Asymmetric crying facies in an elderly, when a facial asymmetry is not a facial paralysis but a marker of possible congenital malformations: case report and review of the literature.

BACKGROUND: Facial asymmetry when crying at birth (then called asymmetric crying facies or ACF) or when smiling or speaking loudly in adulthood is the consequence of the agenesis or hypoplasia of the muscle of one of the labial commissures. This developmental disorder of complex mechanism is well known by pediatricians to be a warning sign for underlying developmental disorders of variable severity. CASE REPORT: An 80-year-old man with medical history of renal agenesis was hospitalized for a transient motor deficit of the right face and arm revealing a lacunar stroke. Clinical examination showed an isolated left facial asymmetry upon smiling or talking out loud which had been known since childhood and was not related to the stroke, leading to the diagnosis of ACF. Cardiac ultrasound revealed a patent foramen. Chromosomal investigations could not be performed. DISCUSSION AND CONCLUSION: ACF is a rare disorder that may conceal associated congenital disorders such as heart, skeletal, or renal malformations. Its causing mechanisms are to this day still poorly understood but may include a genetic component as shown by familial cases and the identification of 22q11.2 deletions or trisomy 18 in some patients. Knowledge of this disorder seems highly relevant for adult neurologists, first because of the differential diagnosis with facial palsy, but mostly because it will allow them to screen patients for other congenital disorders such as heart malformations. Conversely, cardiologists and cardiac surgeon may search for an ACF when faced with a patient with a congruent heart defect.

Facial asymmetry and chewing sides in twins.

OBJECTIVE: To resolve how the preferred chewing side (PCS) affects facial asymmetry in twins, whether there are differences between monozygotic (MZ) and dizygotic (DZ) twins, and whether the twins with PCS have more asymmetric faces compared to symmetrically chewing twins. MATERIAL AND METHODS: The study included 106 Lithuanian twin pairs of the same sex, 59 MZ and 47 DZ pairs. The data were analysed from facial 3D images and manually added landmarks. 3D images were analysed by Rapidform2006 software and statistical analyses were done by using the R software environment version 4.1.0. RESULTS: The contralateral effect of PCS and larger chin side was dominant among right and non-right side chewing twins. Being female increased the whole face symmetry. CONCLUSION: The volume of the chin becomes larger on the side opposite to the twins' habitual chewing side. As the results are quite similar in both twin types, functional factors are more prominent than heredity.

Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants.

We studied a family in which the first-born child, a girl, had developmental delay, facial dysmorphism, and agenesis of the corpus callosum (ACC). The subsequent pregnancy was interrupted as the fetus was found to be also affected by ACC. Both cases were heterozygous for two KDM5B variants predicting p (Ala635Thr) and p (Ser1155AlafsTer4) that were shown to be in trans. KDM5B variants have been previously associated with moderate to severe developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and dysmorphism in a few individuals, but the pathogenetic mechanisms are not clear yet as patients with both monoallelic and biallelic variants have been observed. Interestingly, one individual has previously been reported with ACC and severe ID in association with biallelic KDM5B variants. Together with the observations in this family, this suggests that agenesis of the corpus callosum may be part of the phenotypic spectrum associated with KDM5B variants and that the KDM5B gene should be included in gene panels to clarify the etiology of ACC both in the prenatal and postnatal setting.

Studying factors influencing facial developmental instability.

BACKGROUND: Developmental instability is a component of non-genetic variation that results from random variation in developmental processes. It is considered a sensitive indicator of the physiological state of individuals. It is reflected in various ways, but in this study we focussed on its reflection in fluctuating asymmetry (FA) and morphological integration. AIM: To assess how, if at all, variations of facial morphology mirror developmental instability across childhood with respect to sex, growth rate and socioeconomic/environmental factors. SUBJECTS AND METHODS: A set of 210 three-dimensional facial models (of children aged between 6.3 and 14.3 years) originating from the FIDENTIS 3D Face Database was subjected to landmark-based methods of geometric morphometrics to quantify the degree of facial asymmetry and facial morphological integration. In addition, the association with age, sex, and socioeconomic factors was assessed. RESULTS: Our results showed a nonlinear increase of FA with age up to the age of 14 years. The pattern of sex-related variants in facial FA differed in relation to age, as girls exhibited higher values of FA than boys up to the age of 9 years. We found that a signal of modularity based on functional demands and organisation of the face is of particular importance. Here, girls exhibited higher morphological covariation among modules. During more rapid adolescence-related growth, however, covariation among modules at the asymmetrical level decreased in both sexes. CONCLUSION: We can conclude that facial morphology was shown to be strongly integrated, particularly until adolescence. This covariation can facilitate an increase of FA. In addition, the results of this study indicate there is a weak association between socioeconomic stress and facial asymmetries. In contrast, sex and growth rate are reflected in developmental instability.

