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We present the case of a 7-year-old Ecuadorian mestizo girl with multiple orofacial malformations. The patient is the product of a first-degree relationship (father–daughter). A cytogenetic study revealed a normal karyotype. The genetic mapping array study identified 0.73 Gb of alterations, 727,087,295 bp involved in regions of homozygosity (ROH) in all chromosomes (25.2% of the genome) and 764,028 bp in gains in chromosomes 9 and 14. Genes from the TGFB, BMP, FGF, SHH and WNT families, among others, were identified in the ROH. They are related to craniofacial development and their protein products showed a strong association in the interactome analysis. [ABSTRACT FROM AUTHOR]

Background: Disruption of ALX4 causes autosomal dominant parietal foramina and autosomal recessive frontonasal dysplasia with alopecia, but the mechanisms involving ALX4 in craniofacial and other developmental processes are not well understood. Although mice carrying distinct mutations in Alx4 have been previously reported, the perinatal lethality of homozygous mutants together with dynamic patterns of Alx4 expression in multiple tissues have hindered systematic elucidation of the cellular and molecular mechanisms involving Alx4 in organogenesis and disease pathogenesis. Results: We report generation of Alx4f/f conditional mice and show that tissue‐specific Cre‐mediated inactivation of Alx4 in cranial neural crest and limb bud mesenchyme, respectively, recapitulated craniofacial and limb developmental defects as found in Alx4‐null mice but without affecting postnatal survival. While Alx4‐null mice that survive postnatally exhibited dorsal alopecia, mice lacking Alx4 function in the neural crest lineage exhibited a highly restricted region of hair loss over the anterior skull whereas mice lacking Alx4 in the cranial mesoderm lineage exhibited normal hair development, suggesting that Alx4 plays partly redundant roles in multiple cell lineages during hair follicle development. Conclusion: The Alx4f/f mice provide a valuable resource for systematic investigation of cell type‐ and stage‐specific function of ALX family transcription factors in development and disease. Key Findings: We report successful generation and analysis of Alx4 conditional mice.We demonstrate lineage‐specific requirements of Alx4 in craniofacial, limb, and hair development.Our results demonstrate that Alx4 functions in multiple lineages to control hair follicle development.The Alx4 conditional mice provide a valuable and unique resource for systematic characterization of the cellular and molecular mechanisms involving the ALX family transcription factors in development and disease. [ABSTRACT FROM AUTHOR]

Abstract We present the case of a 7-year-old Ecuadorian mestizo girl with multiple orofacial malformations. The patient is the product of a first-degree relationship (father–daughter). A cytogenetic study revealed a normal karyotype. The genetic mapping array study identified 0.73 Gb of alterations, 727,087,295 bp involved in regions of homozygosity (ROH) in all chromosomes (25.2% of the genome) and 764,028 bp in gains in chromosomes 9 and 14. Genes from the TGFB, BMP, FGF, SHH and WNT families, among others, were identified in the ROH. They are related to craniofacial development and their protein products showed a strong association in the interactome analysis.

Abstract Background Frontonasal dysplasia (FND) is a rare congenital anomaly resulting from the underdevelopment of the frontonasal process, and it can be syndromic or nonsyndromic. The typical features of FND include a deformed nose and ocular hypertelorism, which are sometimes associated with cleft lip and/or palate. Only approximately 10 cases of prenatally diagnosed nonsyndromic FND have been reported in the past 30 years. Case presentation A 33-year-old woman (G2P1) was referred to our center at 20 gestational weeks for bilateral hydrocephaly. We detected typical features of FND, including severe hypertelorism, median nasal bifidity, a minor cleft lip, and multiple limb anomalies using three-dimensional (3D) ultrasound. A hypoplastic corpus callosum, unilateral microtia, and a ventricular septal defect were also detected. Genetic testing, including karyotype analysis, copy number variation (CNV) analysis, trio-whole exome sequencing (trio-WES), and trio-whole-gene sequencing (trio-WGS), was performed; however, we did not find any de novo gene variants in the fetus as compared to the parents. Postmortem examination confirmed the prenatal diagnosis of FND. Conclusion The present case expands the wide phenotypic spectrum of prenatal FND patients. 3D ultrasound is a useful tool for detecting facial and limb deformities.

Frontonasal dysplasia (FND) is a very rare congenital abnormality in which the mid face does not develop normally. It affects mainly the head and face. Cause is unknown but may be sporadic or familial. We report a rare case of a full term baby who presented with classical features of FND in Maiduguri, Nigeria. Management difficulty in resource limited setting is highlighted.

Callosal agenesis is a complex condition with disruption in the steps such as cellular proliferation, migration, axonal growth, guidance, or glial patterning at the midline. Agenesis of the corpus callosum (AgCC) is associated with diverse midline craniofacial malformations affecting the frontal-cranial and midface skeleton. Diagnosing midline abnormalities prenatally can be challenging, especially in twin pregnancies, due to poor resolution of skull base structures on fetal MRI, basal cephalocele could be mistaken for fluid in the nasopharynx, motion limitation, and fetal positioning. Our case highlights the importance of evaluation for other associated midline anomalies when there is callosal agenesis.

