Geospatial and Socioeconomic Disparities Influencing the Management of Craniosynostosis.

BACKGROUND: Various social determinants of health have been described as predictors of clinical outcomes for the craniosynostosis population. However, literature lacks a granular depiction of socioeconomic factors that impact these outcomes, and little is known about the relationship between patients' proximity to the care center and management of the condition. METHODS/DESIGN: This study retrospectively evaluated patients with craniosynostosis who presented to a tertiary children's hospital between 2000 and 2019. Outcomes of interest included age at presentation for surgery, incidence of reoperation, and length of follow-up. Patient addresses were geocoded and plotted on two separate shapefiles containing block group information within San Diego County. The shapefiles included percent parental educational attainment (bachelor's degree or higher) and median household income from 2010. The year 2010 was chosen for the shapefiles because it is the median year of data collection for this study. Multivariate linear, logistic, and polynomial regression models were used to analyze the relationship between geospatial and socioeconomic predictors and clinical outcomes. RESULTS: There were 574 patients with craniosynostosis included in this study. The mean ± SD Haversine distance from the patient's home coordinates to the hospital coordinates was 107.2 ± 321.2 miles. After adjusting for the suture fused and insurance coverage, there was a significant positive correlation between distance to the hospital and age at index surgery (P = 0.018). There was no correlation between distance and incidence of reoperation (P = 0.266) or distance and duration of follow-up (P = 0.369). Using the same statistical adjustments, lower parental percent educational attainment and lower median household income correlated with older age at index surgery (P = 0.008 and P = 0.0066, respectively) but were not correlated with reoperation (P = 0.986 and P = 0.813, respectively) or duration of follow-up (P = 0.107 and P = 0.984, respectively). CONCLUSIONS: The results offer evidence that living a greater distance from the hospital and socioeconomic disparities including parental education and median household income may serve as barriers to prompt recognition of diagnosis and timely care in this population. However, the geospatial and socioeconomic factors studied do not seem to hinder incidence of reoperation or length of follow-up, suggesting that, once care has been initiated, longitudinal outcomes may be less impacted.

Perinatal imaging findings of a fetus with Pfeiffer syndrome and a heterozygous c.1019A>G, p.Tyr340Cys (Y340C) mutation in FGFR2 presenting a cloverleaf skull, craniosynostosis and short limbs on prenatal ultrasound mimicking thanatophoric dysplasia type II.

OBJECTIVE: We present perinatal imaging findings of a fetus with Pfeiffer syndrome and a heterozygous c.1019A>G, p.Tyr340Cys (Y340C) mutation in FGFR2 presenting a cloverleaf skull, craniosynostosis and short limbs on prenatal ultrasound mimicking thanatophoric dysplasia type II (TD2). CASE REPORT: A 37-year-old, gravida 2, para 1, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY. However, craniofacial anomaly was found on prenatal ultrasound at 21 weeks of gestation, which showed a cloverleaf skull with severe craniosynostosis and relatively short straight long bones. Fetal magnetic resonance imaging (MRI) analysis at 22 weeks of gestation showed a cloverleaf skull, proptosis and relatively shallowing of the sylvian fissures. Prenatal ultrasound at 24 weeks of gestation showed a fetus with a cloverleaf skull with a biparietal diameter (BPD) of 6.16 cm (equivalent to 24 weeks), an abdominal circumference (AC) of 18.89 cm (equivalent to 24 weeks) and a femur length (FL) of 3.65 cm (equivalent to 21 weeks). A tentative diagnosis of TD2 was made. The pregnancy was subsequently terminated, and a 928-g malformed fetus was delivered with severe craniosynostosis, proptosis, midface retrusion, a cloverleaf skull, broad thumbs and broad big toes. The broad thumbs were medially deviated. Whole body X-ray showed a cloverleaf skull and straight long bones. However, molecular analysis of FGFR3 on the fetus revealed no mutation in the target regions. Subsequent whole exome sequencing (WES) on the DNA extracted from umbilical cord revealed a heterozygous c.1019A>G, p.Tyr340Cys (Y340C) mutation in the FGFR2 gene. CONCLUSION: Fetuses with a Y340C mutation in FGFR2 may present a cloverleaf skull on prenatal ultrasound, and WES is useful for a rapid differential diagnosis of Pfeiffer syndrome from TD2 under such a circumstance.

