PMID 24999515


Mandibulofacial dysostosis with microcephaly (MFDM) is characterized by malar and mandibular hypoplasia; microcephaly (congenital or postnatal onset); malformations of the pinna, auditory canal, and/or middle ear (ossicles and semi-circular canals) with associated conductive hearing loss; and distinctive facial features (metopic ridge, up- or downslanting palpebral fissures, prominent glabella, broad nasal bridge, bulbous nasal tip, and everted lower lip). Associated craniofacial malformations may include cleft palate, choanal atresia, and facial asymmetry. Intellectual disability is a prominent feature. Major extracranial malformations include: esophageal atresia (~40%), congenital heart disease (~40%), and thumb abnormalities (~25%). Short stature is present in approximately one third of individuals. The diagnosis of MFDM is suspected in individuals with characteristic clinical findings, and confirmed in virtually all affected persons by identification of a heterozygous pathogenic variant or deletion in EFTUD2. Treatment of manifestations: Individualized treatment of craniofacial manifestations is managed by a multidisciplinary team which may include: plastic surgery, otolaryngology, dentistry, orthodontics, oromaxillofacial surgery, and occupational and speech/language therapy. Newborn infants may have airway compromise at delivery due to choanal atresia and/or mandibular hypoplasia, requiring intubation and/or tracheostomy for initial stabilization. Esophageal atresia is managed surgically. Cardiac defects are managed by pediatric cardiology and/or cardiac surgery. Treatment of hearing loss is individualized, and may involve conventional hearing aid(s), bone-anchored hearing aid(s), and/or cochlear implant(s). Occupational, physical, and/or speech/language therapies are involved as needed to optimize developmental outcome. Surveillance: Periodic growth and developmental assessment (preferably by a pediatrician) with inquiry into symptoms of seizures and obstructive sleep apnea; routine follow up by audiology. Pregnancy management: Management of an affected fetus should include a detailed (‘level II’) fetal ultrasound examination and consultation(s) with high-risk obstetrics and/or neonatology, as needed. The delivering team should be aware of the potential for neonatal airway compromise. Polyhydramnios, if present, should prompt urgent postnatal evaluation for esophageal atresia. MFDM is inherited in an autosomal dominant manner. While most affected individuals have a de novo heterozygous EFTUD2 pathogenic sequence variant or deletion, familial recurrence can result from either germline mosaicism or inheritance of the variant from a parent with a milder phenotype. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.