Bifid nose is a rare congenital malformation, and few cases have been reported due to its low incidence. Herein, we report a new surgical procedure to treat patients with excess dorsal nasal tissue and an underfilled tip. A total of 22 patients with bifid nose deformities underwent surgery at our institution between 2012 and 2022. They were characterized by a broad nasal dorsum and a missing or underdeveloped nasal tip. We designed an innovative island flap of nasal dorsum as a new surgical method for treating this bifid nose deformity. Nasal length, tip projection, and photographs of nose morphology were obtained before and after the surgery. Outcomes, complications, indications, and patient satisfaction were analyzed and interviewed. The follow-up time ranges from 6 to 33 months (8.7 ± 5.5 months). The deformity was successfully corrected with an improved nasal appearance. Nasal length increased from initially 4.2 ± 0.3 mm to 4.6 ± 0.3 mm. Tip projection reached 19.9 ± 4.0 mm, which was 15.7 ± 2.9 mm before surgery. No severe complications were observed except poor venous reflux within postoperative 72 hours in four cases. Six patients (27.3%) got moderate healing and acceptable scars, and 14 patients (63.6%) got good healing. Most patients were very satisfied with the outcome (93.9%). The newly designed nasal dorsum island flap is a safe and effective technical approach to correct nose deformity featured by broad nasal dorsum and a missing or underdeveloped nasal tip. [ABSTRACT FROM AUTHOR]

Abstract Background Bifid nose is a rare congenital deformity and the etiology is unknown. The purpose of this study was to report genetic variation in family of patients with bifid nose. Methods Twenty-three consecutive patients who were diagnosed with mild bifid nose were operated with z-plasty from 2009 to 2021. Three underage patients (a pair of twins and a girl) from two family lines, who came to our hospital for surgical treatment, were enrolled. Whole exome sequencing and Sanger sequencing were conducted. Z-shaped flaps were created and the cartilago alaris major were re-stitched. Photographs and CT scan before and after surgery were obtained. Clinical outcomes, complications and patients’ satisfaction were evaluated and analyzed. The follow-up time ranges from 2 to 3 years (2.4 ± 1.2 years). Results Most patients were satisfied with the outcome (96.2%). The nasal deformities were corrected successfully with z-plasty technique in one-stage. FREM1 c.870_876del and c.2 T > C were detected with Whole exome sequencing, which have not been reported before. The results of Sanger sequencing were consistent with those of Whole exome sequencing. Conclusions The newly detected mutations of FREM1 have a certain heritability, and are helpful to make an accurate diagnosis and provide a better understanding of bifid nose mechanism. Z-plasty technique can be an effective technical approach for correcting mild bifid nose deformity.

Cranial neural crest development is governed by positional gene regulatory networks (GRNs). Fine-tuning of the GRN components underlies facial shape variation, yet how those networks in the midface are connected and activated remain poorly understood. Here, we show that concerted inactivation of Tfap2a and Tfap2b in the murine neural crest, even during the late migratory phase, results in a midfacial cleft and skeletal abnormalities. Bulk and single-cell RNA-seq profiling reveal that loss of both TFAP2 family members dysregulates numerous midface GRN components involved in midface morphogenesis, patterning and differentiation. Notably, Alx1, Alx3 and Alx4 (ALX) transcript levels are reduced, whereas ChIP-seq analyses suggest TFAP2 family members directly and positively regulate ALX gene expression. Tfap2a, Tfap2b and ALX co-expression in midfacial neural crest cells of both mouse and zebrafish implies conservation of this regulatory axis across vertebrates. Consistent with this notion, tfap2a zebrafish mutants present with abnormal alx3 expression patterns, Tfap2a binds ALX loci and tfap2a-alx3 genetic interactions are observed. Together, these data demonstrate TFAP2 paralogs regulate vertebrate midfacial development in part by activating expression of ALX transcription factor genes. [ABSTRACT FROM AUTHOR]

Background: Bifid nose is a rare congenital deformity and the etiology is unknown. The purpose of this study was to report genetic variation in family of patients with bifid nose. Methods: Twenty-three consecutive patients who were diagnosed with mild bifid nose were operated with z-plasty from 2009 to 2021. Three underage patients (a pair of twins and a girl) from two family lines, who came to our hospital for surgical treatment, were enrolled. Whole exome sequencing and Sanger sequencing were conducted. Z-shaped flaps were created and the cartilago alaris major were re-stitched. Photographs and CT scan before and after surgery were obtained. Clinical outcomes, complications and patients' satisfaction were evaluated and analyzed. The follow-up time ranges from 2 to 3 years (2.4 ± 1.2 years). Results: Most patients were satisfied with the outcome (96.2%). The nasal deformities were corrected successfully with z-plasty technique in one-stage. FREM1 c.870_876del and c.2 T > C were detected with Whole exome sequencing, which have not been reported before. The results of Sanger sequencing were consistent with those of Whole exome sequencing. Conclusions: The newly detected mutations of FREM1 have a certain heritability, and are helpful to make an accurate diagnosis and provide a better understanding of bifid nose mechanism. Z-plasty technique can be an effective technical approach for correcting mild bifid nose deformity. [ABSTRACT FROM AUTHOR]

