Reassessing the association: Evaluation of a polyalanine deletion variant of RUNX2 in non-syndromic sagittal and metopic craniosynostosis.

The RUNT-related transcription factor RUNX2 plays a critical role in osteoblast differentiation, and alterations to gene dosage cause distinct craniofacial anomalies. Uniquely amongst the RUNT-related family, vertebrate RUNX2 encodes a polyglutamine/polyalanine repeat (Gln23-Glu-Ala17 in humans), with the length of the polyalanine component completely conserved in great apes. Surprisingly, a frequent 6-amino acid deletion polymorphism, p.(Ala84_Ala89)del, occurs in humans (termed 11A allele), and a previous association study (Cuellar et al. Bone 137:115395;2020) reported that the 11A variant was significantly more frequent in non-syndromic sagittal craniosynostosis (nsSag; allele frequency [AF] = 0.156; 95% confidence interval [CI] 0.126-0.189) compared to non-syndromic metopic craniosynostosis (nsMet; AF = 0.068; 95% CI 0.045-0.098). However, the gnomAD v.2.1.1 control population used by Cuellar et al. did not display Hardy-Weinberg equilibrium, hampering interpretation. To re-examine this association, we genotyped the RUNX2 11A polymorphism in 225 individuals with sporadic nsSag as parent-child trios and 164 singletons with sporadic nsMet, restricting our analysis to individuals of European ancestry. We compared observed allele frequencies to the non-transmitted alleles in the parent-child trios, and to the genome sequencing data from gnomAD v.4, which display Hardy-Weinberg equilibrium. Observed AFs (and 95% CI) were 0.076 (0.053-0.104) in nsSag and 0.082 (0.055-0.118) in nsMet, compared with 0.062 (0.042-0.089) in non-transmitted parental alleles and 0.065 (0.063-0.067) in gnomAD v.4.0.0 non-Finnish European control genomes. In summary, we observed a non-significant excess, compared to gnomAD data, of 11A alleles in both nsSag (relative risk 1.18, 95% CI 0.83-1.67) and nsMet (relative risk 1.29, 95% CI 0.87-1.92), but we did not replicate the much higher excess of RUNX2 11A alleles in nsSag previously reported (p = 0.0001).

Pathogenic variants in the paired-related homeobox 1 gene (PRRX1) cause craniosynostosis with incomplete penetrance.

PURPOSE: Studies have previously implicated PRRX1 in craniofacial development, including demonstration of murine Prrx1 expression in the preosteogenic cells of the cranial sutures. We investigated the role of heterozygous missense and loss-of-function (LoF) variants in PRRX1 associated with craniosynostosis. METHODS: Trio-based genome, exome, or targeted sequencing were used to screen PRRX1 in patients with craniosynostosis; immunofluorescence analyses were used to assess nuclear localization of wild-type and mutant proteins. RESULTS: Genome sequencing identified 2 of 9 sporadically affected individuals with syndromic/multisuture craniosynostosis, who were heterozygous for rare/undescribed variants in PRRX1. Exome or targeted sequencing of PRRX1 revealed a further 9 of 1449 patients with craniosynostosis harboring deletions or rare heterozygous variants within the homeodomain. By collaboration, 7 additional individuals (4 families) were identified with putatively pathogenic PRRX1 variants. Immunofluorescence analyses showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localization. Of patients with variants considered likely pathogenic, bicoronal or other multisuture synostosis was present in 11 of 17 cases (65%). Pathogenic variants were inherited from unaffected relatives in many instances, yielding a 12.5% penetrance estimate for craniosynostosis. CONCLUSION: This work supports a key role for PRRX1 in cranial suture development and shows that haploinsufficiency of PRRX1 is a relatively frequent cause of craniosynostosis.

Psychological Adjustment in Apert Syndrome: Parent and Young Person Perspectives.

To date, limited research has been carried out into the psychological impact of having a diagnosis of Apert syndrome (AS) and the life experiences of families living with this condition. The aim of the current study was to explore psychological adjustment to AS from the perspectives of young people, and their parents, with the broader goal of informing care, and support for this population.Four young people (2 male) aged 11 to 15 years and their mothers were interviewed in their homes using a semistructured interview guide and photo-elicitation methods. Transcripts were analyzed using Interpretive Phenomenological Analysis.Three superordinate themes were identified from the data: (1) Acceptance and Adjustment: A Cyclical Journey; (2) A Barrier to Adjustment: Navigating Treatment; and (3) Facilitating Adjustment: Social Support. Families described adjustment as a cyclical process, which was sensitive to change, particularly in the context of ongoing medical treatment. Families also utilized many resources, particularly in the form of social support, to adjust to the challenges of AS and build resilience.The findings of this study have important implications for the implementation of patient-centered care within designated craniofacial treatment centers, which should at a minimum include the provision of reliable information throughout the treatment pathway, additional support from health professionals at key times of transition, and the coordination of support across medical teams, and other key organizations in the child's life.

