Nasal Reconstruction of a Frontonasal Dysplasia via Septal L-Strut Reconstruction Using Costal Cartilage

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.

De novo ZIC2 frameshift variant associated with frontonasal dysplasia in a Limousin calf

Background Bovine frontonasal dysplasias like arhinencephaly, synophthalmia, cyclopia and anophthalmia are sporadic congenital facial malformations. In this study, computed tomography, necropsy, histopathological examinations and whole genome sequencing on an Illumina NextSeq500 were performed to characterize a stillborn Limousin calf with frontonasal dysplasia. In order to identify private genetic and structural variants, we screened whole genome sequencing data of the affected calf and unaffected relatives including parents, a maternal and paternal halfsibling. Results The stillborn calf exhibited severe craniofacial malformations. Nose and maxilla were absent, mandibles were upwardly curved and a median cleft palate was evident. Eyes, optic nerve and orbital cavities were not developed and the rudimentary orbita showed hypotelorism. A defect centrally in the front skull covered with a membrane extended into the intracranial cavity. Aprosencephaly affected telencephalic and diencephalic structures and cerebellum. In addition, a shortened tail was seen. Filtering whole genome sequencing data revealed a private frameshift variant within the candidate gene ZIC2 in the affected calf. This variant was heterozygous mutant in this case and homozygous wild type in parents, half-siblings and controls. Conclusions We found a novel ZIC2 frameshift mutation in an aprosencephalic Limousin calf. The origin of this variant is most likely due to a de novo mutation in the germline of one parent or during very early embryonic development. To the authors’ best knowledge, this is the first identified mutation in cattle associated with bovine frontonasal dysplasia.

Pai syndrome: a review

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.

ALX1-related Frontonasal Dysplasia Results From Defective Neural Crest Cell Development and Migration

ABSTRACTA pedigree of subjects with frontonasal dysplasia (FND) presented with bilateral oblique facial clefts and ocular phenotypes. Genome sequencing and analysis identified a 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 also 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.