Hereditary breast cancer: an update on risk assessment and genetic testing in 2015.

The last 5 years have brought significant innovation and advancement in the genetics of breast cancer. This clinical opinion aims to summarize and update current approaches to the care of women at risk for a hereditary predisposition to breast cancer. Implications of the BRCA mutation and several other hereditary syndromes will be discussed. Risk assessment and criteria for referral to cancer genetic professionals as well as high-risk screening and prophylactic options will be reviewed. Finally, the newly available genetic cancer panels and implications of mutations in some of these lesser known genes will be discussed. As the field of cancer genetics continues to evolve, the education of medical students, residents, and faculty will be paramount to identify appropriate candidates for genetic counseling and testing in conjunction with cancer genetic professionals.

Hereditary breast and ovarian cancer (HBOC): clinical features and counseling for BRCA1 and BRCA2, Lynch syndrome, Cowden syndrome, and Li-Fraumeni syndrome.

This article provides an overview of the molecular changes associated with inherited gynecologic malignancies and the incorporation of this information in the counseling of individuals at increased risk for developing malignancies, as well as conventional and emerging approaches to the screening of the general population. Cancer genetic counseling and its role in women's health care is examined. The focus is hereditary breast and ovarian cancer; however, cancer predisposition caused by genes other than BRCA1 and BRCA2 is also considered. The aim is to provide a foundation for counseling based on fundamental knowledge of the genes and their clinical consequences. The reader is then guided through the mechanics of risk assessment for individual patients, concluding with the psychosocial implications of counseling.

Chemoprevention and treatment of experimental Cowden's disease by mTOR inhibition with rapamycin.

Cowden's disease is an autosomal dominant disorder characterized by the development of multiple mucocutaneous lesions and benign tumors, and enhanced cancer predisposition. Most Cowden's disease patients harbor inactivating mutations in the PTEN tumor suppressor gene which encodes a lipid phosphatase, PTEN, which restrains the phosphatidylinositol 3-kinase-Akt signaling pathway. We observed that the epithelial-specific deletion of Pten in mice causes multiple hyperproliferative and tumor lesions that strikingly resemble Cowden's disease. This animal model system provided an opportunity to explore novel therapeutic approaches in Cowden's disease. Indeed, we show here that rapamycin administration, which inhibits a key downstream target of Akt, mammalian target of rapamycin (mTOR), promotes the rapid regression of advanced mucocutaneous lesions. Furthermore, when administered before disease manifestation, rapamycin can halt the development of Cowden's disease-like lesions, thereby prolonging animal survival. These findings suggest that mTOR inhibition with rapamycin may represent a suitable therapeutic option for the chemoprevention and treatment of Cowden disease patients and others tumor syndromes that involve defective PTEN function.

Hereditary colorectal cancer syndromes.

The purpose of this article is to review the genetic colorectal cancer syndromes including Hereditary Nonpolyposis Colorectal Cancer (HNPCC), Family Polyposis (FAP) and the hamartomatous polyposis syndromes. HNPCC is the most common of the hereditary colorectal cancer syndromes, and is the result of defects in the mismatch repair genes. Individuals with HNPCC have an 80 lifetime risk of colorectal cancer, and in females a 30-50% risk of endometrial cancer, as well as predisposition for a number of other malignancies. Early screening and interval surveillance for colorectal and endometrial cancer are recommended. In FAP, mutations in the Adenomatous Polyposis Coli (APC) tumor suppressor gene give rise to hundreds to thousands of colorectal polyps, some of which will inevitably progress to cancer. Early diagnosis and timely prophylactic colectomy prevent this outcome. Chemoprevention with nonsteroidal anti-inflammatory drugs can reduce adenoma number and size in FAP, but the effect is incomplete. In addtion, surveillance for upper gastrointestinal tract malignancies is necessary. Attenuated forms of FAP may be the result of mutations in the APC gene, or in the recently described MYH gene. Mutations in the MYH gene should be considered in individuals with multiple adenomas whose family history does not reflect an autosomal dominant pattern of inheritance. The hamartomatous polyposis syndromes are uncommon but distinctive disorders in which multiple hamartomatous polyps develop at a young age. Our understanding of the genetic basis of these disorders is improving, and a predisposition for gastrointestinal and other malignancies has recently been recognized. This article summarizes the genetics, clinical manifestations and clinical management of each of these syndromes with an emphasis on genetic testing and prevention.

