Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature.

Schinzel-Giedion syndrome (SGS) is a severe multisystem disorder characterized by distinctive facial features, profound intellectual disability, refractory epilepsy, cortical visual impairment, hearing loss, and various congenital anomalies. SGS is attributed to gain-of-function (GoF) variants in the SETBP1 gene, with reported variants causing canonical SGS located within a 12 bp hotspot region encoding SETBP1 residues aa868-871 (degron). Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron. The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS. This is the first report of a typical SGS caused by a, SETBP1 non-degron missense variant. This case expands the genetic spectrum of SGS and provides new insights into genotype-phenotype correlations.

Deep learning technique to detect craniofacial anatomical abnormalities concentrated on middle and anterior of face in patients with sleep apnea.

OBJECTIVES: The aim of this study is to propose a deep learning-based model using craniofacial photographs for automatic obstructive sleep apnea (OSA) detection and to perform design explainability tests to investigate important craniofacial regions as well as the reliability of the method. METHODS: Five hundred and thirty participants with suspected OSA are subjected to polysomnography. Front and profile craniofacial photographs are captured and randomly segregated into training, validation, and test sets for model development and evaluation. Photographic occlusion tests and visual observations are performed to determine regions at risk of OSA. The number of positive regions in each participant is identified and their associations with OSA is assessed. RESULTS: The model using craniofacial photographs alone yields an accuracy of 0.884 and an area under the receiver operating characteristic curve of 0.881 (95% confidence interval, 0.839-0.922). Using the cutoff point with the maximum sum of sensitivity and specificity, the model exhibits a sensitivity of 0.905 and a specificity of 0.941. The bilateral eyes, nose, mouth and chin, pre-auricular area, and ears contribute the most to disease detection. When photographs that increase the weights of these regions are used, the performance of the model improved. Additionally, different severities of OSA become more prevalent as the number of positive craniofacial regions increases. CONCLUSIONS: The results suggest that the deep learning-based model can extract meaningful features that are primarily concentrated in the middle and anterior regions of the face.

Characterization of craniofacial-based clinical phenotypes in children with suspected obstructive sleep apnea.

STUDY OBJECTIVES: We conducted this study to identify phenotypes of obstructive sleep apnea (OSA) in children based on lifestyle, sleep habits, age, obesity, sex, soft tissue facial features, and specific craniofacial abnormalities. METHODS: Seventy-three children with symptoms of pediatric OSA who underwent overnight observed polysomnography participated in this study. Soft tissue facial features were assessed using a 3-dimensional stereophotogrammetric system. Craniofacial abnormalities were evaluated based on the most common facial features associated with orthodontic treatment needs. Data regarding lifestyle, sleep habits, age, obesity, and sex were also collected. To identify phenotypes of OSA, a sequential analysis was then performed on categories of variables using fuzzy clustering with medoids. RESULTS: Craniofacial abnormalities and soft tissue facial features defined clusters. Three clusters were identified. Cluster 1 comprised a group of younger children (5.9 ± 3.8 years) without obesity, without craniofacial abnormalities, and with smaller soft tissue facial features dimensions. Cluster 2 comprised a group of older children (9.6 ± 3.9 years) without obesity and with larger mandibular dimensions and mildly arched palates (71.4%). Cluster 3 comprised a group of older children (9.2 ± 3.9 years) with obesity and a history of health issues (68.4%), excessive lower facial height (63.2%), and midface deficiency (73.7%). No differences were observed across clusters regarding sleep features. A moderate severity of obstructive and mixed respiratory events was observed in all 3 clusters. CONCLUSIONS: The study results did not identify distinct phenotypes of pediatric OSA based on soft tissue facial features or craniofacial abnormalities alone. Age and body mass index likely modify the effect of soft tissue facial features and craniofacial abnormalities as risk factors for OSA in children. CITATION: Fernandes Fagundes NC, Loliencar P, MacLean JE, Flores-Mir C, Heo G. Characterization of craniofacial-based clinical phenotypes in children with suspected obstructive sleep apnea. J Clin Sleep Med. 2023;19(11):1857-1865.

