Identification of a de novo PUF60 variant associated with craniofacial microsomia.

Craniofacial microsomia (CFM), also known as the oculo-auriculo-vertebral spectrum, is a congenital disorder characterized by hypoplasia of the mandible and external ear due to tissue malformations originating from the first and second branchial arches. However, distinguishing it from other syndromes of branchial arch abnormalities is difficult, and causal variants remain unidentified in many cases. In this report, we performed an exome sequencing analysis of a Brazilian family with CFM. The proband was a 12-month-old boy with clinical findings consistent with the diagnostic criteria for CFM, including unilateral mandibular hypoplasia, microtia, and external auditory canal abnormalities. A heterozygous de novo nonsense variant (c.713C>G, p.S238*) in PUF60 was identified, which was predicted to be pathogenic in silico. PUF60 has been reported as a causal gene in Verheij syndrome, but not in CFM. Although the boy showed craniofacial abnormalities and developmental delay that overlapped with Verheij syndrome, the facial asymmetry with unilateral hypoplasia of the mandible observed in this case did not match the previously reported phenotypes of PUF60 variants. Our findings expand the phenotypic range of PUF60 variants that cover CFM and Verheij syndrome.

Prenatal findings in 11 cases with craniofacial microsomia using the Alberta Congenital Anomalies Surveillance System, 1997-2019.

Craniofacial microsomia (CFM) primarily includes specific head and neck anomalies that co-occur more frequently than expected. The anomalies are usually asymmetric and affect craniofacial features; however, there are frequently additional anomalies of variable severity. Published prenatal findings for CFM are limited. This study contributes 11 cases with CFM and their anomalies identified prenatally. Cases born between January 1, 1997 and December 31, 2019 with CFM were abstracted from the Alberta Congenital Anomalies Surveillance System, which is a population-based program ascertaining congenital anomalies for livebirths, stillbirths, and termination of pregnancies for fetal anomalies. There were 11 cases ascertained with prenatal findings including facial anomalies: one each with left cleft lip, right microtia, and bilateral microphthalmia. Two cases had vertebral anomalies. In addition, anomalies of the kidneys, brain, heart, and radial ray were identified. Six (55%) had a single umbilical artery, five (45%) were small for gestational age, and three (27%) were from a twin pregnancy that were discordant for anomalies. Four (36%) overlapped another proposed recurrent constellations of embryonic malformation condition. This study describes prenatal findings for 11 cases with CFM. Comparable to prior published cases, there were recurring anomalies on prenatal imaging, including anomalies of the brain, eye, heart, kidneys, and radial ray, which may aid in the prenatal diagnosis of CFM.

Goldenhar syndrome with limbal neoformation, microtia and skeletal deformities: a case report and literature review.

BACKGROUND: To report a case of a 4-year-old patient with Goldenhar syndrome. CASE PRESENTATION: The author presents a rare case report involving a 4-year-old boy with multiple malformations. A comprehensive examination showed that the patient primarily had a limbal dermoid. He also has bilateral microtia and ear canal deformities. The skull CT scan and spine X-ray showed Maxillofacial Abnormalities and scoliosis. Whole Exome Sequencing revealed potential gene variations related to microtia. Although certain circumstances prevented us from initiating follow-up treatment for the patient, we have provided a detailed account of the diagnostic methodologies used for this condition. CONCLUSIONS: Goldenhar syndrome is a congenital condition, predominantly presenting as sporadic cases. Its diagnosis and management typically necessitate the involvement of multiple disciplines, including otolaryngology and craniofacial surgery. The syndrome encompasses a variety of craniofacial features, which can facilitate early diagnosis and guide subsequent therapeutic interventions.

Novel risk factors for craniofacial microsomia and assessment of their utility in clinic diagnosis.