New diagnostic criteria for metopic ridges and trigonocephaly: a 3D geometric approach.

BACKGROUND: Trigonocephaly occurs due to the premature fusion of the metopic suture, leading to a triangular forehead and hypotelorism. This condition often requires surgical correction for morphological and functional indications. Metopic ridges also originate from premature metopic closure but are only associated with mid-frontal bulging; their surgical correction is rarely required. Differential diagnosis between these two conditions can be challenging, especially in minor trigonocephaly. METHODS: Two hundred seven scans of patients with trigonocephaly (90), metopic rigdes (27), and controls (90) were collected. Geometric morphometrics were used to quantify skull and orbital morphology as well as the interfrontal angle and the cephalic index. An innovative method was developed to automatically compute the frontal curvature along the metopic suture. Different machine-learning algorithms were tested to assess the predictive power of morphological data in terms of classification. RESULTS: We showed that control patients, trigonocephaly and metopic rigdes have distinctive skull and orbital shapes. The 3D frontal curvature enabled a clear discrimination between groups (sensitivity and specificity > 92%). Furthermore, we reached an accuracy of 100% in group discrimination when combining 6 univariate measures. CONCLUSION: Two diagnostic tools were proposed and demonstrated to be successful in assisting differential diagnosis for patients with trigonocephaly or metopic ridges. Further clinical assessments are required to validate the practical clinical relevance of these tools.

Heart rate variability and vasovagal tone index in brachycephalic dogs.

Brachycephalic breeds of dogs, most of which show signs of the brachycephalic syndrome may have greater parasympathetic stimulation than other breeds, leading to higher values of heart rate variability and vagal tone index. The aim of this study was to establish a computerized electrocardiographic study and an assessment of the vagus sympathetic balance through heart rate variability and vagal tone index of five brachycephalic breeds compared to mesocephalic dogs. Sixty dogs were used, divided into groups made up of Boxers, English Bulldogs, French Bulldogs, Pugs, Shih-Tzu and no defined breed mesocephalic dogs. Statistical analysis was carried out using the Shapiro-Wilk test, Kruskal-Wallis and Dunn's test or ANOVA and Bonferroni (p<0.05). In the evaluation of vagal sympathetic balance among all the dogs, there was a negative correlation between heart rate and HRV 10RR (r = - 0.7678; p < 0.0001), HRV 20RR (r = - 0.8548, p < 0.0001) and VVTI (r = - 0.2770; p = 0.0321). It can therefore be concluded that the dog's breed and morphology did not alter its electrocardiographic parameters or heart rate variability. The vagal tone index, which in other studies differed in brachycephalic dogs, showed no difference when compared separately in brachycephalic breeds.

Cognitive Outcomes of Children With Sagittal Craniosynostosis Treated With Either Endoscopic or Open Calvarial Vault Surgery.

Importance: Several studies have reported a higher incidence of neurodevelopmental delays and cognitive deficits in patients with single-suture craniosynostosis; however, there are few studies examining the associations of repair type with cognitive outcomes. Objective: To measure differences in neuropsychological outcomes between school-age children who were treated for sagittal craniosynostosis and unaffected controls and explore differences in cognitive function among children with sagittal craniosynostosis who were previously treated with either endoscopic strip craniectomy or open calvarial vault surgery. Design, Setting, and Participants: This cohort study was performed between 2018 and 2022. Eligible participants included patients aged 5 to 17 years who had previously been seen as infants or toddlers (<3 years) at 1 of 3 surgical centers for craniosynostosis repair with either endoscopic surgery or open calvarial vault surgery. A separate cohort of unaffected controls were included for comparison. Data analysis was conducted from November 2023 to February 2024. Exposures: Open calvarial vault surgery or endoscopic repair for single-suture craniosynostosis. Main Outcomes and Measures: The primary outcome was the Differential Ability Scales-II (DAS-II) General Conceptual Ability (GCA) score, an index for overall intellectual ability. Secondary outcomes included DAS-II subscale scores (Verbal Ability, Nonverbal Reasoning, Spatial Ability, Working Memory, and Processing Speed), and Patient-Reported Outcomes Measurement Information System (PROMIS) cognitive function scores. Results: A total of 81 patients with sagittal craniosynostosis (59 male [73%]; 22 female [27%]) and 141 controls (81 male [57%]; 60 female [43%]) were included. Of the 81 participants with sagittal craniosynostosis, 46 underwent endoscopic repair and 35 underwent open repair. Median (range) age at time of follow-up assessment was 7.7 (5.0-14.8) years for children with sagittal craniosynostosis and median age at assessment was 8.5 (7.7-10.5) years for controls. After controlling for age at assessment, sex, and socioeconomic status, there was no statistically significant or clinically meaningful difference in GCA scores between children who underwent endoscopic repair (adjusted mean score, 100; 95% CI, 96-104) and open repair (adjusted mean score, 103; 95% CI, 98-108) (P > .99). We found no significant difference in PROMIS scores between repair types (median [range] for endoscopic repair 54 [31-68] vs median [range] for open repair 50 [32-63]; P = .14). When comparing the treatment groups with the unaffected controls, differences in subscale scores for GCA and working memory were observed but were within normal range. Conclusions and Relevance: In this cohort study, there were no statistically or clinically significant differences in cognitive outcomes among school-age children by and type of surgical procedure used to repair nonsyndromic sagittal craniosynostosis. These findings suggest primary care clinicians should be educated about different options for craniosynostosis surgery to ensure early referral of these patients so that all treatment options remain viable.

