Search Results (84)

Biallelic pathogenic variants in DHCR7 result in decreased activity of 7-dehydrocholesterol (7-DHC) reductase, which converts 7-DHC to cholesterol, and causes Smith–Lemli–Opitz syndrome (SLOS). Elevated serum 7-DHC levels are indicative of SLOS as are intellectual disability (ID), growth retardation, microcephaly, craniofacial anomalies, and 2–3 toe syndactyly. Additional congenital malformations may be present in SLOS, and broad clinical variability has been recognized in SLOS. Rarely, biallelic pathogenic DHCR7 variants were reported with low-normal and normal intelligence quotient (IQ) and development. We report here a pair of siblings with mild global developmental delay, infrequent epileptic seizures, and elevated serum 7-DHC levels, associated with the homozygous DHCR7 variant c.988G>A (p.Val330Met). Remarkably, neither sibling displayed congenital anomalies nor dysmorphisms. Quattro-exome sequencing performed for global delay and mild ID in both siblings did not identify other ID causes. c.988G>A affects a highly conserved amino acid and displays a relatively high global population allele frequency of 0.04%, with absence of homozygotes from the population database gnomADv4.1.0. Our observation leads us to suggest that DHCR7 variant c.988G>A and other DHCR7 variants might be generally considered as underlying non-syndromic ID. Full article

Any failure in frontonasal development can lead to malformations at the middle facial region, such as frontonasal dysplasia, midfacial clefts, and hyper/hypotelorism. Various environmental factors influence morphogenesis through epigenetic regulations, including the action of noncoding microRNAs (miRNAs). However, it remains unclear how miRNAs are involved in the frontonasal development. In our analysis of publicly available miRNA-seq and RNA-seq datasets, we found that miR-28a-5p, miR-302a-3p, miR-302b-3p, and miR-302d-3p were differentially expressed in the frontonasal process during embryonic days 10.5 to 13.5 (E10.5–E13.5) in mice. Overexpression of these miRNAs led to a suppression of cell proliferation in cultured mouse embryonic frontonasal mesenchymal (MEFM) cells as well as in O9-1 cells, a cranial neural crest cell line. Through advanced bioinformatic analyses and miRNA-gene regulation assays, we identified that miR-28a-5p regulated a total of 25 genes, miR-302a-3p regulated 23 genes, miR-302b-3p regulated 22 genes, and miR-302d-3p regulated 20 genes. Notably, the expression of miR-302a/b/d-3p—unlike miR-28a-5p—was significantly upregulated by excessive exposure to all-trans retinoic acid (atRA) that induces craniofacial malformations. Inhibition of these miRNAs restored the reduced cell proliferation caused by atRA by normalizing the expression of target genes associated with frontonasal anomalies. Therefore, our findings suggest that miR-302a/b/d-3p plays a crucial role in the development of frontonasal malformations. Full article

Body stalk anomaly (BSA) is a rare and usually fatal congenital disorder involving severe malformations of the body wall, limbs, spine, and internal organs. This study presents the first documented cases of BSA in seven dogs, offering new insights into how the disorder manifests in animals. The affected fetuses consistently exhibited major anomalies, including large abdominal wall defects, structural spinal abnormalities, and a variety of limb malformations ranging from partial agenesis and meromelia to phocomelia and complete amelia. Structural urogenital anomalies and orofacial clefts were also observed, aligning with similar findings in BSA cases reported in pigs and cats. These findings support the hypothesis of a multifactorial etiology involving early embryonic disruptions, such as abnormal folding of the embryo, rupture of the amniotic membrane, and vascular compromise. The frequent occurrence of abdominal wall defects alongside umbilical cord abnormalities further suggests a shared developmental pathway. This study also highlights the value of veterinary cases in comparative embryology and the need to assess congenital anomalies as part of a broader malformation complex. By expanding the phenotypic spectrum of BSA in domestic animals, this work contributes to a deeper understanding of its pathogenesis and emphasizes the importance of further research into the genetic and environmental factors involved. Such efforts could lead to improved classification and diagnosis of complex congenital malformations, as well as facilitate cross-species comparisons. Full article

