Succinate Dehydrogenase (SDH) D Subunit (SDHD) Inactivation in a Growth-Hormone-Producing Pituitary Tumor: A New Association for SDH?
ABSTRACT Mutations in the subunits B, C, and D of succinate dehydrogenase (SDH) mitochondrial complex II have been associated with the development of paragangliomas (PGL), gastrointestinal stromal tumors, papillary thyroid and renal carcinoma (SDHB), and testicular seminoma (SDHD).
Our aim was to examine the possible causative link between SDHD inactivation and somatotropinoma.
A 37-yr-old male presented with acromegaly and hypertension. Other family members were found with PGL. Elevated plasma and urinary levels of catecholamines led to the identification of multiple PGL in the proband in the neck, thorax, and abdomen. Adrenalectomy was performed for bilateral pheochromocytomas (PHEO). A GH-secreting macroadenoma was also found and partially removed via transsphenoidal surgery (TTS). Genetic analysis revealed a novel SDHD mutation (c.298_301delACTC), leading to a frame shift and a premature stop codon at position 133 of the protein. Loss of heterozygosity for the SDHD genetic locus was shown in the GH-secreting adenoma. Down-regulation of SDHD protein in the GH-secreting adenoma by immunoblotting and immunohistochemistry was found. A literature search identified other cases of multiple PGL and/or PHEO in association with pituitary tumors.
We describe the first kindred with a germline SDHD pathogenic mutation, inherited PGL, and acromegaly due to a GH-producing pituitary adenoma. SDHD loss of heterozygosity, down-regulation of protein in the GH-secreting adenoma, and decreased SDH enzymatic activity supports SDHD's involvement in the pituitary tumor formation in this patient. Older cases of multiple PGL and PHEO and pituitary tumors in the literature support a possible association between SDH defects and pituitary tumorigenesis.
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ABSTRACT: Carney Triad(CTr) describes the association of paragangliomas(PGL), pulmonary chondromas, and gastrointestinal(GI) stromal tumors(GISTs) with a variety of other lesions including pheochromocytomas and adrenocortical tumors.The gene(s) causing CTr remain(s) unknown. PGL and GISTs may be caused by loss-of-function mutations in succinate dehydrogenase (SDH) (a condition known as Carney-Stratakis syndrome (CSS)). Mitochondrial structure and function are abnormal in tissues carrying SDH defects but they have not been studied in CTr. For this study, we examined mitochondrial structure in human tumors and GI tissue(GIT) of mice with SDH deficiency. Tissues from 16 CTr tumors (n=12), and those with isolated GIST(n=1), with CSS caused by SDHC(n=1), SDHD(n=2) mutations were studied by electron microscopy (EM).GIT from mice with a heterozygous deletion in Sdhb (Sdhb+/-,n=4) were also studied by EM.CTr patients presented with mostly epithelioid GISTs that were characterized by plump cells containing a centrally located round nucleus and prominent nucleoli; these changes were almost identical to those seen in the GIST of patients with SDH.In tumor cells from patients, regardless of diagnosis or tumor type, cytoplasm contained increased mitochondria with "hypoxic" phenotype: mitochondria were devoid of cristae, exhibited structural abnormalities and of variable size.Occasionally, mitochondria were small/round, rarely thin, elongated with tubular cristae. Many mitochondria exhibited amorphous fluffy material with membranous whorls or cystic structures. Similar mitochondrial hypoxic phenotype was seen in Sdhb+/- mice.We conclude tissues from SDH-deficient tumors and mouse GIT and from CTr tumors shared identical abnormalities in mitochondrial structure and other features.Thus, the still elusive CTr defect(s) is(are) likely to affect mitochondrial function just like germline SDH-deficiency.Endocrine Related Cancer 03/2015; 22(3). DOI:10.1530/ERC-15-0069 · 4.91 Impact Factor
Chapter: Jaffrain-Rea ML, Rotondi S, Alesse E. (2013). New Insights in the Pathogenesis of Pituitary Tumours, Hot Topics in Endocrine and Endocrine-Related Diseases, Dr. Monica Fedele (Ed.), ISBN: 978-953-51-1080-4, InTech, DOI: 10.5772/56028. Available from: http://www.intechopen.com/books/hot-topics-in-endocrine-and-endocrine-related-diseases/new-insights-in-the-pathogenesis-of-pituitary-tumours[Show abstract] [Hide abstract]
ABSTRACT: Introduction: Pituitary adenomas (PA) are frequent and typically benign endocrine neoplasia, which clinical prevalence is estimated around 1/1000 inhabitants . The vast majority are sporadic. PA are endowed with significant clinical morbidity related to hormonal hypersecretion, neurological symptoms due to intracranial mass effects or invasion of the surrounding structures and/or secondary hypopituitarism. Their evolution is quite variable, ranging from indolent tumours with an extremely slow growing potential, to recurrent, aggressive, and exceptionally malignant tumours. Their current clinical management is based on pharmacological treatment, mainly dopamine-agonists (DA) and somatostatin analogues (SSA), surgery and radiotherapy . Despite considerable progress in the management of PA, a significant subset of patients are not satisfactorily controlled. Long-term uncontrolled pituitary hormone hypersecretion, leading to potential severe systemic diseases, and tumour recurrence or aggressiveness still represent a difficult clinical challenge. Understanding the mechanisms involved in the pathogenesis of PA is essential for the development of new therapeutic strategies. In this chapter, we will summarize current concepts in pituitary tumorigenesis and focus our attention on the most recent insights and new perspectives in this field.Hot Topics in Endocrine and Endocrine-Related Diseases, Edited by Dr. Monica Fedele, 01/2013: chapter Chapter 2 - New Insights in the Pathogenesis of Pituitary Tumours: pages 28-84; InTech., ISBN: 978-953-51-1080-4
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ABSTRACT: Germline mutations in the succinate dehydrogenase genes (SDHA, SDHB, SDHC, and SDHD) are established as causes of pheochromocytoma/paraganglioma, renal carcinoma, and gastrointestinal stromal tumor. It has recently been suggested that pituitary adenomas may also be a component of this syndrome. We sought to determine the incidence of SDH mutation in pituitary adenomas. We performed screening immunohistochemistry for SDHB and SDHA on all available pituitary adenomas resected at our institution from 1998 to 2012. In those patients with an abnormal pattern of staining, we then performed SDH mutation analysis on DNA extracted from paraffin-embedded tissue, fresh frozen tissue, and peripheral blood. One of 309 adenomas (0.3%) demonstrated an abnormal pattern of staining, a 30 mm prolactin-producing tumor from a 62-year-old man showing loss of staining for both SDHA and SDHB. Examination of paraffin-embedded and frozen tissues confirmed double-hit inactivating somatic SDHA mutations (c.725_736del and c.989_990insTA). Neither of these mutations was present in the germline. We conclude that, although pathogenic SDH mutation may occur in pituitary adenomas and can be identified by immunohistochemistry, it appears to be a very rare event and can occur in the absence of germline mutation. SDH-deficient pituitary adenomas may be larger and more likely to produce prolactin than other pituitary adenomas. Unless suggested by family history and physical examination, it is difficult to justify screening for SDH mutations in pituitary adenomas. Surveillance programs for patients with SDH mutation may be tailored to include the possibility of pituitary neoplasia; however, this is likely to be a low-yield strategy.The American journal of surgical pathology 04/2014; 38(4):560-6. DOI:10.1097/PAS.0000000000000149 · 4.59 Impact Factor