Craniofacial microsomia (CFM, OMIM%164 210) is one of the most common congenital facial abnormalities worldwide, but it's genetic risk factors and environmental threats are poorly investigated, as well as their interaction, making the diagnosis and prenatal screening of CFM impossible. We perform a comprehensive association study on the largest CFM cohort of 6074 samples. We identify 15 significant (P < 5 × 10-8) associated genomic loci (including eight previously reported) and decipher 107 candidates based on multi-omics data. Gene Ontology term enrichment found that these candidates are mainly enriched in neural crest cell (NCC) development and hypoxic environment. Single-cell RNA-seq data of mouse embryo demonstrate that nine of them show dramatic expression change during early cranial NCC development whose dysplasia is involved in pathogeny of CFM. Furthermore, we construct a well-performed CFM risk-predicting model based on polygenic risk score (PRS) method and estimate seven environmental risk factors that interacting with PRS. Single-nucleotide polymorphism-based PRS is significantly associated with CFM [P = 7.22 × 10-58, odds ratio = 3.15, 95% confidence interval (CI) 2.74-3.63], and the top fifth percentile has a 6.8-fold CFM risk comparing with the 10th percentile. Father's smoking increases CFM risk as evidenced by interaction parameter of -0.324 (95% CI -0.578 to -0.070, P = 0.011) with PRS. In conclusion, the newly identified risk loci will significantly improve our understandings of genetics contribution to CFM. The risk prediction model is promising for CFM prediction, and father's smoking is a key environmental risk factor for CFM through interacting with genetic factors.

Oculoauriculofrontonasal syndrome: Refining the phenotype through a new case series and literature review.

The oculoauriculofrontonasal syndrome (OAFNS) is a rare condition, with unknown etiology, characterized by the association of frontonasal dysplasia (FND) and oculoauriculovertebral spectrum (OAVS). Main clinical findings include widely spaced eyes, epibulbar dermoid, broad nose, mandibular hypoplasia, and preauricular tags. Here, we describe a case series of 32 Brazilian individuals with OAFNS and review the literature ascertaining individuals presenting phenotypes compatible with the diagnosis of OAFNS, aiming to refine the phenotype. This series emphasizes the phenotypic variability of the OAFNS and highlights the occurrence of rare craniofacial clefts as a part of the phenotype. The ectopic nasal bone, a hallmark of OAFNS, was frequent in our series, reinforcing the clinical diagnosis. The absence of recurrence, consanguinity, chromosomal, and genetic abnormalities reinforces the hypothesis of a nontraditional inheritance model. The phenotypic refinement provided by this series contributes to an investigation regarding the etiology of OAFNS.

Oculo-auriculo-vertebral spectrum: new genes and literature review on a complex disease.

Oculo-auriculo-vertebral spectrum (OAVS) or Goldenhar syndrome is due to an abnormal development of first and second branchial arches derivatives during embryogenesis and is characterised by hemifacial microsomia associated with auricular, ocular and vertebral malformations. The clinical and genetic heterogeneity of this spectrum with incomplete penetrance and variable expressivity, render its molecular diagnosis difficult. Only a few recurrent CNVs and genes have been identified as causatives in this complex disorder so far. Prenatal environmental causal factors have also been hypothesised. However, most of the patients remain without aetiology. In this review, we aim at updating clinical diagnostic criteria and describing genetic and non-genetic aetiologies, animal models as well as novel diagnostic tools and surgical management, in order to help and improve clinical care and genetic counselling of these patients and their families.

Craniofacial microsomia - more than a structural malformation.

OBJECTIVES: To analyse the prevalence and distribution of craniofacial microsomia (CFM) cases in Finland and their most frequent comorbidities. The second aim was to analyse the patients' need for specialized healthcare services. MATERIALS AND METHODS: Data were gathered from two complementary registers: The Register of Congenital Malformations and the Care Register for Social Welfare and Health Care (Hilmo) of the Finnish Institute for Health and Welfare (THL). RESULTS: The prevalence of CFM patients in Finland was 1:10 057. They were evenly distributed across the five university hospital districts. Their most frequently used ICD-10 diagnosis codes were F40-48 (Neurotic, stress-related and somatoform disorders), 60% of patients in adolescent and adult psychiatry; Q67.0 (Facial asymmetry), 43% in plastic surgery; Z00.4 (General psychiatric examination, not elsewhere classified), 31% in child psychiatry; Z31.5 (Genetic counselling), 28% in clinical genetics and Q67.40 (Other congenital deformities of the skull, face and jaw, Hemifacial atrophy), 18% in dental, oral and maxillofacial diseases. Of the patients, 70% had had visits in clinical genetics, 60% in plastic surgery, 41% in dental, oral and maxillofacial diseases, 28% in adolescent/adult psychiatry and 21% in child psychiatry. The majority of the patients' plastic surgery visits were concentrated in one university hospital. Other services were mainly provided by patients' own hospital districts. CONCLUSIONS: Even though the majority of CFM patients' visits in specialized healthcare services are related to correction of facial asymmetry and ear malformations, the obvious need for psychiatric care was apparent in all age groups.

