Craniofacial Dysmorphic Features Research Articles

Clinical and genetic spectrum of coloboma: A proposal for a comprehensive approach to pediatric patients

Purposeto analyze pediatric coloboma cases to (1) identify ophthalmological and systemic associations, (2) establish the variables with the highest probability of reaching a genetic diagnosis and worse visual prognosis and (3) propose a clinical and genetical assessment protocol. Design and methodsDescriptive, retrospective and single-center study. Patients under 18 years of age diagnosed with iris, chorio-retinal and/or optic disc coloboma under follow-up by a reference Pediatric Ophthalmology Unit have been selected from January 2012 to December 2022. A comprehensive data collection and analysis was performed to evaluate phenotype, molecular and prognosis correlations. ResultsA total of 214 patients with a mean age of 11.3 years (6.8 SD) were included (57% female). Among them, 50.9% presented with bilateral coloboma and 66.8% with other ophthalmological alterations (28.5% with microphthalmia). Systemic involvement was observed in 28%, being neurological dysfunction (24.8%) and craniofacial dysmorphic features (18.2%) the most frequent. Molecular diagnosis was reached in 19.2% and clinical exome sequencing had the highest diagnostic yield (22.2%). Bilaterality, macula involvement, short stature and neurological, craniofacial dysmorphic, cardiovascular, and renal anomalies were associated with reaching a genetic diagnosis (p < 0.05). Patients with craniofacial dysmorphic features, hearing, neurologic, cardiac abnormalities or short stature had a worse visual prognosis according with a multivariate model (p < 0.05). A diagnosis and follow-up protocol was developed. ConclusionIt is imperative to ascertain diagnostic and prognostic indicators in individuals with coloboma to facilitate genetic counseling, mitigate potential complications, and enhance the overall well-being of patients and their families

Prenatal Diagnosis of Fryns Syndrome through Identification of Two Novel Splice Variants in the PIGN Gene-A Case Series.

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.

Arthrogryposis is a descriptive term, not a specific disease entity: Escobar Syndrome is an example.

Children born with multiple congenital contractures have been almost always given the diagnosis of arthrogryposis multiplex congenita. Arthrogryposis is a descriptive term, not a specific disease entity. A heterogeneous group of conditions associated with multiple congenital joint contractures (mostly syndromic) should be considered. The records of seven children (four boys and three girls aged 6 months - 11 years) of different ethnic origins have been included in this study. The constellation of specific craniofacial dysmorphic features, spine malformation complex, and appendicular skeletal abnormalities in addition to camptodactyly, talipes equinovarus and rocker-bottom feet were a cluster of malformation complex encountered in our patients. Via comprehensive clinical and imaging study (3D reconstruction CT scan), definite diagnosis of Escobar Syndrome has been approached. The clinical and imaging phenotype was the key factor towards etiological understanding, treatment and genotype confirmation. We identified compound heterozygous mutations (c.459dupA [p.Val154Serfs*24] and c.794T>G [p.Leu265Serfs*24] of the CHRNG gene in four patients. Bilateral flexion contractures of the knees have been treated by using Iliazarov external fixator. Simultaneous corrections of scoliosis have been achieved by applying either dual traditional growing rods or single growing rods. The clinical and radiological phenotypic characterizations are the fundamental tool in differentiating Escobar from other forms of multiple contractures. The aim of this study are three folds, firstly to demonstrate the importance of detecting the etiological understanding in children presented with multiple contractures, secondly to refute the general conception among the vast majority of pediatricians and orthopedic surgeons that arthrogryposis multiplex is a diagnostic entity. And thirdly, we were able to detect severe spine deformity via 3D reconstruction CT scan, namely unsegmented posterior spinal bar.

Clinical Genetics Assessment Triangle (CGAT): A simple tool to identify patients with genetic conditions

