Craniofacial morphology and growth in Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis

Objectives To determine whether the midface of patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis is hypoplastic compared to skeletal facial proportions of a Dutch control group. Material and methods We included seventy-four patients (43 patients with Muenke syndrome, 22 patients with Saethre-Chotzen syndrome, and 9 patients with TCF12-related craniosynostosis) who were referred between 1990 and 2020 (age range 4.84 to 16.83 years) and were treated at the Department of Oral Maxillofacial Surgery, Special Dental Care and Orthodontics, Children’s Hospital Erasmus University Medical Center, Sophia, Rotterdam, the Netherlands. The control group consisted of 208 healthy children. Results Cephalometric values comprising the midface were decreased in Muenke syndrome (ANB: β = –1.87, p = 0.001; and PC1: p < 0,001), Saethre-Chotzen syndrome (ANB: β = –1.76, p = 0.001; and PC1: p < 0.001), and TCF12-related craniosynostosis (ANB: β = –1.70, p = 0.015; and PC1: p < 0.033). Conclusions In this study, we showed that the midface is hypoplastic in Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis compared to the Dutch control group. Furthermore, the rotation of the maxilla and the typical craniofacial buildup is significantly different in these three craniosynostosis syndromes compared to the controls. Clinical relevance The maxillary growth in patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis is impaired, leading to a deviant dental development. Therefore, timely orthodontic follow-up is recommended. In order to increase expertise and support treatment planning by medical and dental specialists for these patients, and also because of the specific differences between the syndromes, we recommend the management of patients with Muenke syndrome, Saethre-Chotzen syndrome, or TCF12-related craniosynostosis in specialized multidisciplinary teams.

Quantitative Craniofacial Analysis and Generation of Human Induced Pluripotent Stem Cells for Muenke Syndrome: A Case Report

In this case report, we focus on Muenke syndrome (MS), a disease caused by the p.Pro250Arg variant in fibroblast growth factor receptor 3 (FGFR3) and characterized by uni- or bilateral coronal suture synostosis, macrocephaly without craniosynostosis, dysmorphic craniofacial features, and dental malocclusion. The clinical findings of MS are further complicated by variable expression of phenotypic traits and incomplete penetrance. As such, unraveling the mechanisms behind MS will require a comprehensive and systematic way of phenotyping patients to precisely identify the impact of the mutation variant on craniofacial development. To establish this framework, we quantitatively delineated the craniofacial phenotype of an individual with MS and compared this to his unaffected parents using three-dimensional cephalometric analysis of cone beam computed tomography scans and geometric morphometric analysis, in addition to an extensive clinical evaluation. Secondly, given the utility of human induced pluripotent stem cells (hiPSCs) as a patient-specific investigative tool, we also generated the first hiPSCs derived from a family trio, the proband and his unaffected parents as controls, with detailed characterization of all cell lines. This report provides a starting point for evaluating the mechanistic underpinning of the craniofacial development in MS with the goal of linking specific clinical manifestations to molecular insights gained from hiPSC-based disease modeling.

Facial Asymmetry in Nonsyndromic and Muenke Syndrome–Associated Unicoronal Synostosis: A 3-Dimensional Study Based on Facial Surfaces Extracted From CT Scans