ERF-related craniosynostosis and surgical management in the paediatric cohort.

INTRODUCTION: ERF mutation is one of the most recently identified genetic aberrations associated with syndromic craniosynostosis. Data on the pattern of craniosynostosis, surgical management of ERF-related craniosynostosis and outcomes is limited. We report on our single-centre experience in paediatric cohort of patients with syndromic craniosynostosis secondary to ERF mutation. METHODS: A retrospective review of all paediatric craniofacial cases was performed over an 8-year period (2014-2022). All patients with genetically confirm ERF-related craniosynostosis were identified, and clinical parameters including, age, sex, pattern of craniosynostosis, associated tonsillar herniation and follow-up period were further analysed from electronic clinical and imaging systems. All patients were selected and discussed in multidisciplinary craniofacial meeting (composed of neurosurgical, maxillofacial, plastics and genetics teams) prior to any surgical intervention. RESULTS: Overall, 10 patients with ERF-related craniosynostosis were identified with a male-to-female ratio of 4:1 with mean age at the time of surgery of 21.6 months with a mean follow-up period of 5.2 years. ERF-confirmed cases led to variable craniosynostosis pattern with multi-sutural synostosis with concurrent sagittal and bilateral lambdoid involvement as the most common pattern (7/10). No patient pre-operatively had evidence of papilloedema on ophthalmological assessment. Eight out of 10 patients had associated low-lying tonsils/hind brain hernia pre-operatively. Eight out of 10 patients required surgery which included 2 fronto-orbital advancement, 3 calvarial remodelling, 2 posterior calvarial remodelling/release and 1 insertion of ventriculoperitoneal shunt. CONCLUSION: Involvement of sagittal and lambdoid sutures is the most common pattern of craniosynostosis. ERF-related craniosynostosis can have variable pattern of suture fusion, and management of each patient requires unique surgical planning and execution based on clinical needs for the optimal outcomes.

Posterior Calvarial Distraction in older paediatric population: single centre paediatric neurosurgery craniofacial unit outcomes.

PURPOSE: Posterior calvarial distraction (PCD) is a safe and effective technique used to increase cranial vault volume and therefore reduce intracranial pressure in children with complex craniosynostosis. Optimal timing and method used for PCD is controversial. This procedure is usually performed in children younger than 2 years. Literature regarding calvarial distraction in older children is sparse and limited. We report our single-centre experience with PCD in children aged 6 and above to outline the applications, benefits and challenges of employing this technique in an older paediatric population. METHODS: A retrospective analysis of a database on craniofacial cases from 2006 to 2021 was performed. Patients undergoing PCD were identified and children aged 6 and above at the time of operation were included. Data on demographics and clinical outcomes were obtained from electronic records and relevant imaging was reviewed. All cases were reviewed prior to a decision for surgery by the multidisciplinary craniofacial team (composed of neurosurgery, maxillofacial and plastics teams) and underwent surgery in our paediatric craniofacial centre. RESULTS: Overall, 98 PCD cases were identified during the study period, of which 20 cases were identified as having undergone PCD at age 6 or above with mean age of 8.8 years (range 6-18). The most common indication was pansynostosis associated with raised intracranial pressure. Four cases had calvarial remodelling previously and represented with symptoms of raised intracranial pressure sometime after their initial surgery requiring PCD as rescue procedure. Average duration of inpatient stay was 5.85 days. The average duration of follow-up was 3.5 years (0.3 to 11 years). Mean distraction distance achieved was 22.5 mm (18-29 mm). Five patients experienced complications related to wound infection or distractor. Follow-up assessment in all patients demonstrated evidence of vault expansion and symptomatic improvement and resolution of intracranial pressure signs. Comparison with younger cohort did not reveal any difference in any parameters except lower rate of transfusion in the older cohort compared to young cohort (5% vs 38%). CONCLUSION: Posterior calvarial distraction in older children is safe and effective for vault expansion and treatment of raised intracranial pressure in selected cases. A multidisciplinary craniofacial team approach is crucial for appropriate case selection and management in order to optimise outcomes.

A Simple Method for Eye Protection During Prone Positioning for Craniofacial Surgery.

Surgery in the prone position risks vision loss due to a number of factors. Craniofacial surgery poses an even greater risk due to the anatomical and physiological makeup of these patients. Here, we describe a novel method of providing protection from direct pressure on the globe during prone positioning for craniofacial procedures and our protocol for improving safety and reducing the risk of postoperative vision loss.

A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis.

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10-8): rs781716 (P = 4.71 × 10-9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10-8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10-9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10-8, OR = 0.45; P = 3.31 × 10-8, OR = 0.45; P = 1.09 × 10-8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10-8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10-6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821-55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.

