA and mammalian target of rapamycin (mTOR) pathways in adrenocortical cells and its possible involvement in apoptosis resistance. Impact of PKA signalling on activation of the mTOR pathway and apoptosis was measured in a mouse model of PPNAD (AdKO mice), in human and mouse adrenocortical cell lines in response to pharmacological inhibitors and in PPNAD tissues by immunohistochemistry. AdKO mice showed increased mTOR complex 1 (mTORC1) pathway activity. Inhibition of mTORC1 by rapamycin restored sensitivity of adrenocortical cells to apoptosis in AdKO but not in wild-type mice. In both cell lines and mouse adrenals, rapid phosphorylation of mTORC1 targets including BAD proapoptotic protein was observed in response to PKA activation. Accordingly, BAD hyperphosphorylation, which inhibits its proapoptotic activity, was increased in both AdKO mouse adrenals and human PPNAD tissues. In conclusion, mTORC1 pathway is activated by PKA signalling in human and mouse adrenocortical cells, leading to increased cell survival, which is correlated with BAD hyperphosphorylation. These alterations could be causative of tumor formation.
    Human Molecular Genetics 05/2014; · 7.69 Impact Factor
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    ABSTRACT: Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs) and pulmonary chondromas in a patient. In contrast to Carney-Stratakis Syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase complex (SDH) subunits A, B, C or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of the SDH subunit C (SDHC) in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the succinate dehydrogenase complex as a plausible alternate mechanism of tumorigenesis in CT.
    Endocrine Related Cancer 05/2014; · 5.26 Impact Factor
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    ABSTRACT: The original 4 patients with Cushing syndrome who underwent bilateral adrenalectomy for primary pigmented nodular adrenocortical disease were followed up for an average of 31 years to determine whether they or any of their primary relatives had developed Carney complex or its components. None had. Three of the patients were alive and well; the fourth had died of an unrelated condition. All the adrenal glands contained multiple small, black or brown cortical nodules, up to 4 mm in diameter. The extracapsular extension of the micronodules was limited to the immediate pericapsular adipose tissue and was not considered evidence of low-grade malignancy. Immunocytochemically, the nodules were positive for synaptophysin, inhibin-A, and melan A and negative for vimentin and CD56. Ki-67 antibody stained the cytoplasm of cells in the micronodules but not that of the atrophic cortical cells. The 4 patients had the PRKAR1A deletion that has been associated with the isolated form of primary pigmented nodular adrenocortical disease.
    The American journal of surgical pathology 05/2014; · 4.06 Impact Factor
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    ABSTRACT: Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland. Despite overall poor prognosis, ACC outcome is heterogeneous. We performed exome sequencing and SNP array analysis of 45 ACCs and identified recurrent alterations in known driver genes (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and in genes not previously reported in ACC (ZNRF3, DAXX, TERT and MED12), which we validated in an independent cohort of 77 ACCs. ZNRF3, encoding a cell surface E3 ubiquitin ligase, was the most frequently altered gene (21%) and is a potential new tumor suppressor gene related to the β-catenin pathway. Our integrated genomic analyses further identified two distinct molecular subgroups with opposite outcome. The C1A group of ACCs with poor outcome displayed numerous mutations and DNA methylation alterations, whereas the C1B group of ACCs with good prognosis displayed specific deregulation of two microRNA clusters. Thus, aggressive and indolent ACCs correspond to two distinct molecular entities driven by different oncogenic alterations.
