Frontonasal Dysplasia Research Articles

Detection of regions of homozygosity in an unusual case of frontonasal dysplasia

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.

Overhauling dental implications in a child with rare craniofrontonasal syndrome: a case report

Craniofrontonasal syndrome is an extremely rare X-linked dominant genetic disorder characterized by features such as hypertelorism, craniosynostosis, ocular anomalies, a bifid nasal tip, and longitudinal ridging with splitting of the nails. Heterozygous females are more severely affected, presenting frontonasal dysplasia and coronal craniosynostosis (fusion of the coronal sutures), while males typically only exhibit hypertelorism. This case report describes the dental management of a 9-year-old female with craniofrontonasal syndrome who was referred to the department of paediatric and preventive dentistry for pain in the lower right and left back tooth region. The patient exhibited a clinical spectrum including microcephaly, short neck, axillary pterygium, clinodactyly of the toes, longitudinal ridging with split nails, pectus excavatum, and underdeveloped female genitalia. Extraoral examination revealed hypertelorism, flat nasal bridge, low-set ears, strabismus, antimongoloid slant, and an indistinct philtrum. Intraoral examination showed a high palatal vault, crowding of the upper and lower arches during the mixed dentition period, multiple dental caries, and poor oral hygiene. An orthopantomogram confirmed delayed dental development. Dental treatment was carried out on a dental chair system using adequate behaviour management techniques with short appointments, keeping in mind the reduced cooperative ability of the child. The importance of this report stems from the limited dental literature available on the syndrome. Preventive measures along with home care instructions were emphasized to support professional care.

Genes Related to Frontonasal Malformations Are Regulated by miR-338-5p, miR-653-5p, and miR-374-5p in O9-1 Cells.

Frontonasal malformations are caused by a failure in the growth of the frontonasal prominence during development. Although genetic studies have identified genes that are crucial for frontonasal development, it remains largely unknown how these genes are regulated during this process. Here, we show that microRNAs, which are short non-coding RNAs capable of targeting their target mRNAs for degradation or silencing their expression, play a crucial role in the regulation of genes related to frontonasal development in mice. Using the Mouse Genome Informatics (MGI) database, we curated a total of 25 mouse genes related to frontonasal malformations, including frontonasal hypoplasia, frontonasal dysplasia, and hypotelorism. MicroRNAs regulating the expression of these genes were predicted through bioinformatic analysis. We then experimentally evaluated the top three candidate miRNAs (miR-338-5p, miR-653-5p, and miR-374c-5p) for their effect on cell proliferation and target gene regulation in O9-1 cells, a neural crest cell line. Overexpression of these miRNAs significantly inhibited cell proliferation, and the genes related to frontonasal malformations (Alx1, Lrp2, and Sirt1 for miR-338-5p; Alx1, Cdc42, Sirt1, and Zic2 for miR-374c-5p; and Fgfr2, Pgap1, Rdh10, Sirt1, and Zic2 for miR-653-5p) were directly regulated by these miRNAs in a dose-dependent manner. Taken together, our results highlight miR-338-5p, miR-653-5p, and miR-374c-5p as pathogenic miRNAs related to the development of frontonasal malformations.

Prenatal diagnosis of a severe form of frontonasal dysplasia with severe limb anomalies, hydrocephaly, a hypoplastic corpus callosum, and a ventricular septal defect using 3D ultrasound: a case report and literature review

BackgroundFrontonasal 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 presentationA 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.ConclusionThe present case expands the wide phenotypic spectrum of prenatal FND patients. 3D ultrasound is a useful tool for detecting facial and limb deformities.

Structural Rhinoplasty as an Effective Surgical Approach for Frontonasal Dysplasia.

Frontonasal dysplasia (FND), a rare congenital craniofacial disorder, primarily influences the development of midline craniofacial structures. A notable manifestation of this condition is nasal hypoplasia. This report details the treatment of a 19-year-old male patient diagnosed with FND accompanied by a severe case of nasal hypoplasia. The authors used structural rhinoplasty to achieve total nasal reconstruction. Albeit with some minor sequelae, the outcome of this surgery was markedly positive, enhancing both the cosmetic appearance and functional capacity of the nose. This case underscores the effectiveness of structural rhinoplasty as a feasible therapeutic approach for individuals suffering from FND and its associated nasal hypoplasia.

Lineage-specific requirements of Alx4 function in craniofacial and hair development.

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. 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. 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.

ALX4-related frontonasal dysplasia sequence presenting with alopecia in a 12 year old girl

Children with alopecia are frequently encountered in paediatric dermatological practice. Common causes include alopecia areata, and telogen effluvium. Herein we report a case of alopecia in a 12 year old girl as a part of ALX4-related frontonasal dysplasia (FND) sequence for its rarity.

Dominant frontonasal dysplasia with ectodermal defects results from increased activity of ALX4.

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 variantsin ALX4 exerting a gain-of-function effect.

