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L’interessamento osteoarticolare costituisce un elemento rilevante della patologia acromegalica, spesso presente gia alla diagnosi sotto forma di artralgie; tale complicanza, pur non determinando riduzione dell’aspettativa di vita, causa importante disabilita influenzando in modo negativo la qualita di vita dei pazienti. La patogenesi, ancora non del tutto chiarita, sembrerebbe riconducibile in prima istanza all’eccesso di GH e IGF-I e, in una seconda fase, alle conseguenti modificazioni meccaniche di tipo degenerativo. L’entita delle manifestazioni cliniche, cosi determinante sulla qualita di vita dei soggetti affetti, non trova fedele riscontro nella gravita del quadro radiologico. La Societa Italiana di Endocrinologia ha varato un Gruppo di Studio sulla Disabilita Motoria nell’Acromegalia, a cui partecipano numerosi gruppi endocrinologici italiani.

Few examples of the involvement of a single gene in idiopathic short stature have been described until now. Our aim was to identify the causative gene of proportionate short stature in a large family showing co-segregation of the phenotype with the reciprocal translocation t(10;15)(q22;q24). FISH mapping was carried out with BACs and long-range PCR probes to identify the smallest genomic regions harboring the translocation breakpoints. Real-Time RT-PCR was performed in blood after pre-amplification of target genes cDNA. The affected family members presented with a final height of between − 2.41 and − 4.18 SDS and very mild skeletal dysmorphisms. Growth rates of the proband and of her cousin, whose childhood and pre-pubertal bone age corresponded to the chronological age, showed a poor growth spurt during treatment with rhGH. However, their adult height was greater than that of their untreated mothers, suggesting efficacy of GH therapy. Breakpoint mapping revealed that the translocation t(10;15)(q22.3;q26.1) disrupts, on 15q, the ACAN gene at intron 1, decreasing its transcriptional expression. This is the first description of a chromosome rearrangement disrupting ACAN and leading to its haploinsufficiency. ACAN loss of function should be considered a potential underpinning of short patients who display a poor growth spurt and belong to families with autosomal dominant segregation of proportionate short stature. Besides this core phenotype, literature review suggests that advanced bone age, early onset osteochondritis dissecans, osteoarthritis, intervertebral disc disease as well as craniofacial dysmorphisms can be important suggestive phenotypes in affected families.

L’incidenza dei tumori neuroendocrini (NET) e aumentata negli ultimi anni. Nuove possibilita per il trattamento e la cura dei NET avanzati si prospettano con lo sviluppo di molecole volte a bersagliare punti chiave della proliferazione e differenziazione cellulare. Questo articolo ha lo scopo di fornire una rassegna sui farmaci a bersaglio molecolare recentemente utilizzati nella terapia dei NET e di illustrare i nuovi farmaci in via di sviluppo.

It has been shown that acromegaly is characterized by an autonomic imbalance and by marked sympathoinhibition. However, there is no information available as to whether adrenergic inhibition is confined to selected vascular districts or, rather, is generalized. We examined 17 newly diagnosed active acromegalic patients without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy and 14 healthy subjects matched for age, sex and body mass index. For each subject, we collected information regarding anthropometric parameters and echocardiography, and collected plasma samples to investigate anterior pituitary function, glucose and lipid metabolism and plasma leptin levels. Beat-to-beat mean arterial pressure, heart rate and efferent post-ganglionic muscle and skin sympathetic nerve traffic (MSNA and SSNA, respectively; determined by microneurography) were measured. Both MSNA and SSNA were recorded in a randomized sequence over two 30min periods. Measurements also included evaluation of SSNA responses to emotional stimulus. In addition to significant reductions in plasma leptin levels, acromegalic patients had markedly decreased MSNA compared with the healthy controls. There were no significant differences in SSNA between the two groups, either under basal conditions or in responses to arousal stimuli. There was a significant and direct correlation between MSNA and plasma leptin levels, but not between plasma leptin and SSNA. These data provide the first evidence that the sympathetic inhibition characterizing the early phase of acromegaly is not generalized to the entire cardiovascular system

SummaryObjective Sympathovagal imbalance has been shown in acromegaly by indirect measurements of adrenergic tone. Data regarding direct measurement of sympathetic activity are lacking as yet. Aim of this study was to assess the adrenergic tone through direct recording of muscle sympathetic nerve activity (MSNA) in acromegalic patients. Design Fifteen patients (age 26–66 years, eight women) with newly diagnosed active acromegaly without hyperprolactinaemia, pituitary hormone deficiencies, obstructive sleep apnoea and cardiac hypertrophy, and 15 healthy subjects matched for age, sex and body mass index were recruited. After evaluating anthropometric and echocardiographic parameters, anterior pituitary function, glucose and lipid metabolism, and measuring plasma leptin, direct recording of sympathetic outflow via the microneurographic technique was performed. Results For similar anthropometric and metabolic parameters in patients and controls, HOMA index was significantly increased in the former (4·2 ± 2·39 vs 1·6 ± 0·19, P

