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Stem Cell Research Jul 2020Muenke syndrome is the leading genetic cause of craniosynostosis and results in a variety of disabling clinical phenotypes. To model the disease and study the pathogenic...
Muenke syndrome is the leading genetic cause of craniosynostosis and results in a variety of disabling clinical phenotypes. To model the disease and study the pathogenic mechanisms, a human induced pluripotent stem cell (hiPSC) line was generated from a patient diagnosed with Muenke syndrome. Successful reprogramming was validated by morphological features, karyotyping, loss of reprogramming factors, expression of pluripotency markers, mutation analysis and teratoma formation.
Topics: Craniosynostoses; Humans; Induced Pluripotent Stem Cells; Mutation; Phenotype; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 32505898
DOI: 10.1016/j.scr.2020.101823 -
Clinical Dysmorphology Apr 2020
PubMed: 32141935
DOI: 10.1097/MCD.0000000000000322 -
Clinical Dysmorphology Jan 2020Muenke syndrome is a craniosynostosis syndrome associated with the p.Pro250Arg mutation in FGFR3. An increasing number of individuals with this mutation are reported to...
Muenke syndrome is a craniosynostosis syndrome associated with the p.Pro250Arg mutation in FGFR3. An increasing number of individuals with this mutation are reported to not have craniosynostosis. The purpose of this report is to increase awareness of the high phenotypic variability seen in Muenke syndrome. DNA testing for the p.Pro250Arg mutation is routinely performed in Denmark, in children presenting with isolated coronal synostosis. Verified diagnosis entails detailed family history, drawing of family pedigree, DNA testing of the parents, genetic counseling, skull radiographs, clinical photographs, and follow-up. Sixteen individuals from 5 Danish families with Muenke syndrome are presented. Large phenotypic variation was seen both within and across families. The most striking observations were that 6/16 (38%) cases did not have craniosynostosis and one individual presented with a normal phenotype. In addition, 3 unrelated cases had incomplete cleft palate, submucous cleft palate, and bifid uvula, respectively. There is strong evidence for reduced penetrance of the craniosynostosis trait in Muenke syndrome. We argue that many studies on Muenke syndrome have been influenced by ascertainment bias in regard to craniosynostosis. In addition, it is suggested that oral clefting might be part of the clinical spectrum seen in Muenke syndrome.
Topics: Amino Acid Substitution; Child; Child, Preschool; Craniosynostoses; Denmark; Family; Female; Follow-Up Studies; Humans; Infant; Mutation, Missense; Pedigree; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 31609728
DOI: 10.1097/MCD.0000000000000300 -
Neuro-Chirurgie Nov 2019The aim of the present study was to review the literature on ENT disorders associated with craniosynostosis (CS), focusing on symptoms, diagnostic work-up, treatment and... (Review)
Review
OBJECTIVE
The aim of the present study was to review the literature on ENT disorders associated with craniosynostosis (CS), focusing on symptoms, diagnostic work-up, treatment and outcome.
METHODS
Publications were retrieved by consulting the PubMed® free search engine of the US National Library of Medicine. The term "craniosynostosis" was combined with the following key-words: ENT, apneas, OSAS, sleep-disordered breathing, tonsillectomy, deafness, hearing loss.
RESULTS
The main ENT disorders associated with CS are upper airway obstruction, chronic otitis and hearing loss. Obstructive sleep apnea-hypopnea syndrome (OSAS) is present in 7% to 67% of children suffering from CS and mainly results from midface stenosis with narrow nasal and rhinopharyngeal cavities. OSAS is diagnosed on polysomnography and airway obstruction levels are determined on wake or drug-induced sleep endoscopy and on CT or MRI. OSAS treatment can be surgical (mainly midface advancement, adenoidectomy and tonsillectomy, tracheostomy) or non-surgical (non-invasive ventilation, nasopharyngeal airway). Hearing impairment is frequently associated with CS. Its main cause is otitis media with effusion (OME) but ossicular malformations and sensorineural hearing loss (SNHL) are sometimes observed. SNHL is mostly found in Muenke syndrome. In view of the frequency and potential severity of these disorders into account, yearly ENT visits are recommended in children presenting with CS.
Topics: Airway Obstruction; Child; Craniosynostoses; Hearing Loss; Humans; Otorhinolaryngologic Diseases
PubMed: 31568777
DOI: 10.1016/j.neuchi.2019.09.015 -
Journal of Neurosurgery. Pediatrics Jul 2019The authors evaluated the long-term outcome of their treatment protocol for Muenke syndrome, which includes a single craniofacial procedure.
OBJECTIVE
The authors evaluated the long-term outcome of their treatment protocol for Muenke syndrome, which includes a single craniofacial procedure.
METHODS
This 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.
RESULTS
The 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.
