Specific Craniofacial Features Research Articles

Candidate genes for obstructive sleep apnea in non-syndromic children with craniofacial dysmorphisms - a narrative review.

Pediatric obstructive sleep apnea (POSA) is a complex disease with multifactorial etiopathogenesis. The presence of craniofacial dysmorphisms influencing the patency of the upper airway is considered a risk factor for POSA development. The craniofacial features associated with sleep-related breathing disorders (SRBD) - craniosynostosis, retrognathia and micrognathia, midface and maxillary hypoplasia - have high heritability and, in a less severe form, could be also found in non-syndromic children suffering from POSA. As genetic factors play a role in both POSA and craniofacial dysmorphisms, we hypothesize that some genes associated with specific craniofacial features that are involved in the development of the orofacial area may be also considered candidate genes for POSA. The genetic background of POSA in children is less explored than in adults; so far, only one genome-wide association study for POSA has been conducted; however, children with craniofacial disorders were excluded from that study. In this narrative review, we discuss syndromes that are commonly associated with severe craniofacial dysmorphisms and a high prevalence of sleep-related breathing disorders (SRBD), including POSA. We also summarized information about their genetic background and based on this, proposed 30 candidate genes for POSA affecting craniofacial development that may play a role in children with syndromes, and identified seven of these genes that were previously associated with craniofacial features risky for POSA development in non-syndromic children. The evidence-based approach supports the proposition that variants of these candidate genes could lead to POSA phenotype even in these children, and, thus, should be considered in future research in the general pediatric population.

Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome.

The developmental disorder Burn-McKeown Syndrome (BMKS) is characterised by choanal atresia and specific craniofacial features. BMKS is caused by biallelic variants in the pre-messenger RNA splicing factor TXNL4A. Most patients have a loss-of-function variant in trans with a 34-base pair (bp) deletion (type 1 Δ34) in the promoter region. Here, we identified two patients with BMKS. One individual has a TXNL4A c.93_94delCC, p.His32Argfs *21 variant combined with a type 1 Δ34 promoter deletion. The other has an intronic TXNL4A splice site variant (c.258-3C>G) and a type 1 Δ34 promoter deletion. We show the c.258-3C>G variant and a previously reported c.258-2A>G variant, cause skipping of the final exon of TXNL4A in a minigene splicing assay. Furthermore, we identify putative transcription factor binding sites within the 56 bp of the TXNL4A promoter affected by the type 1 and type 2 Δ34 and use dual luciferase assays to identify a 22 bp repeated motif essential for TXNL4A expression within this promoter region. We propose that additional variants affecting critical transcription factor binding nucleotides within the 22 bp repeated motif could be relevant to BMKS aetiology. Finally, our data emphasises the need to analyse the non-coding sequence in individuals where a single likely pathogenic coding variant is identified in an autosomal recessive disorder consistent with the clinical presentation.

A Novel Homozygous Variant in GJA1 Causing a Hallermann-Streiff/Oculodentodigital Dysplasia Overlapping Phenotype: A Clinical Report

This paper reports the case of a Moroccan girl with a phenotype within the clinical spectrum of both Hallermann-Streiff (HSS, OMIM 234100) and Oculodentodigital Dysplasia (ODDD, OMIM 164200) syndromes. The patient presented with repeated dental abscesses and severe early childhood caries. She had no learning deficit nor psychomotor regression; however, a language delay was noted. She also presented with obstructive sleep apnea syndrome and specific craniofacial features pathognomonic of HSS. Radiographic examination showed enamel and dentin defects, giving a ghost-like tooth appearance. Several clinical features of ODDD overlap those of HSS and may confuse diagnosis, considering that the inheritance of HSS is not described yet. The diagnostic odyssey of this patient ended with the identification by exome sequencing of a novel homozygous alteration in the GJA1 gene. A missense substitution in exon 2 [Chr6(GRCh37): g.121768554C>G NM_000165.4: c.561C>G p.Cys187Trp] was identified by whole-exome sequencing (WES), suggesting a diagnosis of ODDD. This is the first report of a homozygous mutation affecting the second extracellular loop of the CX43 protein.

Potential impact of pediatric obstructive sleep apnea on mandibular cortical width dimensions.

