Facial Phenotype Research Articles

WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features

We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.

Handedness and lower face variability: Findings in three national surveys

ABSTRACTLower face variability in modern humans has been associated with a series of phenotypic characteristics including body architecture and handedness. The aim of this study was to provide a systematic review of lower face variability and handedness in national health surveys conducted in the United States. Three informative surveys with a total of 13,663 participants were identified. Lower face variability was described as one of six facial phenotypes and related to handedness using logistic regression models while adjusting for sex, ancestry, geography, and income. The results on 13,536 participants with complete information showed that bilateral retrognathism—a marker for a lower face phenotype characterized by a convex facial profile and slender jaws—was associated with a 25% increased odds for non-right-handedness (odds ratio, 1.250; 95% confidence interval: 1.076–1.453, p-value < .004). This association between non-right-handedness and a convex facial profile may unexpectedly find its origin in the genetic polymorphisms which determine tuberculosis susceptibility.

Genome-wide association study of facial morphology reveals novel associations with FREM1 and PARK2.

Several studies have now shown evidence of association between common genetic variants and quantitative facial traits in humans. The reported associations generally involve simple univariate measures and likely represent only a small fraction of the genetic loci influencing facial morphology. In this study, we applied factor analysis to a set of 276 facial linear distances derived from 3D facial surface images of 2187 unrelated individuals of European ancestry. We retained 23 facial factors, which we then tested for genetic associations using a genome-wide panel of 10,677,593 single nucleotide polymorphisms (SNPs). In total, we identified genome-wide significant (p < 5 × 10−8) associations in three regions, including two that are novel: one involving measures of midface height at 6q26 within an intron of PARK2 (lead SNP rs9456748; p = 4.99 × 10−8) and another involving measures of central upper lip height at 9p22 within FREM1 (lead SNP rs72713618; p = 2.02 × 10−8). In both cases, the genetic association was stronger with the composite facial factor phenotype than with any of the individual linear distances that comprise those factors. While the biological role of PARK2 in the craniofacial complex is currently unclear, there is evidence from both mouse models and Mendelian syndromes that FREM1 may influence facial variation. These results highlight the potential value of data-driven multivariate phenotyping for genetic studies of human facial morphology.

Heritability maps of human face morphology through large-scale automated three-dimensional phenotyping

The human face is a complex trait under strong genetic control, as evidenced by the striking visual similarity between twins. Nevertheless, heritability estimates of facial traits have often been surprisingly low or difficult to replicate. Furthermore, the construction of facial phenotypes that correspond to naturally perceived facial features remains largely a mystery. We present here a large-scale heritability study of face geometry that aims to address these issues. High-resolution, three-dimensional facial models have been acquired on a cohort of 952 twins recruited from the TwinsUK registry, and processed through a novel landmarking workflow, GESSA (Geodesic Ensemble Surface Sampling Algorithm). The algorithm places thousands of landmarks throughout the facial surface and automatically establishes point-wise correspondence across faces. These landmarks enabled us to intuitively characterize facial geometry at a fine level of detail through curvature measurements, yielding accurate heritability maps of the human face (www.heritabilitymaps.info).

Analysis of facial morphology of UK and US general election candidates: Does the ‘power face’ exist?

To determine the frequency of recognised morphologic facial phenotypes among the UK and US election candidates and to assess whether there is a relationship between facial morphology and success in general elections. Facial morphology analysis of prime ministerial and presidential candidates in the UK and US elections was performed. Direct facial measurements were made from frontal images and facial morphological indices calculated for all candidates. Anthropometric facial phenotype was determined and comparisons made between the elected leaders and unelected runner-up candidates. Paired candidates who had different facial types were analysed as a subgroup, with the probabilities of electoral success calculated. Data were available for 45 subjects: 22 election winners and 23 unelected runner-ups. Our data showed some variation in facial morphology between the groups. The predominant facial phenotype in both groups was leptoprosopic (long and/or narrow face), accounting for 40% (n=18). Mesoprosopic (average dimension) and euryprosopic (short and/or broad) facial type represented 31% (n=14) and 18% (n=8), respectively. A majority of the sample (n=36) demonstrated a malar width to mandibular angle width ratio consistent with the modern 'power face' proportion. Subgroup analysis showed a significant association with success in an election when leptoprosopic candidates were paired against candidates of another facial phenotype (p<0.05). Leptoprosopic (long and/or narrow) facial phenotype with a wide mandibular angle width is predominant in the UK and US election candidates. Moreover, this facial phenotype appears to be associated with greater electoral success, supporting the concept of a modern political 'power face'.

A tissue-specific role for intraflagellar transport genes during craniofacial development.

