The portal for rare diseases and orphan drugs

More than 100 cases have been reported to date in various ethnic groups.

Mandibulofacial dysostosis-microcephaly syndrome (MFDM) has a wide range of manifestations. Affected patients have malar and mandibular hypoplasia, sometimes with upper airway compromise at birth. Congenital or postnatal-onset microcephaly is found in 90 % of patients (rarely associated with epilepsy). Microcephaly is congenital in two thirds of patients and secondary (postnatal) in about one third. Patients also have preauricular skin tags, microtia or malformations of the pinna, auditory canal, and/or the middle ear (ossicles and semi-circular canals) causing hearing loss (HL) in more than 70 % of cases. HL is generally conductive (about 80 % of patients) and occasionally sensorineural or mixed. Esophageal atresia or tracheo-esophageal fistula is also found occasionally. MFDM also includes a distinctive facial appearance with prominent metopic ridge, up- or down-slanting 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. Short stature is found in about 30 % of patients. Mild to severe developmental delay is very common and includes delayed walking and speech. Almost all affected individuals have intellectual disability that is mostly mild or moderate, and sometimes severe. Other major extracranial malformations may also be found and include congenital heart malformations (e.g. atrial and ventricular septal defects, tetralogy of Fallot, patent arterial duct, and aortic arch defects), cryptorchidism, clinodactyly, and thumb abnormalities.

MFDM is caused by heterozygous, mostly de novo, mutations in the EFTUD2 gene (17q21.31), encoding 116 kDa U5 small nuclear ribonucleoprotein component. A range of deletions and rearrangements, as well as pathogenic missense, nonsense, splice, and frameshift mutations, have been identified.

The diagnosis can be challenging but is generally based on the constellation of clinical manifestations and confirmed by molecular genetic testing revealing a mutation in the EFTUD2 gene.

The differential diagnosis includes Treacher Collins, Nager and CHARGE syndromes and oculo-auriculo-vertebral spectrum.

Prenatal testing for at-risk pregnancies is possible when the mutation has been identified in the family.

MFDM follows an autosomal dominant pattern of inheritance, although most mutations occur de novo. Genetic counseling should be offered to affected individuals, informing them of the 50% chance of offspring inheriting the disease-causing mutation and therefore being affected with the syndrome. The syndrome displays high penetrance but variable expressivity. Gonadal mosaicism has been reported.

Intubation and/or tracheostomy may be required in some affected infants at birth. Craniofacial manifestations should be treated on a case-by-case basis and managed by a multidisciplinary team. Occupational, physical, and speech therapies should be provided, along with standard measures for hearing loss and possible cardiac defects.

The prognosis in MFDM is generally good. Life expectancy is normal in the absence of severe congenital anomalies. Feeding is a significant problem during infancy. The functional repercussions of the syndrome are highly variable with some patients being intellectually normal, some living semi-independently and employed, and some being nonverbal and in need of significant assistance.