Frontonasal dysplasia (FND) refers to a group of rare developmental disorders characterized by abnormal morphology of the craniofacial region. We studied a family manifesting with clinical features typical for FND2 including neurobehavioral abnormalities, hypotrichosis, hypodontia, and facial dysmorphism. Whole‐exome sequencing analysis identified a novel heterozygous frameshift insertion in ALX4 (c.985_986insGTGC, p.Pro329Argfs*115), encoding aristaless homeobox 4. This and a previously reported dominant FND2‐causing variant are predicted to result in the formation of a similar abnormally elongated protein tail domain. Using a reporter assay, we showed that the elongated ALX4 displays increased activity. ALX4 negatively regulates the Wnt/β‐catenin pathway and accordingly, patient keratinocytes showed altered expression of genes associated with the WNT/β‐catenin pathway, which in turn may underlie ectodermal manifestations in FND2. In conclusion, dominant FND2 with ectodermal dysplasia results from frameshift variants in ALX4 exerting a gain‐of‐function effect. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Bifid nose generally appears short columellar and lacks the nasal tip. Here, we describe a surgical correction technique for correcting the short columellar and nasal tip of bifid nose using a local flap to discuss outcomes, patient selection, and complications based on 11 years of experience. Thirty-two patients with mild wide bifid nose and shortened columella were included in this retrospective study. All patients underwent nasal rhinoplasty using a propeller flap based on the nasal columella artery. Nasal columella length, horizontal distance of tip-defining point, and angle of facial convexity were evaluated based on three-dimensional simulation technology. Complications including possible underlying reasons were analyzed. Patient satisfaction was evaluated using a self-assessment survey. Nasal esthetics and function were considerably improved. Follow-up examinations during a period of 9 months on average demonstrated stable results. The columella length was 9.7 ± 4.6 mm preoperatively and 19.9 ± 3.2 mm postoperatively (P < 0.05). The horizontal distance of tip-defining point (mm) decreased to 18.9 ± 5.5 mm postoperatively from a preoperative 23.3 ± 5.4 mm (P < 0.05). There were no severe postoperative complications. Complications were scar, temporary hematoma, and mild infection of nasal skin. The majority of patients (97%) rated their outcome as improved and much improved. Surgical correction using a nasal columella artery propeller flap is an effective therapeutic approach for patients with mild bifid nose. The use of a local flap along with minimal donor-site morbidity and reliable outcomes contributes to the high patient acceptance. Meticulous surgical technique and careful patient selection are prerequisites for successful results. [ABSTRACT FROM AUTHOR]

Frontonasal dysplasia (FND) is a rare craniofacial deformity, including severe hypertelorism. We herein presented the case of a 6-year-old female patient with FND and Grade III hypertelorism who underwent a four-wall-orbital box osteotomy with a bicoronal approach. Orbital wall osteotomy was performed behind the lacrimal fossa. Central resection was done to allow for medial translocation of the orbits. At the last, the newly positioned orbitals were fixated using wire, absorbable plates, and screws. Neurosurgical assistance with the frontal bone flap before orbital osteotomy helps to leave the cribriform plate intact to preserve the olfactory. Finally, excessive median soft tissue was excised. The patient's hypertelorism improved after surgery. Careful surgical procedures to correct the soft and bony tissue are beneficial treatments for improving the quality of life and general condition of patients with hypertelorism. [ABSTRACT FROM AUTHOR]

Frontonasal dysplasia (FND) is a rare craniofacial deformity, including severe hypertelorism. We herein presented the case of a 6-year-old female patient with FND and Grade III hypertelorism who underwent a four-wall-orbital box osteotomy with a bicoronal approach. Orbital wall osteotomy was performed behind the lacrimal fossa. Central resection was done to allow for medial translocation of the orbits. At the last, the newly positioned orbitals were fixated using wire, absorbable plates, and screws. Neurosurgical assistance with the frontal bone flap before orbital osteotomy helps to leave the cribriform plate intact to preserve the olfactory. Finally, excessive median soft tissue was excised. The patient's hypertelorism improved after surgery. Careful surgical procedures to correct the soft and bony tissue are beneficial treatments for improving the quality of life and general condition of patients with hypertelorism.

In the practice of pediatric cardiology, situations are possible when a child with congenital heart disease cannot be subjected to radical or even hemodynamic surgery. As a rule, such severe heart defects are combined with other genetic anomalies, which ultimately lead to the palliative status of the newborn. This situa­tion is a serious ethical and psychological challenge for medical workers in both the antenatal and postnatal periods. In the proposed article, we present a case of a child with congenital heart disease, which was part of frontonasal dysplasia due to ZSWIM6 gene mutation. This observation illustrates a number of ethical and psychological problems, difficult decisions and communication questions that are typical for such a difficult life situation as the birth of a terminally ill child. The example is illustrative in general for the ethical problems of a disabling congenital disease, which can be encountered in the practice of a pediatric cardiologist. From a broader perspective, the example illustrates uncertainty as an inevitable component of medical decision making and informing the patient (his legal representatives).

Objectives: Congenital frontonasal dysplasia (CFND) is a rare heterogeneous collection of facial deformities. Due to the range of complexity, surgical management is not standardized. Methods: We present a severe case of CFND and approach to managing multiple defects with a focus on rhinoplasty. Results: This infant was born full term with a large mass instead of a nose, a bilateral cleft lip and palate, and hypertelorbitism. Our primary concerns initially were to address communication with the intracranial cavity, preserve a nasal lining, and improve nasal appearance and airway function in the short term without interfering with subsequent rhinoplasty and adult nasal appearance. Conclusions: This complex case of CFND is more severe than anything we encountered in our literature review and demonstrates the necessity for multidisciplinary approach to multiple craniofacial defects. Future plans for this patient include rhinoplasty with auricular graft, scar revision, and addressing tip support. [ABSTRACT FROM AUTHOR]

Craniofrontonasal Syndrome is a very rare dominant X-linked genetic disorder characterized by symptoms such as hypertelorism, craniosynostosis, eye alterations, bifid nose tip, and longitudinal ridging and splitting of nails. Heterozygous females are usually the patients severely affected. To date, clinical or genetic data have not been published for these patients in Colombia. Here we report a female proband with coronal craniosynostosis, hypertelorism, strabismus, rotational nystagmus, high-arched palate, dental crowding, scoliosis, severe pectus excavatum, unilateral breast hypoplasia, and brachydactyly; diagnosed with Craniofrontonasal Syndrome with the novel heterozygous variant c.374A>C (p.Glu125Ala) in the EFNB1 gene. So far, she has been treated with physical therapy and surgical correction of the bifid nose and an umbilical hernia. To the best of our knowledge, this is the first report of a patient with this rare genetic disorder in Colombia, expanding its mutational spectrum and highlighting the importance of genetic evaluation of patients with craniosynostosis and facial dysmorphism.