Primary cilia are nearly ubiquitous, cellular projections that function to transduce molecular signals during development. Loss of functional primary cilia has a particularly profound effect on the developing craniofacial complex, causing several anomalies including craniosynostosis, micrognathia, midfacial dysplasia, cleft lip/palate and oral/dental defects. Development of the craniofacial complex is an intricate process that requires interactions between several different tissues including neural crest cells, neuroectoderm and surface ectoderm. To understand the tissue-specific requirements for primary cilia during craniofacial development we conditionally deleted three separate intraflagellar transport genes, Kif3a, Ift88 and Ttc21b with three distinct drivers, Wnt1-Cre, Crect and AP2-Cre which drive recombination in neural crest, surface ectoderm alone, and neural crest, surface ectoderm and neuroectoderm, respectively. We found that tissue-specific conditional loss of ciliary genes with different functions produces profoundly different facial phenotypes. Furthermore, analysis of basic cellular behaviors in these mutants suggests that loss of primary cilia in a distinct tissue has unique effects on development of adjacent tissues. Together, these data suggest specific spatiotemporal roles for intraflagellar transport genes and the primary cilium during craniofacial development.

Sella turcica measurements on lateral cephalograms of patients with neurofibromatosis type 1.

The aim of this study was to measure line segments and areas of sella turcica on lateral cephalograms with respect to the clinical diagnosis of facial phenotype of patients with neurofibromatosis type 1 (NF1). Special attention was given to correlate the measured values with certain tumour types that are typical for this disease.Material and methods: Lateral cephalograms of 194 individuals were investigated. Patients with NF1 were further divided according to the detection and topography of facial plexiform neurofibromas (PNF) taking into account the distribution pattern of the trigeminal nerve. All patients with PNF showed unilateral tumour localisation. Patients without any facial PNF constituted a separate group. Healthy volunteers with ideal occlusion and no history of any intervention in the maxillofacial region served as a control group. The following items were determined on the radiographs: sella entrance, sella width, sella depths, sella diagonal, and sella area.Results: Patients with PNF of the first and second trigeminal nerve branch or affected in all branches showed highly statistically significant enlarged sella tucica measurement values. On the other hand, patients with PNF restricted to one branch only or simultaneously in the second and third branches showed measurement values that were not different to those obtained in NF1 patients devoid of facial PNF. The latter group also showed no difference of sella turcica parameters obtained in the control group.Conclusion: This study provides evidence for the association of a certain NF1 phenotype with distinct skeletal alterations of the skull base, shown here using the example of the representation of the sella turcica in the lateral radiograph. These findings are also relevant in the discussion of NF1 as a disease of bones and in the assessment of brain development in NF1. Both items are discussed in relationship to a facial plexiform neurofibroma. Furthermore, the knowledge of this association of findings provides the clinician with relevant information in the planning of skull base procedures in these patients.

Signatures of personality on dense 3D facial images

It has long been speculated that cues on the human face exist that allow observers to make reliable judgments of others’ personality traits. However, direct evidence of association between facial shapes and personality is missing from the current literature. This study assessed the personality attributes of 834 Han Chinese volunteers (405 males and 429 females), utilising the five-factor personality model (‘Big Five’), and collected their neutral 3D facial images. Dense anatomical correspondence was established across the 3D facial images in order to allow high-dimensional quantitative analyses of the facial phenotypes. In this paper, we developed a Partial Least Squares (PLS) -based method. We used composite partial least squares component (CPSLC) to test association between the self-tested personality scores and the dense 3D facial image data, then used principal component analysis (PCA) for further validation. Among the five personality factors, agreeableness and conscientiousness in males and extraversion in females were significantly associated with specific facial patterns. The personality-related facial patterns were extracted and their effects were extrapolated on simulated 3D facial models.

Proteus syndrome: A case report and review of the literature.

Proteus syndrome is a rare complex syndrome involving clinical presentation with atypical skeletal growth. Only a limited number of cases with this syndrome have been reported in the literature to date. We herein report the case of a Chinese male patient with Proteus syndrome and review the clinical and molecular characteristics of this disease. The patient was a 34-year-old man with clinical manifestations suggestive of the Proteus syndrome, including mosaic distribution of the lesions, sporadic occurrence, progressive course, disproportionate overgrowth of the legs, epidermal nevi, lipomas, venous malformations and characteristic facial phenotype. Genetic mosaicism, such as mutations involving the phosphoinositide 3 kinase-AKT pathway in the affected tissues, may be important causes of Proteus syndrome. In the present case, samples from the affected tissues were collected from the patient and were further analyzed using whole-exome sequencing. However, no mutation of the genes reportedly associated with Proteus syndrome was identified in the affected tissues. Proteus syndrome is a complex mosaic disorder with a number of variable characteristics. Although activating AKT1 mutations have been found to be associated with this disorder, the molecular etiology remains to be fully elucidated and diagnostic criteria must be established in the clinical setting.

