Skeletal expansion via craniofacial distraction osteogenesis technique in syndromic craniosynostosis: impact on ophthalmic parameters.

BACKGROUND: This study aims to compare the changes in ophthalmic parameters among syndromic craniosynostosis patients who underwent craniofacial skeletal expansion procedures via distraction osteogenesis (DO). METHOD: A retrospective study was conducted involving syndromic craniosynostosis patients who underwent surgical expansion via the DO technique from the year 2012 to March 2022. Changes in six parameters which consist of visual acuity, refractive error, optic disc health, intraocular pressure, degree of proptosis and orbital volume were measured objectively pre and post-surgery. For categorical parameters, the Chi-square cross-tab test was done. Paired sample T-test was used for normally distributed variables. Wilcoxon signed-rank test was used for non-normally distributed data. RESULTS: Visual impairment was present in 21.4% of eyes before surgery and increased to 28.5% post-surgery. Three patients had changes of refractive error post-surgery with one developed hypermetropia, another developed anisometropia and the last had improvement to no refractive error. Two patients had optic disc swelling which was resolved post-surgery. Intraocular pressure changes were inconsistent post-surgery. All patients achieved a significant reduction in the degree of proptosis post-surgery. Orbital volume calculation using computed tomography (CT) scans shows a significant increase in volume post-surgery for all patients. CONCLUSION: Our study shows a significant increase in orbital volume post-surgery with a reduction in the degree of proptosis. Optic disc and nerve health improved after the surgery. Changes in terms of visual acuity, refractive error and IOP were inconsistent after the surgical intervention.

A novel case of Horner syndrome as the presenting sign of craniosynostosis.

Craniosynostosis, the premature fusion of cranial sutures, can lead to distortion of skull shape and neurological dysfunction. We present a novel case of Horner syndrome as the presenting sign of craniosynostosis associated with elevated intracranial pressure. A 10-year-old boy presenting for strabismus follow-up was noted to have new-onset anisocoria, greater in the dark, and mild right upper eyelid ptosis. Apraclonidine testing was concerning for Horner syndrome. Neuroimaging demonstrated previously undiagnosed sagittal craniosynostosis with tortuous optic nerves and large cerebrospinal fluid spaces around both optic nerves. The patient was referred to neurosurgery and underwent a lumbar puncture with an opening pressure of 44 cm H2O. He underwent surgical cranial expansion. By six months postoperatively, his anisocoria had resolved.

Homozygous SMAD6 variants in two unrelated patients with craniosynostosis and radioulnar synostosis.

BACKGROUND: SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in SMAD6 were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patients harbouring biallelic SMAD6 variants presenting a complex cardiovascular phenotype and facial dysmorphism have been described. CASES: Here, we present the first two patients with craniosynostosis harbouring homozygous SMAD6 variants. The male probands, both born to healthy consanguineous parents, were diagnosed with metopic synostosis and bilateral or unilateral radioulnar synostosis. Additionally, one proband had global developmental delay. Echocardiographic evaluation did not reveal cardiac or outflow tract abnormalities. MOLECULAR ANALYSES: The novel missense (c.[584T>G];[584T>G], p.[(Val195Gly)];[(Val195Gly)]) and missense/splice-site variant (c.[817G>A];[817G>A], r.[(817g>a,817delins[a;817+2_817+228])];[(817g>a,817delins[a;817+2_817+228])], p.[(Glu273Lys,Glu273Serfs*72)];[(Glu273Lys,Glu273Serfs*72)]) both locate in the functional MH1 domain of the protein and have not been reported in gnomAD database. Functional analyses of the variants showed reduced inhibition of BMP signalling or abnormal splicing, respectively, consistent with a hypomorphic mechanism of action. CONCLUSION: Our data expand the spectrum of variants and phenotypic spectrum associated with homozygous variants of SMAD6 to include craniosynostosis.

QEEG findings in nonsyndromic sagittal craniosynostosis.