ObjectiveThe objective of this study was to develop a simple tool for general physicians to promptly identify and refer pediatric patients with a higher probability of having a genetic condition. Study designThis retrospective, descriptive study was conducted at a tertiary pediatric hospital's Clinical Genetics Unit from June 2019 to January 2020. We included patients under 18 years of age who visited the unit, excluding those without genetic testing. Epidemiological, clinical, and genetic variables were collected from electronic medical records. The primary outcome was the diagnosis of a genetic condition based on genetic testing. ResultsAmong 445 patients, 304 were included; 163 (53.6%) were male, and mean age was 7.4 years (SD 5.1 years). A genetic condition was diagnosed in 139 patients (45.7%). Using a multiple logistic regression model, five variables significantly contributed to reaching a diagnosis: suspected diagnosis at referral (OR 3.45, P < 0.001), short stature (OR 3.11, P < 0.001), global developmental delay/intellectual disability (OR 2.65, P < 0.001), dysmorphic craniofacial features (OR 1.99, P = 0.035), and multiple congenital anomalies (OR 2.54, P = 0.033). The association strength (OR) increased when these variables were paired with each other. The study's findings are presented in the form of a triangle, known as the Clinical Genetics Assessment Triangle (CGAT), which summarizes the results. A decision tree model is applied to guide clinical department referrals based on the affected sides of the triangle. ConclusionsThe CGAT has the potential to enable general physicians to promptly identify pediatric patients with an increased probability of having a genetic condition.

Dietary soy prevents fetal demise, intrauterine growth restriction, craniofacial dysmorphic features, and impairments in placentation linked to gestational alcohol exposure: Pivotal role of insulin and insulin-like growth factor signaling networks.

Prenatal alcohol exposure can impair placentation and cause intrauterine growth restriction (IUGR), fetal demise, and fetal alcohol spectrum disorder (FASD). Previous studies showed that ethanol's inhibition of placental insulin and insulin-like growth factor, type 1 (IGF-1) signaling compromises trophoblastic cell motility and maternal vascular transformation at the implantation site. Since soy isolate supports insulin responsiveness, we hypothesized that dietary soy could be used to normalize placentation and fetal growth in an experimental model of FASD. Pregnant Long-Evans rat dams were fed with isocaloric liquid diets containing 0% or 8.2% ethanol (v/v) from gestation day (GD) 6. Dietary protein sources were either 100% soy isolate or 100% casein (standard). Gestational sacs were harvested on GD19 to evaluate fetal resorption, fetal growth parameters, and placental morphology. Placental insulin/IGF-1 signaling through Akt pathways was assessed using commercial bead-based multiplex enzyme-linked immunosorbent assays. Dietary soy markedly reduced or prevented the ethanol-associated fetal loss, IUGR, FASD dysmorphic features, and impairments in placentation/maturation. Furthermore, ethanol's inhibitory effects on the placental glycogen cell population at the junctional zone, invasive trophoblast populations at the implantation site, maternal vascular transformation, and signaling through the insulin and IGF1 receptors, Akt and PRAS40 were largely abrogated by co-administration of soy. Dietary soy may provide an economically feasible and accessible means of reducing adverse pregnancy outcomes linked to gestational ethanol exposure.

"A Rare Presentation of Multiple Eruptive Melanocytic Nevi in a Pediatric Patient with Cardiofaciocutaneous Syndrome Type 4"

Cardiofaciocutaneous syndrome (CFC) type 4 is a rare, phenotypically diverse, autosomal dominant, multiple congenital anomaly disorder, that is characterized by a distinctive set of dysmorphic craniofacial features, congenital heart disease, and cutaneous abnormalities.

FREM2-related Fraser syndrome with popliteal pterygium and structural central nervous system anomalies

Fraser syndrome (FS) is a rare multiple malformation disorder characterized by cryptophthalmos, characteristic craniofacial dysmorphism, cutaneous syndactyly, malformations of the respiratory and urinary tract, and anogenital anomalies. Although the characteristic presentation of FS can be detected prenatally, oligohydramnios often challenges the clinical diagnosis. Here we report on the atypical prenatal and postmortem findings of a fetus with FS caused by a novel homozygous frameshift variant in FREM2. Our study highlights the variable manifestations of the FS and expands the clinical spectrum to include popliteal pterygium and structural central nervous system anomalies.

Dysmorphic craniofacial features in tetralogy of fallot: a case report

Tetralogy of Fallot is characterised by tetrad of pulmonary stenosis, ventricular septal defect, overriding aorta and right ventricular hypertrophy. This case report addresses an array of craniofacial anomalies associated with an operated case of Tetralogy of Fallot.

