Clinical characteristics: TXNL4A-related craniofacial disorders comprise a range of phenotypes that includes: isolated choanal atresia; choanal atresia with minor anomalies; and Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears). Hearing loss is common and cardiac defects and short stature have been reported. Intellectual disability is rare.
Diagnosis/testing: The diagnosis of a TXNL4A-related craniofacial disorder is established in a proband with suggestive findings and biallelic pathogenic variants in TXNL4A identified by molecular genetic testing. All probands described to date have had at least one copy of one of the two partially overlapping 34-bp deletions in the TXNL4A promoter.
Management: Treatment of manifestations: Neonates with airway compromise at delivery may require intubation or surgical correction of choanal stenosis/atresia. Defects of the lower eyelids that can result in corneal exposure require care by an ophthalmologist to reduce the risk of corneal scarring. Treatment of hearing loss is individualized and may involve hearing aids. Treatment of craniofacial manifestations (e.g., cleft lip and/or palate, preauricular tags, prominent ears) is individualized and managed by a multidisciplinary team. Cardiac defects are managed in a routine manner.
Surveillance: Monitoring by an ophthalmologist, audiologist, and craniofacial team is recommended.
Genetic counseling: TXNL4A-related craniofacial disorders are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance inheriting neither of the familial TXNL4A pathogenic variants. Once the TXNL4A pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
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