MID1-Related Opitz G/BBB Syndrome

Clinical characteristics: MID1-related Opitz G/BBB syndrome (MID1-OS) is characterized by facial anomalies (hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum), and laryngotracheoesophageal defects. Developmental delay and intellectual disability are observed in about 30% of affected males. Cleft lip and/or palate are present in approximately half of affected males. Other malformations (present in <50% of affected males) include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Wide clinical variability occurs even among members of the same family. Female heterozygotes usually manifest hypertelorism only.

Diagnosis/testing: The diagnosis of MID1-OS is established in a male proband with suggestive findings and a hemizygous pathogenic variant in MID1 identified by molecular genetic testing. Females with a heterozygous MID1 pathogenic variant usually have isolated hypertelorism and only rarely present with other manifestations of MID1-OS.

Management: Treatment of manifestations: Management of anomalies by a multidisciplinary team; surgical treatment of cleft lip/palate and other craniofacial anomalies; standard treatments for hearing loss including PE tubes; speech therapy; standard dental treatments as needed for hypodontia; standard surgical management of hypospadias; surgical treatment for medically significant laryngotracheoesophageal abnormalities; anti-reflux therapy as needed; neuropsychological and educational support; surgical repair of congenital heart defects and imperforate anus; surgical treatment and/or refractive lenses as needed per ophthalmologist.

Surveillance: Follow up with craniofacial team for cleft lip/palate care; audiology evaluation annually or as needed; follow up with urologist as needed for those with significant hypospadias and/or other urinary tract defects; gastroenterology, pulmonology, and/or surgical team follow up for those with laryngotracheoesophageal defects; monitor developmental and educational needs at each visit; cardiology follow up per cardiologist; gastroenterology follow up as recommended for anal defects; ophthalmology evaluations as recommend by ophthalmologist; assess psychosocial and care coordination needs at each visit.

Genetic counseling: MID1-OS is inherited in an X-linked manner. In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. If the mother of the proband has an MID1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually manifest hypertelorism only. Once the MID1 pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives and prenatal and preimplantation genetic testing are possible.