Isolated Agnathia-Otocephaly Complex Diagnosed Prenatally for Ex-Utero Intrapartum Treatment: A Case Report.

BACKGROUND Agnathia-otocephaly complex (AOC) is a rare congenital malformation due to a first-branch arch disorder and has been considered lethal. However, milder variants of the isolated type of AOC have been reported as nonlethal. The ex-utero intrapartum treatment (EXIT) procedure is basically indicated for a fetus with a high risk of airway obstruction immediately after birth; it is not indicated for all AOC cases but is chosen to treat cases until the airway can be evaluated to achieve a better prognosis. CASE REPORT A 37-year-old woman was referred with reported fetal facial deformity and polyhydramnios at 27 weeks of gestation. Our fetal ultrasound scans showed agnathia, microstomia, and synotia, but not holoprosencephaly. Isolated AOC was diagnosed prenatally. Magnetic resonance imaging and microbubble tests revealed delayed fetal lung maturation, although it was not completely unmatured. With patient agreement, an emergency cesarean section with EXIT was performed because of clinical chorioamnionitis at 35 weeks of gestation. Tracheostomy was attempted for 16 min during EXIT and was completed 4 min after delivery. Despite this, the neonate died 12 h after delivery from severe respiratory failure and a tension pneumothorax caused by a hypoplastic lung. CONCLUSIONS There is controversy surrounding the non-lethality of all isolated AOC cases and the non-contraindication of EXIT procedures. Our case was estimated as the milder variant, and the EXIT procedure was indicated; however, the neonate died of the hypoplastic lung. The evaluation methods of lung maturation are inconsistent, and the indication of the invasive EXIT procedure must be carefully considered.

Complex cerebrovascular diseases in Roberts syndrome caused by novel biallelic ESCO2 variations.

OBJECTIVE: Roberts syndrome (RBS), also known as Roberts-SC phocomelia syndrome, is a rare autosomal recessive developmental disorder caused by mutations in the ESCO2 gene. Cardinal clinical manifestations are pre- and postnatal growth retardation and craniofacial and limb malformations. Here, we report RBS in a Chinese adolescent with novel biallelic ESCO2 variations and complex cerebrovascular diseases. METHODS: Medical history, neurological examinations, neuroimaging, and pathology were collected in the proband and the family. Whole exome sequencing (WES) with copy number variation analysis was performed to screen for genetic variations. RESULTS: The clinical features of the proband were craniofacial and limb malformations together with complex cerebrovascular diseases. She suffered ischemic stroke at 6 years old and died of cerebellar hemorrhage secondary to an aneurysm at 13 years old. Besides, neuroimaging showed the triad of leukoencephalopathy, calcifications, and cysts. Brain histopathology revealed angiomatous changes and perivascular cysts suggesting chronic small cerebral vasculopathy. Whole exome sequencing (WES) identified novel biallelic variations in the ESCO2 gene (c.1220A>T, p.H407L and c.1562delC, p.A521fs). CONCLUSIONS: We describe complex cerebrovascular diseases in Roberts syndrome caused by novel ESCO2 biallelic variations. This case expands not only the cerebral involvement in Roberts syndrome but also the disease spectrum of the neuroimaging triad with leukoencephalopathy, calcifications, and cysts.

Association Between the Clivus Slope and Patient-Reported Japanese Orthopaedic Association (PRO-JOA) Scores in Patients with Basilar Invagination: A Retrospective Study.