Background: Treacher Collins Syndrome (TCS) is a rare, congenital craniofacial syndrome. Its most characteristic feature is mandibular and midface hypoplasia. Due to malformations of the facial skeleton, airway abnormalities can also be observed, predisposing individuals to obstructive sleep apnoea (OSA). OSA in TCS may contribute to significant morbidity, including developmental delays, cardiovascular disorders and reduced quality of life. Objectives: This narrative review aims to present the true prevalence of OSA and the treatment options for TCS patients. Additionally, the pathophysiology and diagnostic tools for this condition were briefly outlined. Methods: The literature search included publications from PubMed, Scopus, Web of Science and Cochrane Library. The chosen period of time for these publications was 2000–2024. Results: The results showed that OSA is a serious problem among TCS patients. Although there is no standardised treatment protocol, the primary methods often include mandibular distraction osteogenesis (MDO) and continuous positive airway pressure (CPAP). Approaches such as hypoglossal nerve stimulation (HNS) need further investigation, especially with longitudinal observations. Conclusions: The development of treatment options seems to be promising, suggesting a favourable outlook for standardising the treatment protocols. Full article

Background: This study aims to evaluate surgical outcomes and compares the prevalence and severity of postoperative complications and reoperations with maxillary osteotomies, focusing on the effectiveness of fixation with demineralized bone matrix (DBM) versus autogenous bone grafts (ABG) in patients with orofacial clefts and craniofacial malformations. Methods: This retrospective cohort study included 138 consecutive patients treated at the Cleft Palate and Craniofacial Center, Helsinki University Hospital, from 2014 to 2022. The cohort consisted of patients with clefts (n = 113), craniosynostosis, and craniofacial syndromes (n = 25). The DBM group (n = 103) received DBX^® (Musculoskeletal Transplant Foundation, Edison, NJ, USA), while the ABG group (n = 35) received autogenous bone grafts. Surgical procedures included Le Fort I and bimaxillary osteotomies. Complications involving the maxilla or both jaws were included in the analysis. Both major and minor complications, as well as reoperations, were analyzed and compared. Results: The DBM group had 13.6% of patients with complications, while the ABG group had 20.0%. Reoperation rates were 6.8% for the DBM group and 5.7% for the ABG group. There were no statistically significant differences in complication or reoperation rates between the DBM and ABG groups. Conclusions: The findings suggest that using DBM or ABG in maxillary osteotomies does not significantly affect complication or reoperation rates, supporting DBM as a viable alternative for maxillary surgeries. Full article

Background: Craniofacial malformations lie at the heart of fetal alcohol spectrum disorders (FASDs). While there is growing evidence for a genetic component in FASDs, little is known of the cellular mechanisms underlying these ethanol-sensitive loci in facial development. The bone morphogenetic protein (Bmp) signaling pathway-dependent endoderm pouch formation is a key mechanism in facial development. We have previously shown that multiple Bmp mutants are sensitized to ethanol-induced facial defects. However, ethanol does not directly impact Bmp signaling. This suggests that downstream effectors, like nkx2.3, may mediate the impact of ethanol on Bmp mutants. Methods: We use an ethanol exposure paradigm with nkx2.3 knockdown approaches to test if nkx2.3 loss sensitizes Bmp mutants to ethanol-induced facial defects. We combine morphometric approaches with immunofluorescence and a hybridization chain reaction to examine the cellular mechanisms underlying Bmp–ethanol interactions. Results: We show that Bmp–ethanol interactions alter the morphology of the endodermal pouches, independent of nkx2.3 gene expression. Knockdown of nkx2.3 does not sensitize wild-type or Bmp mutants to ethanol-induced facial defects. However, we did observe a significant increase in CNCC apoptosis in ethanol-treated Bmp mutants, suggesting an ethanol sensitive, Bmp-dependent signaling pathway driving tissue interactions at the heart of FASDs. Conclusions: Collectively, our work builds on the mechanistic understanding of ethanol-sensitive genes and lays the groundwork for complex multi-tissue signaling events that have yet to be explored. Ultimately, our work provides a mechanistic paradigm of ethanol-induced facial defects and connects ethanol exposure with complex tissue signaling events that drive development. Full article