Enfermedad de Lhermitte-Duclos asociada a esclerosis tuberosa. Presentación de un caso y revisión de la literatura / Lhermitte-Duclos disease associated with tuberous sclerosis. A case report and review of the litarature

Introduction. Lhermitte-Duclos disease is a rare disorder of the cerebellum of unknown origin in which dysplasic thickening of the cerebellar convolutions is seen. It usually occurs in young adults. Currently it is included in the phacomatosis group of disorders. Clinical case. A 19 year old woman attended the Emergency Department complaining of progressive orthostatic headache for the previous three months. On examination there were striking facial micronodular lesions suggestive of angiofibromas, a hypo-pigmented macula in the inframammary region and a hyperpigmented ‘café-au-lait’ macula in the right hypochondrium. On computerized tomography there was tetraventricular hydrocephalia. Cerebral magnetic resonance showed significant descent of the tonsils, hypertensive hydrocephalia and a lesion in the left cerebellum, apparently laminar hyperintensity in DP and T2, with thickening of some folia, not enhanced by intravenous contrast and suggestive of a dysplasic gangliocytoma. Laboratory investigations showed subclinical hypothyroidism. Other investigations were normal. The patient was treated by implanting a ventriculo-peritoneal shunt which has relieved the symptoms to date. Conclusions. Lhermitte-Duclos disease is probably not a single anatomo-clinical condition,assuming that it may be a cerebellar hamartoma associated with a phacomatosis with few clinical signs, whether it be Cowden’s disease, tuberous sclerosis as in this case or an ‘overlapping’ syndrome. The magnetic resonance findings are necessary and sufficient for the diagnosis of Lhermitte-Duclos disease (AU)

Introducción. La enfermedad de LhermitteDuclos es una rara afectación cerebelosa, de causa desconocida y que consiste en el engrosamiento displásico de las circunvoluciones cerebelosas. Se presenta típicamente en adultos jóvenes. En la actualidad, se incluye dentro del espectro de las facomatosis. Caso clínico. Paciente de 19 años que acudió al Servicio de Urgencias por presentar cefalea ortostática progresiva de tres meses de evolución. En la exploración llamaba la atención la presencia de lesiones micronodulares faciales sugerentes de angiofibromas, una mácula hipopigmentada en la región inframamaria y otra hiperpigmentada ‘café con leche’ en el hipocondrio derecho. La tomografía computarizadamostraba una hidrocefalia tetraventricular. La resonancia magnética cerebral evidenciaba un descenso amigdalar significativo, hidrocefalia hipertensiva y una lesión localizada en el hemisferio cerebeloso izquierdo, hiperintensa en DP y T2, de apariencia laminar, con engrosamiento de alguna folia y sin realce tras el contraste intravenoso, sugerente de gangliocitoma displásico. El estudio analítico demostró un hipotiroidismo subclínico. El resto de las pruebas complementarias fueron normales. La paciente fue sometida a una derivación ventrículo-peritoneal tras la cual cedieron los síntomas hasta la actualidad. Conclusiones. Probablemente la enfermedad de LhermitteDuclos no constituya una entidad anatomoclínica aislada, asumiendo que pueda tratarse de un hamartoma cerebeloso enmarcado dentro de una facomatosis con poca expresividad clínica, ya sea la enfermedad de Cowden, la esclerosis tuberosa, como ocurre en este caso, o un síndrome de ‘solapamiento’. Los hallazgos en resonancia magnética son necesarios y suficientes para el diagnóstico de enfermedad de LhermitteDuclos (AU)

Association of Lhermitte-Duclos and Cowden disease: report of a new case and review of the literature.

Lhermitte-Duclos disease is a rare entity, and its pathological features are unique. Pathological findings are characteristic of the disease, with global hypertrophy of the cerebellum, coarse gyri, and the typical "inverted cortex" pattern. Several associated lesions were noted in many patients with Lhermitte-Duclos disease. It is only recently that an association between Lhermitte-Duclos disease and Cowden disease was reported. Cowden disease, or multiple hamartomas syndrome, is a familial disease associating breast cancer, cutaneomucous tricholemmomas, and various other tumoural and dysplasic conditions. A new case of Lhermitte-Duclos disease associated with Cowden disease is reported. A review of the literature found 72 cases of Lhermitte-Duclos disease; 26 had conditions suggesting Cowden disease and seven were definite cases of Cowden disease. The association of Lhermitte-Duclos disease and Cowden disease is probably underestimated. Cowden disease represents a new form of phakomatosis; Lhermitte-Duclos disease may occur as a sporadic disease, or as part of familial Cowden disease. The possibility of preneoplastic states in Cowden syndrome stresses the importance of a thorough screening when Lhermitte-Duclos disease is diagnosed.