Cowden Disease Multiple Hamartoma Syndrome Publications (1638)


Cowden Disease Multiple Hamartoma Syndrome Publications

Am J Med Genet C Semin Med Genet
Am J Med Genet C Semin Med Genet 2016 Dec 18;172(4):402-421. Epub 2016 Nov 18.

The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway plays an essential role in regulation of normal cell growth, metabolism, and survival. Somatic activating mutations in the PI3K/AKT/mTOR pathway are among the most common mutations identified in cancer, and have been shown to cause a spectrum of overgrowth syndromes including PIK3CA-Related Overgrowth Spectrum, Proteus syndrome, and brain overgrowth conditions. Clinical findings in these disorders may be isolated or multiple, including sporadic or mosaic overgrowth (adipose, skeletal, muscle, brain, vascular, or lymphatic), and skin abnormalities (including epidermal nevi, hyper-, and hypopigmented lesions), and have the potential risk of tumorigenesis. Read More

Key negative regulators of the PI3K-AKT signaling pathway include PTEN and TSC1/TSC2 and germline loss-of function mutations of these genes are established to cause PTEN Hamartoma Tumor Syndrome and Tuberous Sclerosis Complex. Mosaic forms of these conditions lead to increased activation of PI3K and mTOR at affected sites and there is phenotypic overlap between these conditions. All are associated with significant morbidity with limited options for treatment other than symptomatic therapies and surgeries. As dysregulation of the PI3K/AKT/mTOR pathway has been implicated in cancer, several small molecule inhibitors targeting different components of the PI3K/AKT/mTOR signaling pathway are under clinical investigation. The development of these therapies brings closer the prospect of targeting treatment for somatic PI3K/AKT/mTOR-related overgrowth syndromes. This review describes the clinical findings, gene function and pathogenesis of these mosaic overgrowth syndromes, and presents existing and future treatment strategies to reduce or prevent associated complications of these disorders. © 2016 Wiley Periodicals, Inc.

J Clin Exp Dent
J Clin Exp Dent 2016 Oct 1;8(4):e472-e474. Epub 2016 Oct 1.
DDS, Department of Surgical sciences for head and neck diseases, School of dentistry, Catholic University of Sacred Heart, Dean: Prof. Massimo Cordaro, Largo A. Gemelli, 1 - 00168 Rome, Italy.

Cowden's Syndrome (CS) is a rare congenital autosomal dominant disorder that affects around 1/200000 patients with an incomplete penetrance and variable expressivity, characterized by alterations in a tumor suppressor gene. A 14-year-old Caucasian male patient came to the attention of the authors complaining of palm nodules, gingival bleeding and painful pedunculated lesions on the lips and on the labial side of anterior sextants. After genetic investigation the final diagnosis of a Cowden Syndrome was made. Read More

The lesions were surgically removed under general anesthesia and no clinical signs of recurrence were found three months after surgical excision. Considering the severe symptoms of the syndrome and the strong tendency to malignant development of the associated lesions all clinicians should focus their efforts to the early diagnosis and, when possible, multidisciplinary treatment. Key words:Early diagnosis, multiple hamartoma syndrome, oral papillomatosis, cancer predisposition, case report.

J. Clin. Gastroenterol.
J Clin Gastroenterol 2016 Sep 22. Epub 2016 Sep 22.
*Department of Pathology, Soroka Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel †Department of Pathology & ARUP Laboratories ∥Department of Internal Medicine ‡Huntsman Cancer Institute §Genetic Counseling ¶Division of Gastroenterology #Division of Epidemiology, University of Utah, Salt Lake City, UT.

To further characterize the gastrointestinal manifestations of Cowden syndrome in clinically well-annotated patients to improve the diagnosis of this syndrome.
The gastrointestinal manifestations of Cowden Syndrome, an important heritable and multiorgan cancer syndrome, are not well defined. Proper diagnosis is essential for effective cancer surveillance and prevention in these patients. Read More

Cowden patients with gastrointestinal polyps were selected for medical record and pathologic slide review.
Of 19 total patients, genetic testing revealed pathogenic PTEN mutations in 12. Pan-colonic (11-patients, 58%) and pan-gastrointestinal (8-patients, 42%) polyp distributions were common. Inflammatory (juvenile) polyps were the most common of the hamartomatous polyp (18 patients, 95%), along with expansive lymphoid follicle polyps (12 patients, 63%), ganglioneuromatous polyps (10 patients, 53%), and intramucosal lipomas (5 patients, 26%). The findings of 2 or more hamartomatous polyp types per patient emerged as a newly described and highly prevalent (79%) feature of Cowden syndrome. Ganglioneuromatous polyps, rare in the general population, and intramucosal lipomas, which may be unique to Cowden syndrome, should both prompt further evaluation. Colonic adenomas and adenocarcinomas were common; 10 patients (53%) had single and 3 (16%) had ≥3 adenomas, whereas 2 (11%) had colonic adenocarcinoma, strengthening the emerging association of colorectal cancer with Cowden syndrome.
The clinical phenotypes and gastrointestinal manifestations in Cowden syndrome are quite variable but this series adds the following new considerations for this syndromic diagnosis: multiple gastrointestinal hamartomas, especially 2 or more hamartoma types, and any intramucosal lipomas or ganglioneuromas. These features should warrant consideration of Cowden syndrome.