To analyze differences in mandibular cortical width (MCW) among children diagnosed with obstructive sleep apnea (OSA) or at high- or low-risk for OSA. A total of 161 children were assessed: 60 children with polysomnographically diagnosed OSA, 56 children presenting symptoms suggestive of high-risk for OSA, and 45 children at low risk for OSA. Children at high- and low-risk for OSA were evaluated through the Pediatric Sleep Questionnaire. MCW was calculated using ImageJ software from panoramic radiograph images available from all participants. Differences between MCW measurements in the 3 groups were evaluated using analysis of covariance and Bonferroni post-hoc tests, with age as a covariate. The association between MCW and specific cephalometric variables was assessed through regression analysis. The participants' mean age was 9.6 ± 3.1 years (59% male and 41% female). The mean body mass index z-score was 0.62 ± 1.3. The polysomnographically diagnosed OSA group presented smaller MCW than the group at low-risk for OSA (mean difference = -0.385 mm, P = .001), but no difference with the group at high-risk for OSA (polysomnographically diagnosed OSA vs high-risk OSA: P = .085). In addition, the MCW in the group at high-risk for the OSA was significantly smaller than the group at low-risk for the OSA (mean difference = -0.301 mm, P = .014). The cephalometric variables (Sella-Nasion-A point angle (SNA) and Frankfort - Mandibular Plane angle (FMA)) explained only 8% of the variance in MCW. Reductions in MCW appear to be present among children with OSA or those at high-risk for OSA, suggesting potential interactions between mandibular bone development and/or homeostasis and pediatric OSA. Fernandes Fagundes NC, d'Apuzzo F, Perillo L, et al. Potential impact of pediatric obstructive sleep apnea on mandibular cortical width dimensions. J Clin Sleep Med. 2021;17(8):1627-1634.

Evaluation and Management of Adults with Obstructive Sleep Apnea Syndrome.

Obstructive sleep apnea syndrome (OSAS) is a common and underdiagnosed medical condition characterized by recurrent sleep-dependent pauses and reductions in airflow. While a narrow, collapsible oropharynx plays a central role in the pathophysiology of OSAS, there are other equally important nonanatomic factors including sleep-stage dependent muscle tone, arousal threshold, and loop gain that drive obstructive apneas and hypopneas. Through mechanisms of intermittent hypoxemia, arousal-related sleep fragmentation, and intrathoracic pressure changes, OSAS impacts multiple organ systems. Risk factors for OSAS include obesity, male sex, age, specific craniofacial features, and ethnicity. The prevalence of OSAS is rising due to increasing obesity rates and improved sensitivity in the tools used for diagnosis. Validated questionnaires have an important but limited role in the identification of patients that would benefit from formal testing for OSA. While an in-laboratory polysomnography remains the gold standard for diagnosis, the widespread availability and accuracy of home sleep apnea testing modalities increase access and ease of OSAS diagnosis for many patients. In adults, the most common treatment involves the application of positive airway pressure (PAP), but compliance continues to be a challenge. Alternative treatments including mandibular advancement device, hypoglossal nerve stimulator, positional therapies, and surgical options coupled with weight loss and exercise offer possibilities of an individualized personal approach to OSAS. Treatment of symptomatic patients with OSAS has been found to be beneficial with regard to sleep-related quality of life, sleepiness, and motor vehicle accidents. The benefit of treating asymptomatic OSA patients, particularly with regard to cardiovascular outcomes, is controversial and more data are needed.

Assessment of craniofacial and dental characteristics in individuals with treacher collins syndrome. A review

Treacher Collins Syndrome (TCS) is a genetic disorder with predominantly autosomal dominant inheritance, associated with different mutations in specific genes. This review aimed to evaluate the facial, temporomandibular, zygomatic and bucco-dental phenotype in TCS individuals, and describe surgical and non-surgical solutions for each case in order to improve the quality of life of these individuals. A review of the literature on the craniofacial characteristics of the TCS was carried out, using the PICO strategy, and then a systematic search method was performed in Medline, Scopus, LILACS and SCIELO databases, identifying articles of impact and relevance until 10 June 2020, 240 articles were recovered and only 35 fulfilled the selection criteria. We found the main craniofacial and oral morphological characteristics of these individuals, and the possible functional alterations inducing repercussion in the stomatognathic apparatus. Among other characteristics, the most representative include hypoplasia in the zygomatic and mandibular complex, which can cause difficulty in breathing and feeding. In some cases, cleft palate and malocclusions such as anterior open bite may lead to Angle’s Class II malocclusion, sometimes causing problems in the temporomandibular joint. In conclusion, individuals with TCS have specific craniofacial features including maxillary hypoplasia, altered orbital zones, mandibular retrognathia, and temporomandibular disorders. Oral deformities produce to a higher prevalence of caries and calculus formation because of poor hygiene due to the malformations present in these patients.