Ultrasound elastography (US-E) is a helpful tool for the diagnosis of thyroid cancer. In acromegaly, multinodular goiter is a common occurrence while the prevalence of thyroid cancer is still matter of debate. Our aims were to evaluate thyroid nodules in acromegaly and to assess the accuracy of US-E in providing information on their nature (benign vs. malignant) using cytological analysis as a reference.US-E was performed in 25 patients with acromegaly (active in 10 cases, medically controlled in 8, and cured by pituitary surgery in 7), each of whom had at least one solid thyroid nodule. A total of 90 nodules were classified according to the elastography scores (ES): ES1 and ES2 for soft nodules, ES3 and ES4 for an elastic lesions. FNAC was performed in 78.6% of the ES 4 lesions and 54.1% of the ES 3 nodules.Fourteen of the 90 nodules (15.5%) displayed an ES of 1, 25 (27.7%) an ES of 2, 37 (41.3%) an ES of 3, and 14 (15.5%) an ES of 4. The prevalence of hard nodules in patients with active acromegaly (68.9%) was greater than that observed in patients with cured (44.4%) or controlled (52.5%) acromegaly. The prevalence of hard nodules in the total series (56.7%) was higher than that reported in nonacromegalic goitrous subjects. All thyroid nodules subjected to FNAC were negative for malignant cells and follicular lesions.Acromegaly (particularly active forms) is associated with a high prevalence of stiff thyroid nodules that exceeds that observed in nonacromegalic patients with goiters (33.7%). However, these nodules were never malignant at cytology, and their firmness is probably due to fibrosis. US-E therefore appears to be of limited value for the diagnosis of thyroid cancer in patients with acromegaly.Sommario INTRODUZIONE: L’elastosonografia (US-E) è un utile strumento per la diagnosi del carcinoma tiroideo. Se nell’acromegalia lo struma multinodulare ha un’elevata prevalenza, ancora non vi è accordo sulla possibilità di un’aumentata prevalenza delle neoplasie maligne tiroidee. Obiettivi dello studio sono stati: a) valutare i noduli tiroidei nell’acromegalia con l’US-E; b) stabilire l’accuratezza di questa tecnica nel fornire informazioni sulla loro natura, usando l’esame citologico come parametro di riferimento. MATERIALI E METODI: L’US-E è stata eseguita in 25 pazienti acromegalici (7 guariti dalla chirurgia ipofisaria, 8 controllati dalla terapia medica, 10 con patologia attiva) che presentavano almeno un nodulo solido. Un totale di 90 noduli sono stati classificati secondo un punteggio elastosonografico (ES) in quattro classi di durezza: ES1 e ES2 per i noduli più elastici, ES3 e ES4 per quelli più duri. L’agoaspirato (FNAC) è stato effettuato nel 78.6% dei noduli ES 4 e nel 54,1% dei noduli ES 3. RISULTATI: Dei 90 noduli, 14 (15,5%) mostravano un ES 1, 25 (27,7%) un ES 2, 37 (41,3%) un ES 3 e 14 (15,5%) un ES 4. La prevalenza di noduli duri nei pazienti con acromegalia attiva (68,9%) era maggiore di quella osservata nei pazienti guariti (44,4%) e nei pazienti controllati (52,5%). Nell’intera popolazione di acromegalici la prevalenza di noduli duri (56,7%) era maggiore di quella riportata dalla letteratura nei pazienti non acromegalici con struma multinodulare (33,7%). Tutti i noduli sottoposti a FNAC sono risultati negativi per cellule tumorali maligne o per sospetta malignità. DISCUSSIONE: Questo studio ha dimostrato un’elevata prevalenza di noduli duri nell’acromegalia, soprattutto nei pazienti con patologia attiva. Tale prevalenza è maggiore di quella riportata in letteratura nei pazienti non acromegalici con patologia nodulare tiroidea. Questi noduli, tuttavia, non sono risultati maligni all’esame citologico e potrebbero essere di natura fibrosa. In conclusione, l’US-E sembra essere uno strumento di valore limitato nella diagnosi del tumore della tiroide nell’acromegalia.

