Fetal phenotype and diagnosis of autosomal dominant Robinow syndrome due to novel DVL1 variant.

Due to abnormal prenatal ultrasound findings of femoral shortening and flattened facial profile, a G2P0 pregnant patient underwent an amniocentesis at 15 weeks of gestation for proband-only exome sequencing. Bioinformatic filtering for genes included on the laboratory's extended skeletal dysplasia panel identified a heterozygous, likely pathogenic, frameshift variant in DVL1 NM_001330311.2:c.1575_1582dup; (p.Pro528ArgfsTer149). Pathogenic variants in DVL1 are associated with autosomal dominant Robinow syndrome (ADRS), a genetic disorder characterized by skeletal dysplasia with genital and craniofacial abnormalities. Prenatal ultrasound in the third trimester noted shortened long bones (first percentile for gestational age), macrocephaly with frontal bossing, short and upturned nose with a wide nasal root, triangular mouth, low pedal arches concerning for rocker-bottom feet, and ambiguous genitalia. A postnatal exam by Medical Genetics confirmed the prenatal findings in addition to hypertelorism, brachydactyly with broad thumbs and halluces, clinodactyly of second fingers, rigid gums with a frontal frenulum, and a sacral dimple. This case describes a novel variant in DVL1 identified in a fetus with prenatal and postnatal phenotypic features consistent with ADRS. To our knowledge, this is the first reported case of a prenatal molecular diagnosis of the dominant form of Robinow syndrome and the third case to describe prenatal ultrasound findings associated with this diagnosis.

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.

BACKGROUND: Frontonasal 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 PRESENTATION: A 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. CONCLUSION: The present case expands the wide phenotypic spectrum of prenatal FND patients. 3D ultrasound is a useful tool for detecting facial and limb deformities.

Postoperative Upper Airway Volume Measurements Among Children With Craniofacial Abnormalities.

OBJECTIVE: To measure postoperative airway volumes among patients with craniofacial abnormalities and compare them to normative values. STUDY DESIGN: Retrospective, comparative study. SETTING: Academic Medical Center. METHODS: Retrospective analysis of imaging of children with craniofacial abnormalities treated at NYU Langone Health from January 2013 to February 2021. Upper airway volumes postcraniofacial surgery were measured using 3D processing software (Dolphin 3D, version 11.95). These values were compared with published normative values. RESULTS: Twenty-one subjects were identified and compared to normative values. The postoperative oropharyngeal volumes were on average 43.7% smaller than the normative values (P < .001), and the total upper airway volumes were 31.6% smaller (P = .003). No significant differences were observed in the nasopharyngeal or hypopharyngeal volumes of the study cohort compared to the normative data. Among children ages 12 to 17 years (n = 13), the mean oropharyngeal volumes were 47.6% smaller than normal (P < .001), and the mean total upper airway volumes were 34.6% smaller than normal (P < .001). Among children ages 7 to 11 years (n = 8), the mean oropharyngeal volumes were 35.1% smaller than normal (P = .049), but no difference in mean total upper airway volume was observed. CONCLUSION: In children with craniofacial anomalies, postoperative airway volumes remain lower than normative values. However, even a slight increase in airway volume can yield a substantial increase in flow rate. 3D airway evaluations are a valuable tool for surgical planning and analysis and can help with optimizing airway dynamics.

Skeletal changes after midface surgery in patients with craniofacial deformities: a three-dimensional quantification method.