Objective: Frontonasal dysplasia (FND) is a rare congenital condition. Its major features include hypertelorism, a large and bifid nasal tip, and a broad nasal root. We present our technique of septal L-strut reconstruction using costal cartilage. Design: Retrospective review from June 2008 and August 2017. Methods: Under general anesthesia, 6 patients with FND underwent septal reconstruction using costal cartilage via open rhinoplasty. We reconstructed the nasal and septal cartilaginous framework by placing columellar struts and cantilever-type grafts. Results: The patients ranged in age from 6 to 13 years old. All were female. The follow-up period ranged from 8 months to 2 years; we encountered no postoperative complications (infection, nasal obstruction, or recurrence). All patients were satisfied with their nasal appearance. Conclusions: Although the results were not entirely satisfactory from an esthetic point of view, we found that FND can be treated via septal reconstruction with costal cartilage and that the clinical outcomes are reliable and satisfactory. Our approach is a useful option for FND patients. [ABSTRACT FROM AUTHOR]

Bifid nose is a rare congenital anomaly. Because of its low incidence, few cases of surgical treatment have been reported. We propose a surgical method using an open W-shaped incision as a treatment option for severe bifid nose. Based on our 10-year experience, we describe the technique and discuss outcomes, patient selection, and complications. From May 2009 to December 2020, 32 patients with bifid nose underwent surgical correction of the nasal deformity characterized by dorsal hypertelorism, midline cleft of nasal bone and cartilage, and shortened nose using an open W-shaped surgical incision. Nasal subunit morphology before and after surgery was measured by three-dimensional simulation technology. Indications, outcomes, and complications including possible underlying reasons were analyzed. Patient satisfaction was evaluated using a self-assessment survey. Correction of the bifid nasal deformity was successfully achieved using an open W-shaped surgical incision with increased nasal length and improved nasal appearance. Patients were followed-up for a period of 10 months on average, ranging from 6 months to 10 years. Follow-up examinations demonstrated stable results. The overall complication rate was 1.9%. Complications included temporary scar, ventilation disorder, and mild infection of the nasal skin. The majority of patients (98.1%) rated their outcome as improved and much improved (Table 1). The open W-shaped incision technique is an effective therapeutic approach for the correction of severe bifid nose. This is a simple and safe method for the treatment of bifid noses with a high patient acceptance and stable postoperative results. [ABSTRACT FROM AUTHOR]

Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well‐known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Based on strict clinical classification criteria, we could confirm only nine (33%) typical and two (7%) atypical PS individuals. The remaining ones were either OAFNS (11/27—41%) or presenting with an overlapping syndrome (5/27—19%). Because of the phenotypic overlap between these entities, OAFNS, ECCL, and SC can be either considered as differential diagnosis of PS or part of the same spectrum. Exome and/or genome sequencing from blood DNA in 12 patients and from affected tissue in one patient failed to identify any replication in candidate genes. Taken together, our data suggest that conventional approaches routinely utilized for the identification of molecular etiologies responsible for Mendelian disorders are inconclusive. Future studies on affected tissues and multiomics studies will thus be required in order to address either the contribution of mosaic or noncoding variation in these diseases. [ABSTRACT FROM AUTHOR]

Aim: The term frontonasal dysplasia (FND) represents a spectrum of anomalies and its genetics have not been well defined. Recently, the critical role of the aristaless-like homeobox (ALX) gene family on the craniofacial development has been discovered. In the present study, we aimed to propose a systematic surgical treatment plan for the ALX -related FNDs according to the genotypic classification as well as demonstrating their clinical characteristics to help surgeons diagnose the underlying pathology accurately. Design: Single-institution retrospective. Setting: Tertiary health care. Patients and Methods: Eighty-nine FND cases were evaluated. Eight of them had ALX1 -related FND3, 3 had ALX3 -related FND1, and 2 had ALX4 -related FND2. Phenotype characteristics of ALX -related FNDs were evaluated, and relevant surgical interventions were assessed. Results: The ALX1 -related FND3 phenotype is striking due to the involvement of the eyes in addition to the presence of hypertelorism, facial clefts, and nasal deformities. A widened philtrum and prominent philtral columns are remarkable features of the ALX3 -related FND1, whereas the ALX4 -related FND2 has more severe deformities: severe hypertelorism, brachycephaly, large parietal bone defects, broad nasal dorsum, and alopecia. Facial bipartition, box osteotomies, eyelid coloboma repair, cleft lip and palate repair, nasal reconstruction, and fronto-orbital advancement can be performed in ALX -related FNDs based on the characteristics of each subtype. Conclusions: This genetic classification system will help surgeon diagnose patients with FND with unique features and draw a roadmap for their treatment with a better surgical perspective. [ABSTRACT FROM AUTHOR]