Evaluation of Research Diagnostic Criteria in Craniofacial Microsomia.

Characteristics of patients with craniofacial microsomia (CFM) vary in type and severity. The diagnosis is based on phenotypical assessment and no consensus on standardized clinical diagnostic criteria is available. The use of diagnostic criteria could improve research and communication among patients and healthcare professionals. Two sets of phenotypic criteria for research were independently developed and based on multidisciplinary consensus: the FACIAL and ICHOM criteria. This study aimed to assess the sensitivity of both criteria with an existing global multicenter database of patients with CFM and study the characteristics of patients that do not meet the criteria. A total of 730 patients with CFM from were included. Characteristics of the patients were extracted, and severity was graded using the O.M.E.N.S. and Pruzansky-Kaban classification. The sensitivity of the FACIAL and ICHOM was respectively 99.6% and 94.4%. The Cohen's kappa of 0.38 indicated a fair agreement between both criteria. Patients that did not fulfill the FACIAL criteria had facial asymmetry without additional features. It can be concluded that the FACIAL and ICHOM criteria are accurate criteria to describe patients with CFM. Both criteria could be useful for future studies on CFM to create comparable and reproducible outcomes.

A new association of Oculoauriculovertebral spectrum and persistent fifth aortic arch -double lumen aorta: a case report.

BACKGROUND: Oculo-auriculo-vertebral spectrum is a heterogeneous group of genetic disorder, also known as Goldenhar Syndrome, which has several phenotypic features including craniofacial anomalies, cardiac, vertebral and central nervous system defects. Cardiovascular anomalies include ventricular septal defects, atrial septal defects, patent ductus arteriosus, Tetralogy of Fallot, double outlet right ventricle, aberrant right subclavian artery, coarctation of aorta, transposition of the great arteries, double inlet left ventricle, cor triatriatum, pulmonary artery stenosis, aortic stenosis, persistent left superior vena cava, partially or totally abnormal pulmonary venous return and bicuspid aortic valve. Persistent fifth aortic arch, also named as double lumen aortic arch, is a very rare cardivascular anomaly and usually associate other cardiac defects. CASE PRESENTATION: We present a 7 month old patient with oculo-auriculo-vertebral spectrum signs as facial asymmetry, short neck, choanal atresia, cleft palate, bilateral preauricular skin tags, bilateral hypoplastic ear lobes, epibulbar dermoid cyst, rib, vertebrae and cardiovascular anomalies. Cardiovascular anomalies detected with echocardiography and computed tomography were malalignment ventricular septal defect and double lumen aorta, known as persistent fifth aortic arch. CONCLUSION: Various cardiovascular anomalies may accompany Goldenhar Syndrome. We present a case with persistent fifth aortic arch and Oculo-auriculo-vertebral spectrum and this is a new association that was not reported before in the literature.

OMENS+ Classification Correlations Analysis of Craniofacial Microsomia in China: The Relationship Between Macrostomia and Mandibular Hypoplasia.