To determine the skeletal changes after midface surgery in patients with syndromic craniosynostosis who underwent Le Fort III (LFIII), monobloc (MB), or facial bipartition (FB). This was a retrospective study including 75 patients: 33 treated by LFIII, 29 by MB, and 13 by FB. Twenty-five had a diagnosis of Apert, 39 Crouzon, and 11 craniofrontonasal syndrome. A three-dimensional mesh was created from the preoperative scan and registered to the postoperative scan to visualise the advancement. LFIII at age 7-12 years effectuated a higher mean advancement in the maxillary (15.5 mm) and zygomatic (7.6 mm) regions when compared to ≥13 years (10.2 mm and 5.5 mm). After MB, mean advancement of the fronto-orbital region was higher at <7 years (16.4 mm), and similarly lower at ages 7-12 (13.8 mm) and ≥13 (12.5 mm). The mean preoperative inter-dacryon distance (34.4 ± 4.4 mm) was reduced by 8.7 ± 4.2 mm after FB without distraction (n = 10). More advancement was seen when midface surgery was performed at a younger age, due to more severe cases and a desire for overcorrection. The highest mean advancement was observed in the fronto-orbital region. Antero-inferior rotational movement was seen after all three techniques.

A Novel Classification System and Surgical Strategies of First Branchial Cleft Anomalies.

OBJECTIVE: To define a novel classification of first branchial cleft anomalies (FBCAs) based on the relationship between lesions and the facial nerve in terms of radiographic imaging findings and to introduce the corresponding surgical managements. METHODS: The clinical data were retrospectively reviewed. Novel classification was proposed according to the head-neck MRI findings and surgical records. FBCAs limited in the cartilaginous segment of external auditory canal (EAC) or superficial parotid gland capsule were classified as type A. Lesions close to the FN and(or) involved into the parotid gland with no scar formation and no previous parotidectomy were classified as type B. FBCAs adhered to the FN and(or) invaded the parotid gland with scar formation due to previous surgery were classified as type C. Appropriate surgery approaches was also described, which was correlated with classification. RESULTS: Fifty-one patients were included, and one patient suffered from bilateral lesions. Thirty-one, twelve, and nine lesions were classified as type A, type B, and type C FBCAs, respectively. One type A patient (1.92%) suffered from recurrence during follow-up. Temporary facial palsy (House-Brackmann II) was identified in 2 type C patients (3.85%) after surgery and recovered to normal within 2 months. One type B patient (1.92%) suffered from facial paralysis due to the FN injury and underwent facial nerve graft simultaneously. No patients with type C complained of hearing loss postoperatively. CONCLUSION: This novel classification clearly illustrates definitely relationship between lesion and the facial nerve and appropriate surgical strategies were proposed based on the novel classification. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:4246-4251, 2024.

Prenatal diagnosis of ROR-2 related Robinow syndrome presenting with fetal ultrasound findings of mesomelia, vertebral, digital and genital abnormalities.

Autosomal recessive ROR2-Robinow syndrome is caused by pathogenic variants in the ROR2 gene. Fetal ultrasound done on our patient at 24 + 3/7 weeks gestation showed macrocephaly, brachycephaly, flat face, prominent forehead, mild frontal bossing, lower thoracic hemivertebrae, digital abnormalities and micropenis. Fetal trio whole exome sequencing done on amniocytes showed two pathogenic compound heterozygous variants in the ROR2 gene, c.1324 C > T; p.(Arg442*) maternally inherited and c.1366dup; p.(Leu456Profs*3) apparently de novo. c.1324 C > T; p.(Arg442*) is a nonsense variant resulting in protein truncation reported to be associated with RRS3. c.1366dup; p.(Leu456Profs*3) is a frameshift variant predicted to result in protein truncation reported to segregate with the disease in multiple affected individuals from a single large family with distal symphalangism of the fourth finger. Fetal autopsy following pregnancy termination showed a large head with low-set ears, facial abnormalities, mesomelic bone shortening, hemivertebra, fused S3 and S4 vertebral bodies, several fused rib heads and short penis with buried shaft.

Proboscis Lateralis With Choanal Atresia.

The case of a female patient who was born with proboscis lateralis, choanal atresia, and telecanthus is submitted. A report is made on the initial management of this patient, the clinical follow-up that has been carried out so far, and a review of the literature is conducted, taking into account the limited information found in this specific pathology, in order to contribute to its diagnostic orientation and treatment from a plastic and craniofacial surgery point of view.