Despite the undertaken treatment, children with nonsyndromic sagittal craniosynostosis (NSC) are burdened with problems with speech development, visuospatial and other cognitive deficits. The electroencephalographic assessment has not influenced the diagnostics and treatment strategy of craniosynostosis so far but the introduction of quantitative EEG (QEEG) protocols renewed an interest in the functional aspect of this disease. In this study we retrospectively assessed the QEEG records of 25 children with NSC aged 1-18 months (mean age 9.62 months) before and after surgery. In each case, the amplitude, interhemispheric (ICoh) and intrahemispheric (HCoh) coherence indices were calculated. Obtained data were compared to age-matched control group of 25 normocephalic children. Children with NSC presented significantly lower values of amplitudes and intrahemispheric coherence in occipital, posterior parietal and posterior temporal regions than normocephalic children. The values of amplitudes, ICoh and HCoh in pre- and postoperative QEEG records mostly remained unchanged, with a slight improvement in HCoh in centro-parietal area. These findings suggest that NSC children present their own QEEG profile. The operative treatment improves an intrahemispheric connectivity, but there still exists a significant difference in the occipitotemporal, frontotemporal and centro-frontal areas, which may be considered as a functional substrate of reported speech and neurocognitive problems. QEEG findings in nonsyndromic sagittal craniosynostosis.

Incidence of Airway Abnormalities in Children With Craniosynostosis.

INTRODUCTION: Children with syndromic craniosynostosis are known to have a high propensity for associated airway abnormalities. However, this has not been investigated using a large-scale national database. METHODS: For this retrospective cohort study, the 2016 Healthcare Cost and Utilization Project Kid's Inpatient Database was queried for craniosynostosis patients. Data on demographics, airway diagnoses, and comorbidities were analyzed. RESULTS: Four thousand nine hundred fourteen children with craniosynostosis with a mean age of 1.7±3.6 years were identified. Of these, 51% were female and 136 children had an associated syndrome. Choanal atresia was present in 31% of patients with an associated syndrome versus 2.5% without. Syndromic patients are 4.59 times more likely (95% CI 2.65-7.94) to have airway anomalies than nonsyndromic patients. After age and sex adjustment, craniosynostosis patients have higher likelihoods of presenting with other anomalies, with syndromic having higher incidences: 5.23 times (95% CI 2.63-10.39) more likely to have laryngomalacia, 18.30 times (95% CI 3.27-102.36) more likely to have tracheal stenosis, and 4.58 times (95% CI 1.36- 15.43) more likely to have tracheomalacia. Incidence of tracheostomy was 5.84 times (95% CI 3.77-9.04) higher in syndromic patients with craniosynostosis. Tracheostomy rates were 28.4% and 4.6% in craniosynostosis patients with and without associated syndrome, respectively. CONCLUSION: Syndromic craniosynostosis patients had significantly higher incidences of choanal atresia and other airway anomalies. Given a high incidence of airway anomalies, syndromic craniosynostosis patients likely warrant routine airway evaluation. Providers should also be vigilant about airway evaluation in patients with nonsyndromic craniosynostosis when aerodigestive symptoms arise.

Prenatal and infantile diagnosis of craniosynostosis in individuals with RASopathies.

Fetuses with RASopathies can have a wide variety of anomalies including increased nuchal translucency, hydrops fetalis, and structural anomalies (typically cardiac and renal). There are few reports that describe prenatal-onset craniosynostosis in association with a RASopathy diagnosis. We present clinical and molecular characteristics of five individuals with RASopathy and craniosynostosis. Two were diagnosed with craniosynostosis prenatally, 1 was diagnosed as a neonate, and 2 had evidence of craniosynostosis noted as neonates without formal diagnosis until later. Two of these individuals have Noonan syndrome (PTPN11 and KRAS variants) and three individuals have Cardiofaciocutaneous syndrome (KRAS variants). Three individuals had single suture synostosis and two had multiple suture involvement. The most common sutures involved were sagittal (n = 3), followed by coronal (n = 3), and lambdoid (n = 2) sutures. This case series confirms craniosynostosis as one of the prenatal findings in individuals with RASopathies and emphasizes the importance of considering a RASopathy diagnosis in fetuses with multiple anomalies in combination with craniosynostosis.

