Conjoined twins (CT) are a very rare developmental accident of uncertain etiology. Prevalence has been previously estimated to be 1 in 50,000 to 1 in 100,000 births. The process by which monozygotic twins do not fully separate but form CT is not well understood. The purpose of the present study was to analyze diverse epidemiological aspects of CT, including the different variables listed in the Introduction Section of this issue of the Journal. The study was made possible using the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) structure. This multicenter worldwide research includes the largest sample of CT ever studied. A total of 383 carefully reviewed sets of CT obtained from 26,138,837 births reported by 21 Clearinghouse Surveillance Programs (SP) were included in the analysis. Total prevalence was 1.47 per 100,000 births (95% CI: 1.32-1.62). Salient findings including an evident variation in prevalence among SPs: a marked variation in the type of pregnancy outcome, a similarity in the proportion of CT types among programs: a significant female predominance in CT: particularly of the thoracopagus type and a significant male predominance in parapagus and parasitic types: significant differences in prevalence by ethnicity and an apparent increasing prevalence trend in South American countries. No genetic, environmental or demographic significant associated factors were identified. Further work in epidemiology and molecular research is necessary to understand the etiology and pathogenesis involved in the development of this fascinating phenomenon of nature.

No abstract

Treacher Collins syndrome (TCS), the best known form of mandibulofacial dysostosis (MFD) comprises a recognizable pattern of anomalies. In 1985, Lowry et al. reported on two Hutterite sisters born to apparently unaffected parents with TCS, raising the possibility of an autosomal recessive (AR) variant of TCS, subsequently given a unique Mendelian Inheritance of Man (MIM) number (248390). Recently, biallelic mutations in POLR1C were found in TCS patients, confirming AR TCS as a distinct entity. The Hutterites, an endogamous Anabaptist group, like other genetically isolated populations, provide a powerful resource for mapping AR disorders. We elected to study the molecular basis of TCS in the Hutterite population including the original kindred described in 1985, and another unrelated Hutterite patient. Prior to starting this study, a TCOF1 mutation had apparently been excluded in the original family at two outside institutions. We hypothesized that an AR variant of TCS was present in the three Hutterite patients, but homozygosity mapping did not show convincing evidence of shared regions between the affected individuals. TCOF1 analysis was undertaken and mutations were found in the three affected patients and an unaffected parent. These data show that the initial Hutterite family reported with AR TCS in fact has classic TCS due to a TCOF1 mutation, despite recent data confirming the existence of AR TCS in other populations. These results have significant counseling implications for the affected families in the Hutterite population and in the population at large.

Appropriate control of impurities from all sources is critically important during the development of a pharmaceutical product. One class of impurity that has gained considerable attention over the past few years is extractables and leachables. We report a model for assessment of the risk posed by leachable impurities for a small-molecule drug substance. The first step of this study consists of a high-level assessment of the risk posed by leachable impurities in the drug substance, by taking into account the drug product’s route of administration. In the case of parenteral route of administration, a more comprehensive process-specific second step risk assessment is typically warranted. This second step consists of risk assessment of polymer component(s) for the potential to release leachable impurities, risk scoring, and classification. For high-risk components, risk mitigation studies can be performed in step 3, such as leachable impurity removal via component pre-flush with the process solvent, extractables’ studies under harsher conditions, and toxicity assessments.