Craniofacial anomalies in a murine model of heterozygous fibroblast growth factor 10 gene mutation.

OBJECTIVE: Dysregulation of Fibroblast Growth Factor 10 (FGF10), a member of the family of Fibroblast Growth Factor (FGF) proteins, has been implicated in craniofacial and dental anomalies, including craniosynostosis, cleft palate, and Lacrimo-Auriculo-Dento-Digital Syndrome. The aim of this murine study was to assess the craniofacial and dental phenotypes associated with a heterozygous FGF10 gene (FGF10+/- ) mutation at skeletal maturity. METHODS: Skulls of 40 skeletally mature mice, comprising two genotypes (heterozygous FGF10+/- mutation, n = 22; wildtype, n = 18) and two sexes (male, n = 23; female, n = 17), were subjected to micro-computed tomography. Landmark-based linear dimensions were measured for the cranial vault, maxilla, mandible, and first molar teeth. Multivariate analysis of variance was performed to assess whether there were significant differences in the craniofacial and dental structures between genotypes and sexes. RESULTS: The craniomaxillary skeleton and the first molar teeth were smaller in the FGF10+/- mice (P < .05), but the mandible was unaffected. Sex did not have a significant effect on these structures (P > .05). Cranial sutural defects were noted in 5/22 (22.7%) mutant versus 2/18 (11.1%) wildtype mice, and cleft palate in only one (4.5%) mutant mouse. None of the mice displayed craniosynostosis, expansive bony lesions, bifid condyles, or impacted teeth. CONCLUSION: The FGF10+/- mutation was associated with craniomaxillary skeletal hypoplasia that probably arose from deficient (delayed) intramembranous ossification of the sutured bones. Overall, the skeletal and dental data suggest that the FGF10 gene plays an important role in the aetiology of craniofacial dysmorphology and malocclusion.

Prenatal Diagnosis of Gómez-López-Hernández Syndrome.

INTRODUCTION: Gómez-López-Hernández syndrome (GLHS), also known as cerebello-trigeminal-dermal dysplasia, is an extremely rare neurocutaneous disease, classically described by the triad of rhombencephalosynapsis (RES), bilateral focal alopecia, and trigeminal anesthesia. The clinical and radiographic spectrum of GLHS is now known to be broader, including craniofacial and supratentorial anomalies, as well as neurodevelopmental issues. CASE PRESENTATION: Here, we present a case of antenatally diagnosed GLHS with RES, hydrocephaly, and craniofacial anomalies identified on ultrasound (low-set ears with posterior rotation, hypertelorism, midface hypoplasia, micrognathia, and anteverted nares) which were confirmed by autopsy after termination of pregnancy at 23 weeks of gestation. DISCUSSION: As no known genetic causes have been identified and the classical triad is not applicable to prenatal imaging, prenatal diagnosis of GLHS is based on neuroimaging and the identification of supporting features. In presence of an RES associated with craniofacial abnormalities in prenatal (brachycephaly, turricephaly, low-set ears, midface retrusion, micrognathia), GLHS should be considered as "possible" according to postnatal criteria.

Coexistence of proboscis lateralis and multiple craniofacial, neurological, cardiac and spinal deformities: a one-of-a-kind case report.

BACKGROUND: Proboscis lateralis (PL) is an uncommon congenital facial deformity marked by the protrusion of a primitive tubular structure made up of skin and soft tissue that generally emerges from the eye's medial canthus and is associated with some craniofacial deformities. We report the first case of PL with multiple craniofacial, neurological, cardiac, and spinal anomalies. CASE PRESENTATION: A full-term female baby delivered by cesarean section cried immediately at birth. The mother reported having a normal pregnancy but has a history of x-ray during her first trimester. The baby was born with a rare presentation of proboscis lateralis which was accompanied by multiple anomalies, including but not limited to bilateral colpocephaly, corpus callosum agenesis, complex cyanotic congenital heart disease, and hemivertebra of the T10 body. CONCLUSION: PL is an uncommon congenital condition that causes a variety of craniofacial abnormalities. Multiple additional defects affecting various organ systems should also be evaluated in a person diagnosed with PL.

