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Paraskevi Xekouki and Constantine A Stratakis

Succinate dehydrogenase (SDH) or mitochondrial complex II is a multimeric enzyme that is bound to the inner membrane of mitochondria and has a dual role as it serves both as a critical step of the tricarboxylic acid or Krebs cycle and as a member of the respiratory chain that transfers electrons directly to the ubiquinone pool. Mutations in SDH subunits have been implicated in the formation of familial paragangliomas (PGLs) and/or pheochromocytomas (PHEOs) and in Carney–Stratakis syndrome. More recently, SDH defects were associated with predisposition to a Cowden disease phenotype, renal, and thyroid cancer. We recently described a kindred with the coexistence of familial PGLs and an aggressive GH-secreting pituitary adenoma, harboring an SDHD mutation. The pituitary tumor showed loss of heterozygosity at the SDHD locus, indicating the possibility that SDHD's loss was causatively linked to the development of the neoplasm. In total, 29 cases of pituitary adenomas presenting in association with PHEOs and/or extra-adrenal PGLs have been reported in the literature since 1952. Although a number of other genetic defects are possible in these cases, we speculate that the association of PHEOs and/or PGLs with pituitary tumors is a new syndromic association and a novel phenotype for SDH defects.

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Maya B Lodish and Constantine A Stratakis

Targeted therapy in oncology consists of drugs that specifically interfere with abnormal signaling pathways that are dysregulated in cancer cells. Tyrosine kinase inhibitors (TKIs) take advantage of unique oncogenes that are activated in certain types of cancer, and also target common mechanisms of growth, invasion, metastasis, and angiogenesis. However, many kinase inhibitors for cancer therapy are somewhat nonselective, and most have additional mechanisms of action at the cellular level, which are not completely understood. The use of these agents has increased our knowledge of important side effects, of which the practicing clinician must be aware. Recently, proposed endocrine-related side effects of these agents include alterations in thyroid function, bone metabolism, linear growth, gonadal function, fetal development, and glucose metabolism, and adrenal function. This review summarizes the most recent data on the endocrine side effects of TKIs.

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Rami Alrezk, Fady Hannah-Shmouni and Constantine A Stratakis

Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor gene MEN1. MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not have MEN1 mutations or deletions. A novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressor CDKN1B. The most common phenotype of the 19 established cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic or germline mutations in CDKN1B were also identified in patients with sporadic PHPT, small intestinal neuroendocrine tumors, lymphoma and breast cancer, demonstrating a novel role for CDKN1B as a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4.

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Catherine Goudie, Fady Hannah-Shmouni, Mahmure Kavak, Constantine A Stratakis and William D Foulkes

As medicine is poised to be transformed by incorporating genetic data in its daily practice, it is essential that clinicians familiarise themselves with the information that is now available from more than 50 years of genetic discoveries that continue unabated and increase by the day. Endocrinology has always stood at the forefront of what is called today ‘precision medicine’: genetic disorders of the pituitary and the adrenal glands were among the first to be molecularly elucidated in the 1980s. The discovery of two endocrine-related genes, GNAS and RET, both identified in the late 1980s, contributed greatly in the understanding of cancer and its progression. The use of RET mutation testing for the management of medullary thyroid cancer was among the first and one of most successful applications of genetics in informing clinical decisions in an individualised manner, in this case by preventing cancer or guiding the choice of tyrosine kinase inhibitors in cancer treatment. New information emerges every day in the genetics or system biology of endocrine disorders. This review goes over most of these discoveries and the known endocrine tumour syndromes. We cover key genetic developments for each disease and provide information that can be used by the clinician in daily practice.

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Samuel M O'Toole, Judit Dénes, Mercedes Robledo, Constantine A Stratakis and Márta Korbonits

The combination of pituitary adenomas (PA) and phaeochromocytomas (phaeo) or paragangliomas (PGL) is a rare event. Although these endocrine tumours may occur together by coincidence, there is mounting evidence that, in at least some cases, classical phaeo/PGL-predisposing genes may also play a role in pituitary tumorigenesis. A new condition that we termed ‘3Pas’ for the association of PA with phaeo and/or PGL was recently described in patients with succinate dehydrogenase mutations and PAs. It should also be noted that the classical tumour suppressor gene, MEN1 that is the archetype of the PA-predisposing genes, is also rarely associated with phaeos in both mice and humans with MEN1 defects. In this report, we review the data leading to the discovery of 3PAs, other associations linking PAs with phaeos and/or PGLs, and the corresponding clinical and molecular genetics.