    Nature Genetics 04/2014; · 35.21 Impact Factor
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    ABSTRACT: Cyclophosphamide-dacarbazine-vincristine (CVD) regimen is recommended for the treatment of malignant pheochromocytoma and paraganglioma (MPP); however, dacarbazine is the only recognized active drug in neuroendocrine tumours. We investigated the therapeutic benefit of temozolomide (TMZ), an oral alternative to dacarbazine, in patients with MPP.This is a retrospective study of consecutive patients with documented progressive MPP. We examined the correlation between Succinate dehydrogenase B (SDHB) mutation and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation and MGMT expression in the French nation-wide independent cohort of 190 pheochromocytomas or paragangliomas (PP). Progression-free survival (PFS) according to RECIST and PERCIST criteria was the primary endpoint.Fifteen consecutive patients with MPP were enrolled; ten (67%) carried a mutation in SDHB. The mean dose intensity of TMZ was 172 mg/m²/d for five days every 28 days. Median PFS was 13.3 months after a median follow-up of 35 months. There were five partial responses (33%), seven stable (47%), and three progressive diseases (20%). Grade 3 toxicities lymphopenia in two patients and hypertension in one. Partial responses were observed only in patients with mutation in SDHB. MGMT immunohistochemistry was negative in tumour samples from four patients who responded to treatment. SDHB germline mutation was associated with hypermethylation of the MGMT promoter and low expression of MGMT in 190 samples of the French nation-wide independent cohort.This study demonstrates that TMZ is an effective anti-tumour agent in patients with SDHB-related MPP. The silencing of MGMT expression as a consequence of MGMT promoter hypermethylation in SDHB-mutated tumours may explain this finding. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 04/2014; · 6.20 Impact Factor
  • Laurence Guignat, Jérôme Bertherat
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    ABSTRACT: Cushing's syndrome includes all the clinical manifestations induced by chronic glucocorticoid excess. The endogenous Cushing's syndrome is rare, but its prevalence, although difficult to define, is much higher in populations at risk. Data suggest that early and effective management would reduce morbidity and mortality after correction of hypercortisolism. It is not recommended to widespread test for Cushing's syndrome but targeted screening is indicated especially in the following indications: facio-troncular obesity, hypercatabolism signs, pituitary and adrenal tumor. In case of potential but less specific manifestation of Cushing's syndrome (diabetes, hypertension, osteoporosis, hypogonadism…), but unusual for age, familial background, or severity, particular attention will be paid to the clinical examination to search for signs of modest hypercortisolism which may justify screening. The positive diagnosis of Cushing's syndrome is based on two stages approach with the first tests simple and sensitive, and the second tests more specific, with investigations to determine the cause following a positive diagnosis.
    La Presse Médicale 03/2014; · 0.87 Impact Factor
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    ABSTRACT: Context: Inactivating germline mutations of the probable tumor suppressor gene Armadillo Repeat Containing 5 (ARMC5) have recently been identified as a genetic cause of macronodular adrenal hyperplasia (MAH). Objective: We searched for ARMC5 mutations in a large cohort of patients with MAH. The clinical phenotype of patients with and without ARMC5 mutations was compared. Methods: Blood DNA from 34 MAH patients was genotyped using Sanger sequencing. Diurnal serum cortisol measurements, plasma ACTH levels, urinary steroids, 6-day Liddle's test, adrenal computed tomography, and weight of adrenal glands at adrenalectomy were assessed. Results: Germline ARMC5 mutations were found in 15 out of 34 patients (44.1%). In silico analysis of the mutations indicated that 7 (20.6%) predicted major implications for gene function. Late-night cortisol levels were higher in patients with ARMC5 damaging mutations compared to those without and/or with non-pathogenic mutations (14.5±5.6 vs. 6.7±4.3, p<0.001). All patients carrying a pathogenic ARMC5 mutation had clinical Cushing's syndrome (7/7, 100%) compared to 14/27 (52%) of those without or with mutations that were predicted to be benign (p=0.029). Repeated measures analysis showed overall higher urinary 17-hydroxycorticosteroids and serum cortisol values in the patients with ARMC5 damaging mutations during the 6 day Liddle's test (p=0.0002). Conclusions: ARMC5 mutations are implicated in clinically severe Cushing's syndrome associated with MAH. Knowledge of a patient's ARMC5 status has important clinical implications for the diagnosis of Cushing's syndrome and genetic counseling of patients and their families.
    The Journal of clinical endocrinology and metabolism 03/2014; · 6.50 Impact Factor
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    ABSTRACT: Objective Silent corticotroph adenomas (SCAs) present as non-functional pituitary tumours in routine preoperative evaluation. The objective of this study was to evaluate the diagnostic accuracy of MRI T2-weighted sequences for detecting the corticotroph subtype preoperatively. DesignThe preoperative T2-weighted MRI sequences were retrospectively evaluated in patients with SCA and two control groups: clinically manifest corticotroph macroadenomas (CSMs) and, non-functional gonadotroph macroadenomas (NFGMs). All were selected from a registry of 1,096 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. Patients17 patients with SCA, 14 with CSM and 60 with NFGM MeasurementsPituitary MRI including 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. ResultsMMs 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 non-functioning 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 non-functional pituitary tumour.This article is protected by copyright. All rights reserved.
