Findings from this series of studies on HFM are still emerging, but thus far the results of the original case-control study are consistent with the vascular disruption hypothesis. Maternal use of vasoactive medications in the first trimester, particularly in combination with cigarette smoking, was associated with increased risks of HFM. Other associations with HFM that might represent vascular events include multiple gestations, diabetes, 2nd
trimester bleeding, and heavy alcohol consumption. Vascular effects have been linked to each of these events and exposures both within the pregnancy period (62
) and outside of pregnancy (67
). However, some of the observed increased risks for HFM could also result from other pathogenetic processes such as neural crest cell apoptosis (69
) or processes involving oxygen free-radical generation (65
). A more detailed discussion of these results has been previously published (61
). Findings from our recently begun study of genetic variation in hemostasis and vasculogenesis will be informative with regard to the vascular disruption hypothesis.
Together, the completed and ongoing risk factor studies should fill an important gap regarding the vascular hypothesis of HFM, because previous studies of possible risk factors for HFM were limited to case-series and lacked information on most vasoactive events and exposures. Among the various exposures we evaluated, multiple gestations and diabetes have been studied by other investigators, and our positive findings are consistent with their reports (71
The pregnancy risk factor case-control study of HFM is the largest to date and the only one in which exposure data were collected directly from mothers. However, maternal interviews were conducted on average 17 months after the first trimester of pregnancy, which is likely to have reduced recall accuracy. If the degree of inaccuracy of reported exposures was similar in cases and controls, odds ratio estimate may have been underestimated. If the accuracy of reported exposures was different for case and control mothers, odds ratio estimates may have been biased in either direction. A further limitation is that inclusion of milder HFM cases may be incomplete due to the study's requirement that cases must have been seen at a craniofacial center. In addition, while the number of HFM cases was sufficient for identifying pregnancy risk factors, the sample size with buccal swabs is smaller, potentially limiting the statistical power to detect associations with genetic variants, particularly those that are less prevalent. The amount of DNA collected by buccal swab is also small, possibly limiting the number of genetic variants that can be studied. Nevertheless, this will be the first non-pedigree-based study of its size to explore genetic risk factors for HFM.
The ongoing follow-up study will provide data on a large range of neurobehavioral and other outcomes in early elementary school-aged children, including quality of life; behavior, adaptive functioning, and social competence; cognition; dental health; and medical and surgical treatments. Preliminary data on a sub-set of the study population suggest that children with HFM may have worse teacher-reported academic performance and higher levels of internalizing behavior problems than children unaffected by craniofacial conditions. If these associations remain in the full data set, further analyses will determine whether they vary by HFM phenotype, parenting style, or indicators of social risk (e.g., level of education or income). In addition, neuropsychological development may be more directly compromised by underlying major or minor CNS malformations associated with HFM (74
Other studies that considered children with a range of craniofacial disorders grouped together suggested that as compared with “typical” children, affected children are more inhibited, depressed, anxious, and introverted, and less socially adept (75
), however children with HFM made up a minority of these case series. The relation between facial symmetry and psychosocial adjustment has been evaluated in a group of 30 children with a variety of craniofacial anomalies, including 11 children with HFM (78
). In comparing children with “symmetric” and “asymmetric” craniofacial conditions, emotional development and social competence appeared to be normal for this small sample, but approximately one third of the HFM cases had scores that suggested clinically significant levels of behavior problems. One in five had scores that suggested depression. A small study of 6 twin pairs who were discordant for HFM, aged 9 to 15 years, suggested that on average, affected twins had worse behavior problems and lower general self-esteem than their unimpaired twins (79
). No differences were found in social competence scores. Although limited to only six twin-pairs, inherent in the study of discordant twin pairs is control of potential confounding factors, such as age, socioeconomic status, and parents.
Given the limitations of previous studies on psychosocial outcomes in children with HFM, the on-going follow-up study should offer important new information The large study population, with participation expected of over 200 children with HFM and 400 control children, allows psycho-social and cognitive outcomes to be examined within subgroups according to severity of HFM and presence and type of associated malformations. Unfortunately, standardized data are not available on craniofacial or CNS morphology, or on speech and hearing function, which could impact psychosocial and cognitive outcomes and may even account for the preliminary findings reported here.
Hemifacial microsomia is estimated to occur in 1 of 3500 births, yet there has been little research on its risk factors and sequelae. Fortunately, starting with the original case-control study, we are beginning to fill gaps in research. That study, and the subsequent genetic and follow-up studies, are each groundbreaking in terms of their multi-disciplinary approach and their potential impact on affected families.