Congenital first branchial cleft anomalies in children: a study of 100 surgical cases and a review of the literature.

OBJECTIVE: To investigate the clinical features and surgical outcomes of pediatric congenital first branchial cleft anomalies (CFBCAs). METHODS: We conducted a retrospective analysis of 100 children who were referred to Shanghai Children's Hospital from March 2014 to March 2022 for the treatment of CFBCAs. RESULTS: This study included 100 patients (33 males, 67 females) with an average age of 4.0 ± 2.7 years. 64 cases were type I FBCAs and 36 were type II. The main clinical manifestations included having a skin pit or discharge from it (62%), painless masses (5%), mucopurulent otorrhea (8%) and recurrent swelling with pain (90%) in the Pochet's triangle area. 92% had infection histories, 84% had incision and drainage histories, and 18% had surgical histories. 6 cases of tympanic membranous attachment were found by auricular endoscopy. Ultrasonography (US) was 55.6% (30/54) accurate and enhanced CT was 75% (75/100) accurate in diagnosing CFBCAs. We dissected the facial nerve (FN) in 46% cases. Lesions ended in the external auditory canal (EAC) wall in 86 cases. 69 exhibited close relationship with the parotid. The patients were followed up 0.25-8.2 years. 11 had postoperative temporary facial paralysis and all improved within 6 months. 3 had recurrence and they were secondarily successfully retreated. No EAC stenosis were found. CONCLUSIONS: CFBCAs often presented with repeated swelling and purulence in Pochet's triangle. CT, US and auricular endoscopy can assist in diagnosis and planning the surgical strategy. Complete excision in non-infection stage as soon as possible is the first choice for the treatment of CFBCAs.

Imaging of Congenital Craniofacial Anomalies and Syndromes.

Craniofacial malformation is one of the most commonly encountered birth defects in the prenatal and postnatal periods. Higher-resolution and 3D antenatal ultrasonography and multidetector computed tomographic scan with 3D reformatted images have improved the definition of the soft tissue and bone structures of the craniofacial anatomy and its malformations. Early diagnosis of these conditions is important to make the clinical decisions and more so in understanding the possibility of malformation recurring in the next pregnancy, which is one of the major concerns for the parents and the treating physicians.

Measurements of craniofacial morphology using photogrammetry in children with sleep-disordered breathing.

OBJECTIVE: To assess the craniofacial morphology in children with sleep-disordered breathing (SDB) using nonradiation and readily accessible photogrammetry technique. METHODS: Included children aged 3-18 years with SDB-related symptoms from April 2019 to February 2020 in a tertiary center. All participants underwent craniofacial photogrammetry and overnight polysomnography (PSG). Participants were stratified into 2 groups (obstructive sleep apnea [OSA] group: apnea-hypopnea index [AHI] ≥ 1 and non-OSA group: AHI <1). Craniofacial photogrammetry was performed to derive variables of craniofacial features in standardized frontal and profile views. The 2 groups were propensity score matched based on age, sex, and body mass index (BMI) percentiles. Associations between craniofacial feature variables and OSA (AHI ≥1) likelihood were examined using logistic regression test. intraclass correlation coefficient (ICC) was used to evaluate the intrarater and interrater reliability. RESULTS: In total, 58 children were enrolled for the analysis after matching. All 3 variables representing the mandibular plane angle in the profile view were increased in the OSA group (mego-tn: 34.85 ± 5.99 vs 31.65 ± 5.96°, odds ratio [OR]: 1.10, 95% CI:1.02 to 1.18, P = .01; tn-gogn: 28.65 ± 6.38 vs 25.91 ± 5.38°, OR: 1.08, 95% CI:1.02 to 1.15, P = .012; and gome-tsup: 26.71 ± 6.13 vs 22.20 ± 5.89°, OR: 1.13, 95% CI:1.04 to 1.23, P = .003). CONCLUSIONS: Craniofacial photogrammetry revealed increased mandibular inclination in children with OSA. A steep mandibular plane with craniofacial photogrammetry is considered a potential predictor of pediatric OSA. Further investigation with a large sample size is required to clarify the validity of photogrammetry in evaluating pediatric OSA.

