Face-brain asymmetry in autism spectrum disorders.

The heterogeneity of autism spectrum disorders (ASDs) confounds attempts to identify causes and pathogenesis. Identifiable endophenotypes and reliable biomarkers within ASDs would help to focus molecular research and uncover genetic causes and developmental mechanisms. We used dense surface-modelling techniques to compare the facial morphology of 72 boys with ASD and 128 first-degree relatives to that of 254 unrelated controls. Pattern-matching algorithms were able to discriminate between the faces of ASD boys and those of matched controls (AUC=0.82) and also discriminate between the faces of unaffected mothers of ASD children and matched female controls (AUC=0.76). We detected significant facial asymmetry in boys with ASD (P<0.01), notably depth-wise in the supra- and periorbital regions anterior to the frontal pole of the right hemisphere of the brain. Unaffected mothers of children with ASD display similar significant facial asymmetry, more exaggerated than that in matched controls (P<0.03) and, in particular, show vertical asymmetry of the periorbital region. Unaffected fathers of children with ASD did not show facial asymmetry to a significant degree compared to controls. Two thirds of unaffected male siblings tested were classified unseen as more facially similar to unrelated boys with ASD than to unrelated controls. These unaffected male siblings and two small groups of girls with ASD and female siblings, all show overall directional asymmetry, but without achieving statistical significance in two-tailed t-tests of individual asymmetry of ASD family and matched control groups. We conclude that previously identified right dominant asymmetry of the frontal poles of boys with ASD could explain their facial asymmetry through the direct effect of brain growth. The atypical facial asymmetry of unaffected mothers of children with ASD requires further brain studies before the same explanation can be proposed. An alternative explanation, not mutually exclusive, is a simultaneous and parallel action on face and brain growth by genetic factors. Both possibilities suggest the need for coordinated face and brain studies on ASD probands and their first-degree relatives, especially on unaffected mothers, given that their unusual facial asymmetry suggests an ASD susceptibility arising from maternal genes.

Further delineation of cardio-facio-cutaneous syndrome: clinical features of 38 individuals with proven mutations.

BACKGROUND: Cardio-facio-cutaneous syndrome (CFC) is a multiple congenital anomaly/mental retardation syndrome named because of a characteristic facies, cardiac anomalies, and ectodermal abnormalities. While considerable literature describes the main features, few studies have documented the frequencies of less common features allowing a greater appreciation of the full phenotype. METHODS: We have analysed clinical data on 38 individuals with CFC and a confirmed mutation in one of the genes known to cause the condition. We provide data on well-established features, and those that are less often described. RESULTS: Polyhydramnios (77%) and prematurity (49%) were common perinatal issues. 71% of individuals had a cardiac anomaly, the most common being pulmonary valve stenosis (42%), hypertrophic cardiomyopathy (39%), and atrial septal defect (28%). Hair anomalies were also typical: 92% had curly hair, 84% sparse hair, and 86% absent or sparse eyebrows. The most frequent cutaneous features were keratosis pilaris (73%), hyperkeratosis (61%) and nevi (76%). Significant and long lived gastrointestinal dysmotility (71%), seizures (49%), optic nerve hypoplasia (30%) and renal anomalies, chiefly hydronephrosis (20%), were among the less well known issues reported. CONCLUSION: This study reports a broad range of clinical issues in a large cohort of individuals with molecular confirmation of CFC.

Autosomal dominant dystonia-plus with cerebral calcifications.

