Syngnathia is an ultrarare craniofacial malformation characterised by an inability to open the mouth due to congenital fusion of the upper and lower jaws. The genetic causes of isolated bony syngnathia are unknown. We used whole exome and Sanger sequencing and microsatellite analysis in six patients (from four families) presenting with syngnathia. We used CRISPR/Cas9 genome editing to generate vgll2a and vgll4l germline mutant zebrafish, and performed craniofacial cartilage analysis in homozygous mutants. We identified homozygous truncating variants in vestigial-like family member 2 (VGLL2) in all six patients. Two alleles were identified: one in families of Turkish origin and the other in families of Moroccan origin, suggesting a founder effect for each. A shared haplotype was confirmed for the Turkish patients. The VGLL family of genes encode cofactors of TEAD transcriptional regulators. Vgll2 is regionally expressed in the pharyngeal arches of model vertebrate embryos, and morpholino-based knockdown of vgll2a in zebrafish has been reported to cause defects in development of pharyngeal arch cartilages. However, we did not observe craniofacial anomalies in vgll2a or vgll4l homozygous mutant zebrafish nor in fish with double knockout of vgll2a and vgll4l. In Vgll2 -/- mice, which are known to present a skeletal muscle phenotype, we did not identify defects of the craniofacial skeleton. Our results suggest that although loss of VGLL2 leads to a striking jaw phenotype in humans, other vertebrates may have the capacity to compensate for its absence during craniofacial development.

Congenital fusion of the jaws (syngnathia) is a rare facial malformation with an unknown etiology. This disease may vary in severity with adhesion of soft tissue and bony fusion. It can be anterior fusion, unilateral or bilateral fusion, and complete fusion. The main problem of these patients is the difficulty of airway maintenance and feeding, and the most common postoperative complication is the relapse of bony fusion. Here, we report a young male patient with bony syngnathia, involving bilateral fusion of the ascending ramus and body of the mandible with the maxillary complex. We performed bone isolation by computer-assisted preoperative planning and used an insertional temporalis flap to fix the wound surface to prevent refusion of bone.

Congenital maxillomandibular syngnathia is a rare craniofacial anomaly leading to difficulties in feeding, breathing and ability to thrive. The fusion may consist of soft tissue union (synechiae) to hard tissue union. Isolated cases of maxillomandibular fusion are extremely rare, it is most often syndromic in etiology. Clinical management of a female newborn with oromaxillofacial abnormities (synechiae, cleft palate, craniofacial dysmorphisms, dental anomaly) and extraoral malformations (skinfold overlying the nails of both halluces, syndactyly, abnormal external genitalia) is presented. The associated malformations addressed to molecular genetic investigations revealing an interferon regulatory factor 6 (IRF6)-related disorder (van der Woude syndrome/popliteal pterygium syndrome). A novel de novo heterozygous mutation in exon 4 of IRF6 gene on chromosome 1q32.2, precisely c.262A > G (p.Asn88Asp), was found. Similarities are discussed with known asparagine missense mutations in the same codon, which may alter IRF6 gene function by reduced DNA-binding ability. A concomitant maternal Xp11.22 duplication involving two microRNA genes could contribute to possible epigenetic effects. Our reported case carrying a novel mutation can contribute to expand understandings of molecular mechanisms underlying synechiae and orofacial clefting and to correct diagnosing of incomplete or overlapping features in IRF6-related disorders. Additional multidisciplinary evaluations to establish the phenotypical extent of the IRF6-related disorder and to address family counseling should not only be focused on the surgical corrections of syngnathia and cleft palate, but also involve comprehensive otolaryngologic, audiologic, logopedic, dental, orthopedic, urological and psychological evaluations.

Cleft palate-lateral synechiae syndrome (CPLSS) is an extremely rare congenital malformation syndrome with undetermined etiology, characterized by a cleft palate and lateral intraoral synechiae linking the free borders of the palate to the mouth floor. We report a case of a female neonate, admitted for suckling difficulties with a cleft lip and palate associated to multiple lateral intraoral synechiae. Resection of the synechiae allowed oral feeding. Cleft palate-lateral synechiae syndrome is an exceptional syndrome as only seventeen cases have been reported in the literature. Synechiae can be isolated or more frequently in association with other congenital anomalies such as cleft lip and/or palate. These synechiae can cause functional deficits, especially in the respiratory and feeding tracts, language disorders or recurrent otitis. Although it is exceptional, this malformative entity must be known by medical practitioners in order to set up a well-adapted therapeutic protocol.