Orbital box osteotomy in frontonasal dysplasia with severe hypertelorism: Our first experience

ABSTRACT 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.

Ethical side of decision-making on palliative care to a child with congenital heart disease associated with frontonasal dysplasia

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).

Hospitalizations from Birth to 28 Years in a Population Cohort of Individuals Born with Five Rare Craniofacial Anomalies in Western Australia

To describe trends, age-specific patterns, and factors influencing hospitalizations for five rare craniofacial anomalies (CFA). Data on livebirths (1983-2010; n=721,019) including rare CFA (craniofacial microsomia, mandibulofacial dysostosis, Pierre Robin sequence, Van der Woude syndrome, and fronto-nasal dysplasia), episodes of death, and demographic and perinatal factors were identified from the Western Australian (WA) Register of Developmental Anomalies, Death Registrations and Midwives Notification System. Information on incident craniofacial and non-craniofacial related admissions, length of hospital stay, and intensive care and emergency related admissions were identified using principal diagnosis and procedural codes were extracted from the Hospital Morbidity Data Collection and linked to other data sources. Associations of hospitalizations by age groups as well as demographic and perinatal factors were expressed as incidence rate ratio (IRR). The incident hospitalizations were three times as high for rare CFA (IRR 3.22 - 3.72) throughout childhood into adolescence than those without. Children with rare CFA had three to four times as many potentially preventable hospitalizations until 18 years of age than those without. Specifically, respiratory infections (IRR 2.13-2.35), ear infections (IRR 7.92 - 26.28), and oral health-related conditions contributed for most non-craniofacial admissions until the adolescence period. Higher incidence of non-craniofacial related hospitalizations was observed among Indigenous children, births with intrauterine growth restrictions and families with high socioeconomic disadvantage. Throughout childhood, individuals with rare CFA had higher hospital service use, specifically for potentially preventable conditions, than those without. These population level findings can inform new preventive strategies and early disease management targeted towards reducing preventable hospitalizations.

Zebrafish models of alx-linked frontonasal dysplasia reveal a role for Alx1 and Alx3 in the anterior segment and vasculature of the developing eye.

ABSTRACTThe 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.

Toward clinical and molecular dissection of frontonasal dysplasia with facial skin polyps: From Pai syndrome to differential diagnosis through a series of 27 patients.

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.

A case of frontonasal dysplasia in a twin

The Journal is the primary organ of Continuing Paediatric Medical Education in Sri Lanka. The journal also has a website. Free full text access is available for all readers.The Sri Lanka Journal of Child Health is now indexed in SciVerse Scopus (Source Record ID 19900193609), Index Medicus for South-East Asia Region (IMSEAR), CABI (Centre for Agriculture and Bioscience International Global Health Database), DOAJ and is available in Google, as well as Google Scholar.The policies of the journal are modelled on the Committee on Publication Ethics (COPE) Guidelines on Principles of Transparency and Best Practice in Scholarly Publishing. Sri Lanka Journal of Child Health is recognised by the International Committee of Medical Journal Editors (ICMJE) as a publication following the ICMJE Recommendations.

Alx1 Deficient Mice Recapitulate Craniofacial Phenotype and Reveal Developmental Basis of ALX1-Related Frontonasal Dysplasia.

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. Alx1 del/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, Alx1 del/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.

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

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. Retrospective review from June 2008 and August 2017. 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. 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. 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.

ALX-Related Frontonasal Dysplasias: Clinical Characteristics and Surgical Management.

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. Single-institution retrospective. Tertiary health care. 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. 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. 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.

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

BackgroundBovine 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.ResultsThe 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.ConclusionsWe 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.

Frontonasal Dysplasia in Yangon, Myanmar

Frontonasal dysplasia (FND) is an uncommon congenital anomaly affecting the eyes, nose and forehead. In this case report, a baby of a 22-year-old mother was diagnosed with a midline facial cleft, bifid nose and hypertelorism during an ultrasound scan at 29th week of gestation. Besides a history of miscarriage on first pregnancy, no other abnormalities findings were found in laboratory or radiological examination of the newborn. Counselling about abnormality and psychological support were given by both obstetrician and neonatologist during the antenatal period. The patient delivered vaginally at 36th week with spontaneous labour and no complication was observed. Further interventions including corrective treatment have been planned as they often interfere with important functions such as breathing and feeding. Thus, the paediatric surgical team decided to do the operation when the baby reaches one year old as then tissues have been developed to 90% of their eventual form to give optimal treatment results. Further life expectancy depends on the severity of the malformation and whether or not surgical intervention can improve the associated health problems. This case report raises the importance of awareness on the nutritional value of pregnant mothers especially carotene and folic acid intake which may be associated with the organ maldevelopment. Overall, this report outlined the management of this rare condition experienced by the patient, particularly in a resource-limited setting like Yangon in Myanmar and also reviewed the literature about the presentation and classification of this condition.

ALX1‐related frontonasal dysplasia results from defective neural crest cell development and migration

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.