Hemifacial microsomia – A case report and review

Hemifacial microsomia (HFM) is a craniofacial disorder characterized by a wide spectrum of anomalies, including conductive hearing loss due to external and middle ear deformities. HFM is a common term used to describe a sporadic complex spectrum of congenital anomalies that primarily involve the skeletal and soft-tissue components derived from the first and second pharyngeal arches. Although there is no universal agreement on the minimum diagnostic criteria, the facial phenotype, which is predominantly characterized by asymmetrical hypoplasia of the facial skeleton, the ear, and facial soft tissues are often distinctive enough to differentiate it from other craniofacial disorders. It is the most common facial congenital disability after cleft lip and palate, with an estimated prevalence of about 1 in 5600 births. We present a case of HFM in 13-year-old female.

Facial phenotype in obstructive sleep apnea-hypopnea syndrome: a systematic review and meta-analysis.

This systematic review and meta-analysis explores the association between facial phenotype and obstructive sleep apnea-hypopnea syndrome in adults. A comprehensive electronic (Medline via Ovid, Scopus, and Embase) database and reference search were undertaken in relation to imaging modalities for surface craniofacial assessments in subjects with sleep apnea. The outcome measures were surface facial dimensions, morphology and profile. The quality of studies was assessed and a meta-analysis conducted. The studies were weighted using the inverse variance method, and the random effects model was used to analyse data. This systematic review identified eight case-control studies. In five studies (906 participants), adults with sleep apnea showed increased weighted mean differences in neck circumference by 1.26mm (P=0.0001) with extensive heterogeneity between studies (I²=93%). Only two studies (467 participants) shared the following outcomes: mandible length, lower facial height, mandible width and anterior mandible height parameters. The pooled results demonstrated obstructive sleep apnea syndrome was associated with larger parameters than controls. In conclusion, the surface facial assessment was able to demonstrate some characteristic morphological features, facilitating a meta-analysis, in adults with obstructive sleep apnea-hypopnea syndrome. The strength of these findings, however, was limited by the heterogeneity of the studies precluding the identification of a clear phenotype.

Craniofacial Ciliopathies Reveal Specific Requirements for GLI Proteins during Development of the Facial Midline.

Ciliopathies represent a broad class of disorders that affect multiple organ systems. The craniofacial complex is among those most severely affected when primary cilia are not functional. We previously reported that loss of primary cilia on cranial neural crest cells, via a conditional knockout of the intraflagellar transport protein KIF3a, resulted in midfacial widening due to a gain of Hedgehog (HH) activity. Here, we examine the molecular mechanism of how a loss of primary cilia can produce facial phenotypes associated with a gain of HH function. We show that loss of intraflagellar transport proteins (KIF3a or IFT88) caused aberrant GLI processing such that the amount of GLI3FL and GLI2FL was increased, thus skewing the ratio of GLIFL to GLIR in favor of the FL isoform. Genetic addition of GLI3R partially rescued the ciliopathic midfacial widening. Interestingly, despite several previous studies suggesting midfacial development relies heavily on GLI3R activity, the conditional loss of GLI3 alone did not reproduce the ciliopathic phenotype. Only the combined loss of both GLI2 and GLI3 was able to phenocopy the ciliopathic midfacial appearance. Our findings suggest that ciliopathic facial phenotypes are generated via loss of both GLI3R and GLI2R and that this pathology occurs via a de-repression mechanism. Furthermore, these studies suggest a novel role for GLI2R in craniofacial development.

PDGFRβ regulates craniofacial development through homodimers and functional heterodimers with PDGFRα.

Craniofacial development is a complex morphogenetic process, disruptions in which result in highly prevalent human birth defects. While platelet-derived growth factor (PDGF) receptor α (PDGFRα) has well-documented functions in this process, the role of PDGFRβ in murine craniofacial development is not well established. We demonstrate that PDGFRα and PDGFRβ are coexpressed in the craniofacial mesenchyme of mid-gestation mouse embryos and that ablation of Pdgfrb in the neural crest lineage results in increased nasal septum width, delayed palatal shelf development, and subepidermal blebbing. Furthermore, we show that the two receptors genetically interact in this lineage, as double-homozygous mutant embryos exhibit an overt facial clefting phenotype more severe than that observed in either single-mutant embryo. We reveal a physical interaction between PDGFRα and PDGFRβ in the craniofacial mesenchyme and demonstrate that the receptors form functional heterodimers with distinct signaling properties. Our studies thus uncover a novel mode of signaling for the PDGF family during vertebrate development.