    Clinical Endocrinology 03/2014; · 3.40 Impact Factor
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    ABSTRACT: Background Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol-producing adrenal adenomas is not well understood. Methods We performed exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated recurrent mutations in candidate genes in an additional 171 patients with adrenocortical tumors. We also performed genomewide copy-number analysis in 35 patients with cortisol-secreting bilateral adrenal hyperplasias. We studied the effects of these genetic defects both clinically and in vitro. Results Exome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase (protein kinase A [PKA]), in 8 of 10 adenomas (c.617A→C in 7 and c.595_596insCAC in 1). Overall, PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome; these mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors. Among 35 patients with cortisol-producing hyperplasias, 5 (including 2 first-degree relatives) carried a germline copy-number gain (duplication) of the genomic region on chromosome 19 that includes PRKACA. In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit, whereas cells from patients with germline chromosomal gains showed increased protein levels of the PKA catalytic subunit; in both instances, basal PKA activity was increased. Conclusions Genetic alterations of the catalytic subunit of PKA were found to be associated with human disease. Germline duplications of this gene resulted in bilateral adrenal hyperplasias, whereas somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas. (Funded by the European Commission Seventh Framework Program and others.).
    New England Journal of Medicine 02/2014; · 51.66 Impact Factor
  • Guillaume Assié, Anne Jouinot, Jérôme Bertherat
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    ABSTRACT: Pan-genomic analyses of genetic and epigenetic alterations and gene expression profiles are providing important new insights into the pathogenesis and molecular classification of cancers. The technologies and methods used for these studies are rapidly diversifying and improving. The use of such methodologies for the analysis of adrenocortical tumours has revealed clear transcriptomic (mRNA and microRNA expression profiles), epigenomic (DNA methylation profiles) and genomic (DNA mutations and chromosomal alterations) differences between benign and malignant tumours. Interestingly, genomic studies of adrenal cancers have also identified subtypes of malignant tumours, which demonstrate distinct patterns of molecular alterations and are associated with different clinical outcomes. These discoveries have created the opportunity for classifying adrenocortical tumours on the basis of molecular analyses. Following these genomic studies, efforts to develop new molecular tools that improve diagnosis and prognostication of patients with adrenocortical tumours have also been made. This Review describes the progress that has been made towards classification of adrenocortical tumours to date based on key genomic approaches. In addition, the potential for the development and use of various molecular tools to personalize the management of patients with adrenocortical tumours is discussed.
    Nature Reviews Endocrinology 02/2014; · 11.03 Impact Factor
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    ABSTRACT: Background: The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushing's disease (CD) despite limited efficacy and significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD but in the absence of large scale study, its efficacy and tolerance are still under debate. Patients and methods: We conducted a French retrospective, multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance in order to better determine the benefits/risk balance. Results: Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/day. Forty patients (20%) received ketoconazole as a pre-surgical treatment; 40-50% of these patients showed improvement of hypertension, hypokalemia and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild (< 5N) and major (>5N) increases in liver enzymes were observed in 13.5 % and 2.5% of patients respectively. No fatal hepatitis was observed. Conclusions: Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolutive after drug withdrawal.
    The Journal of clinical endocrinology and metabolism 01/2014; · 6.50 Impact Factor
  • Laurence Guignat, Jérôme Bertherat
    [Show abstract] [Hide abstract]
    ABSTRACT: Cushing's syndrome includes all the clinical manifestations induced by chronic glucocorticoid excess. The endogenous Cushing's syndrome is rare, but its prevalence, although difficult to define, is much higher in populations at risk. Data suggest that early and effective management would reduce morbidity and mortality after correction of hypercortisolism. It is not recommended to widespread test for Cushing's syndrome but targeted screening is indicated especially in the following indications: facio-troncular obesity, hypercatabolism signs, pituitary and adrenal tumor. In case of potential but less specific manifestation of Cushing's syndrome (diabetes, hypertension, osteoporosis, hypogonadism…), but unusual for age, familial background, or severity, particular attention will be paid to the clinical examination to search for signs of modest hypercortisolism which may justify screening. The positive diagnosis of Cushing's syndrome is based on two stages approach with the first tests simple and sensitive, and the second tests more specific, with investigations to determine the cause following a positive diagnosis.
