Background-Mutations of the transcription factor Nkx2-5 cause pleiotropic heart defects with incomplete penetrance.This variability suggests that additional factors can affect or prevent the mutant phenotype. We assess here the role of genetic modifiers and their interactions. Methods and Results-Heterozygous Nkx2-5 knockout mice in the inbred strain background C57Bl/6 frequently have atrial and ventricular septal defects. The incidences are substantially reduced in the Nkx2-5 ϩ/Ϫ progeny of first-generation (F1) outcrosses to the strains FVB/N or A/J. Defects recur in the second generation (F2) of the F1ϫF1 intercross or backcrosses to the parental strains. Analysis of Ͼ3000 Nkx2-5 ϩ/Ϫ hearts from 5 F2 crosses demonstrates the profound influence of genetic modifiers on disease presentation. On the basis of their incidences and coincidences, anatomically distinct malformations have shared and unique modifiers. All 3 strains carry susceptibility alleles at different loci for atrial and ventricular septal defects. Relative to the other 2 strains, A/J carries polymorphisms that confer greater susceptibility to atrial septal defect and atrioventricular septal defects and C57Bl/6 to muscular ventricular septal defects. Segregation analyses reveal that Ն2 loci influence membranous ventricular septal defect susceptibility, whereas Ն2 loci and at least 1 epistatic interaction affect muscular ventricular and atrial septal defects. Conclusions-Alleles of modifier genes can either buffer perturbations on cardiac development or direct the manifestation of a defect. In a genetically heterogeneous population, the predominant effect of modifier genes is health. (Circulation. 2010;121:1313-1321.)Key Words: genetic variation Ⅲ genetics Ⅲ heart defects, congenital S ignificant progress has been made toward defining genetic origins in congenital heart disease. 1,2 Current knowledge of the few dozen genes implicated in cardiac development, however, does not explain the basis of common epidemiological and clinical observations. The incidence of heart defects in newborns is 0.5% to 1%, making it a leading cause of death in children. Still, the vast majority are born with a normal heart. Selection against fetuses that have cardiac defects does not cause the prevalence of the norm. 3,4 Insults on the embryonic heart may be rare or weak, or mechanisms may have evolved to ensure the robustness of development. Direct evidence for either hypothesis is minimal, but the latter can better explain the breadth of observations related to incomplete penetrance and phenotypic variability. 5,6 Editorial see p 1277 Clinical Perspective on p 1321Although family studies led to the discovery of mutations of prototypical cardiac developmental genes such as TBX5, Nkx2-5, and GATA4, 7-10 most cases of congenital heart disease have no identified cause or association. Such sporadic cases may be due to an unknown teratogen, spontaneous mutation, or inconsistent expression of an inherited origin. The last possibility is supported by the increased incidence of...

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Background The occurrence of a congenital heart defect has long been thought to have a multifactorial basis, but the evidence is indirect. Complex trait analysis could provide a more nuanced understanding of congenital heart disease. Methods and Results We assessed the role of genetic and environmental factors on the incidence of ventricular septal defects caused by a heterozygous Nkx2-5 knockout mutation. We phenotyped >3100 hearts from a second generation intercross of the inbred mouse strains C57BL/6 and FVB/N. Genetic linkage analysis mapped loci with LOD scores of 5-7 on chromosomes 6, 8 and 10 that influence the susceptibility to membranous VSD in Nkx2-5+/- animals. The chromosome 6 locus overlaps one for muscular VSD susceptibility. Multiple logistic regression analysis for environmental variables revealed that maternal age is correlated with the risk of membranous and muscular VSD in Nkx2-5+/- but not wild-type animals. The maternal age effect is unrelated to aneuploidy or a genetic polymorphism in the affected individuals. The risk of a VSD is not only complex but dynamic. Whereas the effect of genetic modifiers on risk remains constant, the effect of maternal aging increases over time. Conclusions Enumerable factors contribute to the presentation of a congenital heart defect. The factors that modify rather than cause congenital heart disease substantially affect risk in predisposed individuals. Their characterization in a mouse model offers the potential to narrow the search space in human studies and to develop alternative strategies for prevention.

The vulva is an unusual site for basal cell carcinoma (BCC). Vulvar BCC accounts for <1% of all BCCs and <5% of all vulvar malignancies. We report the case of an 83 year-old woman who presented with a 2-month history of a tender labial growth, with histopathology confirming nodular BCC. We conducted a systematic literature review of the characteristics of reported cases of vulvar BCCs. A comprehensive systematic review of articles indexed for MEDLINE and Embase yielded 96 reports describing 437 patients with 446 BCCs of the vulva. The mean age at presentation was 70 (range 20-100). Most women had no underlying vulvar disease. Approximately 60% of cases were of the nodular subtype.Treatment approach varied widely with over half of cases treated with wide local or local excision. Mohs micrographic surgery (MMS) for vulvar BCC was first reported in 1988 with seven total MMS cases reported. Twenty-three cases of recurrence have been reported; 21 of these cases after local excision but none following MMS. Vulvar BCC is a rarely reported cancer that affects older women predominantly. MMS represents a promising treatment for BCC in this anatomic location. Case ReportAn 83-year-old woman with a 40-year history of treated lichen sclerosus presented with a tender growth in the genital area for 2 months. Genital examination revealed a 5-mm eroded papule on the right inferolateral labium majus arising on normal skin, and a white, sclerotic appearance of the labia minora and clitoris ( Fig. 1). Biopsy of the papule revealed a nodular BCC.The patient underwent MMS. She has no evidence of disease recurrence at 3 years.

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