Richard E. Ward

Craniofacial variability index : A simple measure of normal and abnormal variation in the head and face

We propose a numerical means of increasing the objectivity of describing, characterizing, and evaluating craniofacial morphology, including dysmorphology. A craniofacial variability index (CVI) can be created for an individual by obtaining a series of anthropometric measurements of the head and face, converting each measurement value to a standardized z-score, and then calculating the standard deviation for the whole set of these z-score values. This value is lowest for those faces in which all of the z-scores are in the same direction and of relatively the same magnitude and highest for faces with pronounced difference in direction and size of the individual z-scores. The CVI has a range of values with an approximately normal distribution in a reference population of 1,312 individuals. Examination of a small sample of individuals with known craniofacial syndromes indicates that the CVI in such cases consistently falls outside of the normal range of the index, and its value is highest in individuals with the greatest subjective degree of facial involvement. Finally, the CVI is robust: age, sex, size of the individual, and changes in the number of variables used in its calculation have little impact on its distribution. When used in conjunction with traditional clinical assessment, the CVI has a number of potential clinical applications including initial diagnostic screening, demonstrating age-related changes in postnatal development of patients with facial syndromes, and pre- and post-surgical assessments of individuals with craniofacial anomalies.

Alcohol-induced facial dysmorphology in C57BL/6 mouse models of fetal alcohol spectrum disorder

Alcohol consumption during pregnancy causes fetal alcohol spectrum disorder (FASD), which includes a range of developmental deficits. Fetal alcohol syndrome is the most severe form of FASD and can be diagnosed with pathognomonic facial features such as a smooth philtrum, short palpebral fissure, and thin upper vermilion. However, many children with developmental damage because of prenatal alcohol exposure exhibit none, or only a subset, of the above features, making diagnosis difficult. This study explored novel analyses to quantify the effect of a known dose of alcohol on specific facial measurements in substrains C57BL/B6J (B6J) and C57BL/6NHsd (B6N) mice. Mouse dams were provided alcohol (Alc) consisting of 4.8% (vol/vol) alcohol in a liquid diet for 16 days prepregnancy and chow and water diet during mating, and then the alcohol liquid diet was reinstated on gestational days 7 (E7) to gestational day 17 (E17). Treatment controls included a pair-fed (PF) group given matched volumes of an alcohol-free liquid diet made isocalorically and a group given ad lib access to lab chow and water (Chow). Maternal diet intake (Alc and PF), blood alcohol concentrations (BACs), embryo weights, and 15 morphometric facial measurements for E17 embryos were analyzed. B6N dams drank more alcohol during pregnancy and generated higher BAC than B6J dams. Both the Alc and PF treatments induced significant reductions in embryo weights relative to Chow in both substrains. Alcohol treatments produced significant changes, relative to controls, in 4 of the 15 facial measures for the B6N substrain but only in two measures for the B6J substrain. Discriminant analysis demonstrated successful classification of the alcohol-exposed versus nonalcohol-exposed B6N embryos, with a high sensitivity of 86%, specificity 80%, and overall classification (total correct 83%), whereas B6J mice yielded sensitivity of 80%, specificity 78%, and overall correct classification in 79%. In addition, B6N mice showed significantly more effects of pair feeding on these facial measures than did B6J mice, suggesting that the B6N substrain may be more vulnerable to nutritional stress during pregnancy. Overall, these data indicate that both B6N and B6J mice were vulnerable to alcohol but show differences in the severity and location of alcohol-induced dysmorphic facial features and may parallel findings from human studies comparing different ethnic groups. Furthermore, these findings suggest that discriminant analysis may be useful in predicting alcohol exposure in either mouse substrains.

Metacarpophalangeal analysis in Crouzon syndrome: Additional evidence for phenotypic convergence with the acrocephalosyndactyly syndromes

Crouzon syndrome (CS) is characterized by premature craniosynostosis, orbital proptosis, and midfacial hypoplasia and is related to the acrocephalosyndactylies (ACS) with limb abnormalities. In CS the hands are considered to be normal, but a previous report indicated that there is consistent alteration in the proportions of the bones of the hands, as shown by metacarpophalangeal analysis (MCPP), in at least some cases of CS. The purpose of this study was to extend these findings by examining affected individuals and their supposedly unaffected first degree relatives. If CS does have an effect on hands, then this should only be evident in the affected individuals and, presuming complete penetrance, not present in their unaffected relatives. PA hand films were taken on 12 CS subjects and 16 of their normal relatives. The lengths of the metacarpals and phalanges were measured and the measurements standardized for age and sex by conversion to z-scores using published normal standards. Mean pattern profiles for the 2 groups were plotted. In CS the phalanges, especially the first and second proximal phalanges and the first distal phalanx, were shorter than average, and shorter than those of unaffected relatives. The metacarpals were not significantly smaller than the reference means in CS. The 19 hand measurements were entered into a stepwise forward discriminant function analysis (DFA) to develop a model that would discriminate between CS subjects and their normal first degree relatives. The function generated used the measurements of 8 hand bones to classify correctly CS subjects and their normal relatives 100% of the time. This study confirmed that there is a radiographically detectable abnormality of the hands in CS and that, at least in this sample, relatives did not display such abnormalities. Therefore, it seems that CS shares postcranial effects with true ACS and that these effects are, like the other aspects of CS, fully penetrant.