    La Presse Médicale. 01/2014;
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    ABSTRACT: Insulin-like growth factor 2 (IGF2) overexpression is an important molecular marker of adrenocortical carcinoma (ACC), which is a rare but devastating endocrine cancer. It is not clear whether IGF2 overexpression modifies the biology and growth of this cancer, thus more studies are required before IGF2 can be considered as a major therapeutic target. We compared the phenotypical, clinical, biological, and molecular characteristics of ACC with or without the overexpression of IGF2, to address these issues. We also carried out a similar analysis in an ACC cell line (H295R) in which IGF2 expression was knocked down with si- or shRNA. We found no significant differences in the clinical, biological and molecular (transcriptomic) traits between IGF2-high and IGF2-low ACC. The absence of IGF2 overexpression had little influence on the activation of tyrosine kinase pathways both in tumors and in H295 cells that express low levels of IGF2. In IGF2-low tumors, other growth factors (FGF9, PDGFA) are more expressed than in IGF2-high tumors, suggesting that they play a compensatory role in tumor progression. In addition, IGF2 knock-down in H295R cells substantially impaired growth (>50% inhibition), blocked cells in G1 phase, and promoted apoptosis (>2-fold). Finally, analysis of the 11p15 locus showed a paternal uniparental disomy in both IGF2-high and IGF2-low tumors, but low IGF2 expression could be explained in most IGF2-low ACC by an additional epigenetic modification at the 11p15 locus. Altogether, these observations confirm the active role of IGF2 in adrenocortical tumor growth, but also suggest that other growth promoting pathways may be involved in a subset of ACC with low IGF2 expression, which creates opportunities for the use of other targeted therapies.
    PLoS ONE 01/2014; 9(8):e103744. · 3.73 Impact Factor
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    ABSTRACT: adrenocortical carcinoma (ACC) is a rare disease with a poor overall outcome. Transcriptome analysis identified two groups of ACCs with different prognosis. In aggressive ACCs, somatic mutations of the tumor suppressor gene TP53 and the proto-oncogene β-catenin are detected in 50% of cases. For the remaining aggressive ACCs and for the group with a better prognosis, molecular alterations are unknown. to identify new molecular actors driving adrenal tumorigenesis. analysis by mass-array of 374 mutations among 32 common oncogenes or tumor suppressor genes was performed on the tumoral DNA of 26 ACCs, using Sequenom® OncoCarta™ Panels. four mutations were identified, two previously known β-catenin mutations and one alteration in two other genes: Janus Kinase 3 (JAK3) and retinoblastoma gene (RB1). The JAK3 alteration was found in leukocyte DNA and therefore considered as a polymorphism and not a somatic event. The full RB1 tumor suppressor gene was subsequently sequenced in a cohort of 49 ACCs (26 ACCs from the "OncoCarta cohort" and 23 other ACCs): three somatic mutations were identified, all in the poor outcome ACC group. By immunohistochemistry, a loss of the retinoblastoma protein (pRb) was found exclusively in aggressive ACCs in 27% of cases (7 out of 26), three of them with an inactivating RB1 mutation. Among the seven pRb negative ACCs, five had an allele loss at the RB1 locus. parallel analysis of somatic mutations among known cancer genes allowed us to identify RB1 as a new actor in aggressive ACCs. These results suggest a prognostic significance of pRb expression loss in ACCs.
    European Journal of Endocrinology 12/2013; · 3.14 Impact Factor
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    ABSTRACT: Background Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing's syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition. Methods We genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models. Results The most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival. Conclusions Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.).
    New England Journal of Medicine 11/2013; 369(22):2105-2114. · 51.66 Impact Factor
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    ABSTRACT: Background Bilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia. We examined the abnormal production of corticotropin in these hyperplastic adrenal glands. Methods We obtained specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease. The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed by means of a polymerase-chain-reaction assay and immunohistochemical analysis. The production of corticotropin and cortisol was assessed in 11 specimens with the use of incubated explants and cell cultures coupled with hormone assays. Corticotropin levels were measured in adrenal and peripheral venous blood samples from 2 patients. Results The expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue. Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens. Adrenal corticotropin levels were higher in adrenal venous blood samples than in peripheral venous samples, a finding that was consistent with local production of the peptide within the hyperplastic adrenals. The release of adrenal corticotropin was stimulated by ligands of aberrant membrane receptors but not by corticotropin-releasing hormone or dexamethasone. A semiquantitative score for corticotropin immunostaining in the samples correlated with basal plasma cortisol levels. Corticotropin-receptor antagonists significantly inhibited in vitro cortisol secretion. Conclusions Cortisol secretion by the adrenals in patients with macronodular hyperplasia and Cushing's syndrome appears to be regulated by corticotropin, which is produced by a subpopulation of steroidogenic cells in the hyperplastic adrenals. Thus, the hypercortisolism associated with bilateral macronodular adrenal hyperplasia appears to be corticotropin-dependent. (Funded by the Agence Nationale de la Recherche and others.).