Objectives: This study examines the association between a predominantly soft-textured diet and clinical signs of maxillary bone hypoplasia, such as maxillary constriction and related malocclusions like crossbite. A secondary aim is to assess whether this diet correlates with dental caries and higher plaque index in children with early mixed dentition. Methods: A total of 106 pediatric patients (4–12 years) were enrolled during routine visits (June 2022–February 2024), divided into 53 “cases” (maxillary hypoplasia and malocclusions) and 53 “controls” (normal maxillary development, no malocclusions). Patients with congenital craniofacial malformations were excluded. Dietary habits were assessed using a food questionnaire categorizing foods into four consistencies (“Semi-Liquid”, “Creamy”, “Soft”, and “Solid”). The DMFT index was calculated, considering only missing teeth due to caries. The plaque index (PI) was recorded at the first visit to evaluate the relationship between food texture and plaque accumulation. Statistical analyses included Student’s t-test, Z-test, Chi-square test, and Fisher’s exact test. Results: Mixed breastfeeding was common in both groups with no significant difference. However, natural breastfeeding was significantly more frequent in the non-crossbite group. A high-arched palate was more prevalent in the crossbite group (p = 0.042 *). Soft food consumption was significantly higher in the crossbite group compared to controls (p = 0.032 *). A statistically significant association was found between caries prevalence (DMFT > 0) and posterior crossbite (p = 0.04). Furthermore, the relationship between the dental plaque index and food consistency demonstrated a statistically significant result. In particular, there was a correlation between soft food and semi-solid foods and the plaque index (χ² = 3.55, p = 0.04). Conclusions: Posterior crossbite is associated with increased consumption of soft foods, potentially reducing the mechanical stimulation essential for maxillary growth. Conversely, non-crossbite subjects consume more hard foods and are more frequently breastfed naturally, reinforcing their role in craniofacial development. Additionally, posterior crossbite is associated with higher caries prevalence, indicating a potential connection between occlusion and oral health. Dietary texture also influences oral hygiene, with soft and semi-solid foods correlating with increased plaque accumulation, while no association was found with solid or hard foods. Full article

Background/Objectives: Ischemic arterial stroke (AIS) is a cerebrovascular event that can occur acutely within the first hours or days of life, presenting as a neurological emergency. To date, clearly defined genetic risk factors for AIS have not been established, although certain genes involved in cerebrovascular regulation mechanisms are suspected to play a role. The Interferon Regulatory Factor 6 (IRF6) gene is a transcription factor involved in craniofacial and epidermal development. Recently, pathogenic variants of IRF6 have been implicated in the cytoprotective pathway of ischemic cerebrovascular disease. The aim of this manuscript is to further support the already-reported association between IRF6 and AIS. Materials and Methods: Genetic counseling and exome sequencing analysis were conducted for diagnostic purposes. Results: We report the case of a female newborn with palatoschisis, cleft palate, sensorineural deafness, facial dysmorphisms, and cutaneous defects who suffered an ischemic stroke in the territory of the left middle cerebral artery on day 1 of life. Family and pregnancy histories revealed no identifiable risk factors, and coagulation studies were normal. Exome sequencing identified a de novo c.1124T>C (p.Phe375Ser) variant in the IRF6 gene. The child developed right spastic hemiplegia and began motor rehabilitation therapy. Recently, a genome-wide association study (GWAS) using m6A-SNPs identified a statistical association between AIS and a single nucleotide polymorphism (SNP) that influences the expression of the IRF6 gene as an expression quantitative trait locus (eQTL). Conclusions: To our knowledge, this is the first report of neonatal ischemic stroke in a child carrying a de novo IRF6 pathogenic variant, further supporting its potential role as a genetic factor influencing cerebrovascular events. Further studies are needed to elucidate the precise relationship between IRF6 and AIS. Full article