ERF-related craniosynostosis: The phenotypic and developmental profile of a new craniosynostosis syndrome.

Mutations in the ERF gene, coding for ETS2 repressor factor, a member of the ETS family of transcription factors cause a recently recognized syndromic form of craniosynostosis (CRS4) with facial dysmorphism, Chiari-1 malformation, speech and language delay, and learning difficulties and/or behavioral problems. The overall prevalence of ERF mutations in patients with syndromic craniosynostosis is around 2%, and 0.7% in clinically nonsyndromic craniosynostosis. Here, we present findings from 16 unrelated probands with ERF-related craniosynostosis, with additional data from 20 family members sharing the mutations. Most of the probands exhibited multisutural (including pan-) synostosis but a pattern involving the sagittal and lambdoid sutures (Mercedes-Benz pattern) predominated. Importantly the craniosynostosis was often postnatal in onset, insidious and progressive with subtle effects on head morphology resulting in a median age at presentation of 42 months among the probands and, in some instances, permanent visual impairment due to unsuspected raised intracranial pressure (ICP). Facial dysmorphism (exhibited by all of the probands and many of the affected relatives) took the form of orbital hypertelorism, mild exorbitism and malar hypoplasia resembling Crouzon syndrome but, importantly, a Class I occlusal relationship. Speech delay, poor gross and/or fine motor control, hyperactivity and poor concentration were common. Cranial vault surgery for raised ICP and/or Chiari-1 malformation was expected when multisutural synostosis was observed. Variable expressivity and nonpenetrance among genetically affected relatives was encountered. These observations form the most complete phenotypic and developmental profile of this recently identified craniosynostosis syndrome yet described and have important implications for surgical intervention and follow-up.

Diagnostic value of exome and whole genome sequencing in craniosynostosis.

BACKGROUND: Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ∼1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing. METHODS: We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative. RESULTS: We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3). CONCLUSIONS: This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results.

The Quality of Life in Adult Patients With Syndromic Craniosynostosis From Their Perspective.

INTRODUCTION: Clinical intuition may perceive those adults with syndromic craniosynostosis to have a lower quality of life (QOL) compared with the normative population. Classification of facial difference; standardization of cognitive capacity and selection of an appropriate QOL measurement tool provides a less intuitive and more evidence-based method of assessing QOL in this particular group of patients. METHODS: Adults with syndromic craniosynostosis treated by the same surgeons underwent Whittaker Classification for facial difference by an independent observer. Neuropsychology screening ensured cognitive ability in patients for independent answering of a World Health Organization QOL postal questionnaire. Data analysis using descriptive and z test statistics allowed comparison to nonsyndromic adult United Kingdom data provided by the World Health Organization. RESULTS: Forty adult patients met authors' inclusion criteria. Whittaker Classification of facial difference ranged from I (31 patients) to II (8 patients) and III (1 patient). Quality of life showed no correlation to facial difference. Quality of life was better in the physical, psychological, and environmental domains compared with the normative adult UK population. However, no statistical difference was found in the social domain. Female Apert syndrome patients had a worse QOL than males in the social domain. CONCLUSIONS: The counterintuitive findings show that adult syndromic patients with similar cognitive capacity perceive their quality of life as being above that experienced in a normative UK nonsyndromic population with no correlation to the degree of facial difference.

Empowerment of Parents of Children With Craniosynostosis by Objective Scoring of Patient Information Websites.

INTRODUCTION: Parental anxiety may be caused by inappropriate information on the world wide web regarding craniosynostosis. The aim of this study was to study the correlation between the first 100 websites ranked on the Google search engine and those ranked based on objective scoring with patient information scoring tool. The results of these findings can then be used to recommend websites based on the quality of information that may not initially appear first on a search engine. METHODS: The DISCERN patient information scoring tool was chosen as a scientific way of measuring the quality of patient information based on previous research by the Picker Institute in Oxford. The word "craniosynostosis" was entered into the Google internet search engine. Patient information provided by the first 100 websites was studied and scored using the DISCERN scoring tool. From this score, each website was ranked with the highest scoring website at the top and worse scoring website at the bottom. This ranking based on the DISCERN tool score was correlated against the ranking of the website by Google. Positive correlation between DISCERN and Google ranking would be demonstrated if a website high in the ranking using DISCERN was also at the top of the first 100 websites on Google. RESULTS: No correlation could be found between those websites ranked highly for patient information on craniosynostosis using the DISCERN tool to the ranking provided by Google. DISCERN scores ranged from 17 to 72 (the lowest possible DISCERN tool score being 15 and the highest 85). The website ranking highest in terms of quality appeared only 50th in the Google rank. CONCLUSION: High-quality patient information on craniosynostosis does exist on the world wide web but may be difficult to find due to the complexity of factors used to rank websites on internet search engines. This results in some high-quality websites not appearing at the top of an internet search. Therefore, parents risk missing useful information relevant to their child's diagnosis. Healthcare professionals can use objective scoring of patient information websites to empower their patients to seek higher quality information.