ABSTRACT: Macrostomia is arare congenital craniofacial deformity that influences the appearance and function of patients. In most cases, it coexists with craniomaxillofacial deformities such as craniofacial microsomia (CFM). This study aimed to analyze the relationship between macrostomia and mandibular hypoplasia so as to facilitate the early detection and diagnosis of children with CFM. It included 236 patients diagnosed with CFM. All underwent facial expression analysis, multi-angle photography, computed tomography, and three-dimensional reconstruction of soft and hard tissues. The clinical classification was performed according to OMENS+. Spearman (rank) correlation analysis was used to analyze the relationship between the severity of macrostomia (C1 and C2) and the degree of mandibular involvement (M1, M2a, M2b, and M3), and the correlation among the components of OMENS+. Of the 80 cases of macrostomia (34%) reported, 72 cases (90%) were C1 and 8 (10%) were C2. The analysis of OMENS+ revealed significant correlations among OMENS+ components. Also, a high correlation was observed between macrostomia (C) and hypoplasia of the mandible (M) ( P  = 0.002). Macrostomia was closely related to mandibular hypoplasia among children diagnosed with CFM. These results suggested that patients with macrostomia, who might also have craniofacial malformations caused by other first branchial arch anomalies, should be comprehensively physically examined for other syndromes.

Dental manifestations of a paediatric patient with Goldenhar syndrome.

Goldenhar syndrome (GS) is a rare congenital disorder. It arises from the first pharyngeal pouch, first branchial cleft, first and second branchial arches, and primordia of the temporal bone. It mainly involves abnormalities in the ear, mandibular, and maxillary arches, and is associated with variable clinical features such as skeletal, cardiac, and renal systems. The presence of extra teeth in the dental arch is called supernumerary teeth, and hypodontia refers to congenitally missing teeth. The occurrence of both these anomalies in the same patient is called concomitant hypohyperdontia. However, the GS itself is not very rare, though the presence of concomitant hypohyperdontia has not been reported. The purpose of the present case report is to describe the first case from Saudi Arabia with a characteristic combination of rare findings in a seven-year-old child with comprehensive oral rehabilitation.

[A case report of the first and second branchial arch syndrome with torticollis].

A 54-month-old female patient presented to the department of ophthalmology with abnormal head posture and facial asymmetry for two years. The patient's facial development was asymmetrical, with the middle 1/3 of the left side shorter than the right side. The left ear is less malformed than the right. There was no obvious abnormality in corneal light reflex and eye movement. Head tilt test ( -). So, paralysis of the superior oblique muscle was excluded. In consultation with the department of maxillofacial surgery, the patient was confirmed as the first and second branchial arch syndrome and torticollis.

Velopharyngeal Insufficiency in Craniofacial Microsomia: Prevalence, Diagnosis, and Treatment.

ABSTRACT: The purpose of this study was to analyze the prevalence, diagnosis, and management of velopharyngeal insufficiency (VPI) in patients with craniofacial microsomia (CFM).Craniofacial microsomia patients 13 years of age and above treated at 2 centers from 1997 to 2019 were reviewed retrospectively for demographics, prevalence of VPI, and management of VPI. Patients with isolated microtia were excluded. Comparisons were made between patients with and without VPI using chi-square and independent samples t tests.Among 68 patients with CFM (63.2% male, mean 20.7 years of age), VPI was diagnosed in 19 patients (27.9%) at an average age of 7.2 years old. Among the total cohort, 61 patients had isolated CFM, of which 12 (19.6%) were diagnosed with VPI. Of the patients with isolated CFM and VPI, 8 patients (66.7%) were recommended for nasoendoscopy, of which only 2 patients completed. Seven isolated CFM patients (58.3%) underwent speech therapy, whereas none received VPI surgery. In contrast, 7 patients were diagnosed with both CFM and cleft lip and/or palate (CL/P), all of whom had VPI and were recommended for nasoendoscopy, with 5 (71.4%) completing nasoendoscopy, 6 (85.7%) undergoing speech therapy, and 6 (85.7%) undergoing corrective VPI surgery. Overall, we demonstrated that VPI was present in 27.9% of all CFM patients. On subset analysis, VPI was diagnosed in 20% of patients with isolated CFM and 100% of patients with CFM and CL/P. In addition, despite clinical diagnosis of VPI, a sizeable proportion of isolated CFM patients did not undergo therapy or surgical interventions.