CONCLUSIONS
Patients 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.
PubMed: 31323628
DOI: 10.3171/2019.5.PEDS1969 -
American Journal of Medical Genetics.... Aug 2019Muenke syndrome (MIM #602849), the most common syndromic craniosynostosis, results from the recurrent pathogenic p.P250R variant in FGFR3. Affected patients exhibit wide...
Muenke syndrome (MIM #602849), the most common syndromic craniosynostosis, results from the recurrent pathogenic p.P250R variant in FGFR3. Affected patients exhibit wide phenotypic variability. Common features include coronal craniosynostosis, hearing loss, carpal and tarsal anomalies, and developmental/behavioral issues. Our study examined the phenotypic findings, medical management, and surgical outcomes in a cohort of 26 probands with Muenke syndrome identified at the Children's Hospital of Philadelphia. All probands had craniosynostosis; 69.7% had bicoronal synostosis only, or bicoronal and additional suture synostosis. Three male patients had autism spectrum disorder. Recurrent ear infections were the most common comorbidity, and myringotomy tube placement the most common extracranial surgical procedure. Most patients (76%) required only one fronto-orbital advancement. de novo mutations were confirmed in 33% of the families in which proband and both parents were genetically tested, while in the remaining 66% one of the parents was a mutation carrier. In affected parents, 40% had craniosynostosis, including 71% of mothers and 13% of fathers. We additionally analyzed the medical resource utilization of probands with Muenke syndrome. To our knowledge, these data represent the first comprehensive examination of long-term management in a large cohort of patients with Muenke syndrome. Our study adds valuable information regarding neuropsychiatric and medical comorbidities, and highlights findings in affected relatives.
Topics: Adolescent; Adult; Autism Spectrum Disorder; Child; Child, Preschool; Cohort Studies; Comorbidity; Craniosynostoses; Disease Management; Female; Gene Expression; Hearing Loss; Humans; Male; Middle Ear Ventilation; Mutation; Osteogenesis, Distraction; Otitis; Pedigree; Philadelphia; Receptor, Fibroblast Growth Factor, Type 3; Recurrence
PubMed: 31111620
DOI: 10.1002/ajmg.a.61199 -
Clinical Oral Investigations Jul 2019To determine whether the intramaxillary relationship of patients with Muenke syndrome and Saethre-Chotzen syndrome or TCF12-related craniosynostosis are systematically...
OBJECTIVES
To determine whether the intramaxillary relationship of patients with Muenke syndrome and Saethre-Chotzen syndrome or TCF12-related craniosynostosis are systematically different than those of a control group.
MATERIAL AND METHODS
Forty-eight patients (34 patients with Muenke syndrome, 8 patients with Saethre-Chotzen syndrome, and 6 patients with TCF12-related craniosynostosis) born between 1982 and 2010 (age range 4.84 to 16.83 years) that 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, were included. Forty-seven syndromic patients had undergone one craniofacial surgery according to the craniofacial team protocol. The dental arch measurements intercanine width (ICW), intermolar width (IMW), arch depth (AD), and arch length (AL) were calculated. The control group existed of 329 nonsyndromic children.
RESULTS
All dental arch dimensions in Muenke (ICW, IMW, AL, p < 0.001, ADmax, p = 0.008; ADman, p = 0.002), Saethre-Chotzen syndrome, or TCF12-related craniosynostosis patients (ICWmax, p = 0.005; ICWman, IMWmax, AL, p < 0.001) were statistically significantly smaller than those of the control group.
CONCLUSIONS
In this study, we showed that the dental arches of the maxilla and the mandible of patients with Muenke syndrome and Saethre-Chotzen syndrome or TCF12-related craniosynostosis are smaller compared to those of a control group.
CLINICAL RELEVANCE
To gain better understanding of the sutural involvement in the midface and support treatment capabilities of medical and dental specialists in these patients, we suggest the concentration of patients with Muenke and Saethre-Chotzen syndromes or TCF12-related craniosynostosis in specialized teams for a multi-disciplinary approach and treatment.
Topics: Acrocephalosyndactylia; Adolescent; Child; Child, Preschool; Craniosynostoses; Dental Arch; Female; Humans; Male; Netherlands; Syndrome
PubMed: 30392078
DOI: 10.1007/s00784-018-2710-9 -
The Cleft Palate-craniofacial Journal :... Sep 2018Craniosynostosis, the premature fusion of cranial sutures, is usually divided into 2 major categories: syndromic and nonsyndromic. Mutations in the , , , , and genes...