Distinctive Skeletal Phenotype in Patients with Kniest Dysplasia

Background: A group of children presented with diverse forms of spine and joint pathologies in correlation with heritable bone disorders. Patients and Methods: Five children aged from 9 -13 years, presented with a constellation of growth retardation, craniofacial dysmorphic features, axial (scoliotic short and barrel chested with marked diminution of spine biomechanics) and painful enlarged joints and sometimes with the propensity to develop mal-alignment (knock knees). We included a 38-years-old-lady, a mother of an affected boy because of her long term history of joint pain and intractable tinnitus. Clinical and radiographic phenotypic characterizations were the first line tools applied. Results: The clinical and radiographic phenotypes of all five children were consistent with the diagnosis of Kniest dysplasia. Strikingly, the reason behind the tinnitus in the short statured 38-years-old- lady was due to congenital hypoplasia of the posterior arch of the atlas (the hypoplastic posterior arch of the atlas was in connection with the developmental failure of chondrogenesis). Two children underwent the genetic testing and showed a genetic defect of encoding type II collagen (COL2A1). Conclusion: Sadly speaking, soon after birth the vast majority of children born with skeletal dysplasia received the misdiagnosis of achondroplasia by their pediatricians and geneticists. In practice, a misdiagnosis can lead to hazardous repercussions for the affected children and their families. Correctly interpreting the clinical and the radiological phenotypes and relating them to etiologies is an essential basis for the proper management. In the field of hereditary bone disorders, the existence of mild and moderate forms of the same disease within other family subjects is a well-known fact (as seen in a 38-years-old- short statured- lady, a mother of an affected boy with Kniest dysplsia). To counter the overlooked maldevelopment of the atlanto-axial effectively, we need to delineate the disrupted anatomical structures of the craniocervical junction as early as possible. It is important to understand that many of these diseases are so mysterious and daunting that they frighten even some practitioners. Therefore, educating physicians is a priority.

2q37 deletion syndrome in a Colombian patient with macrocephaly: a case report

Background2q37 deletion syndrome is a rare autosomal dominant disorder caused by deletions in the 2q37 cytobands leading to developmental delay, intellectual disability, behavioral abnormalities and dysmorphic craniofacial features with more than 115 patients described worldwide.Case presentationWe describe a Colombian 3-year-old patient with verbal communication delay, umbilical hernia, facial dysmorphic features, hypotonia, and macrocephaly with normal magnetic resonance imaging. Microarray-based comparative genomic hybridization revealed a 5.9 Mb deletion in the 2q37.2 and 2q37.3 regions, eliminating 60 protein-coding genes in one of her chromosomes 2 and allowing the diagnosis of 2q37 deletion syndrome in this patient. Therapeutic interventions so far were the surgical correction of the umbilical hernia.ConclusionsGenetic tests are important tools for the diagnosis of clinically complex and infrequent conditions but also for timely diagnosis that allows appropriate surveillance, interventions, and genetic counseling. This case also provides information for expanding the phenotypical and genetic characterization of 2q37 deletion syndrome.

Birk-Barel Intellectual Disability Dimorphism and KCNK9 Imprinting Syndrome: Craniofacial Surgery Considerations for an Exceedingly Rare Syndrome.

Birk-Barel intellectual disability dimorphism syndrome, also referred to as KCNK9 imprinting syndrome, is an exceedingly rare condition described in under 20 cases that presents with intellectual disability, hypotonia, scoliosis, dysphonia, dysphagia, and craniofacial dysmorphic features. The condition follows an autosomal dominant pattern of inheritance in the maternally expressed KCNK9 gene on chromosome 8. Due to the complexity of presentation, patients with Birk-Barel syndrome are optimally managed by a multidisciplinary team including a craniofacial surgeon. Previously described craniofacial dysmorphic features include micrognathia, cleft palate, dolichocephaly, broad nasal tip, and broad philtrum, among others. Here the authors describe a genetically confirmed case that has been managed in our institution's multidisciplinary cleft and craniofacial clinic. The authors aim to discuss Birk-Barel syndrome for a surgical and craniofacial audience with considerations for operative management in the context of a multidisciplinary team.