OBJECTIVE: To report genealogic, clinical, imaging, neuropathologic, and genetic data from a Canadian kindred with dystonia and brain calcinosis originally described in 1985. METHODS: The authors performed clinical examinations and CT and PET studies of the head and analyzed blood samples. One autopsy was performed. RESULTS: The family tree was expanded to 166 individuals. No individuals were newly affected with dystonia, but postural tremor developed in two. The mean age at symptom onset was 19 years. Eight individuals had dystonia: three focal, one segmental, one multifocal, and three generalized. Seven displayed additional signs: chorea, intellectual decline, postural tremor, and dysarthria. CT studies were performed on five affected and 10 at-risk family members. All affected individuals and eight at-risk individuals had brain calcinosis. PET scans in two individuals showed reduced D(1)- and D(2)-receptor binding and reduced uptake of 6-[(18)F]fluoro-l-dopa. Autopsy of one affected individual showed extensive depositions of calcium in the basal ganglia, thalamus, cerebral white matter, and cerebellum. No specific immunohistochemistry abnormalities were seen. Genome search data showed no evidence of linkage to the previously described loci IBGC1, DYT1, and DYT12. CONCLUSIONS: The phenotype of this family consists of dystonia-plus syndrome. Brain calcium deposits vary in severity and distribution, suggesting that calcifications alone are not entirely responsible for the observed clinical signs. Further studies are needed to elucidate the etiology of this heterogeneous group of disorders.

A randomized trial comparing alternative approaches to prenatal diagnosis counseling in advanced maternal age patients.

Prenatal diagnosis (PND) is offered routinely as part of pregnancy care to a large number of women at increased risk of fetal anomalies. Despite an extraordinary growth in the use of PND and significant resource allocation, few studies have examined outcomes of PND counseling, and virtually no research has evaluated the relative efficacy of various approaches to genetic counseling. This study was a randomized trial that compared which counseling methods - individual, group, and use of a decision aid - are effective in PND counseling for women of advanced maternal age (>/=35 years) and their partners. Three hundred and fifty-two women and 225 partners completed pre- and post-intervention questionnaires assessing changes in knowledge, decisional conflict, state anxiety, satisfaction, use of PND, and pregnancy outcomes. All participants showed a significant increase in knowledge and a decrease in decisional conflict post intervention. Those in the group intervention showed a significantly greater increase in knowledge than those in the individual counseling intervention. While high levels of satisfaction were reported by all, those in individual counseling were significantly more satisfied than those receiving group counseling or the decision aid. This study has shown unique benefits with each type of intervention such that women and their partners preferred individual genetic counseling, while they learned best in group-counseling sessions, and experienced the least decisional conflict regarding genetic testing with a decision aid.

Quantitative approach to identifying abnormal variation in the human face exemplified by a study of 278 individuals with five craniofacial syndromes.

We have two objectives in this study: to demonstrate the utility of two summary anthropometric measures for quantifying craniofacial variation and to explore some of their potential uses by physicians and clinical morphologists in general. The Craniofacial Variability Index (CVI) is a summary anthropometric measure of facial "harmony." The mean z-score, based on craniofacial anthropometry, is a measure of overall facial size. Both add an objective component to the assessment of individual facial variation and allow us to place the individual along a scale of continuous variation with predetermined limits of "normality" based on a reference or control series. Our results suggest that these summary measures coincide well with clinical assessments of abnormality in 278 individuals representing five distinct syndromes (Brachmann-de Lange, Prader-Willi, Rubinstein-Taybi, Smith-Magenis, and Sotos), each of which has an associated craniofacial component. Although craniofacial variation is continuous and the normal and syndromic populations overlap to varying degrees, the syndromic cases can be characterized in a variety of ways by using CVI as a measure of facial harmony and Mean-Z as an indicator of overall facial size. Thus, these two-objective measures offer a novel and efficient means of assessing craniofacial variation, whether they are used as tools in the clinical evaluation of subjects or as a means of exploring the nature of craniofacial variation within or between syndromes.

Congenital cholesteatoma and malformations of the facial nerve: rare manifestations of the BOR syndrome.

We describe a 14-month-old girl with unilateral congenital cholesteatoma and anomalies of the facial nerve in addition to the more common branchial arch, otic, and renal malformations comprising the branchio-oto-renal (BOR) syndrome. Her mother also has the BOR syndrome and unilateral duplication of the facial nerve. This is the first study of a BOR patient with congenital cholesteatoma and the second family in which cholesteatoma and anomalies of the facial nerve are described in patients with the BO/BOR syndrome. We review the congenital cholesteatoma literature and discuss hypotheses for the pathogenesis of this entity in light of this new report.

The face of Smith-Magenis syndrome: a subjective and objective study.