Background/Objectives: Schuurs–Hoeijmakers syndrome (SHMS), also known as PACS1 neurodevelopmental disorder, is a rare condition characterized by intellectual disability, distinctive craniofacial abnormalities, and congenital malformations. SHMS has already been associated with variants in the PACS1 gene in 63 patients. In this study, we describe 10 new Italian SHMS patients all harboring the common de novo p.(Arg203Trp) variant. Methods: The 10 patients we studied were evaluated by clinical geneticists and child neurologists and a detailed description of clinical features was recorded. Data were then coded using the Human Phenotype Ontology (HPO) terms. The recurrent p.(Arg203Trp) variant in PACS1 was identified by clinical exome sequencing or whole exome sequencing in trio using standard methodologies. To facilitate mutation identification, we designed a new PCR-RFLP strategy adopting the endonuclease DpnII. Results: We define a detailed clinical phenotyping in patients with intellectual disability and facial characteristics (thick eyebrows, down-slanting palpebral fissures, ocular hypertelorism, low-set ears, a thin upper lip, and a wide mouth) that can help clinicians form a more efficient diagnosis of SHMS even through neuroimaging and neuropsychological evaluation. Conclusions: Our series of 10 newly affected Italian children highlights specific clinical features that may help clinicians recognize and better manage this syndrome, contributing to precision medicine approaches in medical genetics. Full article

With the current state of knowledge regarding disorders of facial bone development, including anodontia, the development of a suitable animal model for preclinical studies is essential. The agenesis of dental buds occurs in about 25% of the human population. Prospects for treatment include the use of growth factors, stem cells, and bioengineering. This study aimed to investigate the influence of a tooth absence on facial bone growth, develop a technique for the application of growth factors to the developing bone, and analyze the comparative effect of the application of selected active proteins on the growth of the maxilla and mandible. Piglets underwent germectomy, followed by computed tomography and X-ray; morphometric and histological analyses of the bones were performed, blood bone morphogenetic protein 2 and platelet-derived growth factor concentrations were determined, and the transcriptomic profile of the dentate ligament was analyzed using DNA microarrays. It was not possible to identify the most effective growth factor application algorithm for achieving normal jaw development. Normal mandibular bone structure and oral mucosa structure were observed in the germectomy groups with growth factor augmentation. The average height of the mandibular alveolar part in the area of the removed dental buds was significantly lower compared with that of the inoperable side, 3 months after surgery. However, no significant differences were found in the serum concentrations of BMP-2 and PDGF between groups. The animal model of bone development disorders (including anodontia) developed in the current study and the scheme for evaluating the efficacy and safety of the application of replacement therapy for craniofacial malformations are important in the development of the discipline and represent an important contribution to the introduction of treatment methods. Full article

Background: Orofacial clefts are the most common craniofacial congenital malformation in humans. Approximately 30% of clefts arise as part of a syndrome or sequence, characterised by co-existing structural and functional anomalies. Many syndromes are thought to be undiagnosed, although the presence of multiple anomalies may indicate the presence of a syndrome or sequence. Aim: To determine the extent to which the presence of additional structural and functional anomalies can help to identify those children with an undiagnosed syndrome. Methods: Secondary data analysis was performed using data from 1701 children born with an orofacial cleft, collected as part of a longitudinal cohort study, the Cleft Collective. Data were collected between 2013 and 2023 across the United Kingdom. The prevalence of structural and functional anomalies and syndromes were explored using descriptive statistics. Logistic regression was used to determine the extent to which anomalies can predict syndromic status. Results: A syndrome and/or sequence was reported in 20.5% children. Among children who reported five or more anomalies, the prevalence of a diagnosed syndrome was 81.5%. When adjusting for cleft subtype and sex, in 27 out of 32 anomalies tested, strong evidence was found to suggest increased odds of having a syndrome if the specific anomaly was present compared to if the anomaly was absent (p-values ranged between 1.4 × 10⁻³⁰ and 0.002). Conclusions: Children born with a cleft who present with two or more anomalies are much more likely to have a syndrome than those with fewer anomalies and should be prioritised for genetic screening and counselling. Full article