Damaging novel mutations in PIGN cause developmental epileptic-dyskinetic encephalopathy: a case report

BackgroundMutations in PIGN, resulting in a glycosylphosphatidylinositol (GPI) anchor deficiency, typically leads to multiple congenital anomalies-hypotonia-seizures syndrome. However, the link between PIGN and epilepsy or paroxysmal non-kinesigenic dyskinesia (PNKD) is not well-described. This study reported a patient with PIGN mutation leading to developmental and epileptic encephalopathy and PNKD, to expand upon the genotype–phenotype correlation of PIGN.Case presentationDuring the first 10 days of life, a girl exhibited paroxysmal staring episodes with durations that ranged from several minutes to hours. These episodes occurred 2–5 times daily and always occurred during wakefulness. Ictal electroencephalography revealed no abnormalities, and PNKD was diagnosed. The patient also exhibited severely delayed psychomotor development and generalized seizures at the age of 4 months. Results of brain magnetic resonance imaging and metabolic screenings were normal, but trio-based whole-exome sequencing identified two novel compound heterozygous PIGN mutations (NM_176787; c.163C > T [p.R55 > X] and c.283C > T [p.R95W]). Flow cytometry analysis of the patient’s granulocytes revealed dramatically reduced expression of GPI-anchored proteins. This indicated that the mutations compromised GPI functions. The patient got seizure-free for 1 year, and her dyskinesia episodes reduced significantly (1–2 times/month) after treatment with levetiracetam (600 mg/day) and clonazepam (1.5 mg/day). No progress was observed with respect to psychomotor development; however, no craniofacial dysmorphic features, cleft lip/palate, brachytelephalangy with nail hypoplasia, and internal malformations have been observed until now (6 years of age).ConclusionThis is the first study to document developmental and epileptic encephalopathy with PNKD in a human with PIGN mutations. This report expanded our understanding of the genotype–phenotype correlation of PIGN, and PIGN may be considered a potentially relevant gene when investigating cases of epilepsy or PNKD.

Синдром Рубінштейна-Тейбі в неонатальній практиці (випадок із практики)

The article presents data on a rare genetic disease - Rubinstein-Taybi syndrome. The disease incidence is 1: 25000-1: 30000. Parents’ lifestyle has no influence on the birth of a child with Rubinstein-Taybi syndrome. The risk of having a second child with the same pathology is 0.1%. The syndrome is characterized by the presence of deformed digits, distinctive facial features and mental retardation. Clinical signs of the disease occur as a result of mutation in the gene encoding a specific GreB protein. This gene is localized on the chromosome 16. The article reports on the main phenotypic deviations and analyzes the literature data on somatic and neurological pathologies. The syndrome is characterized by a combination of delayed physical and psychomotor development, progressive intellectual disability, characteristic craniofacial dysmorphism, deformity of digits (namely broad, short and wide distal phalanges of the thumbs and big toes, sometimes distal phalanges of other fingers and toes), abnormalities of the cardiovascular, respiratory and urogenital systems. The article presents primary data on the diagnosis of Rubinstein-Taybi syndrome in a child of neonatal age. The boy’s parents, young people, and the newborn’s sister, aged 3, are healthy. No phenotypic manifestations of skeletal dysplasia were detected. The relatives’ hereditary history is negative. We have observed the following facial dysmorphia: low forehead, low hair growth line, high-arched eyebrows, moon-shaped face, hypertelorism, downward slanted eyes, «beaked» nose, hypoplastic nasal wings, moderate retrognathia, high narrow palate, dysplastic, small, low-lying auricles. Broad terminal phalanges of thumbs and big toes, as well as valgus deformity of the thumbs were observed. The child was diagnosed with an open aortic duct and congenital choanal atresia on the right. Thus, a severe disabling pathology in a child born to apparently healthy parents indicates a sporadic de novo mutation. The research was carried out in accordance with the principles of the Helsinki declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors. Key words: Rubinstein-Taybi syndrome, craniofacial abnormalities, digit abnormalities, newborns.

EP080: A rare case of mosaic trisomy 15 with chylothorax

eP080: A rare case of mosaic trisomy 15 with chylothorax

Preterm Infant with Craniofacial Dysmorphic Features and Posture.

Preterm Infant with Craniofacial Dysmorphic Features and Posture.

14. Deletions resulting in Brachydactyly Mental Retardation Syndrome (BDMR): Multiple contributing regions in distal 2q37

Brachydactyly mental retardation syndrome (BDMR), due to distal 2q37 deletions, is characterized by a variable phenotype that most often includes DD/ID, autism, behavioral issues, brachydactyly type E, obesity, microcephaly and other dysmorphic craniofacial features. Affected individuals typically have large deletions (>2 to 9 Mb) that include the HDAC4 gene. Haploinsufficiency of HDAC4 is proposed as the primary genetic cause of BDMR-associated phenotypes, with potential incomplete penetrance (Williams et al., 2010; Le et al., 2019; Wheeler et al., 2014).