ObjectiveUltrasound-elastography (US-E) appears to be a helpful tool for the diagnosis of thyroid cancer. In acromegaly, the prevalence of thyroid cancer is still debated. The aims of this study were to evaluate thyroid nodules in acromegaly and to establish the accuracy of US-E in providing information on their nature, using cytological analysis as a reference.Subjects and methodsUS-E was applied to 90 nodules detected in 25 acromegalic patients and to 94 nodules found in 31 non-acromegalic goitrous subjects. The lesions were classified according to the elasticity scores (ES) as soft (ES 1–2) or hard (ES 3–4). Fine needle aspiration cytology could be performed in 60.8% of hard nodules in acromegalics and in 86.7% of hard nodules in controls.ResultsThe prevalence of hard nodules was significantly higher in the whole group of acromegalic patients than in controls (56.8 vs 16.0%, PConclusionsThis study has demonstrated a high prevalence of stiff thyroid nodules in acromegaly, greater than that found in non-acromegalic goitrous subjects. In acromegalics, hard nodules appeared not to be malignant on cytopathological examination and are probably of fibrous nature. Thus, US-E appears to be of limited value for the diagnosis of thyroid cancer in acromegaly.

The diagnosis of Cushing's syndrome requires highly sensitive screening tests. Therefore, diagnostic cutoffs have been lowered to maximize sensitivity and identify all patients. However, few studies have investigated the impact of these refinements on the specificity of first-line tests.The aim of the study was the assessment of the specificity of three widely used screening tests in a large series of Cushing's syndrome suspects referred to our endocrine service.We retrospectively reviewed the results of urinary free cortisol (UFC), 1-mg dexamethasone suppression test [overnight suppression test (OST)], and serum cortisol at midnight in 3,461, 357, and 864 patients, respectively, with clinical features suggestive of Cushing's syndrome but in whom this diagnosis was subsequently excluded.UFC and OST at the 5-microg/dl cutoff exhibited the highest specificities [91% (95% confidence intervals [CI] 90.2-92.1%) and 97% (95% CI 96.3-98.5%), respectively]. Conversely, midnight serum cortisol yielded 87% (95% CI 84.3-91.1%) specificity only with the 7.5-microg/dl cutoff, whereas the 1.8-microg/dl threshold resulted in an unacceptably high proportion of false positives at only 20% specificity (95% CI 16.0-24.4%). Gender and age may lead to misleading results in all three screening tests.Specificity of tests for Cushing's syndrome varies considerably, with OST and UFC presenting the best performances, and circadian rhythm appearing heavily impaired by lowering of diagnostic cutoffs. Indeed, the vast majority of individuals in our series presented midnight serum cortisol values greater than 1.8 microg/dl; thus, caution has to be exercised when this criterion is used to exclude Cushing's syndrome.

Summary Objective Cardiovascular disease is a major contributor to the increased mortality of acromegalic patients. Prolongation of the QT interval is considered an established risk factor for potentially fatal cardiac arrhythmias, an event frequently observed in acromegaly. Changes in ventricular repolarization have been observed with the use of octreotide, one of the somatostatin analogues (SSA) currently used for the medical treatment of this disease. Furthermore, octreotide is listed among the drugs able to prolong the QT interval. Thus, we elected to study the effects of long-term SSA administration on QT duration and left ventricular mass (LVM) in a group of acromegalic patients. Design and patients In a retrospective study, 30 acromegalic patients (19 women and 11 men, aged 25–77 years) were studied under basal conditions; 24 of them (15 women and nine men, aged 25–77 years) were studied again after 3–63 months of treatment (median 18 months) with SSA. Twenty-four healthy volunteers served as controls. Measurements Patients and controls underwent electrocardiographic (ECG) analysis, and QT interval duration corrected for heart rate (QTc) was established according to the Bazett formula. In 17 of the SSA-treated patients, M- and B-mode echocardiography for the assessment of LVM index (LVMi) was performed. Results Baseline QTc was significantly longer in patients than in controls. SSA administration was followed by a significant decrease in QTc, which reached a mean value similar to that measured in the controls. In particular, treatment with SSA normalized QTc in three out of the six patients with abnormally elevated values at baseline. After treatment, a significant reduction in heart rate was recorded, while LVMi displayed a slight but not significant decrease. Conclusions Acromegalic patients frequently display an abnormally prolonged QT interval, a known risk factor for potentially fatal arrhythmias. Treatment of these patients with SSA is able to improve and even normalize this alteration, probably contributing to the beneficial effects of these drugs on cardiac rhythm in this endocrine disorder. The inclusion of octreotide in the list of drugs that may increase QTc should be reconsidered as regards its indication in acromegaly.