Introduction: Hypertelorbitism is a clinical feature that may be present in various types of pathologies and degrees of manifestation. Observing the evolution of techniques over time and understanding the specific characteristics of each case demonstrates the difficulty of establishing treatment protocols. Material and method: Retrospective analysis of over 150 cases of hypertelorbitism operated on over 44 years by the main author. The increased interorbital distance had varied etiologies: dysplasia, meningoencephaloceles, and dysostosis. Results: Retrusion of the facial middle third throughout growth in congenital hypertelorbitism was present in both dysplasia and dysostosis groups. In cases of early treatment with Tessier's glasses osteotomy there was zygomaticmaxillary atrophy with trapping of tooth germs. The cases of grade III and IV Hyperteleorbitism, with or without meningoencephalocele, which were treated without concomitant skullcap expansion, evolved to endocranial hypertension and required further treatment. Retrospective evaluation of their CT scans revealed craniosynostosis of one or more sutures, associated with predominant dysplasia. Patients treated after adolescence showed more stable late postoperative results. Discussion: Hypertelorbitism is a clinical feature that may be present in various types of pathologies and in varying degrees of intensity. Many treatment options have been proposed over the past 50 years. The opportunity to watch and experience the evolution of these techniques made it possible to choose the most appropriate treatment for each patient's clinical characteristics. Conclusion: Due to the variability of manifestation of hypertelorbitism, the massification of procedures and the establishment of treatment protocols are quite limited.

The cellular and genetic mechanisms that coordinate formation of facial sensory structures with surrounding skeletal and soft tissue elements remain poorly understood. Alx1, a homeobox transcription factor, is a key regulator of midfacial morphogenesis. ALX1 mutations in humans are linked to severe congenital anomalies of the facial skeleton (frontonasal dysplasia, FND) with malformation or absence of eyes and orbital contents (micro- and anophthalmia). Zebrafish with loss-of-function alx1 mutations develop with craniofacial and ocular defects of variable penetrance, likely due to compensatory upregulation in expression of a paralogous gene, alx3. Here we show that zebrafish alx1;alx3 mutants develop with highly penetrant cranial and ocular defects that resemble human ALX1-linked FND. alx1 and alx3 are expressed in anterior cranial neural crest (aCNC), which gives rise to the anterior neurocranium (ANC), anterior segment structures of the eye and vascular pericytes. Consistent with a functional requirement for alx genes in aCNC, alx1; alx3 mutants develop with nearly absent ANC and grossly aberrant hyaloid vasculature and ocular anterior segment, but normal retina. In vivo lineage labeling identified a requirement for alx1 and alx3 during aCNC migration, and transcriptomic analysis suggested oxidative stress response as a key target mechanism of this function. Oxidative stress is a hallmark of fetal alcohol toxicity, and we found increased penetrance of facial and ocular malformations in alx1 mutants exposed to ethanol, consistent with a protective role for alx1 against ethanol toxicity. Collectively, these data demonstrate a conserved role for zebrafish alx genes in controlling ocular and facial development, and a novel role in protecting these key midfacial structures from ethanol toxicity during embryogenesis. These data also reveal novel roles for alx genes in ocular anterior segment formation and vascular development and suggest that retinal deficits in alx mutants may be secondary to aberrant ocular vascularization and anterior segment defects. This study establishes robust zebrafish models for interrogating conserved genetic mechanisms that coordinate facial and ocular development, and for exploring gene­–environment interactions relevant to fetal alcohol syndrome.

Frontonasal dysplasia (FND) can have severe presentations that are medically and socially debilitating. Several genes are implicated in FND conditions, including Aristaless-Like Homeobox 1 (ALX1), which is associated with FND3. Breeds of cats are selected and bred for extremes in craniofacial morphologies. In particular, a lineage of Burmese cats with severe brachycephyla is extremely popular and is termed Contemporary Burmese. Genetic studies demonstrated that the brachycephyla of the Contemporary Burmese is a simple co-dominant trait, however, the homozygous cats have a severe craniofacial defect that is incompatible with life. The craniofacial defect of the Burmese was genetically analyzed over a 20 year period, using various genetic analysis techniques. Family-based linkage analysis localized the trait to cat chromosome B4. Genome-wide association studies and other genetic analyses of SNP data refined a critical region. Sequence analysis identified a 12bp in frame deletion in ALX1, c.496delCTCTCAGGACTG, which is 100% concordant with the craniofacial defect and not found in cats not related to the Contemporary Burmese.

Abstract A pedigree of subjects presented with frontonasal dysplasia (FND). Genome sequencing and analysis identified a p.L165F missense variant in the homeodomain of the transcription factor ALX1 which was imputed to be pathogenic. Induced pluripotent stem cells (iPSC) were derived from the subjects and differentiated to neural crest cells (NCC). NCC derived from ALX1L165F/L165F iPSC were more sensitive to apoptosis, showed an elevated expression of several neural crest progenitor state markers, and exhibited impaired migration compared to wild‐type controls. NCC migration was evaluated in vivo using lineage tracing in a zebrafish model, which revealed defective migration of the anterior NCC stream that contributes to the median portion of the anterior neurocranium, phenocopying the clinical presentation. Analysis of human NCC culture media revealed a change in the level of bone morphogenic proteins (BMP), with a low level of BMP2 and a high level of BMP9. Soluble BMP2 and BMP9 antagonist treatments were able to rescue the defective migration phenotype. Taken together, these results demonstrate a mechanistic requirement of ALX1 in NCC development and migration.

