Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (Po0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation. British Journal of Cancer (2008) BRCA2 is a multisite cancer gene. It is generally thought that BRCA2 mutations primarily affect women, but men with mutations are also at elevated cancer risk. The two most important cancer sites for males who carry a mutation are the prostate and the pancreas (Liede et al, 2004). The risk of prostate cancer is elevated approximately fivefold in BRCA2 carriers, compared to noncarriers. Genetic counselors and urologists advise men with BRCA2 mutations to undergo surveillance with annual PSA testing from the age of 40 years -a recommendation based on the perceived effectiveness of prostate screening. It is hoped that screening leads to early diagnosis, when cure rates are high. A recent study from Iceland suggests that prostate cancers in men with a BRCA2 mutation may be unusually aggressive (Tryggvadottir et al, 2007). Tryggvadottir et al (2007) identified the Icelandic founder mutation (BRCA2 999 del5) in 30 of the 527 prostate cancer patients studied (5.7%). Men with a BRCA2 mutation had a median survival of only 2.1 years, compared with 12.4 years for noncarriers (Po0.01). The survival difference could not be explained by stage or grade. It is important that these findings be replicated because of the implications for the screening of men with a BRCA2 mutation. We identified the prostate cancer patients in a panel of 2673 families with a BRCA1 or a BRCA2 mutation and estimated survival of the men in the two subgroups. METHODSMen with prostate cancer were included in the survival analysis if they were from a family with a BRCA mutation and if they were (a) known to carry the familial BRCA mutation, or (b) if they were a first-degree relative of a known carrier, or (c) if they were a firstdegree relative of a woman diagnosed with breast or ovarian cancer. For each eligible man with prostate cancer, information was collected on age at diagnosis, age at death (if deceased) or age when last known alive (if alive). Information was collected by the

The Disorders of Sex Development (DSD) Consensus Conference, held in Chicago in 2005, identified several domains of care where improvement was needed.1 In particular, it called for the establishment of an infrastructure for collaborative interdisciplinary clinical practice and research, with the goal of integrating scientific understanding of DSD with real-time standardization and improvement in clinical practice. The DSD-Translational Research Network (DSD-TRN) was created in response, the first such North American infrastructure, a network of 4 (now expanded to 10) research and clinical sites and a central registry, with the collaboration of Accord Alliance, a nonprofit convener of diverse DSD stakeholders. To address the variability within and across medical, surgical, and behavioral health aspects of care, the DSD-TRN is dedicated to the standardization of diagnostic and treatment protocols in order to enhance clinical and scientific discovery, as well as quality of life outcomes for patients and their families. A critical aspect of this standardization of practice is a commitment to an early and comprehensive diagnostic process (including genetic), associated with extensive standardized phenotyping and psychosocial screening and support of patients and families. A recent review of the state of clinical, biochemical, genetic, and psychosocial evaluations of the newborn or adolescent with DSD, 10 years after the consensus statement, continued to highlight the need for a thorough diagnostic process that sets in motion informed discussions with parents (and newly diagnosed adolescent patients) regarding treatment options.2 Developmental pathways of sex determination and differentiation impacted in isolated and syndromic DSD conditions were recently reviewed.3–5 This article will briefly review the main categories of genetic causes of DSD and the diagnostic revolution promised by the advent of new genomic technology, and will present the DSD-TRN guidelines for genetic diagnosis, features of the registry for future research, and a peek into some early registry data.

The genetic testing and genetic screening of children are commonplace. Decisions about whether to offer genetic testing and screening should be driven by the best interest of the child. The growing literature on the psychosocial and clinical effects of such testing and screening can help inform best practices. This policy statement represents recommendations developed collaboratively by the American Academy of Pediatrics and the American College of Medical Genetics and Genomics with respect to many of the scenarios in which genetic testing and screening can occur. Pediatrics 2013;131:620-622 BACKGROUND In 1953, Watson and Crick described the DNA double helix. Fifty years later, the full sequence of the human genome was published. Our knowledge of genetics grows rapidly, as does consumer interest in undergoing genetic testing. Statements about genetic testing of children in the United States written in the past 2 decades need to be updated to consider the ethical issues arising with new technologies and expanded uses of genetic testing and screening. 1,2 The growing literature on the psychosocial and clinical effects of such testing and screening can help inform us about best practices. Genetic testing and screening of minors are commonplace. Every year, ∼4 million infants in the United States undergo newborn screening for metabolic, hematologic, and endocrine abnormalities for which early treatment may prevent or reduce morbidity or mortality. Outside of newborn screening, genetic testing of children is less commonly performed. Diagnostic genetic testing may be performed on a child with signs or symptoms of a potential genetic condition or for treatment decisions made on the basis of results of pharmacogenetic assays. Genetic testing may also be performed on an asymptomatic child with a positive family history for a specific genetic condition, particularly if early treatment may affect morbidity or mortality. The American Academy of Pediatrics (AAP) and the American College of Medical Genetics and Genomics (ACMG) provide the following recommendations regarding genetic testing and screening of minors. An accompanying technical report provides ethical explanations and empirical data in support of these recommendations (

Autosomal dominant omodysplasia is a rare skeletal dysplasia characterized by short humeri, radial head dislocation, short first metacarpals, facial dysmorphism and genitourinary anomalies. We performed next-generation whole-exome sequencing and comparative analysis of a proband with omodysplasia, her unaffected parents and her affected daughter. We identified a de novo mutation in FRIZZLED2 (FZD2) in the proband and her daughter that was not found in unaffected family members. The FZD2 mutation (c.1644G>A) changes a tryptophan residue at amino acid 548 to a premature stop (p.Trp548*). This altered protein is still produced in vitro, but we show reduced ability of this mutant form of FZD2 to interact with its downstream target DISHEVELLED. Furthermore, expressing the mutant form of FZD2 in vitro is not able to facilitate the cellular response to canonical Wnt signaling like wild-type FZD2. We therefore conclude that the FRIZZLED2 mutation is a de novo, novel cause for autosomal dominant omodysplasia.

Our findings suggest that treatment for infertility does not significantly increase the risk of ovarian cancer among women with a BRCA mutation.