An Ultra-Rare Mixed Phenotype with Combined AP-4 and ERF Mutations: The First Report in a Pediatric Patient and a Literature Review.

The adaptor protein 4 (AP-4) constitutes a conserved hetero-tetrameric complex within the family of adaptor protein (AP) complex, crucial for the signal-mediated trafficking of integral membrane proteins. Mutations affecting all subunits of the AP-4 complex have been linked to autosomal-recessive cerebral palsy and a complex hereditary spastic paraparesis (HSP) phenotype. Our report details the case of a 14-year-old boy born to consanguineous parents, presenting psychomotor delay, severe intellectual disability, microcephaly, and trigonocephaly. Despite a history of febrile seizures, subsequent years were devoid of seizures, with normal EEG. Exome sequencing revealed pathogenic variants in both the AP4B1 and ERF genes. Significantly, the patient exhibited features associated with AP4B1 mutations, including distinctive traits such as cranial malformations. The ERF gene variant, linked to craniosynostosis, likely contributes to the observed trigonocephaly. This case represents the initial documentation of a concurrent mutation in the AP4B1 and ERF genes, underscoring the critical role of exome analysis in unraveling complex phenotypes. Understanding these complex genotypes offers valuable insights into broader syndromic conditions, facilitating comprehensive patient management.

Flat Head Syndrome in Infants.

This JAMA Patient Page describes the types of flat head syndrome and its prevention and treatment.

Long-term results of minimally invasive strip craniectomy without helmet therapy for scaphocephaly - a single-centre experience.

Scaphocephaly is the most common type of craniosynostosis and various surgical techniques are used for treatment. Due to late postoperative changes of the head shape, long-term outcome data is important for evaluating any new surgical technique. At our institution, minimally invasive strip craniectomy without regular helmet therapy is the standard treatment in scaphocephalic patients. Between October 2021 and February 2023, we retrospectively examined the skull shape of patients who underwent minimally invasive strip craniectomy for scaphocephaly using a 3D surface scan technique. The cephalic index (CI), the need for helmet therapy and additional cosmetic outcome parameters were investigated. We included 70 patients (72.5% male). The mean follow-up time was 46 (10-125) months and the mean CI was 75.7 (66.7-85.2). In 58 patients, the final cosmetic result was rated as "excellent/good" (mean CI: 76.3; 70.4-85.0), in 11 as "intermediate" (mean CI: 73.3; 66.7-77.6), and in one case as "unsatisfactory" (CI 69.3). The presence of a suboccipital protrusion was associated with a "less than good" outcome. The CI correlated significantly with the overall outcome, the presence of frontal bossing, and the interval between scan and surgery (age at scan). Minimally invasive strip craniectomy is an elegant and safe method to correct scaphocephaly. Our data show good cosmetic results in the long term even without regular postoperative helmet therapy.

Whole genome sequencing identifies associations for nonsyndromic sagittal craniosynostosis with the intergenic region of BMP2 and noncoding RNA gene LINC01428.

Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.

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.

Vertebral and spinal malformations in small brachycephalic dog breeds: Current knowledge and remaining questions.