Loss of ALX1 function causes the frontonasal dysplasia syndrome FND3, characterized by severe facial clefting and microphthalmia. Whereas the laboratory mouse has been the preeminent animal model for studying developmental mechanisms of human craniofacial birth defects, the roles of ALX1 in mouse frontonasal development have not been well characterized because the only previously reported Alx1 mutant mouse line exhibited acrania due to a genetic background-dependent failure of cranial neural tube closure. Using CRISPR/Cas9-mediated genome editing, we have generated an Alx1-deletion mouse model that recapitulates the FND craniofacial malformations, including median orofacial clefting and disruption of development of the eyes and alae nasi. In situ hybridization analysis showed that Alx1 is strongly expressed in frontonasal neural crest cells that give rise to periocular and frontonasal mesenchyme. Alx1del/del embryos exhibited increased apoptosis of periocular mesenchyme and decreased expression of ocular developmental regulators Pitx2 and Lmxb1 in the periocular mesenchyme, followed by defective optic stalk morphogenesis. Moreover, Alx1del/del embryos exhibited disruption of frontonasal mesenchyme identity, with loss of expression of Pax7 and concomitant ectopic expression of the jaw mesenchyme regulators Lhx6 and Lhx8 in the developing lateral nasal processes. The function of ALX1 in patterning the frontonasal mesenchyme is partly complemented by ALX4, a paralogous ALX family transcription factor whose loss-of-function causes a milder and distinctive FND. Together, these data uncover previously unknown roles of ALX1 in periocular mesenchyme development and frontonasal mesenchyme patterning, providing novel insights into the pathogenic mechanisms of ALX1-related FND.

Frontonasal dysplasia (FND) is a rare complex genetic facial malformation, mostly characterized by affecting the face and head regions of the body. Craniofacial defects can have a severe impact, revealing different types of clinical phenotypes, which are broadly grouped as frontonasal dysplasias (FNDs). FNDs have been classified along with selected disorders on the genetic and molecular basis. FND is clinically diagnosed on the basis of at least two features including median facial cleft, broad nasal bridge, ocular hypertelorism, widened philtrum, median cleft upper lip, widow's peak frontal hairline and missing or underdeveloped nasal tip. The three types of FNDs are caused by the ALX genes (ALX1, ALX3, ALX4). Genes and pathways related to facial development are associated with direct or indirect expression of the FGF8, the SHH, and the BMP4. The present review provides a detail literature review on the FND phenotypes and mutation update of different genes involved that will help in proper classification, genetic counseling, and diagnosis of the affected families. [JBCGenetics 2018; 1(2.000): 66-76]

We report a case of mild frontonasal dysplasia, a complex and rare malformation affecting the central portion of the face, especially the eyes, nose, and forehead, which was diagnosed at 20 weeks of gestation. The diagnosis was made by two- and four-dimensional ultrasound and confirmed at autopsy after pregnancy termination. A review of the literature is presented. [ABSTRACT FROM AUTHOR]

Background: Pai syndrome is a rare idiopathic developmental condition characterized by midline craniofacial abnormalities. It was originally described as the presence of a median cleft lip, cutaneous polyps of the nasal mucosa and face, and midline lipomas of the central nervous system, mostly at the corpus callosum. However, there is great phenotypical variability and these characteristics are rarely all present at once. Objective: The aim of this review was to analyze the available evidence regarding Pai syndrome in order to better delineate this rare condition and its features. Methods: We analyzed the PubMed database using the words "Pai syndrome", "frontonasal dysplasia", "cleft lip", "nasal polyp", "facial polyp", and "corpus callosum lipoma", including reviews, case reports and case series. Conclusion: There is no consensus regarding the diagnostic criteria of Pai syndrome up to date. It is usually diagnosed at birth, and its incidence is often underestimated. At present, the etiology of Pai syndrome is unknown. Several hypotheses regarding its genetic background have been made; however, there are not enough data yet to elucidate this point. An improved awareness could help in diagnosing the condition and performing the necessary investigations. These patients should have a multidisciplinary follow-up. [ABSTRACT FROM AUTHOR]

A pedigree of subjects presented with frontonasal dysplasia (FND). Genome sequencing and analysis identified a p.L165F missense variant in the homeodomain of the transcription factor ALX1 which was imputed to be pathogenic. Induced pluripotent stem cells (iPSC) were derived from the subjects and differentiated to neural crest cells (NCC). NCC derived from ALX1L165F/L165FiPSC were more sensitive to apoptosis, showed an elevated expression of several neural crest progenitor state markers, and exhibited impaired migration compared to wild‐type controls. NCC migration was evaluated in vivo using lineage tracing in a zebrafish model, which revealed defective migration of the anterior NCC stream that contributes to the median portion of the anterior neurocranium, phenocopying the clinical presentation. Analysis of human NCC culture media revealed a change in the level of bone morphogenic proteins (BMP), with a low level of BMP2 and a high level of BMP9. Soluble BMP2 and BMP9 antagonist treatments were able to rescue the defective migration phenotype. Taken together, these results demonstrate a mechanistic requirement of ALX1 in NCC development and migration. Synopsis: Variants of the transcription factor ALX1 are implicated in the development of Frontonasal Dysplasia. This study explores the role of ALX1 in neural crest cell development and migration in patient‐derived induced pluripotent stem cells and zebrafish. A novel missense mutation of ALX1 was associated with familial Frontonasal Dysplasia in a pedigree of four children born with bilateral oblique clefts and ocular malformations.Neural Crest Cells harboring the L165F variant within ALX1 showed transcriptomic differences of marker genes indicative of a prolonged progenitor state, dysbalance of BMPs, increased rate of apoptosis, and delayed migration.Disruption of alx1 in zebrafish resulted in perturbed Neural Crest Cell migration and increased expression of other alx family members. [ABSTRACT FROM AUTHOR]