AIM: To determine a quantitative relationship between the postoperative clivus slope (CS) and the change in the Patient-Reported Japanese Orthopaedic Association (PRO-JOA) scores following reduction surgery of the basilar invagination (BI). MATERIAL AND METHODS: A single center retrospective study was conducted. Patients who met the inclusion and exclusion criteria at our hospital during the period from August 2015 to August 2020 were identified. The CS was introduced. Radiographic parameters including the CS were measured to assess realignment preoperatively and postoperatively. The PRO-JOA score was recorded to reveal the clinical outcome. The PRO-JOA score and the radiographic parameters that included the CS were compared between postoperative BI patients. RESULTS: Ninety-four patients with BI were included in the study. The CS (0.96, 0.93-1.00) was inversely correlated with the PROJOA score. The CS was negatively associated with the ΔPRO-JOA score in the crude model, while no significant associations in the fully adjusted model, although in the case of the latter, a slight trend was found (p for trend < < 0.05). In the non-linear model, the CS was negatively associated with the ΔPRO-JOA score in patients diagnosed with BI, unless the CS exceeded 63.4°. CONCLUSION: A reduction in the CS affects the postoperative PRO-JOA score of BI patients. This relationship can be employed as a quantitative reference in determining preoperative design with respect to the intraoperative correction needed to reduce craniovertebral junction deformity in BI.

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.

A very rare syndrome and its rare urological complication: Incomplet bladder duplication in Robinow syndrome.

OBJECTIVES: Robinow syndrome is a very rare syndrome characterized by short stature, extremity deformities, costovertebral abnormalities, renal/external genital malformations, and fetal facial appearance. It might be inherited by either autosomal dominant or severe recessive form. Diagnosis is generally established by the aid of genetic mutation and phenotypic findings. The urogenital component of the disease frequently presents with microgenitalia such as micropenis and/or cryptorchidism. METHODS: Herein, a four-year-old boy with Robinow syndrome accompanied by incomplete bladder duplication is discussed. RESULTS: The duplication in the bladder was screened by cystoscopy and corrective surgery was performed. CONCLUSIONS: This rare manifestation is the first for urological findings of Robinow syndrome in literature.

Gómez-López-Hernández syndrome: a case report on pediatric neurotrophic corneal ulcers and review of the literature.

We present a case of Gómez-López-Hernández syndrome (GLHS), a rare neurocutaneous syndrome, in a 10-month-old girl with neurotrophic keratopathy secondary to trigeminal anesthesia.

Kleefstra syndrome: Recurrence in siblings due to a paternal mosaic mutation.

Kleefstra syndrome (KS) is a rare autosomic dominant genetic disorder caused by euchromatic histone methyltransferase 1 (EHMT1) alterations. Patients mainly present with moderate to severe intellectual disability, a severe delay in/or absence of speech, autism spectrum disorder, childhood hypotonia, neuropsychiatric anomalies, and distinctive dysmorphic features. Here, we report the cases of a male and a female, two younger siblings of three, with asymptomatic parents. An EHMT1 new mutation was identified. Both presented with a typical core phenotype. Some specific features were noted, such as macrocephaly (previously reported) and enuresis (not yet described). Parental analysis identified the mutation in the mosaic state in the father. Reverse phenotyping enabled us to highlight the pauci phenotype features of inguinal hernia, azoospermia, and possible behavioral disorders. This allowed us to adapt his follow-up and genetic counseling for the family. Our three reported cases provide a new description of KS with an intragenic EHMT1 mutation, whereas in the literature most reported cases have EHMT1 deletions. Moreover, in the areas of next-generation sequencing and trio techniques with parental segregation, it is important to remain cautious about disregarding variants based on an autosomal recessive hypothesis.

Just Breathe: Tips and Highlights for Managing Pediatric Respiratory Distress and Failure.

Anatomically, the airway is ever changing in size, anteroposterior alignment, and point of most narrow dimension. Special considerations regarding obesity, chronic and acute illness, underlying developmental abnormalities, and age can all affect preparation and intervention toward securing a definitive airway. Mechanical ventilation strategies should focus on limiting peak inspiratory pressures and optimizing lung protective tidal volumes. Emergency physicians should work toward minimizing risk of peri-intubation hypoxemia and arrest. With review of anatomic and physiologic principles in the setting of a practical approach toward evaluating and managing distress and failure, emergency physicians can successfully manage critical pediatric airway encounters.