Treacher Collins syndrome: New insights from animal models

Treacher Collins syndrome (TCS, OMIM: 154500), an autosomal-dominant craniofacial developmental syndrome that occurs in 1 out of every 50,000 live births, is characterized by craniofacial malformation. Mutations in TCOF1, POLR1C, or POLR1D have been identified in affected individuals. In addition to established mouse models, zebrafish models have recently emerged as an valuable method to study facial disease. In this report, we summarized the two updated articles working on the pathogenesis of the newly identified polr1c and polr1d TCS mutations (Lau et al., 2016; Noack Watt et al., 2016) and discussed the possibility of using the anti-oxidants to prevent or rescue the TCS facial phenotype (Sakai et al., 2016). Taken together, this article provides an update on the disease from basic information to pathogenesis, and further summarizes the suggested therapies from recent laboratory research.

Cutis tricolor: a literature review and report of five new cases.

Cutis tricolor is a skin abnormality consisting in a combination of congenital hyper- and hypopigmented skin lesions (in the form of paired macules, patches or streaks) in close proximity to each other in a background of normal skin. It is currently regarded as a twin-spotting (mosaic) phenomenon and today is clear that not all cases of cutis tricolor represent one single entity. This phenomenon has been reported so far either: (I) as an purely cutaneous trait; (II) as a part of a complex malformation phenotype (Ruggieri-Happle syndrome, RHS) including distinct facial features, eye (cataract), skeletal (skull and vertebral defects, and long bones dysplasia), nervous system (corpus callosum, cerebellar and white matter anomalies, cavum vergae and holoprosencephaly) and systemic abnormalities; (III) as a distinct type with multiple, disseminated smaller skin macules (cutis tricolor parvimaculata); and (IV) in association with other skin disturbances [e.g., cutis marmorata telangectasica congenita (phacomatosis achromico-melano-marmorata)] or in the context of other skin (e.g., ataxia-telangiectasia and phacomatosis pigmentovascularis, PPV) or complex malformation phenotypes (e.g., microcephaly and dwarfism). (I) Review of the existing literature; and (II) information on our personal experience (clinical, laboratory and imaging data) on new cases with cutis tricolor seen and followed-up at our institutions during years 2010-2016. The existing literature revealed 19 previous studies (35 cases) with pure cutaneous or syndromic cutis tricolor phenomena. Our personal experience included 5 unpublished patients (3 boys; 2 girls; currently aged 2 to 14 years) seen and followed-up at our Institutions in Italy who had: (I) skin manifestations of the cutis tricolor type (N=5); (II) skeletal abnormalities including small skull (n=2), obtuse angle of mandible (n=3), mild to moderate scoliosis (n=3), vertebral defects (n=3), and long bones bowing (n=3); mild psychomotor delay (n=3); epilepsy (n=2); anomalies of the corpus callosum (n=3); and cavum vergae (n =2). This study further confirms and expands the overall phenotype of cutis tricolor. By literature review and personal experience we conclude that the skin abnormalities of the cutis tricolor type are stable over time; the skeletal defects are mild to moderate and do not progress or cause relevant orthopaedic complications; the neurological/behavioural phenotype does not progress and the paroxysmal events (when present) tend to decrease over time; there is a typical facial phenotype in some patients (long, elongated face, thick and brushy eyebrows, hypertelorism, deep nasal bridge with large bulbous nose and anteverted nostrils), which characterizes a somewhat distinct syndromic phenotype; some patients may develop early onset cataracts. The allelic dydymotic hypothesis of post-zygotic mutations likely involving the same gene loci could well explain the overall skin, bone, lens and nervous system phenomena of migration of different streaks of clones in the different tissues.

Genetic and Environmental Contributions to Facial Morphological Variation: A 3D Population-Based Twin Study.