Small brachycephalic dog breeds, such as the French bulldog, English bulldog and pug have become increasingly popular. These breeds are predisposed to a variety of vertebral and spinal malformations, including hemivertebra, caudal articular process dysplasia, transitional vertebra, cranial thoracic vertebral canal stenosis, spinal arachnoid diverticulum and meningeal fibrosis. Recent studies have provided new insights into the prevalence, anatomical characteristics, pathophysiology and treatment of these conditions. Thoracic hemivertebra, caudal articular process dysplasia, transitional vertebra, and cranial thoracic vertebral canal stenosis occur commonly in neurologically normal dogs. Although the clinical relevance of these vertebral anomalies has therefore been questioned, severe kyphosis and hemivertebra in pugs have been associated with an increased likelihood of neurological signs. Meningeal fibrosis is characterised by the formation of dense intradural fibrotic adhesions, constricting the spinal cord. This condition has been heavily associated with the pug breed. It is in pugs further common to observe multiple concurrent spinal disorder in association with chronic progressive pelvic limb gait abnormalities. This clinical presentation has been referred to as 'pug dog thoracolumbar myelopathy' and potential genetic risk factors have recently been identified. Despite our increased knowledge, many questions remain currently unanswered. This review discusses our current understanding and controversies surrounding vertebral and spinal malformations in small brachycephalic dog breeds.

Factors associated with late surgical correction of craniosynostosis: A decade-long review of the United States nationwide readmission database.

Late-repair craniosynostosis (LRC), defined as craniosynostosis surgery beyond 1 year of age, is often associated with increased complexity and potential complications. Our study analyzed data from the 2010-2019 Nationwide Readmissions Database to investigate patient factors related to LRC. Of 10 830 craniosynostosis repair cases, 17% were LRC. These patients were predominantly from lower-income families and had more comorbidities, indicating that socioeconomic status could be a significant contributor. LRC patients were typically treated at teaching hospitals and privately owned investment institutions. Our risk-adjusted analysis revealed that LRC patients were more likely to belong to the lowest-income quartile, receive treatment at privately owned investment hospitals, and use self-payment methods. Despite these challenges, the hospital stay duration did not significantly differ between the two groups. Interestingly, LRC patients faced a higher predicted mean total cost compared with those who had surgery before turning 1. This difference in cost did not translate to a longer length of stay, further emphasizing the complexity of managing LRC. These findings highlight the urgent need for earlier intervention in craniosynostosis cases, particularly in lower-income communities. The medical community must strive to improve early diagnosis and treatment strategies in order to mitigate the socioeconomic and health disparities observed in LRC patients.

Prevalence and Severity of Positional Posterior Plagiocephaly and Positional Posterior Brachycephaly in Children and Adolescents in Japan.

This study aimed to assess the prevalence, severity, and natural history of positional posterior plagiocephaly (PPP) and positional posterior brachycephaly in Japan. We conducted a cross-sectional study of pediatric patients, ranging from 0 to 15 years old, evaluated for head trauma with negative computed tomography (CT) findings. The cranial vault asymmetry index (CVAI) was calculated using CT images at the superior orbital rim. Asymmetry according to CVAI values was subcategorized as follows: mild (3.5%-7%), moderate (7%-12%), and severe (>12%). The results were analyzed according to different age groups: group 1, 2-23 months (54 patients); group 2, 2-6 years (123 patients); and group 3, 7-15 years (123 patients). Overall, 300 patients were included (109 [36.3%] girls and 191 [63.7%] boys). The overall prevalence of PPP in the 300 patients was 46.7% (140 patients). PPP prevalence decreased consistently with age group: group 1, 57.4%; group 2, 47.2%; and group 3, 41.5%. Severe asymmetry was seen in all age groups. The overall mean cephalic index (CI) was 85.2. Cephalic index scores decreased consistently with age: group 1, 87.4; group 2, 85.1; and group 3, 84.3. The prevalence of PPP in Japan was higher than that reported in other countries. Although there was an overall decrease in the prevalence and severity of PPP with increasing patient age, PPP does not necessarily resolve spontaneously in all children. Furthermore, severe asymmetry was seen across all age groups.

Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies.

Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. These individuals exhibit both shared and unique clinical manifestations, highlighting the complexity and variability of the disorder. We propose that the involvement of MAP3K20 in endothelial-mesenchymal transition provides a plausible etiology of these features. Together, these findings characterize a disorder that both expands the phenotypic spectrum associated with MAP3K20 and highlights the need for further studies on its role in early human development.

The most common congenital malformations in dogs: Literature review and practical guide.

Congenital malformations can affect almost 7% of canine newborns. The increase of commercial dog breeding and inbreeding used to maintain the striking characteristics of each breed, the appearance of malformations has become increasingly common, especially in brachycephalic dogs. The causes are diverse, and include genetic, nutritional, iatrogenic, and infectious factors, often making it difficult to establish a cause-consequence relationship. The high mortality associated with malformations comes not only from the fact that some are incompatible with life, but also because even if many undergo surgical treatment or correction, they require specific management, monitoring, and clinical treatment for an indefinite period of time. The most common malformations such as cleft lip and palate, hydrocephalus and anasarca have been studied for a long time, and it is currently known that brachycephalic dogs have a greater predisposition, however, for other less common conditions as gastroschisis and hypospadias, there is only a few case reports. The appearance of congenital defects in a litter leads to financial losses for the breeder, emotional losses for the owner and the veterinarian and harms the well-being of that individual. For this reason, the aim of this review article is to gather relevant information on the characteristics, diagnosis, and management of the main malformations in puppies. It is essential that the veterinarian is prepared to diagnose and treat these conditions, reducing negative impacts on animals and owners.

Changes in mandibular position during midface distraction in patients with syndromic craniosynostosis.

The purpose of this study was to evaluate changes in mandibular position during midface distraction. Midface distraction was performed in patients with syndromic craniosynostosis to increase upper airway volume. Although this treatment resulted in changes in occlusion, the concomitant changes in mandibular position were poorly understood. In this retrospective study, three-dimensional (3D) cephalograms were obtained before and after midface distraction in 15 patients with syndromic craniosynostosis. Perioperative polysomnography scores and changes in maxillary and mandibular position, mandibular volume, and upper airway volume were analyzed. Results showed a significant improvement in apnea-hypopnea index (AHI) (from 20.6 ± 21.3 to 6.9 ± 5.1, p < 0.05) and upper airway volume (from 2951.65 ± 2286.38 to 5218.04 ± 3150.05 mm3, p < 0.001). When the lowest point of the sella turcica was set as the reference point, the mandible moved significantly in an anterior direction (from 47.9 ± 11.5 to 51.9 ± 9.8 mm, p < 0.05). Mandibular volume did not change significantly perioperatively (from 32530.19 ± 10726.01 to 35590.50 ± 14879.21 mm3, p = 0.10). There were positive correlations between the rates of improvement in AHI and the amount of mandibular movement in the anterior and inferior directions (both p < 0.05). Within the limitations of the study, it seems that the mandible moved in the anterior-inferior direction after midface distraction, and the amount of movement correlated with improvement in respiratory function. Therefore, it is important to consider the position of the mandible when determining the direction of midface distraction, as it may influence the therapeutic effect.

Association of cranial base suture/synchondrosis fusion with severity of increased intracranial pressure in Crouzon syndrome.

This study investigated how the fusion states of the cranial base is related to the degree of increased intracranial pressure (ICP) in patients with Crouzon syndrome. This retrospective cohort study enrolled patients who were diagnosed with Crouzon syndrome between May 2007 and April 2022. We categorized the patients into three groups: A, B, and C, according to the severity of increased ICP and the number of cranial vault remodeling procedures for corrective operation. The preoperative fusion states of the cranial base sutures/synchondroses were examined using facial bone computed tomography and compared between groups. Overall, 22 patients were included in Groups A, B, and C, including 8, 7, and 7 patients, respectively. The preoperative average grades of the total cranial base suture/synchondrosis fusion appeared to significantly increase with severity, except for the frontoethmoidal suture, which showed the opposite tendency. In the subgroup analysis, frontosphenoidal, sphenoparietal, sphenosquamosal, parietomastoid, and occipitomastoid suture and petro-occipital synchondrosis were associated with earlier fusion in the more severe group. Premature closure of the cranial base sutures/synchodroses seems to be associated with increased ICP severity in patients with Crouzon syndrome. Precise evaluation of minor sutures/synchondroses at the first visit might help build subsequent operative plans and predict disease prognosis.