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. Full article

Fryns syndrome (FS) is a multiple congenital anomaly syndrome with different multisystemic malformations. These include congenital diaphragmatic hernia, pulmonary hypoplasia, and craniofacial dysmorphic features in combination with malformations of the central nervous system such as agenesis of the corpus callosum, cerebellar hypoplasia, and enlarged ventricles. We present a non-consanguineous northern European family with two recurrent cases of FS: a boy with multiple congenital malformations who died at the age of 2.5 months and a female fetus with a complex developmental disorder with similar features in a following pregnancy. Quad whole exome analysis revealed two likely splicing-affecting disease-causing mutations in the PIGN gene: a synonymous mutation c.2619G>A, p.(Leu873=) in the last nucleotide of exon 29 and a 30 bp-deletion c.996_1023+2del (NM_176787.5) protruding into intron 12, with both mutations in trans configuration in the affected patients. Exon skipping resulting from these two variants was confirmed via RNA sequencing. Our molecular and clinical findings identified compound heterozygosity for two novel splice-affecting variants as the underlying pathomechanism for the development of FS in two patients. Full article

Hemifacial microsomia (HFM) is a rare congenital genetic syndrome primarily affecting the first and second pharyngeal arches, leading to defects in the mandible, external ear, and middle ear. The pathogenic genes remain largely unidentified. Whole-exome sequencing (WES) was conducted on 12 HFM probands and their unaffected biological parents. Predictive structural analysis of the target gene was conducted using PSIPRED (v3.3) and SWISS-MODEL, while STRING facilitated protein-to-protein interaction predictions. CRISPR/Cas9 was applied for gene knockout in zebrafish. In situ hybridization (ISH) was employed to examine the spatiotemporal expression of the target gene and neural crest cell (NCC) markers. Immunofluorescence with PH3 and TUNEL assays were used to assess cell proliferation and apoptosis. RNA sequencing was performed on mutant and control embryos, with rescue experiments involving target mRNA injections and specific gene knockouts. CDC27 was identified as a novel candidate gene for HFM, with four nonsynonymous de novo variants detected in three unrelated probands. Structural predictions indicated significant alterations in the secondary and tertiary structures of CDC27. cdc27 knockout in zebrafish resulted in craniofacial malformation, spine deformity, and cardiac edema, mirroring typical HFM phenotypes. Abnormalities in somatic cell apoptosis, reduced NCC proliferation in pharyngeal arches, and chondrocyte differentiation issues were observed in cdc27^−/− mutants. cdc27 mRNA injections and cdkn1a or tp53 knockout significantly rescued pharyngeal arch cartilage dysplasia, while sox9a mRNA administration partially restored the defective phenotypes. Our findings suggest a functional link between CDC27 and HFM, primarily through the inhibition of CNCC proliferation and disruption of pharyngeal chondrocyte differentiation. Full article

Craniofacial surgery is proposed and performed for a variety of reasons, ranging from congenital or acquired malformations to emotional disorders and parafunctions of the masticatory, respiratory, auditory, and visual systems. Surgery of the mandible and its orthostatic repositioning is the most common of these corrections of craniofacial anomalies. Throughout the history of these procedures, various techniques have been proposed and perfected, but always with a high rate of minor and major complications. The recurrence rate of mandibular malposition is high, as is the temporary loss of facial sensitivity and motor skills. These outcomes are often related to the choice of surgical technique rather than the skill of the surgeon, which is considered to be one of the most important factors in the final outcome. Surgical techniques involving direct manipulation of the vascular-nervous bundles, such as bilateral sagittal split osteotomy, clearly present the possibility of major or minor complications. In this study, an orthognathic surgical technique, performed by the same team for over 40 years and now available through a 20-year postoperative patient follow-up study, is presented with a literature review relating it to biomechanical concepts and bone remodeling to analyze the evolution of orthognathic surgery since it became common practice to correct maxillofacial discrepancies. In this review, we also present a case report in which previous orthodontic treatment prepared a patient for surgical correction of mandibular bone discrepancy without the need for combined maxillary and/or genioplasty, and we describe the most commonly used techniques today, as well as their advantages and disadvantages. The combination of established concepts together promotes favorable stability of mandibular osteotomies, functional anatomical positioning of the temporomandibular joint, reduced risk of injury to the mandibular vasculo-nervous bundle, and good aesthetics with positive patient acceptance and no relapse, thus these are the objectives for proposing innovative treatments that combine the technologies available today. Full article