We report a study of 55 subjects with Smith-Magenis syndrome, aged 9 months to 35 years. Each person has been evaluated with an assessment of "gestalt" and detailed facial measurement, using previously published methodology, with compilation of Z score pattern profiles. The facial phenotype of SMS is quite distinctive, even in the young child. The overall face shape is broad and square. The brows are heavy, with excessive lateral extension of the eyebrows. The eyes slant upwards and appear close set and deep set. The nose has a depressed root and, in the young child, a scooped bridge. With time, the bridge becomes more ski jump shaped. The height of the nose is markedly reduced while the nasal base is broad and the tip of the nose is full. The shape of the mouth and upper lip are most distinctive. The mouth is wide with full upper and lower lips. The central portion of the upper lip is fleshy and everted with bulky philtral pillars, producing a tented appearance that, in profile, is striking. With age, mandibular growth is greater than average and exceeds that of the maxilla. This leads to increased jaw width and protrusion and marked midface hypoplasia. Craniofacial pattern analysis supports these subjective impressions. After mid-childhood, mandibular dimensions consistently exceed their maxillary counterparts. Craniofacial widths are greater than corresponding depths and heights. Nasal height is reduced while nasal width is increased. There is mild brachycephaly. The most marked age related changes are increased width of the nose and lower face (mandibular width) with reduction in nasal height and midfacial depth.

Classical lissencephaly syndromes: does the face reflect the brain?

Both Miller-Dieker syndrome and isolated lissencephaly sequence are associated with classical lissencephaly. Both have been shown to be associated with deletions and mutations in LIS1 on 17p. Traditionally, the two disorders have been distinguished by the presence of a characteristic facial appearance in Miller-Dieker syndrome. The forehead is tall and prominent and may have vertical furrowing. There is narrowing at the temples. Eyes are widely spaced with upward slanting fissures. The nose is very short with anteverted nares. The upper lip is long, wide, and thick. The ears may have minor flattening of the helices. By contrast, these features are not seen in isolated lissencephaly sequence. We have measured five children with Miller-Dieker syndrome (MDS) and 25 children and adolescents with isolated lissencephaly sequence (ILS). Z score (standard deviation score) pattern profiles have been formulated and compared. Patients with ILS at all ages show reduced head circumference, a round head, and a wide and flat face with a broad nose and widely spaced eyes. The most unexpected finding is the similarity of pattern profiles of ILS and MDS in the age group 6 months to 4 years. Correlation coefficient is 0.812 (p<0.001). In MDS there are a few distinguishing features, including brachycephaly, a slightly wider face, and a considerably shorter nose. Given the striking similarity of these objective pattern profiles, it seems likely that the principal diagnostic discriminators are qualitative features, specifically the tall, furrowed forehead and the long, broad, thickened upper lip, which is so thick that the vermilion border of the upper lip is inverted and angled down.

Turner syndrome in a mother and daughter: r(X) and fertility.

A patient with mosaic Turner syndrome and normal fertility had three documented pregnancies. She had a 45,X/46,X,r(X) karyotype and did not undergo spontaneous sexual maturation and menarche. Conception occurred while on hormone replacement therapy. Her first pregnancy ended with the birth of a normal 46,XY male, while the third pregnancy resulted in a healthy 45,X/46,X,r(X) female. A review of the literature reveals a myriad of theories to account for the variability of ovarian function in Turner syndrome, but, as yet, there are insufficient data to yield any conclusions. There appears to be an increased risk of trisomy 21 in the offspring of females with Turner syndrome.

Rubinstein-Taybi syndrome: objective evaluation of craniofacial structure.

