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The precise diagnosis of thyroid neoplasias will guide surgical management. Primary thyroid paraganglioma has been rarely reported. Data on prevalence, immunohistochemistry (IHC), and molecular genetics in a systematic series of such patients are pending. We performed a multinational population-based study on thyroid paraganglioma and analyzed prevalence, IHC, and molecular genetics. Patients with thyroid paraganglioma were recruited from the European-American-Head-and-Neck-Paraganglioma-Registry. Demographic and clinical data were registered. Histopathology and IHC were re-investigated. All patients with thyroid paraganglioma underwent molecular genetic analyses of theSDHA,SDHB,SDHC,SDHD,SDHAF2,VHL,RET,TMEM127, andMAXgenes. Analyses included Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) for detection of large rearrangements. Of 947 registrants, eight candidates were initially identified. After immunohistochemical analyses of these eight subjects, 5 (0.5%) were confirmed to have thyroid paraganglioma. IHC was positive for chromogranin, synaptophysin, and S-100 and negative for calcitonin in all five thyroid paragangliomas, whereas the three excluded candidate tumors stained positive for pan-cytokeratin, a marker excluding endocrine tumors. Germline variants, probably representing mutations, were found in four of the five confirmed thyroid paraganglioma cases, two each inSDHAandSDHB, whereas the excluded cases had no mutations in the tested genes. Thyroid paraganglioma is a finite entity, which must be differentiated from medullary thyroid carcinoma, because medical, surgical, and genetic management for each is different. Notably, approximately 80% of thyroid paragangliomas are associated with germline variants, with implications for additional tumors and a potential risk for the family. As opposed to sporadic tumors, surgical management and extent of resection are different for heritable tumors, each guided by the precise gene involved.

Carotid body paragangliomas (PGLs) are highly vascularized lesions that arise from the paraganglia located at the carotid bifurcation.To evaluate the usefulness of gray-scale ultrasound (US) and color Doppler ultrasound (CDUS) in the detection and follow-up of carotid PGLs of the neck.The authors retrospectively reviewed US and CDUS examinations of the neck performed in 40 patients with PGL syndrome type 1 and single or bilateral neck PGLs confirmed by CT or MRI; the patients had a total of 60 PGLs of the neck. US and CDUS outcome was compared to the outcome of second-line imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT). The following findings were considered: presence/absence of focal lesions at US imaging and difference in maximum diameter of the lesion measured at US and MRI/CT. Results were compared using the Student's t-test.Of the 60 PGLs of the neck only 5 (8.3%) were not visualized at US or CDUS examination. The difference in maximum diameter of these lesions measured at CT/MRI and US/CDUS ranged between -5 mm and +16 mm (mean difference 2.2 ± 6.0). This difference was statistically significant (p = 0.008).US and CDUS are useful methods for identifying carotid PGLs also measuring less than 10 mm in diameter. However, diagnostic accuracy of US and CDUS is reduced in the measurement of the exact dimensions of the lesions.I paragangliomi (PGLs) carotidei sono lesioni altamente vascolarizzate che originano dai paragangli localizzati a livello della biforcazione carotidea.Valutare l’utilità dell’ecografia (US) e dell’Eco color Doppler (USD) del collo nella diagnosi e nel follow-up dei PGLs carotidei.Abbiamo visionato retrospettivamente tutte le US e gli USD del collo, eseguiti nell’Ospedale Santa Chiara di Trento tra il 2007 e il 2011, di soggetti affetti da sindrome paraganglioma di tipo 1 con sicuri paragangliomi del collo singoli o bilaterali. Abbiamo quindi confrontato i risultati con quelli di metodiche di imaging di secondo livello, Risonanza Magnetica (RM) o Tomografia Computerizzata (TC). Sono stati calcolati i casi discordanti in termini di presenza/assenza della lesione focale alle immagini ecografiche e in termini di differenze del diametro maggiore rilevate tra le due metodiche.Sono stati revisionati i dati di imaging (US e/o USD, RM o TC) eseguiti tra il 2007 e il 2011 di 40 pazienti aventi 60 sicuri paragangliomi del collo. Di questi solo 5/60 (8,3%) non sono stati visualizzati mediante US e/o USD. La differenza nella misura del diametro maggiore di tali lesioni rilevate dalle due tecniche di imaging, è risultata compresa tra -5 e +16 mm (media di 2,2 ± 6,0). Tale differenza è risultata statisticamente significativa (L’US e l’USD del collo risultano metodiche di imaging utili nell’identificazione dei PGL carotidei anche in caso di dimensioni inferiori al centimetro. La loro accuratezza diagnostica si riduce se consideriamo le misure esatte delle lesioni.

Context: Anecdotal evidence suggests a high incidence in Trentino, Italy, of head and neck paragangliomas (HNPGL), a rare autosomal dominant disease called paraganglioma type 1 syndrome and caused by germ-line mutations of the SDHD gene. Objective: The aim of this study was to investigate the origin, spread, and clinical expression of the disease in this geographic region. Design, Setting, and Participants: Trentino natives with HNPGL were recruited for establishing clinical expression of the disease, presence of a founder effect, and age of common ancestor. A large sample of the local population was recruited for determination of mutation prevalence and spread. Main Outcome Measures: SDHD genetic testing was offered to first-degree relatives, and clinical surveillance was offered to at-risk carriers. The hypothesis of a founder effect was explored by haplotype analysis, and time to the most recent common ancestor was estimated by decay of haplotype sharing over time. Results: A total of 287 of the 540 recruited individuals from 95 kindreds carried the SDHD c.341A>G p.Tyr114Cys mutation. The prevalent phenotype was bilateral or multiple HNPGL, with low prevalence of pheochromocytoma and malignant forms. Penetrance was high. A common ancestor was dated between the 14th and 15th century, with the mutation spreading from the Mocheni Valley, a geographic, cultural and, presumably, a genetic isolate to 1.5% of the region's population. Conclusions: A combination of particular demographic, geographical, and historical conditions has resulted in the oldest and largest SDHD founder effect so far characterized and has transformed a rare disease into an endemic disease with major public health implications.

BackgroundGermline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and the p27KIP1 encoding gene CDKN1B have been associated with two well-defined hereditary conditions, familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 4 (MEN4). Somatotropinomas are present in most AIP mutated FIPA kindreds, as well as in two-thirds of MEN4 patients who carry pituitary tumors.MethodsGermline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated.ResultsTwo novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1%) with relatively high age at diagnosis (49±18, range 30–67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families.ConclusionAIP is mutated in about 3% of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27KIP1 is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer.