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American Journal of Medical Genetics.... Apr 2016Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal, and calcaneal fusions, and...
Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal, and calcaneal fusions, and behavioral differences. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings. Muenke syndrome constitutes the most common syndromic form of craniosynostosis, with an incidence of 1 in 30,000 births and is defined by the presence of the p.Pro250Arg mutation in FGFR3. Participants were recruited from international craniofacial surgery and genetic clinics. Affected individuals, parents, and their siblings, if available, were enrolled in the study if they had a p.Pro250Arg mutation in FGFR3. One hundred and six patients from 71 families participated in this study. In 51 informative probands, 33 cases (64.7%) were inherited. Eighty-five percent of the participants had craniosynostosis (16 of 103 did not have craniosynostosis), with 47.5% having bilateral and 28.2% with unilateral synostosis. Females and males were similarly affected with bicoronal craniosynostosis, 50% versus 44.4% (P = 0.84), respectively. Clefting was rare (1.1%). Hearing loss was identified in 70.8%, developmental delay in 66.3%, intellectual disability in 35.6%, attention deficit/hyperactivity disorder in 23.7%, and seizures in 20.2%. In patients with complete skeletal surveys (upper and lower extremity x-rays), 75% of individuals were found to have at least a single abnormal radiographical finding in addition to skull findings. This is the largest study of the natural history of Muenke syndrome, adding valuable clinical information to the care of these individuals including behavioral and cognitive impairment data, vision changes, and hearing loss.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Craniosynostoses; Facies; Female; Four-Dimensional Computed Tomography; Genetic Association Studies; Humans; Infant; Male; Middle Aged; Mutation; Pedigree; Phenotype; Receptor, Fibroblast Growth Factor, Type 3; Young Adult
PubMed: 26740388
DOI: 10.1002/ajmg.a.37528 -
Journal of Oral and Maxillofacial... Dec 2015Midfacial hypoplasia is a characteristic feature of the syndromic craniosynostoses and predisposes these patients to developing obstructive sleep apnea (OSA). The... (Comparative Study)
Comparative Study
PURPOSE
Midfacial hypoplasia is a characteristic feature of the syndromic craniosynostoses and predisposes these patients to developing obstructive sleep apnea (OSA). The purpose of this study was to identify anatomic factors associated with airway obstruction in patients with syndromic craniosynostoses.
MATERIALS AND METHODS
This was a retrospective cohort study. The authors enrolled a study sample composed of patients with syndromic craniosynostoses. The predictor variables were age, gender, body mass index (BMI), syndromic diagnosis, and parameters of upper airway length and size measured on lateral cephalograms. To control for age, upper airway length was corrected for differences in patient height. The outcome variable was OSA status (present or absent). Descriptive, bivariate, and regression statistics were computed. For all analyses, a P value less than or equal to .05 was considered statistically significant.
RESULTS
The sample was composed of 50 patients with a mean age of 10.3 ± 0.6 years, 50% were boys, and 24 (48%) had OSA. Patients with and without OSA did not differ statistically in age, gender, BMI, or syndromic diagnosis. Those with OSA had increased upper airway length (P = .016), decreased posterior airway space (P = .001), and more severe midfacial retrusion (P = .022) compared to patients without OSA. After adjusting for covariates, the odds ratio for OSA was 32.9 in patients with an upper airway longer than 45.3 mm per meter of height (P = .018), and for every 1-mm decrease in posterior airway space, the risk of OSA increased by 30% (P = .022).
CONCLUSIONS
Patients with syndromic craniosynostosis and OSA have a longer upper airway, smaller posterior airway space, and more severe midfacial retrusion than those without OSA.
Topics: Acrocephalosyndactylia; Body Height; Body Mass Index; Cephalometry; Child; Cohort Studies; Craniofacial Dysostosis; Craniosynostoses; Facial Bones; Female; Forecasting; Humans; Hyoid Bone; Male; Mandible; Maxilla; Palate, Hard; Palate, Soft; Pharynx; Polysomnography; Retrospective Studies; Sleep Apnea, Obstructive; Syndrome; Vertical Dimension
PubMed: 26608151
DOI: 10.1016/j.joms.2015.04.017 -
American Journal of Medical Genetics.... Dec 2015Craniosynostosis, the premature closure of cranial sutures, is a common craniofacial disorder with heterogeneous etiology and appearance. The purpose of this study was...
Craniosynostosis, the premature closure of cranial sutures, is a common craniofacial disorder with heterogeneous etiology and appearance. The purpose of this study was to investigate the clinical and molecular characteristics of craniosynostoses in Hungary, including the classification of patients and the genetic analysis of the syndromic forms. Between 2006 and 2012, 200 patients with craniosynostosis were studied. Classification was based on the suture(s) involved and the associated clinical features. In syndromic cases, genetic analyses, including mutational screening of the hotspot regions of the FGFR1, FGFR2, FGFR3, and TWIST1 genes, karyotyping and FISH study of TWIST1, were performed. The majority (88%) of all patients with craniosynostosis were nonsyndromic. The sagittal suture was most commonly involved, followed by the coronal, metopic, and lambdoid sutures. Male, twin gestation, and very low birth weight were risk factors for craniosynostosis. Syndromic craniosynostosis was detected in 24 patients. In 17 of these patients, Apert, Crouzon, Pfeiffer, Muenke, or Saethre-Chotzen syndromes were identified. In one patient, multiple-suture craniosynostosis was associated with achondroplasia. Clinical signs were not typical for any particular syndrome in six patients. Genetic abnormalities were detected in 18 syndromic patients and in 8 relatives. In addition to 10 different, known mutations in FGFR1,FGFR2 or FGFR3, one novel missense mutation, c.528C>G(p.Ser176Arg), was detected in the TWIST1 gene of a patient with Saethre-Chotzen syndrome. Our results indicate that detailed clinical assessment is of paramount importance in the classification of patients and allows indication of targeted molecular testing with the highest possible diagnostic yield.
Topics: Acrocephalosyndactylia; Adolescent; Adult; Child; Child, Preschool; Craniosynostoses; Female; Humans; Hungary; Infant; Male; Mutation; Nuclear Proteins; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3; Risk Factors; Twist-Related Protein 1
PubMed: 26289989
DOI: 10.1002/ajmg.a.37298 -
The Journal of Pediatrics Aug 2015To investigate executive function and adaptive behavior in individuals with Muenke syndrome using validated instruments with a normative population and unaffected...
OBJECTIVE
To investigate executive function and adaptive behavior in individuals with Muenke syndrome using validated instruments with a normative population and unaffected siblings as controls.
STUDY DESIGN
Participants in this cross-sectional study included individuals with Muenke syndrome (P250R mutation in FGFR3) and their mutation-negative siblings. Participants completed validated assessments of executive functioning (Behavior Rating Inventory of Executive Function [BRIEF]) and adaptive behavior skills (Adaptive Behavior Assessment System, Second Edition [ABAS-II]).
RESULTS
Forty-four with a positive FGFR3 mutation, median age 9 years, range 7 months to 52 years were enrolled. In addition, 10 unaffected siblings served as controls (5 males, 5 females; median age, 13 years; range, 3-18 years). For the General Executive Composite scale of the BRIEF, 32.1% of the cohort had scores greater than +1.5 SD, signifying potential clinical significance. For the General Adaptive Composite of the ABAS-II, 28.2% of affected individuals scored in the 3rd-8th percentile of the normative population, and 56.4% were below the average category (<25th percentile). Multiple regression analysis did not identify craniosynostosis as a predictor of BRIEF (P = .70) or ABAS-II scores (P = .70). In the sibling pair analysis, affected siblings performed significantly poorer on the BRIEF General Executive Composite and the ABAS-II General Adaptive Composite.
CONCLUSION
Individuals with Muenke syndrome are at an increased risk for developing adaptive and executive function behavioral changes compared with a normative population and unaffected siblings.
Topics: Adaptation, Psychological; Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; Cohort Studies; Craniosynostoses; Cross-Sectional Studies; Executive Function; Female; Humans; Infant; Male; Middle Aged; Risk Factors; Siblings; Young Adult
PubMed: 26028288
DOI: 10.1016/j.jpeds.2015.04.080 -
Journal of Cranio-maxillo-facial... Jul 2015Patients with craniosynostosis syndromes are at risk of increased intracranial pressure (ICP) and Chiari I malformation (CMI), caused by a combination of restricted... (Comparative Study)
Comparative Study
OBJECTIVE
Patients with craniosynostosis syndromes are at risk of increased intracranial pressure (ICP) and Chiari I malformation (CMI), caused by a combination of restricted skull growth, venous hypertension, obstructive sleep apnea (OSA), and an overproduction or insufficient resorption of cerebrospinal fluid. This study evaluates whether craniosynostosis patients with CMI have an imbalance between cerebellar volume (CV) and posterior fossa volume (PFV), that is, an overcrowded posterior fossa.
METHODS
Volumes were measured in 3D-SPGR T1-weighted MR scans of 28 'not-operated' craniosynostosis patients (mean age: 4.0 years; range: 0-14), 85 'operated' craniosynostosis patients (mean age: 8.0 years; range: 1-18), and 34 control subjects (mean age: 5.4 years; range: 0-15). Volumes and CV/PFV ratios were compared between the operated and not-operated craniosynostosis patients, between the individual craniosynostosis syndromes and controls, and between craniosynostosis patients with and without CMI. Data were logarithmically transformed and studied with analysis of covariance (ANCOVA).