Rubinstein-Taybi syndrome (RTS) is a rare multiple congenital anomaly syndrome comprising mental and growth retardation, broad thumbs and great toes, and an unusual face. The classical facial appearance is well-established, striking and easy to recognize. It includes downslant of the palpebral fissures, epicanthic folds, ptosis, strabismus, highly arched palate, simple ears and a small mouth. The nose is distinctive with a beaked appearance, broad fleshy bridge, deviated septum and short low columella. Previous studies have documented considerable change in this facial phenotype with time. In this study, we evaluated 31 individuals with RTS from Great Britain and The Netherlands. They range in age from 1 to 39 years. Detailed craniofacial measurements were obtained on each subject and composite pattern profiles were compiled. There was remarkable concordance of patterns at all ages from infancy to adulthood. Microcephaly was present consistently. The head was relatively round with head width equal to head length. There was narrowness at the skull base with relative broadening of the minimal frontal diameter and lower facial width. The mouth was small and ears were broad and short. Eyes were wide-spaced in comparison to upper facial width and head circumference. The child under 4 years demonstrated some differences. Width and depth of the upper face exceeded that of the lower face, whereas with increasing age, mandibular dimensions were closer to normal than their maxillary counterparts. Despite these differences, the similarity of the profiles of all age groups seems to belie the phenotypic changes that can be appreciated subjectively. This suggests that major components of the change in appearance are those which have not been assessed in this study, such as palpebral fissure slant, deviation of the nasal bridge, presence of epicanthal folds or ptosis; or for which norms are not available, for example, beaking of the nose, and low nasal septum.

De Lange syndrome: subjective and objective comparison of the classical and mild phenotypes.

Classical de Lange syndrome presents with a striking face, pronounced growth and mental retardation, and variable limb deficiencies. Over the past five years, a mild variant has been defined, with less significant psychomotor retardation, less marked pre- and postnatal growth deficiency, and an uncommon association with major malformations, although mild limb anomalies may be present. We have evaluated 43 subjects with de Lange syndrome, 30 with classical features, aged from birth to 21 years, and 13 with the mild phenotype, aged from 18 months to 30 years. In addition to assessment of gestalt and facial change with time, detailed craniofacial measurements have been obtained on each subject and composite pattern profiles compiled. The characteristic face of classical de Lange syndrome is present at birth and changes little throughout life, although there is some lengthening of the face with age and the jaw becomes squared. In mild de Lange syndrome, the characteristic classical appearance may be present at birth, but in some subjects it may be two or three years before the typical face is obvious. In general, the overall impression is less striking, perhaps because of increased facial expression and greater alertness. With age, the face loses the characteristic appearance, the nasal height increases, the philtrum does not seem as long, and the upper vermilion is full and everted, although the crescent shaped mouth with downturned corners remains. Eyebrows may be full and bushy. Objective comparison of the face in mild and classical de Lange syndrome, through the use of craniofacial pattern profiles, shows marked similarity of patterns at 4 to 9 years; both groups have microbrachycephaly, but the individual dimensions of the mild group are slightly closer to normal than their classical counterparts. The correlation coefficient is high (0.83). In the adult groups, similarity of patterns remains but is less marked. The normalisation of scores in the mild group is more dramatic. The correlation coefficient is lower (0.71). These objective findings substantiate clinical impressions of a phenotypic dichotomy. Early in life, the craniofacial features in mild de Lange syndrome may be indistinguishable from the classical phenotype and alternative discriminators must be sought in order to identify those subjects in whom the prognosis is more optimistic. Birth weight of more than 2500 g and absence of major limb anomalies may help in this regard.

Objective techniques for craniofacial assessment: what are the choices?

The approach to an individual with unusual facial appearance has traditionally involved a subjective assessment coupled with a few craniofacial measurements. Our ability to describe facial morphology has improved in recent years through the development of new techniques such as computerized tomography, magnetic resonance imaging, ultrasound studies, and stereoscopic imaging. However, the relatively simpler techniques of anthropometry, cephalometry, and photogrammetry, developed prior to the advent of microchips and imaging software, continue to provide unique advantages not afforded by these technically more sophisticated methods. These objective methods should enhance pattern recognition, particularly in rare syndromes, and allow for earlier diagnosis.

Sotos syndrome: evolution of facial phenotype subjective and objective assessment.