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Maya B Lodish, Urania Dagalakis, Ninet Sinaii, Ethan Bornstein, AeRang Kim, Kelsey B Lokie, Andrea M Baldwin, James C Reynolds, Eva Dombi, Constantine A Stratakis and Brigitte C Widemann

Concern for impaired bone health in children with neurofibromatosis type 1 (NF-1) has led to increased interest in bone densitometry in this population. Our study assessed bone mineral apparent density (BMAD) and whole-body bone mineral content (BMC)/height in pediatric patients with NF-1 with a high plexiform neurofibroma burden. Sixty-nine patients with NF-1 (age range 5.2–24.8; mean 13.7±4.8 years) were studied. Hologic dual-energy X-ray absorptiometry scans (Hologic, Inc., Bedford, MA, USA) were performed on all patients. BMD was normalized to derive a reference volume by correcting for height through the use of the BMAD, as well as the BMC. BMAD of the lumbar spine (LS 2–4), femoral neck (FN), and total body BMC/height were measured and Z-scores were calculated. Impaired bone mineral density was defined as a Z-score ≤−2. Forty-seven percent of patients exhibited impaired bone mineral density at any bone site, with 36% at the LS, 18% at the FN, and 20% total BMC/height. BMAD Z-scores of the LS (−1.60±1.26) were more impaired compared with both the FN (−0.54±1.58; P=0.0003) and the whole-body BMC/height Z-scores (−1.16±0.90; P=0.036). Plexiform neurofibroma burden was negatively correlated with LS BMAD (rs=−0.36, P=0.01). In pediatric and young adult patients with NF-1, LS BMAD was more severely affected than the FN BMAD or whole-body BMC/height.

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Emmanouil Saloustros, Paraskevi Salpea, Matthew Starost, Sissi Liu, Fabio R Faucz, Edra London, Eva Szarek, Woo-Jin Song, Mehboob Hussain and Constantine A Stratakis

Carney complex (CNC) is a rare disease associated with multiple neoplasias, including a predisposition to pancreatic tumors; it is caused most frequently by the inactivation of the PRKAR1A gene, a regulator of the cyclic AMP (cAMP)-dependent kinase (PKA). The method used was to create null alleles of prkar1a in mouse cells expressing pdx1 (Δ-Prkar1a). We found that these mice developed endocrine or mixed endocrine/acinar cell carcinomas with 100% penetrance by the age of 4–5 months. Malignant behavior of the tumors was seen as evidenced by stromal invasion and metastasis to locoregional lymph nodes. Histologically, most tumors exhibited an organoid pattern as seen in the islet-cell tumors. Biochemically, the lesions exhibited high PKA activity, as one would expect from deleting prkar1a. The primary neuroendocrine nature of these tumor cells was confirmed by immunohistochemical staining and electron microscopy, the latter revealing the characteristic granules. Although the Δ-Prkar1a mice developed hypoglycemia after overnight fasting, insulin and glucagon levels in the plasma were normal. Negative immunohistochemical staining for the most commonly produced peptides (insulin, c-peptide, glucagon, gastrin and somatostatin) suggested that these tumors were non-functioning. We hypothesize that the recently identified multipotent pdx1+/insulin− cell in adult pancreas, gives rise to endocrine or mixed endocrine/acinar pancreatic malignancies with complete prkar1a deficiency. In conclusion, this mouse model supports the role of prkar1a as a tumor suppressor gene in the pancreas and points to the PKA pathway as a possible therapeutic target for these lesions.

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Sisi Liu, Emmanouil Saloustros, Annabel Berthon, Matthew F Starost, Isabelle Sahut-Barnola, Paraskevi Salpea, Eva Szarek, Fabio R Faucz, Antoine Martinez and Constantine A Stratakis

Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to ACTH-independent Cushing's syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1α) of cAMP-dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase 2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1500 mg/kg celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, celecoxib caused histological changes that, at least in part, reversed BAH and this was associated with a reduction of corticosterone levels.

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Evgenia Gourgari, Maya Lodish, Meg Keil, Robert Wesley, Suvimol Hill, Paraskevi Xekouki, Charalampos Lyssikatos, Elena Belyavskaya, Sierra Maria De La Luz and Constantine A Stratakis