Intraoral scanning of neonates and infants with craniofacial disorders: feasibility, scanning duration, and clinical experience.

OBJECTIVE: The aim of this study was to evaluate intraoral scanning (IOS) in infants, neonates, and small children with craniofacial anomalies for its feasibility, scanning duration, and success rate. Impression taking in vulnerable patients can be potentially life-threatening, with the risk of airway obstruction and aspiration of impression material. The advantage of increasingly digitalized dentistry is demonstrated. MATERIALS AND METHODS: IOS was captured with the Trios 3® (3Shape, Copenhagen, Denmark) intraoral scanner. The underlying disorders were divided into cleft lip and palate (CLP), Trisomy 21 (T21), Robin Sequence (RS), Treacher Collins syndrome (TC), and isolated mandibular retrognathia (MR). Scan data were analysed by scanning duration, number of images, possible correlations of these factors with the different craniofacial disorders, patient age, and relationship between first and subsequent scans. Clinical experiences with the repeated digital impressions are described. RESULTS: Patient data of 141 scans in 83 patients were analysed within an 11-month period. Patients had a median age of 137 days. Median scanning duration was 138 seconds, resulting in a median of 352 images. There was a statistically significant difference in scanning duration (P = 0.001) between infants and neonates. IOS took longest in patients with CLP (537 seconds) and shortest in T21 patients (21 seconds), although there was no statistically significant difference between aetiologies. There was no statistically significant difference between first and subsequent scans in scanning duration. In four cases the IOS had to be repeated, and one patient ultimately required conventional impression taking (all CLP patients; success rate 94%). No severe adverse events occurred. CONCLUSION: IOS is a fast, safe, and feasible procedure for neonates, small children, and infants with craniofacial malformations. One special challenge for both technician and user was identified in patients with CLP, though implementing this new approach of digital impression taking was otherwise found to be highly successful in everyday clinical routine.

Síndrome de Gardner: informe de un caso y revisión de la literatura / Gardner syndrome: case report and literature review

El síndrome de Gardner es una enfermedad genética de herencia autosómica dominante, presenta múltiples manifestaciones craneofaciales caracterizadas por hipercrecimientos óseos conocidos como osteomas, riesgo de desarrollo de pólipos gastrointestinales con alto potencial de malignidad y de tumores o quistes en piel, así como alteraciones dentales, entre las que destacan la presencia de dientes supernumerarios, retenciones dentarias, permanencia de dientes deciduos y odontomas, estas últimas de gran importancia para el odontólogo. Se trata de una enfermedad que afecta a mujeres y hombres de forma indistinta, no obstante, su prevalencia es mayor en el sexo femenino. El objetivo del presente artículo es explicar las manifestaciones clínicas y radiográficas dentales y craneofaciales del síndrome de Gardner mediante la presentación de un caso clínico y revisión de la literatura (AU)

Gardner syndrome is a genetic disease of autosomal dominant inheritance, it presents multiple craniofacial manifestations characterized by bone overgrowths known as osteomas, risk of development of gastrointestinal polyps with high potencial of malignancy, and skin tumors or cysts, as well as dental alterations, among the characteristics of the presence of supernumerary teeth, dental retention, permanence of deciduous teeth and odontomas, the latter of great importance for the dentist. It is a disease that affects women and men indistinctly, however, its prevalence is higher in the female sex. The aim of this article is to explain the dental and craniofacial clinical and radiographic manifestations of Gardner syndrome by presenting a clinical case and a review of the literature (AU)

Twenty-year follow-up of the facial phenotype of Brazilian patients with Sotos syndrome.