Our improved tools to identify the aetiologies in patients with multiple abnormalities resulted in the finding that some patients have more than a single genetic condition and that some of the diagnoses made in the past are acquired rather than inherited. However, limited knowledge has been accumulated regarding the phenotypic outcome of the interaction between different genetic conditions identified in the same patients. We report a newborn girl with brachytelephalangic chondrodysplasia punctata (BCDP) as well as frontonasal dysplasia, ptosis, bilateral hearing loss, vertebral anomalies, and pulmonary hypoplasia who was found, by whole exome sequencing, to have a de novo pathogenic variant in RAF1 (c.770C>T, [p.Ser257Leu]) and a likely pathogenic variant in SIX2 (c.760G>A [p.A254T]), as well as maternal systemic lupus erythematosus (SLE). This case shows that BCDP is most probably not a diagnostic entity and can be associated with various conditions associated with CDP including maternal SLE. [ABSTRACT FROM AUTHOR]

Background: Frontonasal dysplasia (FND) is a rare developmental disorder characterized by mild to severe changes in skull and brain structures. It is a phenotypically variable and heterogeneous disorder. This study was designed to provide a clinical and genetic analysis of FND in a consanguineous family of Pakistani origin. Methodology and Results: Affected individuals in the family showed characteristic features of frontonasal dysplasia type-2 (FND2), such as nasal bone hypoplasia, hypertelorism, and alopecia. Skull and brain imaging of affected members revealed ossification defects and various types of brain structural anomalies that created a split-brain. Sanger sequencing of the ALX4 gene revealed a homozygous missense variant [NM_021926.4: c.652C>T; p.(Arg218Trp)] in three affected members who demonstrated severe craniofacial anomalies. Heterozygous carriers in the family showed mild FND2 phenotypes. Conclusion: Clinical and genetic analysis of a family, exhibiting FND2 phenotypes, revealed several previously unreported clinical features and a novel missense variant in the ALX4 gene. These results will facilitate diagnosis and genetic counseling of the FND patients in the Pakistani population. [ABSTRACT FROM AUTHOR]

Frontonasal dysplasia is an uncommon congenital anomaly with diverse clinical phenotypes and highly variable clinical characteristics, including hypertelorism, a broad nasal root, median facial cleft, a missing or underdeveloped nasal tip, and a widow's peak hairline. Frontonasal dysplasia is mostly inherited and caused by the ALX genes (ALX1, ALX3, and ALX4). We report a rare case of a frontonasal dysplasia patient with mild hypertelorism, a broad nasal root, an underdeveloped nasal tip, an accessory nasal tag, and a widow's peak. We used soft tissue re-draping to achieve aesthetic improvements. [ABSTRACT FROM AUTHOR]

SIX1 and SIX2 encode closely related transcription factors of which disruptions have been associated with distinct craniofacial syndromes, with mutations in SIX1 associated with branchiootic syndrome 3 (BOS3) and heterozygous deletions of SIX2 associated with frontonasal dysplasia defects. Whereas mice deficient in Six1 recapitulated most of the developmental defects associated with BOS3, mice lacking Six2 function had no obvious frontonasal defects. We show that Six1 and Six2 exhibit partly overlapping patterns of expression in the developing mouse embryonic frontonasal, maxillary, and mandibular processes. We found that Six1 -/- Six2 -/- double-mutant mice were born with severe craniofacial deformity not seen in the Six1 -/- or Six2 -/- single mutants, including skull bone agenesis, midline facial cleft, and syngnathia. Moreover, whereas Six1 -/- mice exhibited partial transformation of maxillary zygomatic bone into a mandibular condyle-like structure, Six1 -/-Six2 +/- mice exhibit significantly increased penetrance of the maxillary malformation. In addition to ectopic Dlx5 expression at the maxillary-mandibular junction as recently reported in E10.5 Six1 -/- embryos, the E10.5 Six1 -/- Six2 +/- embryos showed ectopic expression of Bmp4, Msx1, and Msx2 messenger RNAs in the maxillary-mandibular junction. Genetically inactivating 1 allele of either Ednra or Bmp4 significantly reduced the penetrance of maxillary malformation in both Six1 -/- and Six1 -/- Six2 +/- embryos, indicating that Six1 and Six2 regulate both endothelin and bone morphogenetic protein-4 signaling pathways to pattern the facial structures. Furthermore, we show that neural crest-specific inactivation of Six1 in Six2 -/- embryos resulted in midline facial cleft and frontal bone agenesis. We show that Six1 -/- Six2 -/- embryos exhibit significantly reduced expression of key frontonasal development genes Alx1 and Alx3 as well as increased apoptosis in the developing frontonasal mesenchyme. Together, these results indicate that Six1 and Six2 function partly redundantly to control multiple craniofacial developmental processes and play a crucial neural crest cell-autonomous role in frontonasal morphogenesis. [ABSTRACT FROM AUTHOR]

Abstract Pai syndrome was originally described as the association of a midline cleft lip, midline facial polyps, and lipoma of the central nervous system. However, only a few patients present with the full triad, and most exhibit a wide spectrum of phenotypic variability. The aim of this study was to phenotypically delineate Pai syndrome and to propose new criteria to facilitate a clinical diagnosis in the future. The study cohort consisted of seven case patients and an additional 60 cases diagnosed with Pai syndrome identified in a literature review. Only 23 of 67 patients presented the full triad as historically described by Pai et al. (1987). A congenital facial midline skin mass was always encountered, particularly affecting the nasal structures (60/67). A midline facial cleft was reported in 45 of 67 patients and a pericallosal lipoma in 42 of 67 patients. The proposed definition of Pai syndrome is the association of (1) a congenital nasal and/or mediofrontal skin mass and/or a mid-anterior alveolar process polyp as a mandatory criterion, and at least one of the following criteria: (2) midline cleft lip and/or midline alveolar cleft, and/or (3) a pericallosal lipoma or interhemispheric lipoma in the case of corpus callosum dysgenesis. [ABSTRACT FROM AUTHOR]