Craniosynostosis in molecularly diagnosed Kabuki syndrome: Prevalence and clinical implications.

Kabuki syndrome (KS) is characterized by growth impairment, psychomotor delay, congenital heart disease, and distinctive facial features. KMT2D and KDM6A have been identified as the causative genes of KS. Craniosynostosis (CS) has been reported in individuals with KS; however, its prevalence and clinical implications remain unclear. In this retrospective study, we investigated the occurrence of CS in individuals with genetically diagnosed KS and examined its clinical significance. Among 42 individuals with genetically diagnosed KS, 21 (50%) exhibited CS, with 10 individuals requiring cranioplasty. No significant differences were observed based on sex, causative gene, and molecular consequence among individuals with KS who exhibited CS. Both individuals who underwent evaluation with three-dimensional computed tomography (3DCT) and those who required surgery tended to exhibit cranial dysmorphology. Notably, in several individuals, CS was diagnosed before KS, suggesting that CS could be one of the clinical features by which clinicians can diagnose KS. This study highlights that CS is one of the noteworthy complications in KS, emphasizing the importance of monitoring cranial deformities in the health management of individuals with KS. The findings suggest that in individuals where CS is a concern, conducting 3DCT evaluations for CS and digital impressions are crucial.

[Studies of sleep and therapeutic actions in children and adolescents with craniofacial anomalies]. / Estudios de sueño y conducta terapéutica en niños y adolescentes con alteraciones craneofaciales.

OBJECTIVE: To describe the presence of obstructive sleep apnea syndrome (OSAS) in children with craniofacial anomalies (CFA), associate biodemographic characteristics and polygraph variables, and analyze the therapeutic management decided after the sleep study and the evaluation by a multidisciplinary team. PATIENTS AND METHOD: Retrospective study. Polygraphs were performed on patients aged between 1 month and 19 years with CFA. An initial and projected management was established categorized into ventilatory support, tracheostomy, surgery, dental, and medical treatment. Descrip tive and inferential statistics were performed, evaluating the association between demographic and polygraph variables and therapeutic management. RESULTS: 34 patients were included with a median age of 4.0 years (IQR 0.9 - 6.5). Diagnosis was 41.2% cleft lip and palate, 35.3% craniosynostosis, and 23.5% micrognathia. Polygraphs were altered in 70.6% of the cases; of these, 26.5% were diagnosed as mild, 5.9% moderate, and 38.2% severe OSAS. There was an association between minimum satu ration and diagnosis of OSAS (p = 0.0036), and in the presence of OSAS with the initial management applied (p=0.0013). There was no significant relationship between the different types of CFA with the initial therapeutic management (p = 0.6565). Initial and projected managements, respectively: Venti latory support (11.8% and 2.9%), tracheostomy (11.8% and 0%), surgery (35.2% and 26.5%), dental (20.6% and 53%), and medical treatment (20.6% and 17.6 %). CONCLUSIONS: 70% of the patients with CFA presented OSAS. The greatest severity was found in Cleft Lip and Palatine and Craniosynostosis. Therapeutic management was mainly oriented towards initial surgical and planned dental treatments based on the diagnosis of OSAS and not on the type of CFA.

Rare IFT140-Associated Phenotype of Cranioectodermal Dysplasia and Features of Diagnostic Journey in Patients with Suspected Ciliopathies.

Here we present a patient with a cranioectodermal phenotype associated with pathogenic variants in the IFT140 gene. Most frequently, pathogenic variants in IFT140 correspond to the phenotype of Mainzer-Saldino syndrome. Only four patients have previously been described with this cranioectodermal phenotype and variants in IFT140. In comparison to other IFT140-cranioectodermal patients, our proband had similar skeletal features among with early onset end-stage renal failure that required kidney transplantation but did not have common ophthalmological features such as retinopathy, optic nerve atrophy, or nystagmus. Following exome sequencing, a splicing variant and exons 27-30 tandem duplication were suspected and further validated. The two other patients with Mainzer-Saldino syndrome that we described displayed a typical clinical picture but a special diagnostic journey. In both cases, at first only one pathogenic variant was detected following panel or exome NGS sequencing. Further WGS was performed for one of them where tandem duplication was found. Screening the third patient for the same tandem duplication was successful and revealed the presence of this duplication. Thus, we suggest that the description of the clinical feature polymorphism in a rare IFT140-cranioectodermal phenotype is extremely important for providing genetic counseling for families, as well as the formation of the correct diagnostic path for patients with a variant in IFT140.