Sotos syndrome is characterised by pre- and post-natal growth acceleration, advanced bone age, developmental delay and a typical facial Gestalt. We have evaluated 45 individuals with Sotos syndrome who were between age 1 and 25 years, in order to better define the change in facial appearance over time. In each individual, a thorough assessment was made, serial photographs were reviewed, and a series of anthropometric craniofacial measurements was obtained. These were compared with age- and sex-matched normal standards. Both clinical and anthropometric evaluations show that the facial appearance which most clinical geneticists would regard as "classical" is established early in life. The head is large and dolichocephalic, with a rounded and prominent forehead, accentuated by frontoparietal balding. There is narrowing at the temples, fullness of the cheeks, and tapering to a pointed chin. With time, the normal process of facial change occurs, superimposed on that typical Gestalt. As the face lengthens, the dominance of the forehead diminishes and the chin achieves greater prominence. The mandible is long and narrow inferiorly, square or pointed, but prognathism is rare. In a small proportion of patients, a rounder face early in life may challenge diagnosis, but follow-up of these large newborn and older infants should allow diagnosis by early childhood. Visualisation of pattern profiles at different ages, supplemented by statistical measures of variability and similarity, support the clinical impressions outlined above.

Opitz syndrome is genetically heterogeneous, with one locus on Xp22, and a second locus on 22q11.2.

Opitz syndrome (OS, McKusick 145410) is a well described genetic syndrome affecting multiple organ systems whose cardinal manifestations include widely spaced eyes and hypospadias (Fig. 1). It was first reported as two separate entities, BBB syndrome, and G syndrome. However, subsequent reports of families in which the BBB and G syndrome segregated within a single kindred suggested that they were a single clinical entity. Although the original pedigrees were consistent with X-linked and autosomal dominant inheritance, male-to-male transmission in subsequent reports suggested that OS was inherited as an autosomal dominant trait. Here we report that OS is a heterogeneous disorder, with an X-linked and an autosomal locus. Three families were linked to DXS987 in Xp22, with a lod score of 3.53 at zero recombination. Five families were linked to D22S345 from chromosome 22q11.2, with a lod score of 3.53 at zero recombination. This represents the first classic multiple congenital anomaly syndrome with an X-linked and an autosomal form.

Linkage of Pfeiffer syndrome to chromosome 8 centromere and evidence for genetic heterogeneity.

Pfeiffer syndrome (PS) is an autosomal dominant disorder characterized by craniosynostosis, midfacial hypoplasia, and broad thumbs and great toes. We examined 129 individuals from 11 families with PS and performed linkage studies using microsatellite markers spanning the entire genome. Strongest support for linkage was with DNA markers (D8S255, GATA8G08) from chromosome 8. Obligate crossovers exclude close linkage to this region in six families, and there was significant evidence for genetic heterogeneity. A multipoint lod score of 7.15 was obtained in five families. The 11 cM interval between D8S278 and D8S285 contains one gene for PS and also spans the centromere of chromosome 8.

Follow-up study of patients with Wiedemann-Beckwith syndrome with emphasis on the change in facial appearance over time.

We have carried out a follow-up study of 13 children with Wiedemann-Beckwith syndrome (WBS) using a standard protocol which included facial anthropometric measurements. We confirm that most patients with WBS do well and that their clinical abnormalities become less apparent with age. We suggest that there is a characteristic neonatal appearance in WBS and that the expected pattern of facial growth generally results in a normal appearance by mid- to late childhood. We tentatively propose that there is a distinct facial anthropometric pattern profile in WBS.

Anthropometric craniofacial pattern profiles in Down syndrome.

A series of 21 anthropometric craniofacial measurements was performed on 199 individuals with Down syndrome (DS), age 6 months to 61 years. These were compared to age and sex-matched normal standards, and Z score pattern profiles were constructed. These profiles confirmed brachycephaly and reduced ear length. With increasing age, maxillary growth was reduced in comparison to mandibular growth. Clinically, this was manifested by a change in facial shape from the characteristic round face of infancy to an oval shape in later life. Stepwise forward discriminant function analysis identified a subset of three variables (ear length, maxillary arc, and upper facial depth) which could accurately classify greater than 99% of the individuals in the combined sample of affected and unaffected individuals. Of the subjects with DS, 96.8% were classified correctly. These findings demonstrate the usefulness of anthropometric craniofacial pattern profiles in defining abnormal facial dimensions in particular syndromes and documenting the changes that occur with age. The technique should facilitate syndrome recognition, identification of carriers, and comparisons between syndromes.