INTRODUCTION
Craniosynostosis, the premature fusion of cranial sutures, is usually divided into 2 major categories: syndromic and nonsyndromic. Mutations in the , , , , and genes cause the common craniosynostosis syndromes Muenke, Crouzon and Crouzon with acanthosis nigricans, Apert, Pfeiffer, Saethre-Chotzen, and Craniofrontonasal. Overlapping features among craniosynostosis syndromes, phenotypic heterogeneity even within the same syndrome, especially in the case of Muenke syndrome, and inadequate clinical evaluation can lead to misdiagnosis, which molecular testing can help clarify.
OBJECTIVE
The aim of this study is to investigate the underlying genetic cause in 46 patients with syndromic or nonsyndromic craniosynostosis by direct sequencing and/or microdeletion/microduplication analysis of the , , and genes.
RESULTS
Genetic analysis identified 3 novel mutations, c.413T>C - p.(Leu138Pro) [p.(L138P)] in , the previously reported c.373G>A - p.(Glu125Lys) [p.(E125K)], and c.717dupA - p.(Leu240IlefsTer79) [p.(L240fs)] mutation in gene as well as 6 previously known mutations and a heterozygous gene deletion. The 2 novel mutations within gene arose de novo, but the novel mutation p.(L138P) within gene was inherited from the patient's father, who was found to be mosaic for the mutation. To our knowledge, this is the first case of mosaicism described for gene.
CONCLUSIONS
The contribution of molecular genetic analysis to the diagnosis of patients with syndromic craniosynostosis was useful because some were originally misdiagnosed. Conversely, thorough clinical evaluation can guide molecular testing and result in a correct diagnosis.
PubMed: 29561715
DOI: 10.1177/1055665618760412 -
Radiographics : a Review Publication of... Oct 2017Fibroblast growth factors and fibroblast growth factor receptors (FGFRs) play important roles in human axial and craniofacial skeletal development. FGFR1, FGFR2, and... (Review)
Review
Fibroblast growth factors and fibroblast growth factor receptors (FGFRs) play important roles in human axial and craniofacial skeletal development. FGFR1, FGFR2, and FGFR3 are crucial for both chondrogenesis and osteogenesis. Mutations in the genes encoding FGFRs, types 1-3, are responsible for various skeletal dysplasias and craniosynostosis syndromes. Many of these disorders are relatively common in the pediatric population, and diagnosis is often challenging. These skeletal disorders can be classified based on which FGFR is affected. Skeletal disorders caused by type 1 mutations include Pfeiffer syndrome (PS) and osteoglophonic dysplasia, and disorders caused by type 2 mutations include Crouzon syndrome (CS), Apert syndrome (AS), and PS. Disorders caused by type 3 mutations include achondroplasia, hypochondroplasia, thanatophoric dysplasia (TD), severe achondroplasia with developmental delay and acanthosis nigricans, Crouzonodermoskeletal syndrome, and Muenke syndrome. Most of these mutations are inherited in an autosomal dominant fashion and are gain-of-function-type mutations. Imaging plays a key role in the evaluation of these skeletal disorders. Knowledge of the characteristic imaging and clinical findings can help confirm the correct diagnosis and guide the appropriate molecular genetic tests. Some characteristics and clinical findings include premature fusion of cranial sutures and deviated broad thumbs and toes in PS; premature fusion of cranial sutures and syndactyly of the hands and feet in AS; craniosynostosis, ocular proptosis, and absence of hand and foot abnormalities in CS; rhizomelic limb shortening, caudal narrowing of the lumbar interpediculate distance, small and square iliac wings, and trident hands in achondroplasia; and micromelia, bowing of the femora, and platyspondyly in TD. RSNA, 2017.
Topics: Bone Diseases; Child; Diagnosis, Differential; Genetic Predisposition to Disease; Humans; Mutation; Receptors, Fibroblast Growth Factor; Syndrome
PubMed: 29019756
DOI: 10.1148/rg.2017170017 -
Brain & Development Nov 2017We report a patient with Muenke syndrome who had repetitive apneic spell followed by focal status epilepticus in the early infancy. Ictal EEG showed focal spikes bursts...
We report a patient with Muenke syndrome who had repetitive apneic spell followed by focal status epilepticus in the early infancy. Ictal EEG showed focal spikes bursts originated from the left hemisphere and sifted to the right hemisphere, during which he had migrating tonic seizures from right side of the body to the left side of the body. Brain MRI showed abnormal development of bilateral hippocampus, which was characterized as abnormal folding of hippocampal gyri. However, the long-term seizure prognosis was favorable. Results from this and previous studies failed to support the notion that FGFR3 (P250) mutation results in epileptic encephalopathy.
Topics: Brain; Child, Preschool; Craniosynostoses; Electroencephalography; Epilepsies, Partial; Epilepsy, Temporal Lobe; Hippocampus; Humans; Japan; Magnetic Resonance Imaging; Male; Seizures; Temporal Lobe
PubMed: 28551036
DOI: 10.1016/j.braindev.2017.05.007