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Journal of Developmental Biology Sep 2021In 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...
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.
PubMed: 34698187
DOI: 10.3390/jdb9040039 -
Acta Neurochirurgica Nov 2021Management of ventriculomegaly in pediatric patients with syndromic craniosynostosis (SC) requires understanding the underlying mechanisms that cause increased...
INTRODUCTION
Management of ventriculomegaly in pediatric patients with syndromic craniosynostosis (SC) requires understanding the underlying mechanisms that cause increased intracranial pressure (ICP) and the role of cerebrospinal fluid (CSF) in cranial vault expansion in order to select the best treatment option for each individual patient.
METHODS
A total of 33 pediatric patients with SC requiring craniofacial surgery were retrospectively evaluated. Cases of nonsyndromic craniosynostosis and shunt-induced craniosynostosis were excluded. Six syndrome-based categories were distinguished: Crouzon syndrome, Pfeiffer syndrome, Apert syndrome, cloverleaf skull syndrome, and others (Muenke syndrome, Sensenbrenner syndrome, unclassified). All of the patients were treated surgically for their cranial deformity between 2010 and 2016. The presence of ventriculomegaly and ventriculoperitoneal (VP) shunt requirement with its impact in cranial vault expansion were analyzed. Clinical and neuroimaging studies covering the time from presentation through the follow-up period were revised. The mean postoperative follow-up was 6 years and 3 months. A systematic review of the literature was conducted through a PubMed search.
RESULTS
Of the total of 33 patients with SC, 18 (54.5%) developed ventriculomegaly and 13 (39.4%) required ventriculoperitoneal (VP) shunt placement. Six patients (18.2%) required shunt placement previous to craniofacial surgery. Seven patients (21.2%) required a shunt after craniofacial surgery. Seven fixed pressure ventriculoperitoneal shunts and six programmable valves were placed as first choice. All patients improved their clinical symptoms after shunt placement. Aesthetic results seemed to be better in patients with programmable shunts.
CONCLUSIONS
Unless clear criteria for overt hydrocephalus are present, it is recommended to perform craniofacial surgery as a first step in the management of patients with SC in order to preserve the expansive effect of CSF for cranial vault expansion. In our experience, the use of externally programmable valves allows for the treatment of hydrocephalus while maintaining the expansive effect of CSF for the remodeling of the cranial vault. Prospective evaluations are needed to determine causality.
Topics: Child; Craniosynostoses; Humans; Hydrocephalus; Retrospective Studies; Skull; Ventriculoperitoneal Shunt
PubMed: 34570275
DOI: 10.1007/s00701-021-04980-3 -
European Journal of Orthodontics May 2022To determine whether dental maturity (dental development) was delayed in patients with Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis,...
OBJECTIVES
To determine whether dental maturity (dental development) was delayed in patients with Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis, compared with a Dutch control group without syndromes.
MATERIALS AND METHODS
This study included 60 patients (38 patients with Muenke syndrome, 17 patients with Saethre-Chotzen syndrome, and 5 with TCF12-related craniosynostosis), aged 5.8-16.8 years that were treated at the Department of Oral Maxillofacial Surgery, Special Dental Care, and Orthodontics, in Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands. Dental age was calculated according to Demirjian's index of dental maturity. The control group included 451 children without a syndrome.
RESULTS
Compared with the control group, dental development was delayed by an average of one year in 5- to 8-year-old patients with Muenke syndrome (P = 0.007) and in 8- to 10-year-old patients with Saethre-Chotzen syndrome (P = 0.044), but not in patients with TCF12-related craniosynostosis.
CONCLUSIONS
Our results indicated that dental development was delayed by one year, on average, in patients with Muenke syndrome and Saethre-Chotzen syndrome, compared with a Dutch control group without syndromes.
IMPLICATIONS
Our findings have improved the understanding of dental development in patients with Muenke and Saethre-Chotzen syndrome. These results can provide guidance on whether the orthodontist needs to consider growth disturbances related to dental development.
Topics: Acrocephalosyndactylia; Basic Helix-Loop-Helix Transcription Factors; Child; Child, Preschool; Craniosynostoses; Humans; Netherlands; Syndrome
PubMed: 34424951
DOI: 10.1093/ejo/cjab056 -
NeoReviews Apr 2021Craniosynostosis is the premature fusion of 1 or more sutures that normally separate the bony plates of an infant's skull and occurs in about 1 in 2,000 to 2,500 live...