IntroductionFacial phenotype is influenced by genes and environment; however, little is known about their relative contributions to normal facial morphology. The aim of this study was to assess the relative genetic and environmental contributions to facial morphological variation using a three-dimensional (3D) population-based approach and the classical twin study design.Materials and Methods3D facial images of 1380 female twins from the TwinsUK Registry database were used. All faces were landmarked, by manually placing 37 landmark points, and Procrustes registered. Three groups of traits were extracted and analysed: 19 principal components (uPC) and 23 principal components (sPC), derived from the unscaled and scaled landmark configurations respectively, and 1275 linear distances measured between 51 landmarks (37 manually identified and 14 automatically calculated). The intraclass correlation coefficients, rMZ and rDZ, broad-sense heritability (h2), common (c2) and unique (e2) environment contributions were calculated for all traits for the monozygotic (MZ) and dizygotic (DZ) twins.ResultsHeritability of 13 uPC and 17 sPC reached statistical significance, with h2 ranging from 38.8% to 78.5% in the former and 30.5% to 84.8% in the latter group. Also, 1222 distances showed evidence of genetic control. Common environment contributed to one PC in both groups and 53 linear distances (4.3%). Unique environment contributed to 17 uPC and 20 sPC and 1245 distances.ConclusionsGenetic factors can explain more than 70% of the phenotypic facial variation in facial size, nose (width, prominence and height), lips prominence and inter-ocular distance. A few traits have shown potential dominant genetic influence: the prominence and height of the nose, the lower lip prominence in relation to the chin and upper lip philtrum length. Environmental contribution to facial variation seems to be the greatest for the mandibular ramus height and horizontal facial asymmetry.

New Entries in the Lottery of Facial GWAS Discovery.

New Entries in the Lottery of Facial GWAS Discovery.

Update on the Toriello-Carey syndrome.

Toriello and Carey described a provisionally-unique syndrome comprised of agenesis of the corpus callosum, Pierre Robin anomaly, and a characteristic facial phenotype. Because the condition affected siblings, this entity was postulated to be an autosomal recessive multiple anomaly syndrome. Several patients were subsequently reported, and over time, it became apparent that the Toriello-Carey syndrome was etiologically heterogeneous. Based on previous reports, it is estimated that at least 20% of patients with a clinical diagnosis of Toriello-Carey syndrome have a chromosomal anomaly as the basis of the phenotype. However, no basis for the non-chromosomal cases has been found. This review summarizes the literature to date and provides speculation regarding the possible explanations for failing to find the cause of Toriello-Carey syndrome. © 2016 Wiley Periodicals, Inc.

Expanding the clinical picture of the MECP2 Duplication syndrome.

Individuals with two or more copies of the MECP2 gene, located at Xq28, share clinical features and a distinct facial phenotype known as MECP2 Duplication syndrome. We have examined perinatal characteristics, early childhood development and medical co-morbidities in this disorder. The International Rett Syndrome Phenotype Database (InterRett), which collects information from caregivers and clinicians on individuals with Rett syndrome and MECP2 associated disorders, was used as the data source. Data were available on 56 cases (49 males and 7 females) with MECP2 Duplication syndrome. Median age at ascertainment was 7.9 years (range: 1.2-37.6 years) and at diagnosis 3.0 years (range: 3 weeks-37 years). Less than a third (29%) learned to walk. Speech deterioration was reported in 34% and only 20% used word approximations or better at ascertainment. Over half (55%) had been hospitalised for respiratory infections in the first 2 years of life. Just under half (44%) had seizures, occurring daily in nearly half of this group. The majority (89%) had gastrointestinal problems and a third had a gastrostomy. Following the recent demonstration of phenotype reversal in a mouse model of MECP2 Duplication, a clear understanding of the natural history is crucial to the design and implementation of future therapeutic strategies.

Validation of the Polish Version of the Washington 4-Digit Diagnostic Code for the Assessment of Fetal Alcohol Spectrum Disorders.

The aim of this paper is a quantitative assessment of FASD facial phenotype in the Polish population using the Polish version of the 4-Digit Diagnostic Code. The study covered 2 groups of children: 30 children aged 4-7 and 30 children aged 8-11 with a facial phenotype characteristic for the Fetal Alcohol Syndrome (FAS). The control group consisted of 60 children (4-11 years old) developing normally. We compared 3 facial features (small palpebral fissure lengths, smooth philtrum and thin upper lip). The repeatability, conformity and diagnostic accuracy of particular dysmorphic features of the study were assessed. Obtained values for palpebral fissure were "poor", "good" and "very good", for philtrum "good" and "very good" and for upper lip "good" and "very good". As for conformity, values for palpebral fissure were "moderate" and 'good", for philtrum - "good" and for upper lip also "good". In the experimental group, the FAS diagnostic criteria were met by 13 subjects, partial FAS criteria were met by 37 subjects and the criteria of static encephalopathy with no FAS phenotype were met by 2 subjects. None of the subjects in the control group met these criteria. The pictorial scale for the assessment of the facial dysmorphic features proved to be a useful tool in the clinical diagnostics of FAS in the Polish conditions. Due to the problems associated with the measurement of the palpebral fissure, it is necessary to verify the normal growth charts for the Polish population.