Effect of prenatal alcohol exposure on bony craniofacial development: a mouse MicroCT study.

Craniofacial bone dysmorphology is an important but under-explored potential diagnostic feature of fetal alcohol spectrum disorders. This study used longitudinal MicroCT 3D imaging to examine the effect of prenatal alcohol exposure on craniofacial bone growth in a mouse model. C57BL/6J dams were divided into 3 groups: alcohol 4.2% v/v in PMI® liquid diet (ALC), 2 weeks prior to and during pregnancy from embryonic (E) days 7-E16; pair-fed controls (PF), isocalorically matched to the ALC group; chow controls (CHOW), given ad libitum chow and water. The MicroCT scans were performed on pups on postnatal days 7 (P7) and P21. The volumes of the neurocranium (volume encased by the frontal, parietal, and occipital bones) and the viscerocranium (volume encased by the mandible and nasal bone), along with total skull bone volume, head size, and head circumference were evaluated using general linear models and discriminant analyses. The pups in the alcohol-treated group, when compared to the chow-fed controls (ALC vs CHOW) and the isocaloric-fed controls (ALC vs PF), showed differences in head size and circumference at P7 and P21, the total skull volume and parietal bone volume at P7, and volume of all the tested bones except nasal at P21. There was a growth trend of ALC < CHOW and ALC < PF. While covarying for gender and head size or circumference, the treatment affected the total skull and mandible at P7 (ALC > CHOW), and the total skull, parietal bone, and occipital bone at P21 (ALC < CHOW, ALC < PF). While covarying for the P7 measures, the treatment affected only the 3 neurocranial bones at P21 (ALC < CHOW, ALC < PF). Discriminant analysis sensitively selected between ALC and CHOW (AUC = 0.967), between ALC and PF (AUC = 0.995), and between PF and CHOW (AUC = 0.805). These results supported our hypothesis that craniofacial bones might be a reliable and sensitive indicator for the diagnosis of prenatal alcohol exposure. Significantly, we found that the neurocranium (upper skull) was more sensitive to alcohol than the viscerocranium (face).

Heterogeneity in Wiedemann-Beckwith syndrome: Anthropometric evidence

Wiedemann-Beckwith syndrome (WBS) has attracted a great deal of attention because of its genetic complexity. Individuals with WBS can be identified objectively by anthropometric analysis. Craniofacial anthropometry in conjunction with multivariate statistical analysis can be used to define patterns of variability that appear to relate to specific modes of inheritance that have been proposed for WBS. Our data on 19 affected individuals and their first-degree relatives indicate that the pattern of inheritance rather than the age of subjects may be responsible for the highly variable craniofacial phenotype found in individuals diagnosed with WBS.

Use of Computerized Anthropometry and Morphometrics to Identify Fetal Alcohol Syndrome

Direct craniofacial anthropometry has changed little in the century and a half since Reitzius used calipers to calculate the first “cranial index.” It remains an inexpensive, readily learned technique for objectively measuring facial size and proportion. However, the development of new imaging technologies coupled with powerful computer programs for manipulating data and multivariate analysis for exploring data have opened new frontiers for the clinical application of anthropometry. Computerized anthropometry holds promise for improving our ability to define and recognize craniofacial disorders and for exploring the developmental forces behind variation in facial size and form. Such applications could have a great impact on the diagnosis, treatment, and prevention of fetal alcohol spectrum disorders (FASD), where simple, cost-effective methods for large-scale screening, diagnosis, and surveillance are needed. We review the various methods of indirect or computerized anthropometry that have been used to explore FASD. The vast majority of these studies have focused on creating an objective counterpart to the subjective “gestalt” that dysmorphologists have developed to recognize the phenotypic extreme of FASD known as fetal alcohol syndrome (FAS). Although several studies have demonstrated that computerized anthropometry can successfully recognize individuals previously diagnosed by clinicians as having FAS, no universally accepted “gold standard” has emerged from this work. In addition, only a few of these studies have addressed the potential of computerized anthropometry to recognize a wider range of individuals who have more subtle evidence of damage from gestational exposure to alcohol than is present in the extreme of FAS. However, the wide availability of commercial 3D imaging systems and the convergence of neural imaging studies that allow research to correlate alcohol-induced changes in brain structure to patterns of facial dysmorphology should allow for the collection and analysis of large samples of data, and in the near future may lead to improved recognition of both FAS and FASD individuals as well as greatly improve our understanding of the pathophysiology of alcohol on human development.