Congenital maxillomandibular syngnathia is characterized by fusion of jaws. Depending on the severity, it has a wide range of clinical presentations. It can be complete /incomplete and may be unilateral or bilateral. Primary concern in such patients is maintenance of airway and feeding difficulties. Therefore, early recognition and management is important to reduce nutritional, feeding, airway difficulties and growth-related problems in such new-borns. This case report presents a case of syngnathia in a 4-day infant with bilateral fusion of maxilla and mandible, leaving a small anterior portion. Early intervention was planned and the fusion was released to facilitate feeding. Good mouth opening was seen on 1week follow-up. Most commonly, IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end. In rare instances, IRF6 pathogenic variants have also been reported in individuals with nonsyndromic orofacial cleft (18/3,811; 0.47%) and in individuals with spina bifida (2/192). Individuals with VWS show one or more of the following anomalies: Congenital, usually bilateral, paramedian lower-lip fistulae (pits) or sometimes small mounds with a sinus tract leading from a mucous gland of the lip. Cleft lip (CL). Cleft palate (CP). Note: Cleft lip with or without cleft palate (CL±P) is observed about twice as often as CP only. Submucous cleft palate (SMCP). The PPS phenotype includes the following: CL±P. Fistulae of the lower lip. Webbing of the skin extending from the ischial tuberosities to the heels. In males: bifid scrotum and cryptorchidism. In females: hypoplasia of the labia majora. Syndactyly of fingers and/or toes. Anomalies of the skin around the nails. A characteristic pyramidal fold of skin overlying the nail of the hallux (almost pathognomonic). In some nonclassic forms of PPS: filiform synechiae connecting the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon). Other musculoskeletal anomalies may include spina bifida occulta, talipes equinovarus, digital reduction, bifid ribs, and short sternum. In VWS, PPS, IRF6-related neural tube defect, and IRF6-related orofacial cleft, growth and intelligence are typical. Diagnosis of an IRF6-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in IRF6 identified by molecular genetic testing. A heterozygous pathogenic variant in IRF6 is identified in approximately 72% of individuals with the VWS phenotype, approximately 97% of individuals with the PPS phenotype, and fewer than 1% of individuals with a neural tube defect or orofacial cleft. Treatment of manifestations: Supportive/symptomatic treatment of VWS and PPS may include surgical treatment of lip pits and cleft lip and palate pediatric dentistry, orthodontia, speech therapy, feeding therapy, timely treatment of otitis media due to eustachian tube dysfunction to prevent secondary hearing loss, physical therapy, orthopedic care, and surgical treatment for cryptorchidism. Surgical treatment may be needed for those with oral and/or eyelid synechiae. IRF6-related neural tube defects are treated in a standard manner as per neurosurgeon. IRF6-related orofacial clefts are treated in a standard manner. Surveillance: Surveillance for those with cleft lip and/or cleft palate includes weekly assessment of nutritional intake and weight gain during the first month of life; otolaryngologic evaluation within the first six months of life and continued throughout adolescence; audiologic evaluation with infant's first visit to cleft clinic, with the frequency of subsequent evaluations based on the history of ear disease or hearing loss; speech-language pathology evaluation by age six months, twice during the first two years of life, at least annually until age six years, at least annually until after adenoid involution, and at least every two years until dental and skeletal maturity; dental evaluation within six months of the first tooth erupting and no later than age 12 months, and routine dental evaluation continued throughout life. In individuals with myelomeningocele, assessment of walking and mobility and bowel and bladder management with each visit throughout life. IRF6-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with an IRF6-related clefting disorder (e.g., VWS or PPS) inherited an IRF6 pathogenic variant from a heterozygous parent who may or may not have manifestations of the disorder. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if a parent of the proband is affected and/or has an IRF6 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Once an IRF6 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Prenatal ultrasound examination may detect a cleft lip with/without cleft palate in some fetuses later in the second trimester, but it is much less likely to detect an isolated cleft palate or lip pits.