Familiar occurrence of facial asymmetry: a pilot study.

BACKGROUND: The point at which "normal" asymmetry becomes "abnormal" can be defined by an aesthetic limit and a functional limit. The underlying causes are still not fully discovered; the etiology includes congenital disorders, acquired diseases, and traumatic and developmental deformities. Our purpose was to investigate the possible genetic liability in the transmissibility of the asymmetric traits, through an analysis developed by twofold approach: 1) exploring and recording the family history through the use of a specific questionnaire; and 2) examining differences in laterality between the patients and their corresponding parent by a facial analysis. METHODS: A total of 52 Italian subjects (57% females, 43% males; mean age: 11.7 years), showing a clinically detectable asymmetry, were selected. Individuals in the sample were selected according to the diagnosis of facial asymmetry, non-syndromic patients, participation by informed consent, and negative medical history of the maxillo-facial complex. A specifically designed questionnaire was used to investigate the presence of the asymmetric trait in the family. Differences in length between distance from the anthropometric points to the facial midline and to horizontal reference were measured on a frontal facial photograph. For all the subjects recruited the same analysis was performed on the frontal facial photographs of both the parents. A descriptive and interferential statistical analysis was performed on the data. RESULTS: Concerning the linear measurement, in a high percentage of parent-child pairs there is a correspondence of laterality of asymmetry traits, with a more common relation with the maternal trait. Sixty-five percent of parents with correspondence of laterality reported a positive family history of asymmetry. CONCLUSIONS: The analysis of the obtained data shows that the mother is the parent most involved in the correspondence of laterality. Further analysis would be appropriate to investigate this result.

Unilateral condylar hyperplasia in hemifacial hyperplasia, is there genetic proof of overgrowth?

Hemifacial hyperplasia (HFH) is characterized by an increase in volume of all affected tissues of half of the face. It is present at birth, subsequently grows proportionally, and stops growing before adulthood. Unilateral condylar hyperplasia (UCH) consists of progressive asymmetric growth of the mandible and develops typically in early adulthood. Both disorders have an unknown aetiology. The overgrowth limited to one body part suggests somatic mosaicism, as this has been found in other similar localized overgrowth disorders. Often this includes a variant in a gene in the (PIK3CA)/PI3K/(PTEN)/AKT1/mTOR pathway. Here we report the case of an HFH patient with asymmetry present at birth, in whom a progressive growth pattern similar to UCH subsequently occurred, causing marked mandibular asymmetry. A condylectomy was successfully performed to stop the progressive growth. Somatic mosaicism for a mutation in PIK3CA was detected in the condylar tissue. This finding might indicate that both HFH and UCH can be caused by variants in genes in the (PIK3CA)/PI3K/(PTEN)/AKT1/mTOR pathway, similar to other disorders that result in asymmetrical bodily overgrowth.

Ectopic Posterior Pituitary, Polydactyly, Midfacial Hypoplasia and Multiple Pituitary Hormone Deficiency due to a Novel Heterozygous IVS11-2A>C(c.1957-2A>C) Mutation in the GLI2 Gene

A novel heterozygous IVS11-2A>C(c.1957-2A>C) mutation in the GLI2 gene is reported. There was an extremely distinct phenotypical expression in two siblings and their father. The index case was a boy who developed cholestasis and hypoglycaemia in the neonatal period. He had bilateral postaxial polydactyly, mid-facial hypoplasia, high palatal arch, micropenis, and bilateral cryptorchidism. Laboratory examination revealed a diagnosis of multiple pituitary hormone deficiency. There was severe anterior pituitary hypoplasia, absent pituitary stalk and ectopic posterior pituitary on magnetic resonance imaging which suggested pituitary stalk interruption syndrome with no other midline structural abnormality. Molecular genetic analysis revealed a novel heterozygous splicing IVS11-2A>C(c.1957-2A>C) mutation detected in the GLI2 gene. His father and a six-year-old brother with the identical mutation also had unilateral postaxial polydactyly and mid-facial hypoplasia although there was no pituitary hormone deficiency. This novel heterozygous GLI2 mutation detected appears to present with an extremely variable clinical phenotype, even in related individuals with an identical mutation, suggesting incomplete penetrance of this GLI2 mutation.