Genome-Wide DNA Methylation Analysis of a Cohort of 41 Patients Affected by Oculo-Auriculo-Vertebral Spectrum (OAVS).

Oculo-auriculo-vertebral-spectrum (OAVS; OMIM 164210) is a rare disorder originating from abnormal development of the first and second branchial arch. The clinical phenotype is extremely heterogeneous with ear anomalies, hemifacial microsomia, ocular defects, and vertebral malformations being the main features. MYT1, AMIGO2, and ZYG11B gene variants were reported in a few OAVS patients, but the etiology remains largely unknown. A multifactorial origin has been proposed, including the involvement of environmental and epigenetic mechanisms. To identify the epigenetic mechanisms contributing to OAVS, we evaluated the DNA-methylation profiles of 41 OAVS unrelated affected individuals by using a genome-wide microarray-based methylation approach. The analysis was first carried out comparing OAVS patients with controls at the group level. It revealed a moderate epigenetic variation in a large number of genes implicated in basic chromatin dynamics such as DNA packaging and protein-DNA organization. The alternative analysis in individual profiles based on the searching for Stochastic Epigenetic Variants (SEV) identified an increased number of SEVs in OAVS patients compared to controls. Although no recurrent deregulated enriched regions were found, isolated patients harboring suggestive epigenetic deregulations were identified. The recognition of a different DNA methylation pattern in the OAVS cohort and the identification of isolated patients with suggestive epigenetic variations provide consistent evidence for the contribution of epigenetic mechanisms to the etiology of this complex and heterogeneous disorder.

The effects of Goldenhar Syndrome on hearing and speech development.

Goldenhar syndrome is a congenital abnormality with an incidence of 1 in 5,200 to 26,500 births. This syndrome is characterized by facial asymmetry, ear malformation, and/or defects in the eyes and vertebrae. The hearing disorder manifests as both conductive or sensorineural due to the abnormalities occurring in the inner and outer ear. We report a case of a 1-year-3-month-old child presenting with left anotia and right microtia, severe bilateral conductive hearing loss, and global delayed development. The patient was also found to have a hemifacial microsomia, a secundum atrial septal defect (ASD), and a ventricular septal defect (VSD). The patient was advised to use hearing aids and participate in speech therapy. The management of this Goldenhar syndrome patient should be done comprehensively, appropriate to the abnormalities found to achieve the best result.

Candidate genes of oculo-auriculo-vertebral spectrum in 22q region: A systematic review.

Oculo-auriculo-vertebral spectrum (hemifacial microsomia/OAVS, OMIM #164210) is a heterogenous and congenital condition caused by a morphogenesis defect of the first and second pharyngeal arches. Etiology includes unknown genetic, environmental factors and chromosomal alterations, which 22q11.2 region is the most frequently reported. Several candidate genes for OAVS have been proposed; however, none has been confirmed as causative of the phenotype. This review aims to sum up all clinical and molecular findings in 22q region of individuals diagnosed with OAVS and to investigate genes that may be involved in the development of the spectrum. A search was performed in PubMed using all entry terms to OAVS and Chromosome 22q11. After screening, 11 papers were eligible for review. Deletions and duplications in the q11.2 region were the most frequent (18/22) alterations reported and a total of 68 genes were described. Our systematic review reinforces the hypothesis that 22q11 region is a candidate locus for OAVS as well as CLTCL1, GSC2, HIRA, MAPK1, TBX1, and YPEL1 as potential candidates genes for genotype-phenotype correlation. Complementary studies regarding genes interaction involved in the 22q11 region are still necessary in the search for a genotype-phenotype association, since the diagnosis of OAVS is a constant medical challenge.

Ophthalmic features and management outcomes of 30 children having Goldenhar syndrome.