Objective: To quantify soft tissue facial asymmetry (FA) in children with nonsyndromic and Muenke syndrome–associated unicoronal synostosis (NS-UCS and MS-UCS), hypothesizing that MS-UCS presents with significantly larger FA than NS-UCS. Design: Retrospective cohort study. Patients and Methods: Twenty-one children (mean age: 0.6 years; range: 0.1-1.4 years) were included in the study (NS-UCS = 14; MS-UCS = 7). From presurgical computed tomography scans, facial surfaces were constructed for analysis. A landmark guided atlas was deformed to match each patient’s surface, obtaining spatially detailed left-right point correspondence. Facial asymmetry was calculated in each surface point across the face, as the length (mm) of an asymmetry vector, with its Cartesian components providing 3 directions. Mean FA was calculated for the full face, and the forehead, eye, nose, cheek, mouth, and chin regions. Results: For the full face, a significant difference of 2.4 mm ( P = .001) was calculated between the 2 groups, predominately in the transverse direction (1.5 mm; P < .001). The forehead and chin regions presented with the largest significant difference, 3.5 mm ( P = .002) and 3.2 mm ( P < .001), respectively; followed by the eye (2.4 mm; P = .004), cheek (2.2 mm; P = .004), nose (1.7 mm; P = .001), and mouth (1.4 mm; P = .009) regions. The transverse direction presented with the largest significant difference in the forehead, chin, mouth, and nose regions, the sagittal direction in the cheek region, and the vertical direction in the eye region. Conclusions: Muenke syndrome–associated unicoronal synostosis presented with significantly larger FA in all regions compared to NS-UCS. The largest significant differences were found in the forehead and chin regions, predominantly in the transverse direction.

Dental Age, Agenesis, and Morphology in Patients With Operated Single-Suture Craniosynostoses

Objective: The aim of this study was to evaluate the dental age, agenesis, and morphology of children with surgically operated single-suture craniosynostoses from orthopantomographs. Design: A single-centered cross-sectional observational archival study. Patients: A sample of 196 Finnish patients with single-suture craniosynostosis without additional birth defects or syndromes (excluding Muenke syndrome) was included in this study. Main Outcome Measures: Dental age was assessed using the method developed by Demirjian et al. and modified by Nyström et al. for the Finnish population. Methods described by Tulensalo et al. and Oehlers et al. were used to study taurodontism and dens invaginatus, respectively. Results: The study sample of 149 patients was divided into 3 groups: patients with sagittal synostosis (n = 103), coronal synostosis (n = 25), and metopic synostosis (n = 21). Orthopantomographs taken on average at ages 8.20 to 8.33 were used. The dental ages in different groups were on average 0.37, 0.60, and 0.66 years ahead of normative values, for sagittal, coronal, and metopic groups, respectively. Tooth agenesis, taurodontism, and invaginated teeth were found in all groups with invaginations having a high prevalence. Peg-shaped upper lateral incisors and one geminated lower lateral incisor were also found. Conclusions: These descriptive data may help improve dental care in patients with single-suture craniosynostosis.

Muenke syndrome: long-term outcome of a syndrome-specific treatment protocol

OBJECTIVEThe authors evaluated the long-term outcome of their treatment protocol for Muenke syndrome, which includes a single craniofacial procedure.METHODSThis was a prospective observational cohort study of Muenke syndrome patients who underwent surgery for craniosynostosis within the first year of life. Symptoms and determinants of intracranial hypertension were evaluated by longitudinal monitoring of the presence of papilledema (fundoscopy), obstructive sleep apnea (OSA; with polysomnography), cerebellar tonsillar herniation (MRI studies), ventricular size (MRI and CT studies), and skull growth (occipital frontal head circumference [OFC]). Other evaluated factors included hearing, speech, and ophthalmological outcomes.RESULTSThe study included 38 patients; 36 patients underwent fronto-supraorbital advancement. The median age at last follow-up was 13.2 years (range 1.3–24.4 years). Three patients had papilledema, which was related to ophthalmological disorders in 2 patients. Three patients had mild OSA. Three patients had a Chiari I malformation, and tonsillar descent < 5 mm was present in 6 patients. Tonsillar position was unrelated to papilledema, ventricular size, or restricted skull growth. Ten patients had ventriculomegaly, and the OFC growth curve deflected in 3 patients. Twenty-two patients had hearing loss. Refraction anomalies were diagnosed in 14/15 patients measured at ≥ 8 years of age.CONCLUSIONSPatients with Muenke syndrome treated with a single fronto-supraorbital advancement in their first year of life rarely develop signs of intracranial hypertension, in accordance with the very low prevalence of its causative factors (OSA, hydrocephalus, and restricted skull growth). This illustrates that there is no need for a routine second craniofacial procedure. Patient follow-up should focus on visual assessment and speech and hearing outcomes.