Position statement on the diagnosis and management of acromegaly: The French National Diagnosis and Treatment Protocol (NDTP).

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.

Pituitary surgery as alternative to dopamine agonists treatment for microprolactinomas: a cohort study.

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.

Structural analysis of the impact of a novel androgen receptor gene mutation in two adult patients with mild androgen insensitivity syndrome.

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.

Foetal exposure to mitotane/Op'DDD: Post-natal study of four children.

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.

[Adrenocortical carcinoma and pregnancy]. / Corticosurrénalome et grossesse.

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.

Very low frequency of germline GPR101 genetic variation and no biallelic defects with AIP in a large cohort of patients with sporadic pituitary adenomas.

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.

Pregnancy in Women Previously Treated for an Adrenocortical Carcinoma.

CONTEXT: Adrenocortical carcinomas (ACCs) are rare, aggressive tumors, of which some express receptors for estradiol, progesterone, and/or human chorionic gonadotoropin. Because this disease is encountered frequently in young women, pregnancy is a relevant issue. OBJECTIVE: to evaluate the impact of pregnancy on outcome of patients previously treated for ACC. DESIGN/SETTING: retrospective observational multicenter study of the European Network for the Study of Adrenal Tumors. PATIENTS: Seventeen ACC patients (21 pregnancies), becoming pregnant at least 3 months after the initial treatment, were compared with 247 nonpregnant ACC patients less than 47 years old. A control group of 34 patients matched for age, sex, and tumor stage was used for survival analysis. MAIN OUTCOME MEASURE(S): Overall survival, tumors characteristics at diagnosis, pregnancy outcome. RESULTS: All 17 patients with pregnancies had localized ACC. The median time between surgery and conception was 4 years (0.3-12 y). Two pregnancies were terminated at 8 weeks. Sixteen women gave birth to 19 live infants. With exception of 1 (presumably unrelated) cardiac malformation, no severe fetal or maternal complication was observed. After a median follow-up time of 8.36 years and 5.26 years after the first conception, 1 of the 17 patients had died and 5 had experienced a recurrence, among whom 3 occurred before conception. Overall survival was not significantly different between the "pregnancy group" and the matched controls. CONCLUSION: Pregnancy in patients previously treated for ACC seems to not be associated with worse clinical outcome, although a "healthy mother effect" cannot be excluded.

Hormonal, Radiological, NP-59 Scintigraphy, and Pathological Correlations in Patients With Cushing's Syndrome Due to Primary Pigmented Nodular Adrenocortical Disease (PPNAD).

CONTEXT: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing's syndrome that may occur in an isolated form or as part of Carney complex. The diagnosis of this disease can be difficult preoperatively because computed tomography (CT) scan can be normal or suggest unilateral adrenal lesion, which can impede the correct diagnosis of bilateral adrenal disease. OBJECTIVE: The aim of our study was to describe the results of preoperative imaging (adrenal [6ß-(131)I]iodomethyl-19-norcholesterol] [NP-59] scintigraphy and standard adrenal CT scan) and their correlations with clinical, pathological, and genetics investigations in patients with PPNAD. PATIENTS AND METHODS: Seventeen patients with ACTH-independent syndrome due to PPNAD were investigated with a standard adrenal CT scan and NP-59 scintigraphy. Hormonal, pathological, and genetics data were analyzed. RESULTS: Four males and 13 females (median age, 27 y) were included. PPNAD was isolated in 11 patients (with PRKAR1A mutation, n = 7; and without PRKAR1A mutation, n = 4) and was associated with extra-adrenal manifestations of Carney complex in six patients (with PRKAR1A mutation, n = 4; and without PRKAR1A mutation, n = 2). Standard adrenal CT scan revealed micronodules in 11 patients, macronodules in three patients, and was normal in three patients. All patients demonstrated bilateral adrenal radiocholesterol uptake. Adrenal uptake was asymmetrical in 10 of 17 patients (59%). Asymmetrical uptake correlated with the presence of macronodules at pathological analysis (P = .03). CONCLUSION: Standard adrenal CT scan most often reveals micronodules but there is no specific CT imaging. NP-59 scintigraphy always shows a bilateral adrenal uptake confirming the bilateral nature of the disease, but asymmetrical scintigraphic uptake can be observed in patients with macronodules.

Management of nonfunctioning pituitary incidentaloma.

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.

Silent, but not unseen: multimicrocystic aspect on T2-weighted MRI in silent corticotroph adenomas.

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.

Inactivation of the Carney complex gene 1 (PRKAR1A) alters spatiotemporal regulation of cAMP and cAMP-dependent protein kinase: a study using genetically encoded FRET-based reporters.

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.

Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients.