    New England Journal of Medicine 11/2013; 369(22):2115-2125. · 51.66 Impact Factor
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    ABSTRACT: One of the key messages of recent Salpea and Stratakis work is to underline the clinical similarities shared by these syndromes that could be explained by a defect in the same signaling pathway, i.e. activation of the cAMP pathway. That being said, we would like to emphasize that hepatopancreato-biliary lesions are one additional feature shared both by Carney complex and McCune Albright syndrome.
    Molecular and Cellular Endocrinology 10/2013; · 4.04 Impact Factor
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    ABSTRACT: Point mutations of the PRKAR1A gene are a genetic cause of Carney complex (CNC) and primary pigmented nodular adrenocortical disease (PPNAD), but in 30% of the patients no mutation is detected. Set up a routine-based technique for systematic detection of large deletions or duplications of this gene and functionally characterize these mutations. Multiplex Ligation-dependent Probe Amplification (MLPA) of the 12 exons of the PRKAR1A gene was validated and used to detect large rearrangements in 13 typical CNC and 39 confirmed or putative PPNAD without any mutations of the gene. An in-frame deletion, was characterized by Western blot and BRET technique for its interaction with the catalytic subunit. MLPA allowed identification of exon 3-6 deletion in three patients of a family with typical CNC. The truncated protein is expressed, but rapidly degraded, and does not interact with the protein kinase A catalytic subunit. MLPA is a powerful technique that may be used following the lack of mutations detected by direct sequencing in patients with bona fide CNC or PPNAD. We report here one such new deletion, as an example. However, these gene defects are not a frequent cause of CNC or PPNAD.
    European Journal of Endocrinology 10/2013; · 3.14 Impact Factor

Publication Stats

6k Citations
1,484.17 Total Impact Points

Institutions

  • 2008–2014
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2004–2014
    • Institut Cochin
      Lutetia Parisorum, Île-de-France, France
  • 2000–2014
    • Université René Descartes - Paris 5
      • Faculty of medicine
      Lutetia Parisorum, Île-de-France, France
  • 1993–2014
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2013
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
  • 2004–2013
    • Université Blaise Pascal - Clermont-Ferrand II
      • Laboratoire Génétique, Reproduction et Développement
      Clermont, Auvergne, France
  • 2009–2012
    • Hôpital Européen Georges-Pompidou (Hôpitaux Universitaires Paris-Ouest)
      Lutetia Parisorum, Île-de-France, France
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      • Program in Developmental Endocrinology and Genetics (PDEGEN)
      Maryland, United States
    • Hôpital Foch
      Lutetia Parisorum, Île-de-France, France
  • 2008–2012
    • Hôpital Cochin (Hôpitaux Universitaires Paris Centre)
      • Service de Radiologie A
      Paris, Ile-de-France, France
  • 2000–2012
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1992–2012
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2010
    • Mayo Foundation for Medical Education and Research
      Rochester, Michigan, United States
  • 2006–2010
    • National Institutes of Health
      • Section on Endocrinology and Genetics
      Bethesda, MD, United States
    • Groupe Hospitalier Saint Vincent
      Strasburg, Alsace, France
  • 2003–2008
    • Université de Rouen
      • Microbiology Signals and Microenvironment Lab (LMSM) (EA 4312)
      Mont-Saint-Aignan, Upper Normandy, France
  • 2007
    • Institut de Cancérologie Gustave Roussy
      • Department of Radiotherapy
      Île-de-France, France
  • 2005–2006
    • Centre Hospitalier Universitaire Rouen
      Rouen, Upper Normandy, France
  • 2002
    • University Hospital Estaing of Clermont-Ferrand
      Clermont, Auvergne, France
    • Institut de Génétique Moléculaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France
  • 1994–1995
    • Salk Institute
      • • Clayton Foundation Laboratories for Peptide Biology
      • • Peptide Biology Laboratory
      La Jolla, CA, United States