Treatment Delays in Nonsyndromic Craniosynostosis: A 30-Year Retrospective Case-Control Analysis of the Impact of Socioeconomic and Family Status on Access to Care.

BACKGROUND: Patients with nonsyndromic craniosynostosis (NSC) generally undergo corrective surgery before 1 year of age to the mitigate morbidities and risks of delayed repair. The cohort of patients who receive primary corrective surgery after 1 year and factors associated with their gaps to care is poorly characterized in literature. METHODS: A nested case-control study was conducted for NSC patients who underwent primary corrective surgery at our institution and affiliates between 1992 and 2022. Patients whose surgery occurred after 1 year of age were identified and matched 1:1 by surgical date to standard-care control subjects. Chart review was conducted to gather patient data regarding care timeline and sociodemographic characteristics. RESULTS: Odds of surgery after 1 year of age were increased in Black patients (odds ratio, 3.94; P < 0.001) and those insured by Medicaid (2.57, P = 0.018), with single caregivers (4.96, P = 0.002), and from lower-income areas (+1% per $1000 income decrease, P = 0.001). Delays associated with socioeconomic status primarily impacted timely access to a craniofacial provider, whereas caregiver status was associated with subspecialty level delays. These disparities were exacerbated in patients with sagittal and metopic synostosis, respectively. Patients with multisuture synostosis were susceptible to significant delays related to familial strain (foster status, insurer, and English proficiency). CONCLUSIONS: Patients from socioeconomically strained households face systemic barriers to accessing optimal NSC care; disparities may be exacerbated by the diagnostic/treatment complexities of specific types of craniosynostosis. Interventions at primary care and craniofacial specialist levels can decrease health care gaps and optimize outcomes for vulnerable patients.

Oxycephaly-systematic review, case presentation, and diagnostic clarification.

PURPOSE: Oxycephaly is a specific phenotype of multi-suture craniosynostosis that is often misrepresented. This study aims to review the relevant literature, clarify the diagnostic criteria, and present an alternate approach to its management. METHODS: Published literature regarding oxycephaly was reviewed from 1997, when the largest series was published, until 2022. All cases at a single institution were then retrospectively reviewed. RESULTS: Over the last 25 years, four studies met the inclusion criteria, none of which specifically defined oxycephaly. One case, in one study, was potentially consistent with the phenotype. An institutional review yielded two patients who met the original diagnostic criteria set forth by Renier and Marchac. Both patients had unexplained speech delays, mild retinal nerve fiber layer thickening, and diffuse inner table scalloping, along with the characteristic oxycephalic phenotype. One patient also had a direct intracranial pressure (ICP) measurement of 25 mmHg, and the other had a Chiari I malformation. Both were treated with posterior vault distraction osteogenesis (PVDO) to alleviate the cephalo-cranial disproportion while simultaneously allowing for turricephaly correction. CONCLUSIONS: Oxycephaly presents with late onset multi-suture fusion. Patients have patent sutures at birth. Midface hypoplasia and known syndromic associations are absent. Patients demonstrate supraorbital recession, an obtuse fronto-nasal angle, and turricephaly without substantial brachycephaly. Over 60% of patients have symptomatic ICP elevation, the presentation of which ranges from headaches to rapidly progressive blindness. This rare form of craniosynostosis is particularly virulent and likely often missed due to diagnostic ambiguity and its relatively mild phenotype.

Isolated frontosphenoidal craniosynostosis: An argument for genetic testing.