RESULTS
The CV, PFV, and CV/PFV ratios of not-operated craniosynostosis patients and operated craniosynostosis patients were similar to those of the control subjects. None of the individual syndromes was associated with a restricted PFV. However, craniosynostosis patients with CMI had a significantly higher CV/PFV ratio than the control group (0.77 vs. 0.75; p = 0.008). The range of CV/PFV ratios for craniosynostosis patients with CMI, however, did not exceed the normal range.
CONCLUSION
Volumes and CV/PFV ratio cannot predict which craniosynostosis patients are more prone to developing CMI than others. Treatment should focus on the skull vault and other contributing factors to increased ICP, including OSA and venous hypertension.
Topics: Acrocephalosyndactylia; Adolescent; Arnold-Chiari Malformation; Brain Stem; Cerebellum; Child; Child, Preschool; Cranial Fossa, Posterior; Craniofacial Dysostosis; Craniosynostoses; Female; Foramen Magnum; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Infant; Infant, Newborn; Magnetic Resonance Imaging; Male; Organ Size; Plastic Surgery Procedures
PubMed: 25979575
DOI: 10.1016/j.jcms.2015.04.001 -
Neurosurgical Focus May 2015The authors describe the case of a boy with Muenke syndrome, an autosomal dominant disorder associated with craniosynostosis. The family history was significant for...
The authors describe the case of a boy with Muenke syndrome, an autosomal dominant disorder associated with craniosynostosis. The family history was significant for syndromic craniosynostosis in the patient's maternal grandmother, who died in adulthood after a craniofacial reconstruction. The patient, her grandson, underwent craniofacial reconstruction surgery at the age of 9 months and developed upward transtentorial herniation. Imaging findings revealed remote cerebellar hemorrhage after a large quantity of supratentorial CSF was drained during postoperative Day 1. The clinical course was further complicated by cerebral sinus thrombosis, which was diagnosed after a fourth surgical procedure. Upward transtentorial herniation can occur when a significant increase in intracranial pressure in the posterior fossa causes displacement of the central lobule and superior surfaces of the cerebellum upward through the incisura tentorii. This is a rare but well-documented phenomenon that commonly occurs in the setting of an expansive posterior fossa lesion or excessive supratentorial CSF loss. To help clinicians recognize and prevent this rare but potentially fatal complication, the authors review the postulated mechanisms by which this process may occur.
Topics: Cerebellum; Child, Preschool; Craniosynostoses; Frontal Bone; Hernia; Humans; Intracranial Hemorrhages; Male; Orbit; Postoperative Complications
PubMed: 25929970
DOI: 10.3171/2015.2.FOCUS151 -
International Journal of Pediatric... Dec 2014This review addresses hearing loss as it occurs and has been reported in Muenke syndrome as well as six additional FGFR related craniosynostosis syndromes (Apert... (Review)
Review
OBJECTIVE
This review addresses hearing loss as it occurs and has been reported in Muenke syndrome as well as six additional FGFR related craniosynostosis syndromes (Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, Beare-Stevenson syndrome, Crouzon syndrome with acanthosis nigricans, and Jackson-Weiss syndrome.
DATA SOURCES
Pub-Med, Medline, Cochrane Database, Science Direct, NLM Catalog.
REVIEW METHODS
A Medline search was conducted to find all reported cases of the 7 FGFR related syndromic craniosynostosis. Special attention was paid to literature that reported hearing findings and the audiology literature.
RESULTS
Hearing loss occurs in variable percentage as a component part of all FGFR related craniosynostosis syndromes. Our literature review revealed the following incidences of hearing loss in FGFR craniosynostoses: 61% in Muenke syndrome, 80% in Apert Syndrome, 92% in Pfeiffer syndrome, 74% in Crouzon syndrome, 68% in Jackson Weiss syndrome, 4% in Beare Stevenson syndrome and 14% in Crouzon syndrome with Acanthosis Nigricans. The majority of the hearing loss is a conductive hearing loss, with the exception of Muenke syndrome where the majority of patients have a sensorineural hearing loss and Crouzon syndrome where almost half of patients have a pure or component of sensorineural hearing loss.
CONCLUSION
This manuscript presents a diagnostic and management algorithm for patients with syndromic craniosynostosis. It will aid clinicians in treating these patients and further, the recognition of a possible syndrome in patients with hearing loss who also have syndromic features.
