Sarah R. McWhinney

Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.

Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and platelet-derived growth factor receptor-α (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of ‘paraganglioma and gastric stromal sarcoma’; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the cause of a subgroup of GISTs and this offers a therapeutic target for GISTs that may not respond to STI571 and its analogs.

Early-Onset Renal Cell Carcinoma as a Novel Extraparaganglial Component of SDHB-Associated Heritable Paraganglioma

Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (SDHB, SDHC, and SDHD) of the four genes that encode mitochondrial succinate dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were SDHB mutation positive, one family with germline SDHB mutation c.847-50delTCTC had two members with renal cell carcinoma (RCC), of solid histology, at ages 24 and 26 years. Both also had paraganglioma. A registry of early-onset RCCs revealed a family comprising a son with clear-cell RCC and his mother with a cardiac tumor, both with the germline SDHB R27X mutation. The cardiac tumor proved to be a paraganglioma. All RCCs showed loss of the remaining wild-type allele. Our observations suggest that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas and carry implications for medical surveillance.

Functioning paraganglioma and gastrointestinal stromal tumor of the jejunum in three women: Syndrome or coincidence

Functioning paraganglioma and gastrointestinal stromal tumor (GIST) are uncommon tumors that occur mostly in a sporadic and isolated form, occasionally as components of multiple neoplasia syndromes, either separately or together. Separately, they occur in several inherited syndromes including multiple endocrine neoplasia 2, and the GIST, lentigines, and mast cell tumor syndrome. Together, they are variably prominent components of three syndromes: the familial paraganglioma and gastric GIST syndrome, neurofibromatosis type 1, and the Carney triad. The two former conditions are inherited as autosomal dominant traits; the latter does not appear to be inherited and affects young women predominantly. This article reports the nonfamilial occurrence of functioning paraganglioma and GIST of the jejunum in 3 women, 1 young (22 years) at initial presentation. The occurrences were unexpected because of the infrequency of the tumors. The neoplasms, respectively, did not show germline SDHA, SDHB, SDHC, and SDHD, and KIT mutations associated with familial paraganglioma and familial GIST. The paraganglioma-jejunal GIST combination may be the harbinger of a rare genetic syndrome, a variant of the Carney triad or the paraganglioma-gastric stromal sarcoma syndrome, or be coincidental.

cDNA microarray analysis assists in diagnosis of malignant intrarenal pheochromocytoma originally masquerading as a renal cell carcinoma

Intrarenal pheochromocytoma (paraganglioma) is a very rare tumour. Its diagnosis is often difficult to establish because of its rarity and its histological similarity to renal cell carcinoma (RCC). Recently, we examined the molecular signatures of different subtypes of kidney tumours by using cDNA microarray. The signature pattern for one tumour, which was originally diagnosed as granular cell RCC, was clearly distinct from that of any other subtype of kidney tumour, and led us to re-evaluate the case. Haematoxylin and eosin staining revealed histological features suggestive of pheochromocytoma, and immunohistochemical studies showed positive staining for neuroendocrine markers but not for keratin. A germline missense mutation, D119E, in the familial paraganglioma related gene succinate dehydrogenase subunit D (SDHD), was subsequently identified. The treatment modality was revised and radiotherapy was given, to which the patient responded, leading to a reduction in tumour size of 25% within the first month. To our knowledge, this is the first report of an intrarenal pheochromocytoma that was diagnosed with the assistance of cDNA microarray analysis.

Mutazioni germinali nel feocromocitoma non sindromico

RiassuntoPremessaIl gruppo dei geni che predispongono al feocromocitoma, che include il proto-oncogene RET [associato alla neoplasia endocrina multipla tipo 2 (MEN-2)] e il gene onco-soppressore VHL (associato con la malattia di von Hippel-Lindau) comprende ora anche i geni di recente scoperta della subunità D (SDHD) e della subunità B (SDHB) della succinodeidrogenasi che predispongono i portatori allo sviluppo di feocromocitomi e di tumori glomici.Abbiamo usato metodi molecolari per classificare un ampio gruppo di pazienti con feocromocitoma in rapporto alla presenza o assenza di mutazioni di uno di questi quattro geni e per valutare I’importanza dell’analisi genetica nella pratica clinica.Metodisangue periferico prelevato da pazienti con feocromocitoma non imparentati, consenzienti e appartenenti ad un registro è stato testato per mutazioni di RET, VHL, SDHD e SDHB.Sono stati valutati i dati clinici alla prima osservazione e durante il follow-up.RisultatiFra i 271 pazienti che si sono presentati con una feocromocitoma non sindromico e senza una storia familiare per la malattia, 66 (24%) sono stati trovati affetti da mutazioni (età media 25 anni; 32 uomini e 34 donne). Di questi 66, 30 avevano mutazioni del VHL, 13 di RET, 11 di SDHD e 12 di SDHB. Giovane età, tumori multipli e tumori extrasurrenalici erano significativamente associati con la presenza di una mutazione. Comunque, fra i 66 pazienti che erano affetti da mutazioni, solo 21 avevano feocromocitomi multipli. 23 (35%) hanno presentato la malattia dopo i 30 anni di età e 17 (8%) dopo i 40 anni. 61 (92%) dei pazienti con la mutazione sono stati identificati solo con l’analisi genetica di VHL, RET, SDHD e SDHB; questi pazienti non presentavano segni o sintomi associati.ConclusioniAlmeno un quarto di pazienti con feocromocitoma apparentemente sporadico possono essere portatori di mutazioni; l’analisi sistematica per mutazioni di RET, VHL, SDHD e SDHB è indicata per l’identificazione delle sindromi associate a feocromocitoma che altrimenti sfuggirebbero alla diagnosi.