Semin Cutan Med Surg
Semin Cutan Med Surg 2016 Sep;35(3):161-9
Departments of Dermatology and Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.

This review provides a clinically-oriented summary of the most commonly encountered overgrowth syndromes associated with vascular malformations. This manuscript will outline morphologic features, clinical evaluation and management of this complex group of patients. Recent genetic advances have aided in classification and help to explain overlapping clinical features in many cases. Read More

Nucl Med Mol Imaging
Nucl Med Mol Imaging 2016 Sep 4;50(3):255-7. Epub 2016 Jun 4.
Department of Radiology, The Catholic University of Korea, Daejeon Saint Mary's Hospital, 64, Daeheung-ro, Jung-gu, Daejeon, 34943 Republic of Korea.

Cowden syndrome (CS) is a rare autosomal dominant disorder characterized by multiple hamartomas in various tissues and cancers (breast, thyroid, and endometrium). We report CS of the esophagus and gastrointestinal tract that was incidentally detected by positron emission tomography/computed tomography (PET/CT) at postoperative surveillance in an endometrial cancer patient. PET/CT showed mildly increased FDG uptake along the entire esophagus and stomach. Read More

Upper GI endoscopy and histologic examination revealed glycogenic acanthosis of the esophagus and several hundred gastric polyps. In our case, increased FDG uptake of the esophageal wall contributed to the diagnosis of CS.

Oncoscience 2016 30;3(5-6):149-55. Epub 2016 Jun 30.
Translational Neurooncology Laboratory, Department of Neurosurgery, Universitätsklinikum Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany; BiMECON Ent., Berlin, Germany.

Cowden syndrome is an autosomal dominant disorder with a predisposition to multiple benign and malignant tumors. In our patient, in addition to breast and endometrial malignancies as well as facial trichilemmomas, she was noted to have multiple meningiomas, pancreatic lipomas and lung cysts. These latter lesions have been noted in previous Cowden syndrome case reports, but are not included in the diagnostic criteria at this time. Read More

To our knowledge, this is the first case of multiple meningiomas in this syndrome. Further studies are therefore warranted to assess the significance of these findings in Cowden syndrome.
A middle-aged Afro-Caribbean known endometrial carcinoma patient (post surgery and adjuvant radiotherapy), presented with a locally advanced breast carcinoma. She received neoadjuvant chemotherapy followed by a modified radical mastectomy and axillary lymph node clearance. Her past medical history included a sphenoid wing meningioma for which she received definitive external beam radiotherapy. She was also known to have a multinodular goiter, anal polyp and longstanding mucocutaneous lesions. Further workup revealed additional smaller meningiomas, a parotid arteriovenous malformation, a lung cyst and pancreatic lipomas. Overall, consortium criteria were met for the diagnosis of Cowden syndrome. Furthermore, genetic testing identified a pathogenic mutation in the PTEN gene. She will be closely followed with annual clinical examination, dermatologic assessment and screening colonoscopies. She will perform interval whole body contrast enhanced CT for continued surveillance for metastatic disease.
Cowden syndrome is likely to be an under diagnosed condition, but critically important to identify due to its cancer predisposition. When encountering multi-organ tumors, diagnostic criteria for Cowden syndrome should be sought in order to increase the diagnostic rates. Cancer surveillance for carcinoma detection in the early and curative stages remains the most critical aspect of management.

Am. J. Hum. Genet.
Am J Hum Genet 2016 Aug 21;99(2):423-9. Epub 2016 Jul 21.
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. Electronic address:

Hypothalamic hamartoma (HH) with gelastic epilepsy is a well-recognized drug-resistant epilepsy syndrome of early life.(1) Surgical resection allows limited access to the small deep-seated lesions that cause the disease. Here, we report the results of a search for somatic mutations in paired hamartoma- and leukocyte-derived DNA samples from 38 individuals which we conducted by using whole-exome sequencing (WES), chromosomal microarray (CMA), and targeted resequencing (TRS) of candidate genes. Read More

Somatic mutations were identified in genes involving regulation of the sonic hedgehog (Shh) pathway in 14/38 individuals (37%). Three individuals had somatic mutations in PRKACA, which encodes a cAMP-dependent protein kinase that acts as a repressor protein in the Shh pathway, and four subjects had somatic mutations in GLI3, an Shh pathway gene associated with HH. In seven other individuals, we identified two recurrent and three single brain-tissue-specific, large copy-number or loss-of-heterozygosity (LOH) variants involving multiple Shh genes, as well as other genes without an obvious biological link to the Shh pathway. The Shh pathway genes in these large somatic lesions include the ligand itself (SHH and IHH), the receptor SMO, and several other Shh downstream pathway members, including CREBBP and GLI2. Taken together, our data implicate perturbation of the Shh pathway in at least 37% of individuals with the HH epilepsy syndrome, consistent with the concept of a developmental pathway brain disease.