Topics: Acanthosis Nigricans; Acrocephalosyndactylia; Craniofacial Dysostosis; Craniosynostoses; Ear; Foot Deformities, Congenital; Hearing Loss, Conductive; Hearing Loss, Sensorineural; Humans; Receptors, Fibroblast Growth Factor; Scalp Dermatoses; Skin Abnormalities
PubMed: 25441602
DOI: 10.1016/j.ijporl.2014.09.019 -
The Journal of Craniofacial Surgery Sep 2014Posterior distraction (PD) is rapidly emerging as an important technique to increase the intracranial volume and correct calvarial morphology in patients with severe...
INTRODUCTION
Posterior distraction (PD) is rapidly emerging as an important technique to increase the intracranial volume and correct calvarial morphology in patients with severe brachycephaly or turribrachycephaly.
METHODS
A retrospective review was performed of all 31 patients who underwent PD at the Oxford Craniofacial Unit between 2007 and 2012.
RESULTS
Twenty-three patients (74.2%) underwent PD as a primary procedure at a median age of 8 months. Eight patients (25.8%) had PD as a secondary transcranial procedure at a median age of 48 months. Full distraction to 20 mm was achieved in 28 patients (90.3%). Of these, all but 1 demonstrated a significant improvement in morphology, with a resolution of the symptoms and signs of raised intracranial pressure in all proven to have it preoperatively. Unanticipated events occurred in 61.3% of patients, with 19.4% undergoing one or more unplanned procedures. Wound infection (29.0%) and tissue necrosis (22.6%) were the commonest. Cerebrospinal fluid leaks were rarer (6.5%) but prevented full distraction. Nine patients (29.0%) had a consolidation period of less than 30 days without experiencing relapse. In 11 patients who had a later fronto-orbital advancement and remodeling, wound closure was tight, resulting in dehiscence in 3 cases (27.3%).
CONCLUSIONS
Posterior distraction is an effective procedure in the management of severe brachycephaly or turribrachycephaly but has associated risks. Our protocol has evolved with experience to favor a reduced latency period and consolidation phase and the use of 2 distractor devices.
Topics: Acrocephalosyndactylia; Cerebrospinal Fluid Leak; Child; Child, Preschool; Craniofacial Dysostosis; Craniosynostoses; Craniotomy; Female; Follow-Up Studies; Humans; Infant; Intracranial Hypertension; Male; Necrosis; Osteogenesis, Distraction; Retrospective Studies; Skull; Surgical Wound Dehiscence; Surgical Wound Infection
PubMed: 25162545
DOI: 10.1097/SCS.0000000000000995 -
Indian Journal of Pediatrics Nov 2014Muenke syndrome is a nonsyndromic coronal craniosynostosis, characterised by clinical and radiological variability, with occurrence of both familial and sporadic cases....
Muenke syndrome is a nonsyndromic coronal craniosynostosis, characterised by clinical and radiological variability, with occurrence of both familial and sporadic cases. Pro250Arg (P250R) is a pathogenic mutation, causing this highly clinically heterogeneous syndrome reported worldwide irrespective of race and ethnicity. The authors describe three Indian cases in two different families showing phenotypic spectrum of the disease, which was later confirmed by genetic testing.
Topics: Child, Preschool; Craniosynostoses; Diagnosis, Differential; Diagnostic Imaging; Female; Genetic Testing; Humans; India; Infant; Male; Mutation; Phenotype; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 24705944
DOI: 10.1007/s12098-014-1424-5 -
The Journal of Maternal-fetal &... Sep 2014Muenke is a fibroblast growth factor receptor 3 (FGFR-3)-associated syndrome, which was first described in late 1990 s. Muenke syndrome is an autosomal dominant disorder... (Review)
Review
Muenke is a fibroblast growth factor receptor 3 (FGFR-3)-associated syndrome, which was first described in late 1990 s. Muenke syndrome is an autosomal dominant disorder characterized mainly by coronal suture craniosynostosis, hearing impairment and intellectual disability. The syndrome is defined molecularly by a unique point mutation c.749C > G in exon 7 of the FGFR3 gene which results to an amino acid substitution p.Pro250Arg of the protein product. Despite the fact that the mutation rate at this nucleotide is one of the most frequently described in human genome, few Muenke familial case reports are published in current literature. We describe individuals among three generations of a Greek family who are carriers of the same mutation. Medical record and physical examination of family members present a wide spectrum of clinical manifestations. In particular, a 38-year-old woman and her father appear milder clinical findings regarding craniofacial characteristics compared to her uncle and newborn female child. This familial case illustrates the variable expressivity of Muenke syndrome in association with an identical gene mutation.
Topics: Adult; Amino Acid Substitution; Arginine; Craniosynostoses; Family; Female; Greece; Humans; Infant, Newborn; Mutation, Missense; Pedigree; Phenotype; Pregnancy; Prenatal Diagnosis; Proline; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 24168007
DOI: 10.3109/14767058.2013.860520