Oligogenic Effects of 16p11.2 Copy-Number Variation on Craniofacial Development

SUMMARYA copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood. To determine the influence of 16p11.2 genes on development, we investigated the effects of CNV on craniofacial structure in humans and model organisms. We show that deletion and duplication of 16p11.2 have “mirror” effects on specific craniofacial features that are conserved between human and rodent models of the CNV. By testing dosage effects of individual genes on the shape of the mandible in zebrafish, we identify seven genes with significant effects individually and find evidence for others when genes were tested in combination. The craniofacial phenotypes of 16p11.2 CNVs represent a model for studying the effects of genes on development, and our results suggest that the associated facial gestalts are attributable to the combined effects of multiple genes.

Defect in dermatan sulfate in urine of patients with Ehlers-Danlos syndrome caused by a CHST14/D4ST1 deficiency

PurposeDermatan sulfate (DS) plays a number of roles in a wide range of biological activities such as cell signaling and tissue morphogenesis through interactions with various extracellular matrix proteins including collagen. Mutations in the carbohydrate sulfotransferase 14 gene (CHST14) encoding CHST14/dermatan 4-O-sulfotransferase-1 (D4ST1), which is responsible for the biosynthesis of DS, cause a recently delineated form of Ehlers-Danlos syndrome (EDS, musculocontractural type 1), an autosomal recessive connective tissue disorder characterized by congenital malformations (specific craniofacial features, and congenital multiple contractures) and progressive fragility-related complications (skin hyperextensibility, bruisability, and fragility with atrophic scars; recurrent dislocations; progressive talipes or spinal deformities; and large subcutaneous hematomas). In an attempt to develop a diagnostic screening method for this type of EDS, the amount of DS in the urine of patients was analyzed. MethodsUrinary DS was quantified by an anion-exchange chromatography after treatment with DS-specific degrading enzyme. ResultsDS was not detected in the urine of patients with homo- or compound heterozygous mutations in CHST14. These results suggest that the quantification of DS in urine is applicable to an initial diagnosis of DS-defective EDS. ConclusionsThis is the first study to perform a urinary disaccharide compositional analysis of chondroitin sulfate (CS)/DS chains in patients with EDS caused by a CHST14/D4ST1 deficiency, and demonstrated the absence of DS chains. This result suggests systemic DS depletion in this disorder, and also proposes the usefulness of a urinary disaccharide compositional analysis of CS/DS chains as a non-invasive screening method for this disorder.

Hajdu-Cheney syndrome: a review.

Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by acroosteolysis, severe osteoporosis, short stature, specific craniofacial features, wormian bones, neurological symptoms, cardiovascular defects and polycystic kidneys. HCS is rare and is inherited as autosomal dominant although many sporadic cases have been reported. HCS is associated with mutations in exon 34 of NOTCH2 upstream the PEST domain that lead to the creation of a truncated and stable NOTCH2 protein with enhanced NOTCH2 signaling activity. Although the number of cases with NOTCH2 mutations reported are limited, it would seem that the diagnosis of HCS can be established by sequence analysis of exon 34 of NOTCH2. Notch receptors are single-pass transmembrane proteins that determine cell fate, and play a critical role in skeletal development and homeostasis. Dysregulation of Notch signaling is associated with skeletal developmental disorders. There is limited information about the mechanisms of the bone loss and acroosteolysis in HCS making decisions regarding therapeutic intervention difficult. Bone antiresorptive and anabolic agents have been tried to treat the osteoporosis, but their benefit has not been established. In conclusion, Notch regulates skeletal development and bone remodeling, and gain-of-function mutations of NOTCH2 are associated with HCS.

Beyond Gómez-López-Hernández syndrome: recurring phenotypic themes in rhombencephalosynapsis.

Rhombencephalosynapsis (RES) is an uncommon cerebellar malformation characterized by fusion of the hemispheres without an intervening vermis. Frequently described in association with Gómez-López-Hernández syndrome, RES also occurs in conjunction with VACTERL features and with holoprosencephaly (HPE). We sought to determine the full phenotypic spectrum of RES in a large cohort of patients. Information was obtained through database review, patient questionnaire, radiographic, and morphologic assessment, and statistical analysis. We assessed 53 patients. Thirty-three had alopecia, 3 had trigeminal anesthesia, 14 had VACTERL features, and 2 had HPE with aventriculy. Specific craniofacial features were seen throughout the cohort, but were more common in patients with alopecia. We noted substantial overlap between groups. We conclude that although some distinct subgroups can be delineated, the overlapping features seen in our cohort suggest an underlying spectrum of RES-associated malformations rather than a collection of discrete syndromes.