First episode of psychosis in Kleefstra syndrome: a case report.

Kleefstra syndrome (KS) is a genetic syndrome caused by a haploinsufficiency of the EHMT1 gene and characterized by intellectual disability, language disorders, childhood hypotonia and distinct facial features. Only a few cases of first episode of psychosis in KS have already been reported. We describe a young female patient with KS who presented a first episode of psychosis. In a context of an initial diagnosis wavering and a lack of recommendations, this clinical observation illustrates the importance of psychiatric comorbidities and their diagnostic and therapeutic complexity in KS; with a need for multidisciplinary management considering its specific aspects and vulnerabilities.

Craniofrontonasal dysplasia: hypertelorism correction in late presenting patients.

BACKGROUND: Craniofrontonasal dysplasia (CFND) is a rare congenital craniofacial syndrome characterized by single suture synostosis, hypertelorism, other clinical facial features, and abnormalities in the upper extremities. There are only a few studies in the applicable literature that address hypertelorism management for CFND patients and outcomes and complication rates. METHODS: A retrospective study was performed on consecutive late presenting CFND patients referred to our hospital with substantially completed craniofacial skeleton growth, who underwent hypertelorism correction between 2007 and 2019 following intracranial pressure screening, and who received at least 1 year of follow-up care. None of the patients in this study underwent prior craniofacial surgery. Only those patients with a confirmed mutation of the EFNB1 gene were included in this study. All patients in this study underwent hypertelorism correction by facial bipartition or box osteotomy. RESULTS: A total of ten late presenting CFND patients (all female) were treated at our hospital during the study period. None of the patients presented signs of elevated intracranial pressure. The average patient age at hypertelorism correction was 13.4 ± 7.68 years of age. Major complications, defined as complications requiring a return to the operating room, were limited to infection of the frontal bone, which required partial bone removal, and cerebrospinal fluid (CSF) leak, which was completely resolved by insertion of a lumbar shunt for a 7-day period. CONCLUSION: The absence of elevated intracranial pressure enables hypertelorism correction in late presenting CFND patients via facial bipartition or box osteotomy without the need for additional operations that provide for cranial expansion.

Kallmann syndrome in a patient with Weiss-Kruszka syndrome and a de novo deletion in 9q31.2.

Patients with deletions on chromosome 9q31.2 may exhibit delayed puberty, craniofacial phenotype including cleft lip/palate, and olfactory bulb hypoplasia. We report a patient with congenital HH with anosmia (Kallmann syndrome, KS) and a de novo 2.38 Mb heterozygous deletion in 9q31.2. The deletion breakpoints (determined with whole-genome linked-read sequencing) were in the FKTN gene (9:108,331,353) and in a non-coding area (9:110,707,332) (hg19). The deletion encompassed six protein-coding genes (FKTN, ZNF462, TAL2, TMEM38B, RAD23B, and KLF4). ZNF462 haploinsufficiency was consistent with the patient's Weiss-Kruszka syndrome (craniofacial phenotype, developmental delay, and sensorineural hearing loss), but did not explain his KS. In further analyses, he did not carry rare sequence variants in 32 known KS genes in whole-exome sequencing and displayed no aberrant splicing of 15 KS genes that were expressed in peripheral blood leukocyte transcriptome. The deletion was 1.8 Mb upstream of a KS candidate gene locus (PALM2AKAP2) but did not suppress its expression. In conclusion, this is the first report of a patient with Weiss-Kruszka syndrome and KS. We suggest that patients carrying a microdeletion in 9q31.2 should be evaluated for the presence of KS and KS-related features.

A novel MEIS2 mutation explains the complex phenotype in a boy with a typical NF1 microdeletion syndrome.