Subtelomeric Rearrangements: Presentation of 21 Probands with Emphasis on Familial Cases.

INTRODUCTION: Intellectual disability affects 2% - 3% of the general population, with a chromosomal abnormality being found in 4% - 28% of these patients and a cryptic subtelomeric abnormality in 3% - 16%. In most cases, these subtelomeric rearrangements are submicroscopic, requiring techniques other than conventional karyotype for detection. They may be de novo or inherited from an affected parent or from a healthy carrier of a balanced chromosomal abnormality. The aim of this study was to characterize patients from our medical genetics center, in whom both a deletion and duplication in subtelomeric regions were found. MATERIAL AND METHODS: Clinical and cytogenetic characterization of 21 probands followed at our center, from 1998 until 2017, with subtelomeric rearrangements. RESULTS: There were 21 probands from 19 families presenting with intellectual disability and facial dysmorphisms. Seven had behavior changes, five had epilepsy and 14 presented with some other sign or symptom. Four had chromosomal abnormalities detected by conventional karyotype and four were diagnosed by array-comparative genomic hybridization. In four cases, parental studies were not possible. The online mendelian inheritance in man classification was provided whenever any of the phenotypes (deletion or duplication syndrome) was dominant. DISCUSSION: Patients and relevant family members were clinically and cytogenetically characterized. Although rare, subtelomeric changes are a substantial cause of syndromic intellectual disability with important familial repercussions. It is essential to remember that a normal array-comparative genomic hybridization result does not exclude a balanced rearrangement in the parents. CONCLUSION: Parental genetic studies are essential not only for a complete characterization of the rearrangement, but also for accurate genetic counselling and screening of family members at risk for recurrence.

Introdução: O défice intelectual afeta 2% ­ 3% da população geral, sendo encontrada uma alteração cromossómica em 4% ­ 28% dos casos e uma alteração subtelomérica em 3% ­ 16%. Estas alterações subteloméricas são, na maioria dos casos, submicroscópi- cas, não sendo detetadas no cariótipo convencional. Podem ser de novo ou herdadas de um progenitor afetado ou de um progenitor saudável portador de um rearranjo equilibrado. O objetivo deste estudo foi caracterizar os doentes seguidos no nosso centro de gené- tica médica com uma deleção e uma duplicação nas regiões subteloméricas. Material e Métodos: Caracterização clínica e citogenética de 21 probandos com alterações subteloméricas seguidos no nosso centro entre 1998 e 2017. Resultados: Foram caracterizados 21 probandos que apresentavam défice intelectual e dismorfia facial, pertencentes a 19 famílias. Sete tinham alterações do comportamento, cinco epilepsia e 14 outro sinal ou sintoma. Quatro tinham alterações no cariótipo e quatro foram diagnosticados por array-comparative genomic hybridization. Em quatro famílias não foi possível o estudo dos progenitores. Quando um dos fenótipos era dominante (síndrome de deleção ou duplicação), foi atribuída a classificação online mendelian inheri- tance in man. Discussão: Foi realizada classificação dos doentes e das famílias. As alterações nas regiões subteloméricas são, apesar de raras, uma causa substancial para défice intelectual sindrómico com repercussões familiares importantes. É essencial lembrar que um array- comparative genomic hybridization normal não exclui um rearranjo equilibrado familiar. Conclusão: O estudo dos progenitores é essencial não só para caracterização completa do rearranjo mas também para um aconse- lhamento genético preciso e identificação de familiares em risco de recorrência.

A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardation.

Objective The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in IGF1 and IGF1R determine intrauterine growth restriction and affect postnatal body growth. However, to date, there are only few reports of pathogenic IGF2 mutations causing severe prenatal, as well as postnatal growth retardation. Results Here we describe a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93)) in a 4-year-old patient with severe pre- and post-natal growth retardation in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) IGF2 gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation. Conclusion The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders.

Facial recognition software in clinical dysmorphology.