Sotos syndrome is characterized by overgrowth starting before birth through childhood with intellectual disability and craniofacial anomalies. The majority of patients are large for gestational age with developmental delay or intellectual disability. The majority of cases are caused by pathogenic variants in NSD1. The most consistent physical features in this disorder are facial dysmorphisms including prominent forehead, downslanted palpebral fissures, prognathism with a pointed chin, and a long and narrow face. We present a follow-up to a cohort of 11 individuals found to harbor heterozygous, pathogenic, or likely pathogenic variants in NSD1. We analyzed the facial dysmorphisms and the condition using retrospective over 20 years. Among these patients, followed in our medical genetics outpatient clinic for variable periods of time, all had a phenotype compatible with the characteristic Sotos syndrome facial features, which evolved with time and became superimposed with natural aging modifications. We present here a long-term follow-up of facial features of Brazilian patients with molecularly confirmed Sotos syndrome. In this largest Brazilian cohort of molecularly confirmed patients with Sotos syndrome to date, we provide a careful description of the facial phenotype, which becomes less pronounced with aging and possibly more difficult to recognize in adults. These results may have broad clinical implications for diagnosis and add to the global clinical delineation of this condition.

Prenatal diagnosis of Baraitser - Winter syndrome using exome sequencing: Clinical report and review of literature.

Baraitser - Winter Cerebrofrontofacial Syndrome (BWCFF) is a rare disorder characterized by facial dysmorphism and mental retardation of varying grades. The clinical phenotype of BWCFF indicates variable phenotypic expression involving various congenital malformations such as cardiac, renal and musculoskeletal abnormalities. Nevertheless, the prenatal presentation of BWCFF is rarely described, making prenatal diagnosis challenging. This report describes a prenatal diagnosis of BWCFF syndrome to date; a case of a fetus with intrauterine growth restriction, increased nuchal fold, bilateral hydronerphosis, rocker bottom foot and clubfoot detected on Anomaly Scan is outlined. Molecular karyotype failed to detect any abnormality. Assessment with Next Generation Sequencing was then performed, revealing a heterozygous de novo mutation in ACTB gene setting the diagnosis of BWCFF.

Duplication of the Pituitary Gland (DPG)-Plus Syndrome Associated With Midline Anomalies and Precocious Puberty: A Case Report and Review of the Literature.

Duplication of the pituitary gland (DPG)-plus syndrome is a very rare developmental disorder with few cases described in the literature and characterized by multiple midline and central nervous system malformations. The hypothalamus and hypophysis involvement may be clinically associated with endocrine abnormalities. A 5.9-year-old female child was admitted to our Clinic for premature thelarche and acceleration of growth. DPG-plus syndrome with paired infundibula and pituitary glands was diagnosed after birth, when she appeared small for gestational age and she presented with lingual hypoplasia, cleft palate, right choanal stenosis, nasopharyngeal teratoma, and facial dysmorphisms. Neuroimaging revealed a duplication of the infundibula, the pituitary gland, and the dens of the epistropheus despite surgical removal of a rhino-pharyngeal mass performed at the age of two months. An array-CGH revealed a 2p12 deletion. At our evaluation, bone age assessment resulted advanced and initial pubertal activation was confirmed by Gonadotropin-Releasing Hormone stimulation test. Hormonal suppression treatment was started with satisfactory results. This case shows that DPG-plus syndrome must be considered in presence of midline and craniofacial malformations and endocrinological evaluations should be performed for the prompt and appropriate management of pubertal anomalies.