ABSTRACT
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.
Subject(s)
Craniosynostoses/diagnosis , Craniosynostoses/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , Facies , Female , Four-Dimensional Computed Tomography , Genetic Association Studies , Humans , Infant , Male , Middle Aged , Mutation , Pedigree , Phenotype , Receptor, Fibroblast Growth Factor, Type 3/genetics , Young AdultABSTRACT
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.