PURPOSE OF REVIEW: The current review aims to discuss the incorporation of facial recognition software into the clinical practice of dysmorphology and medical genetics. RECENT FINDINGS: Facial recognition software has improved the process of generating a differential diagnosis for rare genetic syndromes, and recent publications demonstrate utility in both research and clinical applications. Software programs are freely available to verified medical providers and can be incorporated into routine clinic encounters. SUMMARY: As facial recognition software capabilities improve, two-dimensional image capture with artificial intelligence interpretation may become a useful tool within many areas of medicine. Geneticists and researchers can use such software to enhance their differential diagnoses, to study similarities and differences between patient cohorts, and to improve the interpretation of genomic data. Pediatricians and subspecialists may use tools to identify patients who may benefit from a genetic evaluation, and educators can use these tools to interest students in the study of dysmorphoplogy and genetic syndromes.

A study of familial Char syndrome involving the TFAP2B gene with a focus on facial shape characteristics.

In this case study, we investigate a child presenting with patent ductus arteriosus, short philtrum, duck-bill lips, strabismus, a flat nasal bridge, a broad forehead, low-set ears, hypertelorism, up-slanting palpebral fissures, almond-shaped eyes, and hypodontia, all leading to the clinical diagnosis of Char syndrome. Genetic analysis showed heterozygosity for the novel variant c.851T>C, p. Leu284Ser in the TFAP2B gene. Family analysis suggested that at least 20 members, extending six generations back, were affected. All 10 members available for genetic testing were heterozygous for the novel pathogenic variant. Qualitative analysis of the facial dysmorphology in the proband and three of the affected family members using three-dimensional surface scanning showed that the major deviations were observed in the forehead/eyebrow, nose, upper lip, and chin regions with, for example, a flattened nose and reduced height of the upper lip and the face. Furthermore, it is suggested that Char syndrome is associated with disturbances of tooth formation and eruption.

ENPP1 and ESR1 genotypes associated with subclassifications of craniofacial asymmetry and severity of temporomandibular disorders.

INTRODUCTION: We investigated whether ACTN3, ENPP1, ESR1, PITX1, and PITX2 genes which contribute to sagittal and vertical malocclusions also contribute to facial asymmetries and temporomandibular disorders (TMD) before and after orthodontic and orthognathic surgery treatment. METHODS: One hundred seventy-four patients with a dentofacial deformity were diagnosed as symmetric or subdivided into 4 asymmetric groups according to posteroanterior cephalometric measurements. TMD examination diagnosis and jaw pain and function (JPF) questionnaires assessed the presence and severity of TMD. RESULTS: Fifty-two percent of the patients were symmetric, and 48% were asymmetric. The asymmetry classification demonstrated significant cephalometric differences between the symmetric and asymmetric groups, and across the 4 asymmetric subtypes: group 1, mandibular body asymmetry; group 2, ramus asymmetry; group 3, atypical asymmetry; and group 4, C-shaped asymmetry. ENPP1 SNP-rs6569759 was associated with group 1 (P = 0.004), and rs858339 was associated with group 3 (P = 0.002). ESR1 SNP-rs164321 was associated with group 4 (P = 0.019). These results were confirmed by principal component analysis that showed 3 principal components explaining almost 80% of the variations in the studied groups. Principal components 1 and 2 were associated with ESR1 SNP-rs3020318 (P <0.05). Diagnoses of disc displacement with reduction, masticatory muscle myalgia, and arthralgia were highly prevalent in the asymmetry groups, and all had strong statistical associations with ENPP1 rs858339. The average JPF scores for asymmetric subjects before surgery (JPF, 7) were significantly higher than for symmetric subjects (JPF, 2). Patients in group 3 had the highest preoperative JPF scores, and groups 2 and 3 were most likely to be cured of TMD 1 year after treatment. CONCLUSIONS: Posteroanterior cephalometrics can classify asymmetry into distinct groups and identify the probability of TMD and genotype associations. Orthodontic and orthognathic treatments of facial asymmetry are effective at eliminating TMD in most patients.

Maxillofacial features and systemic malformations in expanded spectrum Hemifacial Microsomia.