The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo‐auriculo‐vertebral spectrum (OAVS)‐associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features (micro/anophtalmia, cataract, thyroid agenesis, polymicrogyria, olfactory bulb hypoplasia, and mandibular cleft), and emphasize the high frequency of nasal polyps in OAFNS (56%). We report the negative results of ALX1, ALX3, and ALX4 genes sequencing and next‐generation sequencing strategy performed on blood‐derived DNA from respectively, four and four individuals. Exome sequencing was performed in four individuals, genome sequencing in one patient with negative exome sequencing result. Based on the data from this series and the literature, diverse hypotheses can be raised regarding the etiology of OAFNS: mosaic mutation, epigenetic anomaly, oligogenism, or nongenetic cause. In conclusion, this series represents further clinical delineation work of the rare OAFNS, and paves the way toward the identification of the causing mechanism. [ABSTRACT FROM AUTHOR]

Background Median cleft lip is a rare anomaly consisting of a midline vertical cleft through the upper lip. It can also involve the premaxillary bone, the nasal septum, and the central nervous system. In our current report, we present the clinical features of 6 patients with a median cleft lip and their surgical management according to the accompanying anomalies. Methods From December 2010 to January 2014, 6 patients with a median cleft lip were reviewed. Five of these cases underwent surgical correction; alveolar bone grafting was performed in a patient with a median alveolar cleft. The surgical technique included inverted-U excision of the upper lip and repair of the orbicularis oris muscle. The mean follow-up period was 20.4 months (range, 7.4–44.0 months). Results The study patients presented various anomalous features. Five patients received surgical correction, 4 with repair of the median cleft lip, and one with iliac bone grafting for median alveolar cleft. A patient with basal sphenoethmoidal meningocele was managed with transoral endoscopic surgery for repair of the meningocele. Successful surgical repair was achieved in all cases with no postoperative complications. Conclusions Relatively mild forms of median cleft lip can be corrected with inverted-U excision with good aesthetic outcomes. In addition, there is a broad spectrum of clinical features and various anomalies, such as nasal deformity, alveolar cleft, and short upper frenulum, which require close evaluation. The timing of the operation should be decided considering the presence of other anomalies that can threaten patient survival.

We report two unrelated boys with frontonasal dysplasias type‐2 (FND‐2) who shared an identical novel homozygous ALX4 mutation c.291delG (p.Q98Sfs*83). Both patients presented with a large skull defect but one had bilateral parietal meningocele‐like cysts that lie along with the bony defect and increased in size with age. Scalp alopecia, hypertelorism, and clefted alae nasi were also detected in both of them. Furthermore, impalpable gonads were noted, being unilateral in one and bilateral in the other. Neuroimaging showed small dysplastic occipital lobes with dysgyria and midline subarachnoid cyst. Additional dysplastic corpus callosum and small cerebellar vermis were observed in one patient. Parietal foramina were noted in the parents of one patient. Our findings highlight the dosage effect of ALX4 and underscore the challenges of prenatal genetic counseling. Further, the indirect role of ALX4 in the development of the occipital lobe and posterior fossa is discussed. [ABSTRACT FROM AUTHOR]

Frontonasal dysplasias are rare congenital malformations of frontonasal process-derived structures, characterized by median cleft, nasal anomalies, widely spaced eyes, and cranium bifidum occultum. Several entities of syndromic frontonasal dysplasia have been described, among which, to date, only a few have identified molecular bases. We clinically ascertained a cohort of 124 individuals referred for frontonasal dysplasia. We identified six individuals with a similar phenotype, including one discordant monozygous twin. Facial features were remarkable by nasal deformity with creased ridge and depressed or absent tip, widely spaced eyes, almond-shaped palpebral fissures, and downturned corners of the mouth. All had apparently normal psychomotor development. In addition, upper limb anomalies, frontonasal encephalocele, corpus callosum agenesis, choanal atresia, and congenital heart defect were observed. We identified five reports in the literature of patients presenting with the same phenotype. Exome sequencing was performed on DNA extracted from blood of two individuals, no candidate gene was identified. In conclusion, we report six novel simplex individuals presenting with a specific frontonasal dysplasia entity associating recognizable facial features, limb and visceral malformations, and apparently normal development. The identification of discordant monozygotic twins supports the hypothesis of a mosaic disorder. Although previous patients have been reported, this is the first series, allowing delineation of a clinical subtype of frontonasal dysplasia, paving the way toward the identification of its molecular etiology. [ABSTRACT FROM AUTHOR]

Oculo-auriculo-vertebral spectrum and frontonasal dysplasia are two well-known examples of dysmorphology syndromes. Oculoauriculofrontonasal syndrome (OAFNS) is a clinical entity involving the characteristics of both OAVS and FND and is thought to be a result of the abnormal development of structures in the first and the second branchial arches, including the abnormal morphogenesis of maxillary processes. Herein we report a case of OAFNS with cliteral hypertrophy, premaxillary teeth, and inguinal hernia, features not previously reported in the literature. [ABSTRACT FROM AUTHOR]

The article presents study on tooth abnormalities and occlusal disorders in individuals with frontonasal dysplasia. It mentions clinical oral examination and analysis of patient records in the study. It adds total of 19 individuals presented at least one tooth abnormality and individuals presented with agenesis of lateral incisors and second premolars in radiographs.