Isolated frontosphenoidal craniosynostosis (IFSC) is a rare congenital defect defined as premature fusion of the frontosphenoidal suture in the absence of other suture fusion. Until now, IFSC was regarded as a phenomenon with an unclear genetic etiology. We have identified three cases with IFSC with underlying syndromic diagnoses that were attributable to pathogenic mutations involving FGFR3 and MN1, as well as 22q11.2 deletion syndrome. These findings suggest a genetic predisposition to IFSC may exist, thereby justifying the recommendation for genetic evaluation and testing in this population. Furthermore, due to improved imaging resolution, cases of IFSC are now readily identified. With the identification of IFSC with underlying genetic diagnoses, in combination with significant improvements in imaging resolution, we recommend genetic evaluation in children with IFSC.

Ophthalmic Manifestations of Unilateral Coronal Synostosis.

PURPOSE: To summarize the ophthalmic manifestations of unilateral coronal synostosis patients. METHODS: We performed a literature search in the electronic database of PubMed, CENTRAL, Cochrane, and Ovid Medline guided by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement for studies evaluating ophthalmic manifestations of unilateral coronal synostosis. RESULTS: Unilateral coronal synostosis, also called unicoronal synostosis, may be mistaken for deformational plagiocephaly, an asymmetric skull flattening common in newborns. Characteristic facial features, however, distinguish the two. Ophthalmic manifestations of unilateral coronal synostosis include a "harlequin deformity", anisometropic astigmatism, strabismus, amblyopia, and significant orbital asymmetry. The astigmatism is greater on the side opposite the fused coronal suture. Optic neuropathy is uncommon unless unilateral coronal synostosis accompanies more complex multi-suture craniosynostosis. In many cases, surgical intervention is recommended; without intervention, skull asymmetry and ophthalmic disorders tend to worsen with time. Unilateral coronal synostosis can be managed by early endoscopic stripping of the fused suture and helmeting through a year of age or by fronto-orbital-advancement at approximately 1 year of age. Several studies have demonstrated that anisometropic astigmatism, amblyopia, and severity of strabismus are significantly lower after earlier intervention with endoscopic strip craniectomy and helmeting compared to treatment by fronto-orbital-advancement. It remains unknown whether the earlier timing or the nature of the procedure is responsible for the improved outcomes. As endoscopic strip craniectomy can only be performed in the first few months of life, early recognition of the facial, orbital, eyelid, and ophthalmic characteristics by consultant ophthalmologists enables expeditious referral and optimized ophthalmic outcomes. CONCLUSION: Timely identification of craniofacial and ophthalmic manifestations of infants with unilateral coronal synostosis is important. Early recognition and prompt endoscopic treatment appears to optimize ocular outcomes.

Presentation and Treatment of a Patient With Jacobs Syndrome and Metopic Craniosynostosis.

Jacobs syndrome is a rare trisomy (47, XYY) found in ~1 in 1000 male children associated with infertility, autism spectrum disorders, macrocephaly, hypertelorism, tall stature, and macroorchidism. Diagnosis is often delayed due to relatively subtle phenotypic changes. Craniosynostosis, a fusion of the cranial sutures, has been described in ~1 in 2000 live births, of which 25% are related to a diagnosed syndrome with the most common being Apert and Crouzon. Craniosynostosis does not have a known association with Jacobs syndrome and no prior cases have been reported. This case report seeks to describe the presentation and treatment of a patient with Jacobs syndrome and metopic craniosynostosis.

Further validation of craniosynostosis as a part of phenotypic spectrum of BCL11B-related BAFopathy.

Heterozygous disease-causing variants in BCL11B are the basis of a rare neurodevelopmental syndrome with craniofacial and immunological involvement. Isolated craniosynostosis, without systemic or immunological findings, has been reported in one of the 17 individuals reported with this disorder till date. We report three additional individuals harboring de novo heterozygous frameshift variants, all lying in the exon 4 of BCL11B. All three individuals presented with the common findings of this disorder i.e. developmental delay, recurrent infections with immunologic abnormalities and facial dysmorphism. Notably, craniosynostosis of variable degree was seen in all three individuals. We, thus add to the evolving genotypes and phenotypes of BCL11B-related BAFopathy and also review the clinical, genomic spectrum along with the underlying disease mechanisms of this disorder.