Isolated Unilateral Frontosphenoidal Suture Synostosis in Six Patients: Lessons Learned in Diagnosis and Treatment.

INTRODUCTION: Due to the rarity of isolated frontosphenoidal suture synostosis clinical diagnosis can be challenging. This study of 6 patients aims to review the clinical, radiological findings, and operative techniques used to correct the underlying pathology. METHODS: Patients with isolated frontosphenoidal suture craniosynostosis were selected from a retrospective review of 88 patients with unicoronal synostosis treated during a 3-year period. Two-dimensional photography of patients' soft tissue morphology from the vertex view allowed assessment of the following morphology: frontal bossing, brow depression, nasal tip deviation, and ear position. Quantitative measure of the extent of bony deformity was measured using various angles measured from two-dimensional axial views of computerized tomography scans. Last, technical variations in correction of isolated frontosphenoidal craniosynostosis were collected from operative notes. RESULTS: On the side of isolated frontosphenoidal craniosynostosis, contralateral bossing and ipsilateral brow depression was present in all 6 patients. Ipsilateral nasal tip deviation was seen in 3 out of the 6 patients. Ear position was symmetrical in the cranial-caudal and anterior-posterior axes. No radiological evidence of harlequin deformity was seen on skull X-ray in all 6 patients, but computerized tomography scans demonstrated isolated frontosphenoidal suture craniosynostosis. The angle drawn between the foramen magnum, sella turcica, and anterior cribriform plate in 3 of 6 patients showed deflection of the anterior cranial fossa opposite to the side of isolated frontosphenoidal suture craniosysnotosis. There was no difference in the angle between the petrosal pyramid and the midline. In all patients, operative technique involved taking a deeper fronto-orbital bandeau to capture and reshape the pathological suture. CONCLUSIONS: In isolated frontosphenoidal suture craniosynostosis, contralateral bossing and ipsilateral flattening of the forehead were the most consistent clinical features with nasal tip deviation away from the side of pathology less consistent. Ear position is unaffected. Measurements of various angles of the skull base were not consistent. A deeper vertical osteotomy at the site of isolated frontosphenoidal suture craniosysnotosis on removing the fronto-orbital bandeau was 1 operative technical variation.

The increase of metopic synostosis: a pan-European observation.

Metopic synostosis is thought to have an incidence of about 1 in 15,000 births. Traditionally, this makes it the third most frequent single-suture craniosynostosis, after scaphocephaly (1 in 4200-8500) and plagiocephaly (1 in 11,000). Our units have, independently from each other, noted a marked increase in the number of metopic synostosis over the recent years. This is a pan-European, retrospective epidemiological study on the number of cases with metopic synostosis born between January 1, 1997, and January 1, 2006. This number was compared to the prevalence of scaphocephaly, the most frequently seen craniosynostosis. In the 7 units, a total of 3240 craniosynostosis were seen from 1997 until 2006. Forty-one percent (n = 1344) of those were sagittal synostosis, and 23% (n = 756) were metopic synostosis. There was a significant increase of the absolute number as well as of the percentage of metopic synostosis over these years (regression analysis, P = 0.017, R2 = 0.578) as opposed to a nonsignificant increase in the percentage of sagittal synostosis (P > 0.05, R2 = 0.368). The most remarkable increase occurred around 2000-2001, with the average of metopics being 20.1% from 1997 to 2000 and 25.5% from 2001 to 2005 (independent t-test, P = 0.002). The sagittal synostosis showed a smaller and nonsignificant increase in the same years: from 39.9% in 1997-2000 leading up to 42.5% in 2001-2005 (independent t-test, P > 0.05). The number of metopic synostosis has significantly increased over the reviewed period in all of our units, both in absolute numbers as in comparison to the total number of craniosynostosis.

Posterior calvarial vault expansion using distraction osteogenesis.

OBJECTIVES: Management of raised intracranial pressure in syndromic multi-suture craniosynostosis by cranial vault expansion can be achieved by a number of techniques. We present our initial experience in treating this group of patients with posterior calvarial distraction. MATERIALS AND METHODS: Six patients underwent distraction osteogenesis of their posterior calvarial vault. RESULTS: The mean period of distraction was 28 days. The mean consolidation period was 49 days. The mean distance of advancement was 24 mm. Five out of six patients completed their period of distraction and three of these cases also completed their period of consolidation. Significant calvarial expansion and improvement of head shape was achieved in all cases. CONCLUSIONS: Posterior calvarial distraction is a safe and more efficient method of calvarial expansion than conventional techniques. These are early promising results, and future modification of the distraction devices will be needed if the effective consolidation time is to be increased.