Hemifacial microsomia (HFM) is a rare, multisystemic congenital disease with estimated frequency of 1/26370 births in Europe. Most cases are sporadic and caused by unilateral abnormal morphogenesis of the first and second pharyngeal arches. The aim of this study is to define the types and frequency of maxillofacial and systemic malformations in HFM patients. This is a case series study of patients with HFM evaluated at a single institution. Data were acquired through history, physical examination, photographs, diagnostic radiology, and laboratory and analyzed by the FileMakerPro database on 95 patients (54F; 41M) of which 89 met the inclusion criteria. Mandibular hypoplasia was observed in 86 patients with right-side preponderance (50). One patient had bilateral mandibular hypoplasia. Seventy-four had external ear anomalies (anotia or microtia). Eleven had bilateral malformed ears. Hearing impairment, associated with stenosis or atresia of the external ear canal, was found in 69 patients (eight with bilateral canal defects). Ocular anomalies were seen in 41 (23 with dermoid cysts) and 39 had orbital malformations. Facial nerve paralysis was observed in 38 patients. Cleft lip/palate (10), preauricular tags (55), and macrostomia (41) were also described. A total of 73/86 had systemic malformations, mainly vertebral (40), genitourinary (25), and cardiovascular (28). Sixteen had cerebral anomalies (four with intellectual disability). All patients suspected of HFM should undergo a complete systematic clinical and imaging investigation to define the full scope of anomalies. Since the disease is rare and complex, affected patients should be monitored by specialized multidisciplinary team centers.

Socioeconomic Status Is Not Related with Facial Fluctuating Asymmetry: Evidence from Latin-American Populations.

The expression of facial asymmetries has been recurrently related with poverty and/or disadvantaged socioeconomic status. Departing from the developmental instability theory, previous approaches attempted to test the statistical relationship between the stress experienced by individuals grown in poor conditions and an increase in facial and corporal asymmetry. Here we aim to further evaluate such hypothesis on a large sample of admixed Latin Americans individuals by exploring if low socioeconomic status individuals tend to exhibit greater facial fluctuating asymmetry values. To do so, we implement Procrustes analysis of variance and Hierarchical Linear Modelling (HLM) to estimate potential associations between facial fluctuating asymmetry values and socioeconomic status. We report significant relationships between facial fluctuating asymmetry values and age, sex, and genetic ancestry, while socioeconomic status failed to exhibit any strong statistical relationship with facial asymmetry. These results are persistent after the effect of heterozygosity (a proxy for genetic ancestry) is controlled in the model. Our results indicate that, at least on the studied sample, there is no relationship between socioeconomic stress (as intended as low socioeconomic status) and facial asymmetries.

Minor physical anomalies are more common among the first-degree unaffected relatives of schizophrenia patients - Results with the Méhes Scale.

Minor physical anomalies are external markers of abnormal brain development,so the more common appearance of these signs among the relatives of schizophrenia patients can confirm minor physical anomalies as intermediate phenotypes. The aim of the present study was to investigate the rate and topological profile of minor physical anomalies in the first-degree unaffected relatives of patients with schizophrenia compared to matched normal control subjects. Using a list of 57 minor physical anomalies (the Méhes Scale), 20 relatives of patients with the diagnosis of schizophrenia and as a comparison 20 matched normal control subjects were examined. Minor physical anomalies were more common in the head and mouth regions among the relatives of schizophrenia patients compared to normal controls. By the differentiation of minor malformations and phenogenetic variants, we have found that only phenogenetic variants were more common in the relatives of schizophrenia patients compared to the control group, however individual analyses showed, that one minor malformation (flat forehead) was more prevalent in the relative group. The results can promote the concept, that minor physical anomalies can be endophenotypic markers of the illness.

Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction.

Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.

A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome.

Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to a heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: (i) intrauterine growth retardation and postnatal short stature, (ii) feeding difficulties and/or gastro-oesophageal reflux, (iii) microcephaly, (iv) intellectual disability, and (v) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and 3 in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for 20 cases which do not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counselling.

Recognition of the Cornelia de Lange syndrome phenotype with facial dysmorphology novel analysis.

Facial analysis systems are becoming available to healthcare providers to aid in the recognition of dysmorphic phenotypes associated with a multitude of genetic syndromes. These technologies automatically detect facial points and extract various measurements from images to recognize dysmorphic features and evaluate similarities to known facial patterns (gestalts). To evaluate such systems' usefulness for supporting the clinical practice of healthcare professionals, the recognition accuracy of the Cornelia de Lange syndrome (CdLS) phenotype was examined with FDNA's automated facial dysmorphology novel analysis (FDNA) technology. In the first experiment, 2D facial images of CdLS patients with either an NIPBL or SMC1A gene mutation as well as non-CdLS patients which were assessed by dysmorphologists in a previous study were evaluated by the FDNA technology; the average detection rate of experts was 77% while the system's detection rate was 87%. In the second study, when a new set of NIPBL, SMC1A and non-CdLS patient photos was evaluated, the detection rate increased to 94%. The results from both studies indicated that the system's detection rate was comparable to that of dysmorphology experts. Therefore, utilizing such technologies may be a useful tool in a clinical setting.