Craniosynostosis is the premature fusion of 1 or more sutures that normally separate the bony plates of an infant's skull and occurs in about 1 in 2,000 to 2,500 live births. Primary or congenital craniosynostoses represent the majority of cases and consist of single-suture and multisuture synostoses. Multisuture synostoses are typically associated with distinct craniofacial syndromes, including Muenke syndrome, Apert syndrome, Crouzon syndrome, and Pfeiffer syndrome, and are thus categorized under syndromic craniosynostoses. Secondary causes of craniosynostoses include metabolic or hematologic disorders that affect bone metabolism and typically present much later than primary synostoses. The severity of the deformity and the presence of increased intracranial pressure dictate the need for early surgical intervention, prompting the importance of early recognition and timely referral. Infants with craniosynostosis are also at increased risk for neurodevelopmental impairment and thus require close follow-up and monitoring. The early recognition and referral of craniosynostosis is imperative for the optimization of management and minimization of potential neurologic impairments that may develop.
Topics: Craniofacial Dysostosis; Craniosynostoses; Humans; Infant, Newborn; Skull; Syndrome
PubMed: 33795400
DOI: 10.1542/neo.22-4-e250 -
Annals of Plastic Surgery Nov 2021Premature fusion of both coronal sutures (anterior brachycephaly) alters skull shape and potentially affects intracranial volume (ICV). Currently little is known about...
BACKGROUND
Premature fusion of both coronal sutures (anterior brachycephaly) alters skull shape and potentially affects intracranial volume (ICV). Currently little is known about preoperative ICV in anterior brachycephaly. Aim is to measure preoperative ICV and compare this with normative data. Additionally, ICV will be correlated to most used clinical method of quantification: cephalic index (CI).
METHODS
Preoperative patients with anterior brachycephaly (age, ≤12 months) were included and categorized by syndrome (when present). Computed tomography scans were used for ICV measurement by manual segmentation (OsiriX (Fondation OsiriX, Geneva, Switzerland)). Intracranial volume of each subgroup was compared with Lichtenberg normative cranial volume growth curves for controls. Cephalic index was calculated and correlated to ICV using Pearson correlation coefficient.
RESULTS
Thirty-four patients with both syndromic and nonsyndromic anterior brachycephaly were included: 17 with Apert syndrome, 6 with Muenke syndrome, 5 with Saethre Chotzen syndrome, 3 with Crouzon, 1 with craniofrontonasal dysplasia, and 2 nonsyndromal. Mean age at preoperative computed tomography scan was 4 months (1-10 months). Mean ICV was 847.31 cm3 (473.91-1459.22 cm3). Nineteen of 34 patients had skull volumes between ±2 SD curves of Lichtenberg, none of the patients had an ICV smaller than -2 SD and 15 of 34 had an ICV larger than +2 SD. Mean ICV in Apert syndrome was 829.85 cm3 (473.91-1061.53 cm3), in Muenke syndrome 942.06 cm3 (768.02-1136.75 cm3), in Saethre Chotzen syndrome 779.72 cm3 (609.21-1002.95 cm3), in Crouzon syndrome 700.57 cm3 (652.31-784.32 cm3), in craniofrontonasal dysplasia 738.97 cm3, and in the nonsyndromal group 1154.64 cm3 (850.07-1459.22 cm3). Apert had a mean greater than +2SD above the mean, the other subgroups had a mean within normal ranges (±2 SD). Correlation between severity of brachycephaly and overall ICV was low (r = 0.42).
CONCLUSIONS
Mean preoperative ICV in both syndromic and nonsyndromic anterior brachycephaly was 847.31 cm3. Intracranial volume in anterior brachycephaly is in 55.9% between normal ranges (±2 SD). In 44.1% ICV was greater than +2 SD, especially in Apert syndrome (11/16 Apert patients). None of the included patients had a deviant small ICV of less than -2 SD. Additionally, low correlation between ICV and CI (r = 0.42) was found and therefore CI is not suitable for estimating ICV in anterior brachycephaly.
Topics: Acrocephalosyndactylia; Craniofacial Dysostosis; Craniosynostoses; Humans; Infant; Skull; Syndrome
PubMed: 33587462
DOI: 10.1097/SAP.0000000000002750 -
Neurological Sciences : Official... May 2021Temporal lobe abnormalities and focal epilepsy have been documented in FGFR3-related clinical condition, including hypochondroplasia and Muenke syndrome. FGFR3 is...
Temporal lobe abnormalities and focal epilepsy have been documented in FGFR3-related clinical condition, including hypochondroplasia and Muenke syndrome. FGFR3 is expressed in the brain during development and could play a role in nervous system development and hippocampal formation. These observations suggest a non-casual association between temporal malformation, epilepsy, and FGFR3 mutations. Herein, we report clinical, electroclinical, and neuroimaging findings of three additional cases of focal epilepsy and temporal lobe malformations occurring in children with FGFR3 gene mutations.
Topics: Child; Dwarfism; Epilepsies, Partial; Epilepsy, Temporal Lobe; Hippocampus; Humans; Magnetic Resonance Imaging; Mutation; Receptor, Fibroblast Growth Factor, Type 3; Temporal Lobe
PubMed: 33389251
DOI: 10.1007/s10072-020-04923-3 -
Plastic and Reconstructive Surgery Jan 2021The purpose of this study was to quantify change in cranioorbital morphology from presentation, after fronto-orbital advancement, and at 2-year follow-up.
