Kaufman Oculocerebrofacial Syndrome

Clinical characteristics: Kaufman oculocerebrofacial syndrome (KOS) is characterized by developmental delay, severe intellectual disability, and distinctive craniofacial features. Most affected children have prenatal-onset microcephaly, hypotonia, and growth deficiency. Feeding issues, ocular abnormalities, hearing impairment, and respiratory tract abnormalities are common. Ocular abnormalities can include structural abnormalities (microcornea or microphthalmia, coloboma, optic nerve hypoplasia), refractive errors (myopia ± astigmatism, hyperopia), strabismus, and entropion. Both conductive and sensorineural hearing loss have been reported as well as mixed conductive-sensorineural hearing loss of variable severity. Breathing problems can lead to prolonged hospitalization after birth in more than half of individuals. Less common findings include ectodermal abnormalities, cardiac manifestations, urogenital abnormalities, seizures, and skeletal abnormalities.

Diagnosis/testing: The diagnosis of KOS is established in a proband with developmental delay/intellectual disability and biallelic UBE3B pathogenic variants.

Management: Treatment of manifestations: Educational intervention and speech therapy beginning in infancy; standard treatment with anti-seizure medication in those with seizures; early intervention as needed for feeding problems and respiratory problems; routine management of ophthalmologic issues, hearing impairment, congenital heart defects, urogenital abnormalities, and skeletal abnormalities.

Surveillance: At least annual assessment of developmental progress, growth, vision, and hearing. Assess for seizures and respiratory issues at each visit. At least annual examination for contractures and scoliosis.

Genetic counseling: KOS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a UBE3B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the UBE3B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.