Can prenatal ultrasound detect the effects of in‐utero alcohol exposure? A pilot study

The aim of this pilot study was to explore possible ultrasound parameters for the early detection of alcohol-mediated fetal somatic and central nervous system (CNS) maldevelopment. Maternal alcohol ingestion during pregnancy may lead to fetal alcohol spectrum disorders (FASD), which encompass a broad range of structural abnormalities including growth impairment, specific craniofacial features and CNS abnormalities. Early detection of fetuses at risk of FASD would support earlier interventions. We performed a longitudinal prospective pilot study from 2004 to 2006 at two sites in Ukraine. A sample of pregnant women who reported consuming moderate-to-heavy amounts of alcohol participated in a comprehensive maternal interview, and received ultrasound evaluation of fetal growth and specific fetal brain measurements during the second and third trimesters. These measurements were compared with those collected from a group of pregnant women who consumed little-to-no alcohol during pregnancy, and who were recruited and followed in the same manner. From 6745 screened women, 84 moderate-to-heavy alcohol users and 82 comparison women were identified and ultrasound examinations performed. After controlling for maternal smoking, alcohol-exposed fetuses had shorter mean femur length, caval-calvarial distance and frontothalamic measurements in the second trimester (P < 0.05), and alcohol-exposed fetuses also had shorter frontothalamic distance measurements in the third trimester relative to comparison fetuses (P < 0.05). In addition, after controlling for maternal smoking, both mean orbital diameter and biparietal diameter measurements were significantly smaller on average in the alcohol-exposed group in the third trimester relative to comparison fetuses (P < 0.05). Significant differences in selected somatic and brain measurements were noted between alcohol-exposed and comparison fetuses, suggesting these markers may be further explored for clinical utility in prenatal identification of affected children. Further study correlating these findings with alcohol-related physical features of the newborn and subsequent comparisons of neuro-developmental outcomes will help define potential uses of prenatal ultrasound for intervention and prevention of FASD.

Submandible Angle in Nonobese Patients with Difficult Tracheal Intubation

Although functional immobility of craniofacial structures during direct laryngoscopy may cause difficult tracheal intubation (DTI), there may be an unfavorable specific craniofacial feature for successful tracheal intubation. The aim of this study was to identify the specific craniofacial features associated with DTI. Digital photographs of nonobese patients with DTI (23 males and 18 females) and age- and body mass index-matched patients with easy tracheal intubation (ETI) (16 males and 16 females) were taken and used for measurements of various craniofacial dimensions. Composite facial pictures of each patient group were constructed for visualization of differences of the craniofacial features. Mandible position angle was significantly smaller in DTI males than in male patients with ETI. Submandible angle was significantly larger in both male and female DTI patients than in patients with ETI. Logistic regression analysis revealed that the submandible angle was a significant and independent variable associated with DTI among the craniofacial dimensions for both sexes. The specific craniofacial features were visually more evident in the profile in than frontal composites. Increased submandible angle characterizes craniofacial features of patients with DTI.

Sotos syndrome common deletion is mediated by directly oriented subunits within inverted Sos-REP low-copy repeats

Sotos syndrome (Sos) is an overgrowth disorder also characterized clinically by mental retardation, specific craniofacial features and advanced bone age. As NSD1 haploinsufficiency was determined in 2002 to be the major cause of Sos, many intragenic mutations and chromosomal microdeletions involving the entire NSD1 gene have been described. In the Japanese population, half of the cases analyzed appear to have a common microdeletion; however, in the European population, deletion cases account for only 9%. Blast analysis of the Sos genomic region on 5q35 revealed two complex mosaic low-copy repeats (LCRs) that are centromeric and telomeric to NSD1. We termed these proximal Sos-REP (Sos-PREP, approximately 390 kb) and distal Sos-REP (Sos-DREP, approximately 429 kb), respectively. On the basis of the analysis of DNA sequence, we determined the size, structure, orientation and extent of sequence identity of these LCRs. We found that Sos-PREP and Sos-DREP are composed of six subunits termed A-F. Each of the homologous subunits, with the exception of one, is located in an inverted orientation and the order of subunits is different between the two Sos-REPs. Only the subunit C' in Sos-DREP is oriented directly with respect to the subunit C in Sos-PREP. These latter C' and C subunits are greater than 99% identical. Using pulsed-field gel electrophoresis analysis in eight Sos patients with a common deletion, we detected an approximately 550 kb junction fragment that we predicted according to the non-allelic homologous recombination (NAHR) mechanism using directly oriented Sos-PREP C and Sos-DREP C' subunits as substrates. This patient specific junction fragment was not present in 51 Japanese and non-Japanese controls. Subsequently, using long-range PCR with restriction enzyme digestion and DNA sequencing, we identified a 2.5 kb unequal crossover hotspot region in six out of nine analyzed Sos patients with the common deletion. Our data are consistent with an NAHR mechanism for generation of the Sos common deletion.