Concurrence of distinct genetic conditions in the same patient is not rare. Several cases involving neurofibromatosis type 1 (NF1) have recently been reported, indicating the need for more extensive molecular analysis when phenotypic features cannot be explained by a single gene mutation. Here, we describe the clinical presentation of a boy with a typical NF1 microdeletion syndrome complicated by cleft palate and other dysmorphic features, hypoplasia of corpus callosum, and partial bicoronal craniosynostosis caused by a novel 2bp deletion in exon 2 of Meis homeobox 2 gene (MEIS2) inherited from the mildly affected father. This is only the second case of an inherited MEIS2 intragenic mutation reported to date. MEIS2 is known to be associated with cleft palate, intellectual disability, heart defects, and dysmorphic features. Our clinical report suggests that this gene may also have a role in cranial morphogenesis in humans, as previously observed in animal models.

Advanced Practice Provider Clinics: Expediting Care For Children Undergoing Tympanostomy Tube Placement.

OBJECTIVE/HYPOTHESIS: Advanced practice provider (APP) employment is becoming common in pediatric otolaryngology practices, though few studies have evaluated the consequences that APP-led clinics have on access to care. The objectives of this study were: 1) to investigate whether access to bilateral myringotomy with tympanostomy tube placement (BMT) for recurrent acute otitis media (RAOM) differed between patients seen in otolaryngologist and APP-led clinics 2) to compare clinical characteristics of patients seen by provider type. METHODS: Retrospective cohort study at an academic, tertiary care pediatric otolaryngology practice. All children were <18 years old and underwent evaluation for RAOM followed by BMT. We compared time in days from scheduling pre-operative appointment to appointment date and time from appointment to BMT between patients seen by APPs and otolaryngologists using Mann-Whitney U tests and multivariate linear regression models. We compared clinical characteristics by provider type using Mann-Whitney U tests and Fisher exact tests. RESULTS: A total of 957 children were included. Children seen by APPs had significantly shorter wait times for appointments (median 19 vs. 39 days, P < .001) and shorter times from preoperative appointment to BMT (median 25 vs. 37 days, P < .001). Patients seen by otolaryngologists had increased prevalence of craniofacial abnormalities, Down Syndrome, hearing loss, history of otologic surgery, and higher ASA physical status classification. CONCLUSIONS: Children seen by APPs received care more quickly than those seen by otolaryngologists. Patients seen by otolaryngologists tended to be more medically complex. Implementation of independent APP clinics may expedite and improve access to BMT for children with RAOM. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:2133-2140, 2021.

An unexpected cyst of the ear lobule.

Branchial cleft anomalies (BCA) are among the most common congenital anomalies found in the pediatric head and neck. The embryology of these congenital anomalies is well understood, which allows clinicians to anticipate their diagnosis when a pediatric patient presents with a head or neck mass. The predictable anatomy of the various types of BCA allows for improved surgical planning to prevent recurrence and ensure complete resection. This report details an unusual location of a first BCA located in the ear lobule of a 10-month old male. There has been no documented first BCA at the ear lobule in the literature.

Generalised hypomineralisation of enamel in oculodentodigital dysplasia: comprehensive dental management of a case.

Oculodentodigital dysplasia (ODDD) is a rare congenital disorder characterised by developmental abnormalities of the eye, dentition and digits of the hands and feet, with neurological symptoms reported in 30% of individuals. Dental anomalies associated with ODDD include enamel hypoplasia and subsequent caries, microdontia, missing teeth, amelogenesis imperfecta, pulp stones and delayed tooth development. Here, we describe the comprehensive dental management of a 3-year-old girl who presented with rapid deterioration of the primary dentition due to generalised enamel hypomineralisation. Conservative, comprehensive restorative management was performed under general anaesthesia. Within 6 months, further breakdown of the remaining unrestored enamel was noted. This case documents the challenges of conservative management in dental anomalies that are not well documented due to the extreme rarity of the disorder.