Description of a novel method for detection of sleep-disordered breathing in brachycephalic dogs.

BACKGROUND: Sleep-disordered breathing (SDB), defined as any difficulty in breathing during sleep, occurs in brachycephalic dogs. Diagnostic methods for SDB in dogs require extensive equipment and laboratory assessment. OBJECTIVES: To evaluate the usability of a portable neckband system for detection of SDB in dogs. We hypothesized that the neckband is a feasible method for evaluation of SDB and that brachycephaly predisposes to SDB. ANIMALS: Twenty-four prospectively recruited client-owned dogs: 12 brachycephalic dogs and 12 control dogs of mesocephalic or dolicocephalic breeds. METHODS: Prospective observational cross-sectional study with convenience sampling. Recording was done over 1 night at each dog's home. The primary outcome measure was the obstructive Respiratory Event Index (OREI), which summarized the rate of obstructive SDB events per hour. Additionally, usability, duration of recording, and snore percentage were documented. RESULTS: Brachycephalic dogs had a significantly higher OREI value (Hodges-Lehmann estimator for median difference = 3.5, 95% confidence interval [CI] 2.2-6.8; P < .001) and snore percentage (Hodges-Lehmann estimator = 34.2, 95% CI 13.6-60.8; P < .001) than controls. A strong positive correlation between OREI and snore percentage was detected in all dogs (rs = .79, P < .001). The neckband system was easy to use. CONCLUSIONS AND CLINICAL IMPORTANCE: Brachycephaly is associated with SDB. The neckband system is a feasible way of characterizing SDB in dogs.

Metopic ridge presenting to pediatric dermatology and vascular anomalies clinics.

Metopic ridge (MeR) is a midline osseous forehead prominence resulting from physiologic closure of the underlying metopic suture. This mass-like ridge can be mistaken for serious conditions such as a craniosynostosis or vascular anomaly, prompting concern and workup. We reviewed patients presenting for a forehead mass to Vascular Anomalies and Dermatology clinics and diagnosed with MeR to increase familiarity with this finding and to encourage MeR in the differential diagnosis of pediatric midline forehead masses.

Early Ophthalmology Findings in Nonsyndromic Craniosynostosis.

Craniosynostosis (CS) occurs 1 in 2500 births and surgical intervention is indicated partly due to risk for elevated intracranial pressure (EICP). Ophthalmological examinations help identify EICP and additional vision concerns. This study describes preoperative and postoperative ophthalmic findings in CS patients (N=314) from chart review. Patients included nonsyndromic CS: multisuture (6.1%), bicoronal (7.3%), sagittal (41.4%), unicoronal (22.6%), metopic (20.4%), and lambdoidal (2.2%). Preoperative ophthalmology visits were at M =8.9±14.1 months for 36% of patients and surgery was at M =8.3±4.2 months. Postoperative ophthalmology visits were at age M =18.7±12.6 months for 42% with follow-up at M =27.1±15.1 months for 29% of patients. A marker for EICP was found for a patient with isolated sagittal CS. Only a third of patients with unicoronal CS had normal eye exams (30.4%) with hyperopia (38.2%) and anisometropia (16.7%) at higher rates than the general population. Most children with sagittal CS had normal exams (74.2%) with higher than expected hyperopia (10.8%) and exotropia (9.7%). The majority of patients with metopic CS had normal eye exams (84.8%). About half of patients with bicoronal CS had normal eye exams (48.5%) and findings included: exotropia (33.3%), hyperopia (27.3%), astigmatism (6%), and anisometropia (3%). Over half of children with nonsyndromic multisuture CS had normal exams (60.7%) with findings of: hyperopia (7.1%), corneal scarring (7.1%), exotropia (3.6%), anisometropia (3.6%), hypertropia (3.6%), esotropia (3.6%), and keratopathy (3.6%). Given the range of findings, early referral to ophthalmology and ongoing monitoring is recommended as part of CS care.