Here, we describe neurobehavioral features in patients with RASopathies (i.e., Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome), developmental disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. Parents of 70 individuals with a RASopathy were asked to fill out the following questionnaires: Child Behavior Checklist (CBCL), Social Communication Questionnaire version lifetime (SCQ-L), and Modified Checklist for Autism in toddlers (M-CHAT). Data analysis indicated high rates of internalizing (37%) and externalizing problems (31%) on CBCL. Scores over the cut-off were documented in 64% of patients with cardiofaciocutaneous syndrome, 44% with Costello syndrome, and 12% with Noonan syndrome on SCQ-L/M-CHAT. Our findings indicate that mutations promoting dysregulation of the RAS-MAPK cascade mark an increased psychopathological risk and highlight that autistic-like behavior could be underdiagnosed in patients with RASopathies.

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We underline the importance of multicentric studies with standardized neuropsychological assessments in large series of young children.

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Auriculo-Condylar Syndrome (ACS) is a craniofacial malformation syndrome characterized by external ear anomalies, hypoplasia of the mandibular condyle, temporomandibular joint abnormalities, micrognathia, and microstomia. Glossoptosis, masticatory abnormalities, orthodontic problems, and malocclusion occur in a majority of affected subjects. The clinical diagnosis is usually suggested by the pathognomonic ear appearance ("question mark ear"), consisting of a variable degree of clefting between the helix and earlobe. The genetic mechanisms underlying ACS have recently been identified. Both autosomal dominant and recessive inheritance of mutations in phospholipase C, beta 4 (PLCB4) and endothelin 1 (EDN1) have been reported along with autosomal dominant mutations in guanine nucleotide-binding protein (G protein) α inhibiting activity polypeptide 3 (GNAI3). We report 6 years of follow-up of a child with a clinical phenotype consistent with ACS due to a homozygous frameshift mutation in PLCB4. The baby presented feeding difficulties associated with failure to thrive and a complex sleep-related respiratory disorder, characterized by central and obstructive apnoeas. Our observations of this case further delineate the phenotype of ACS associated with autosomal recessive PLCB4 loss-of-function mutations, underscoring gastrointestinal dysfunction and severe sleep-related breathing abnormalities as additional features when compared to patients with heterozygous mutations with a presumed dominant negative effect. © 2016 Wiley Periodicals, Inc.