Dietary Soy Prevents Fetal Demise, Intrauterine Growth Restriction, Craniofacial Dysmorphic Features, and Impairments in Placentation Linked to Gestational Alcohol Exposure Pivotal Role of Insulin and Insulin-Like Growth Factor Signaling Networks

Dietary Soy Prevents Fetal Demise, Intrauterine Growth Restriction, Craniofacial Dysmorphic Features, and Impairments in Placentation Linked to Gestational Alcohol Exposure Pivotal Role of Insulin and Insulin-Like Growth Factor Signaling Networks

Case report : a novel ASXL3 gene variant in a Sudanese boy

BackgroundBainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, moderate to severe intellectual disability, poor or absent speech, feeding difficulties, growth failure, dysmorphic craniofacial features and minor skeletal features. The aim of this study was to investigate the genetic etiology of a Sudanese boy with severe developmental delay, intellectual disability, and craniofacial phenotype using trio-based whole-exome sequencing. To our knowledge, no patients with ASXL3 gene variant c.3043C>T have been reported detailedly in literature.Case presentationThe patient (male, 3 years 6 months) was the first born of a healthy non-consanguineous couple originating from Sudan, treated for “psychomotor retardation” for more than 8 months in Yiwu. The patient exhibited severely delayed milestones in physiological and intellectual developmental stages, language impairment, poor eye-contact, lack of subtle motions of fingers, fear of claustrophobic space, hypotonia, clinodactyly, autistic features. Peripheral blood samples were collected from the patient and his parents. Trio-based whole-exome sequencing(Trio-WES) identified a de novo heterozygous ASXL3 gene variant c.3043C>T;p.Q1015X. Sanger sequencing verified variants of this family.ConclusionTrio-WES analysis identified a de novo nonsense variant (c.3043C>T) of ASXL3 gene in a Sudanese boy. To our knowledge, the patient with this variant has not been reported previously in literature. This study presents a new case for ASXL3 gene variants, which expanded the mutational and phenotypic spectrum.

A human importin-β-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8

Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-β protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-β signaling components such as SMAD1-4 have been suggested to be among them. Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm (TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes. Seven individuals from six unrelated families showed a consistent phenotype with early-onset TAA, motor developmental delay, connective tissue findings, and craniofacial dysmorphic features. A C57BL/6N Ipo8 knockout mouse model recapitulates TAA development from 8-12weeks onward in both sexes but most prominently shows ascending aorta dilatation with a propensity for dissection in males. Compliance assays suggest augmented passive stiffness of the ascending aorta in male Ipo8-/- mice throughout life. Immunohistological investigation of mutant aortic walls reveals elastic fiber disorganization and fragmentation along with a signature of increased TGF-β signaling, as evidenced by nuclear pSmad2 accumulation. RT-qPCR assays of the aortic wall in male Ipo8-/- mice demonstrate decreased Smad6/7 and increased Mmp2 and Ccn2 (Ctgf) expression, reinforcing a role for dysregulation of the TGF-β signaling pathway in TAA development. Because importin 8 is the most downstream TGF-β-related effector implicated in TAA pathogenesis so far, it offers opportunities for future mechanistic studies and represents a candidate drug target for TAA.

De novo variants in TCF7L2 are associated with a syndromic neurodevelopmental disorder.

TCF7L2 encodes transcription factor 7-like 2 (OMIM 602228), a key mediator of the evolutionary conserved canonical Wnt signaling pathway. Although several large-scale sequencing studies have implicated TCF7L2 in intellectual disability and autism, both the genetic mechanism and clinical phenotype have remained incompletely characterized. We present here a comprehensive genetic and phenotypic description of 11 individuals who have been identified to carry de novo variants in TCF7L2, both truncating and missense. Missense variation is clustered in or near a high mobility group box domain, involving this region in these variants' pathogenicity. All affected individuals present with developmental delays in childhood, but most ultimately achieved normal intelligence or had only mild intellectual disability. Myopia was present in approximately half of the individuals, and some individuals also possessed dysmorphic craniofacial features, orthopedic abnormalities, or neuropsychiatric comorbidities including autism and attention-deficit/hyperactivity disorder (ADHD). We thus present an initial clinical and genotypic spectrum associated with variation in TCF7L2, which will be important in informing both medical management and future research.