Mandibulofacial Dysostosis with Microcephaly

Clinical characteristics: Mandibulofacial dysostosis with microcephaly (MFDM) is characterized by malar and mandibular hypoplasia, microcephaly (congenital or postnatal onset), intellectual disability (mild, moderate, or severe), malformations of the external ear, and hearing loss that is typically conductive. Associated craniofacial malformations may include cleft palate, choanal atresia, zygomatic arch cleft (identified on cranial CT scan), and facial asymmetry. Other relatively common findings (present in 25%-35% of individuals) can include cardiac anomalies, thumb anomalies, esophageal atresia/tracheoesophageal fistula, short stature, spine anomalies, and epilepsy.

Diagnosis/testing: The diagnosis of MFDM is confirmed in a proband with typical clinical findings and a heterozygous pathogenic variant in EFTUD2 identified by genetic testing.

Management: Treatment of manifestations: Individualized treatment of craniofacial manifestations is managed by a multidisciplinary team which may include: oromaxillofacial surgery, plastic surgery, otolaryngology, dentistry/orthodontics, 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/tracheoesophageal fistula, cardiac defects, renal anomalies, and thumb anomalies are treated in a routine manner. Short stature is managed expectantly. Treatment of hearing loss is individualized, and may involve conventional hearing aid(s), bone-anchored hearing aid(s), and/or cochlear implant(s). Early individualized educational and therapy plans are devised as needed to optimize developmental outcome.

Surveillance: Annual growth assessment and periodic developmental assessment with evaluation for obstructive sleep apnea and epilepsy as needed.

Genetic counseling: MFDM is an autosomal dominant disorder. Most individuals diagnosed with MFDM to date are presumed to have the disorder as the result of a de novo EFTUD2 pathogenic variant; in some individuals, the causative pathogenic variant was inherited from a parent with a milder phenotypic presentation. If a parent of the proband has the pathogenic variant identified in the proband, the risk to sibs of the proband (at conception) is 50%. Once the causative EFTUD2 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.