BACKGROUND
The purpose of this study was to quantify change in cranioorbital morphology from presentation, after fronto-orbital advancement, and at 2-year follow-up.
METHODS
Volumetric, linear, and angular analyses were performed on computed tomographic scans of consecutive bilateral coronal synostosis patients. Comparisons were made across three time points, between syndromic and nonsyndromic cases, and against normal controls. Significance was set at p < 0.05.
RESULTS
Twenty-five patients were included: 11 were nonsyndromic, eight had Saethre-Chotzen syndrome, and six had Muenke syndrome. Total cranial volume was comparable to normal, age-matched control subjects before and 2 years after surgery despite an expansion during surgery. Axial and sagittal vector analyses showed advancement and widening of the lower forehead beyond control values with surgery and comparable anterior position, but increased width compared to controls at 2 years. Frontal bossing decreased with a drop in anterior cranial height and advanced lower forehead position. Middle vault height was not normalized and turricephaly persisted at follow-up. Posterior fossa volume remained lower at all three time points compared to control subjects. Supraorbital retrusion relative to anterior corneal position was overcorrected by surgery, with values comparable to those of control subjects at 2 years because of differential growth. There was no difference at 2 years between syndromic and nonsyndromic groups.
CONCLUSIONS
Open fronto-orbital advancement successfully remodels the anterior forehead but requires overcorrection to be comparable to normal at 2 years. Although there are differences in syndromic cases at presentation, they do not result in significant morphometric differences on follow-up. Posterior fossa volume remains lower at all time points.
CLINICAL QUESTION/LEVEL OF EVIDENCE
Therapeutic, IV.
Topics: Acrocephalosyndactylia; Case-Control Studies; Cephalometry; Child, Preschool; Craniosynostoses; Female; Follow-Up Studies; Forehead; Humans; Infant; Male; Orthopedic Procedures; Retrospective Studies; Skull; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 33370058
DOI: 10.1097/PRS.0000000000007494 -
The Journal of Craniofacial Surgery May 2021The early fusion of the cranial sutures was described as a craniosynostosis. The early diagnosis and management of craniosynostosis is very important. Environmental...
The early fusion of the cranial sutures was described as a craniosynostosis. The early diagnosis and management of craniosynostosis is very important. Environmental factors and genetic abnormalities plays a key role during the development of craniosynostosis. Syndromic craniosynostosis cases are related with autosomal dominant disorders but nearly half of the affected cases carry a new mutation. In this study, in order to identify the genetic etiology of craniosynostosis the authors analyzed 20 craniosynostosis patients by using conventional karyotype, aCGH, sanger sequencing, next generation sequencing (NGS) and Multiplex ligation-dependent probe amplification (MLPA) techniques. The authors identified mutations on FGFR2 and FGFR3 genes which were associated with Muenke syndrome, Crouzon syndrome and skeletal dysplasia syndromes. NGS applied all of the cases and 7 clinical variations in 5 different gene were detected in %20 of cases. In addition to these abnormalities; del(11)(q14.1q22.2), del(17)(q21.31), dup(22)(q13.31) and t(2;16)(q37;p13) have been identified in our cohort which are not previously detected in craniosynostosis cases. Our study demonstrates the importance of detailed genetic analysis for the diagnosis, progression and management of the craniosynostosis.
Topics: Cranial Sutures; Craniofacial Dysostosis; Craniosynostoses; Genetic Background; Humans; Mutation; Pilot Projects
PubMed: 33252532
DOI: 10.1097/SCS.0000000000007285 -
The Cleft Palate-craniofacial Journal :... Jun 2021To quantify soft tissue facial asymmetry (FA) in children with nonsyndromic and Muenke syndrome-associated unicoronal synostosis (NS-UCS and MS-UCS), hypothesizing that...
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 ( = .001) was calculated between the 2 groups, predominately in the transverse direction (1.5 mm; < .001). The forehead and chin regions presented with the largest significant difference, 3.5 mm ( = .002) and 3.2 mm ( < .001), respectively; followed by the eye (2.4 mm; = .004), cheek (2.2 mm; = .004), nose (1.7 mm; = .001), and mouth (1.4 mm; = .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.
Topics: Child; Craniosynostoses; Facial Asymmetry; Humans; Imaging, Three-Dimensional; Infant; Retrospective Studies; Tomography, X-Ray Computed
PubMed: 32969272
DOI: 10.1177/1055665620959983 -
The Cleft Palate-craniofacial Journal :... Mar 2021The aim of this study was to evaluate the dental age, agenesis, and morphology of children with surgically operated single-suture craniosynostoses from...
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.
Topics: Child; Cranial Sutures; Craniosynostoses; Cross-Sectional Studies; Facial Bones; Humans; Infant; Sutures
PubMed: 32815397
DOI: 10.1177/1055665620950145