CONTEXT: Germline mutations of the AIP (aryl-hydrocarbon receptor interacting protein) gene are associated with a predisposition to pituitary adenomas. Such mutations are found in about half of patients with familial acromegaly, but penetrance is incomplete. OBJECTIVE: We studied the prevalence of germline AIP mutations in a large cohort of patients with apparently sporadic pituitary adenomas. PATIENTS AND SETTING: A total of 443 patients with pituitary adenomas of all histotypes, who had no familial history of pituitary adenomas or multiple endocrine neoplasia and who were examined at Bicêtre University Hospital, a tertiary referral center, between 2007 and 2010, were enrolled in this prospective study. METHODS: The entire coding sequence of the AIP gene was screened for germline mutations. A subgroup of patients were screened for large deletions or duplications of the AIP and MEN1 genes by multiplex ligation-dependent probe amplification. RESULTS: AIP mutations were detected in 16 (3.6%) of the 443 patients, comprising six of 148 patients with acromegaly (4.1%), six of 132 patients with prolactinomas (4.5%), one of 113 patients with nonfunctioning adenomas (0.9%), three of 44 patients with corticotropic adenomas (6.8%), and none of the six patients with thyrotropic adenomas. This is the first report of an AIP mutation leading to a truncated protein in a patient with Cushing's disease. Patients with AIP mutation were younger at diagnosis (24.1 vs. 42.8 yr) and had predominantly macroadenoma (12 of 16). No mutations were found in patients diagnosed after age 40 yr, whereas the prevalence before this age was 7.2% (16 of 222). Studies of seven of the AIP-mutated patients' families showed that one asymptomatic parent carried the same mutation in each case. CONCLUSION: This large prospective cohort study confirms the very low prevalence of germline AIP mutations in patients with apparently sporadic pituitary adenomas. We propose to limit AIP testing to patients diagnosed before age 40 yr with apparently sporadic large pituitary adenomas, especially GH- or PRL-secreting adenomas.

Clinical features and treatment of pediatric somatotropinoma: case study of an aggressive tumor due to a new AIP mutation and extensive literature review.

CONTEXT: Pediatric somatotropinoma is uncommon but usually more aggressive than in adults, creating therapeutic challenges. No treatment guidelines are available. OBJECTIVES: To describe the features of pediatric somatotropinomas and to assess therapeutic strategies based on an extensive literature review. DESIGN: We describe a pediatric case of aggressive somatotropinoma with an AIP mutation. We identified 137 pediatric somatotropinoma cases published between 1981 and 2010, and found 41 cases with AIP mutations in the main review. RESULTS: We found a slight male preponderance (59%). Median age was 9 years at symptom onset and 14 years at diagnosis. Macroadenomas accounted for 90% of the tumors; 2/3 of the children had hyperprolactinemia at diagnosis. The first-line treatment was pharmacotherapy in one third and surgery in 2/3 of the patients. Pegvisomant was used in 7 patients and produced significant improvement in 4. The male preponderance was higher in the subgroup with AIP mutations. Mutations leading to severe protein abnormalities were more common than reported in adults. CONCLUSION: Higher invasiveness and tumor volume in pediatric somatotropinomas require complex treatment combinations, which produce variable results. Pegvisomant is an effective drug whose usefulness in children remains to be determined. Genetic screening, particularly for AIP mutations, should be performed routinely.

Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.

CONTEXT: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN: This study was an international, multicenter, retrospective case collection/database analysis. SETTING: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): an update.

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.

Pituitary tumours: acromegaly.

Excessive production of the growth hormone (GH) is responsible for acromegaly. It is related to a pituitary GH-secreting adenoma in most cases. Prevalence is estimated 40-130 per million inhabitants. It is characterised by slowly progressive acquired somatic disfigurement (mainly involving the face and extremities) and systemic manifestations. The rheumatologic, cardiovascular, respiratory and metabolic consequences determine its prognosis. The diagnosis is confirmed by an increased serum GH concentration, unsuppressible by an oral glucose load and by detection of increased levels of insulin-like growth factor-I (IGF-I). Treatment is aimed at correcting (or preventing) tumour compression by excising the disease-causing lesion, and at reducing GH and IGF-I levels to normal values. When surgery, the usual first-line treatment, fails to correct GH/IGF-I hypersecretion, medical treatment with somatostatin analogues and/or radiotherapy can be used. The GH-receptor antagonist (pegvisomant) is helpful in patients who are resistant to somatostatin analogues. Thanks to this multistep therapeutic strategy, adequate hormonal disease control is achieved in most cases, allowing a normal life expectancy.

Inactivation of the Carney complex gene 1 (protein kinase A regulatory subunit 1A) inhibits SMAD3 expression and TGF beta-stimulated apoptosis in adrenocortical cells.

The cyclic AMP signaling pathway can be altered at multiple levels in endocrine tumors. Its central component is the protein kinase A (PKA). Carney complex (CNC) is a hereditary multiple neoplasia syndrome resulting from inactivating mutations of the gene encoding the PKA type I alpha regulatory subunit (PRKAR1A). Primary pigmented nodular adrenocortical disease is the most frequent endocrine tumor of CNC. Transforming growth factor beta (TGFbeta) regulates adrenal cortex physiology and signals through SMAD2/3. We used an interference approach to test the effects of PRKAR1A inactivation on PKA and TGFbeta pathways and on apoptosis in adrenocortical cells. PRKAR1A silencing stimulates PKA activity and increases transcriptional activity of a PKA reporter construct and expression of the endogenous PKA target, NR4A2, under basal conditions or after forskolin stimulation. PRKAR1A inactivation also decreased SMAD3 mRNA and protein levels via PKA, altering the cellular response to TGFbeta. SMAD3 expression was also inhibited by adrenocorticorticotropic hormone in the mouse adrenal gland and by forskolin in H295R cells. TGFbeta stimulates apoptosis in H295R cells, and this effect was counteracted by PRKAR1A inactivation. PRKAR1A silencing decreased the percentage of apoptotic cells and the cleavage of apoptosis mediators [caspase-3, poly(ADP-ribose) polymerase, and lamin A/C]. Inactivating mutations of PRKAR1A observed in adrenocortical tumors alter SMAD3, leading to resistance to TGFbeta-induced apoptosis. This cross-talk between the PKA and the TGFbeta signaling pathways reveals a new mechanism of endocrine tumorigenesis.