PURPOSE: To study the ophthalmic clinical profile and the management outcomes of children having Goldenhar syndrome (GS). METHODS: Retrospective review of included children fulfilling the diagnostic criteria of GS was performed. The demography, ophthalmic features, systemic anomalies, and treatment outcomes were recorded manually from patient files. An ENT, pediatrics, cardiology, and orthopedics consultation was sought for all GS patients before taking up for any ophthalmic surgical procedure. The anatomical (ocular surface and eyelid) and functional {vision and extraocular movements (EOM)} factors were exclusively studied. We ensured a minimum postoperative follow-up of 12 months, and our data were compared with the major studies featuring 'ophthalmic features' of GS. RESULTS: Totally 30 children (females = 18, 60%) were included with a median presenting age of 48 months. Twenty-seven (90%) had unilateral ophthalmic involvement with major features being upper eyelid coloboma (n = 25, 75.76%), lipodermoid (n = 18, 54.55%), and limbal dermoid (n = 10, 30.3%). Diminution of visual acuity was recorded in 22 (73.3%), while five (16.7%) had limitation of EOM. Systemically, the prominent features included hemifacial hypotrophy (100%), auricular anomalies (80%), cardiac anomalies (10%), and scoliosis (6.67%). The eyelid colobomas were repaired with the direct closure ± cantholysis technique or using a Tenzel's flap. All children had satisfactory anatomical and functional outcomes after ophthalmic surgical interventions without any significant complications. CONCLUSION: The tailored ophthalmic surgical intervention(s) provides satisfactory restoration of anatomy and functionality of the eye. These children need specific multi-discipline consultations for the holistic management and complete care.

Preferential Associated Malformation in Patients With Anotia and Microtia.

OBJECTIVE: Few epidemiological studies have investigated the external ear malformations anotia and microtia. The authors' study aimed to investigate the relationships between age, sex, type of microtia, and birth place and associated malformation as seen in 1 private Japanese clinic. METHODS: Cases of anotia/microtia that presented in Nagata Microtia and Reconstructive Plastic Surgery Clinic (Saitama, Japan) between 2005 and 2018 were included in the study. The authors identified 1896 patients with anotia/microtia with or without associated malformation. Most were primary cases, with some secondary reconstruction cases wherein the primary surgery was performed at another hospital. Cases were classified with Nagata classification; lobule type, small concha type, concha type, and anotia. Cryptotia was also observed in this study. RESULTS: Among the patients, 61.1% were male, 85.4% had unilateral defects (69.0% LB), and 59.1% had a right-sided defect. Most patients were less than 1 year old (15.0%) or 8 to 10 years old (5.5%-6.3%) on first examination, while 58% were from the Kanto region, including Tokyo. Regarding concomitant disorders, 32.7% had an accompanying malformation, while 13.3% had associated syndromes (eg, craniofacial microsomia, Treacher Collins syndrome). To conclude, in the authors' clinic, most cases of anotia/microtia were LB, unilateral, and seen in male patients. Information regarding several characteristic clinical features was obtained, especially that clefts and musculoskeletal deformities of the skull/face and jaw were the main accompanying malformations.

Clinical and cytogenomic findings in OAV spectrum.

The oculoauriculovertebral spectrum (OAVS) is characterized by anomalies involving the development of the first and second pharyngeal arches during the embryonic period. The phenotype is highly heterogeneous, involving ears, eyes, face, neck, and other systems and organs. There is no agreement in the literature for the minimum phenotypic inclusion criteria, but the primary phenotype involves hemifacial microsomia with facial asymmetry and microtia. Most cases are sporadic and the etiology of this syndrome is not well known. Environmental factors, family cases that demonstrate Mendelian inheritance, such as preauricular appendages, microtia, mandibular hypoplasia, and facial asymmetry; chromosomal abnormalities and some candidate genes suggest a multifactorial inheritance model. We evaluated clinical, cytogenomic and molecularly 72 patients with OAVS, and compared our findings with patients from the literature. We found 15 CNVs (copy number variations) considered pathogenic or possibly pathogenic in 13 out of 72 patients. Our results did not indicated a single candidate genomic region, but recurrent chromosomal imbalances were observed in chromosome 4 and 22, in regions containing genes relevant to the OAVS phenotype or related to known OMIM diseases suggesting different pathogenic mechanisms involved in this genetically and phenotypic heterogeneous spectrum.