Burn-McKeown syndrome

Burn-McKeown syndrome

Overview

Burn-McKeown syndrome is a rare, congenital genetic disorder characterized by nasal passage blockages, distinctive facial features, hearing loss, and heart or growth abnormalities, while generally leaving intelligence unaffected

Symptoms

• Nasal Passage Abnormalities:

• Bilateral choanal stenosis (narrowing) or bilateral choanal atresia (complete blockage of the nasal passages), which can lead to life-threatening breathing and respiratory distress issues in newborns if not surgically repaired.

• Craniofacial (Facial) Features:

• Short palpebral fissures: Narrow openings of the eyelids, sometimes accompanied by downslanting.

• Coloboma: A gap or defect in the lower eyelids, often with eyelashes present medial to the defect.

• Hypertelorism: Widely spaced eyes.

• Prominent nasal bridge: A high or prominent bridge of the nose.

• Philtrum abnormalities: A short space between the nose and the upper lip.

• Mouth and lips: A small opening of the mouth (microstomia) and thin lips.

• Cleft lip and/or palate: Unilateral or bilateral cleft lip or palate occurs in a significant number of cases.

• Ears: Large and protruding (dysplastic/prominent) ears.

• Other facial signs: Malar flattening (hypoplastic cheekbones) and preauricular tags.

• Hearing Loss:

• Congenital hearing loss affecting both ears (varying in severity), which is often mixed—combining both sensorineural and conductive hearing loss.

• Cardiac (Heart) Defects:

• Structural heart abnormalities such as patent ductus arteriosus (PDA) or patent foramen ovale (PFO), and cardiac septal defects. Un-repaired PDA can cause rapid breathing, poor feeding, and slow weight gain in infants.

• Other Features:

• Mild, proportionate short stature (uncommon).

• Occasional kidney (renal) anomalies.

• Intellectual Development: Intelligence is typically normal in affected individuals.

Causes

• Gene Involved: Mutations occur in the TXNL4A gene (located on chromosome 18q23) or its regulatory promoter region.

• Spliceosome Disruption: The TXNL4A gene provides instructions for making a subunit of the major spliceosome, a vital cell machinery complex responsible for processing messenger RNA (mRNA) by removing non-coding regions (introns).

• Reduced Protein: The mutations reduce the amount of functional protein produced, which impairs the assembly of the major spliceosome and disrupts normal cellular expression during early development. Craniofacial (head and face) development is particularly sensitive to these spliceosome defects.

• Alternative Genes: Rarely, a few cases have also been associated with mutations in the POLR1A gene.

• Autosomal Recessive: The condition is inherited in an autosomal recessive manner, meaning an affected individual must inherit a mutated or variant copy of the gene from both parents.

• Typical Combination: Most affected individuals have a compound heterozygous state—typically a small deletion in the promoter region on one allele combined with a damaging loss-of-function mutation or deletion on the other allele. (Homozygous promoter deletions have also been documented in some families).

• Carriers: Parents who carry only one copy of the mutation are generally unaffected themselves, but each pregnancy carries a 25% chance of producing an affected child.

Diagnosis

Doctors suspect the syndrome based on physical signs present at birth, which include:

• Nasal abnormalities: Bilateral choanal stenosis or atresia (narrowing or complete blockage of the back of the nasal passages).

• Craniofacial features: Short palpebral fissures (narrow eyelids), lower eyelid colobomas (gaps), hypertelorism (widely spaced eyes), a prominent nasal bridge, a short philtrum, microstomia (small mouth opening), large/protruding ears, and sometimes a cleft lip or palate.

• Associated anomalies: Congenital hearing loss (mixed or sensorineural), cardiac defects such as patent ductus arteriosus (PDA), and mild short stature, while intelligence is typically normal.

• Diagnostic imaging: Nasal endoscopy or computed tomography (CT) scans are used to confirm choanal atresia and assess nasal or structural defects.

• Targeted sequencing / Whole-genome sequencing: The diagnosis is confirmed by molecular genetic testing (such as sequencing of the coding and promoter regions).

• TXNL4A gene: The condition is caused by biallelic (both copies) pathogenic variants or deletions in the TXNL4A gene or its promoter region (located on chromosome 18q23). (A few atypical cases have also been associated with POLR1A variants).

Treatment

• Airway Management:

• Newborns with bilateral choanal atresia (blocked nasal passages) often experience severe respiratory distress and require immediate intubation.

• Surgical repair is necessary to open the blocked or narrowed nasal passages.

• Craniofacial and Ocular Care:

• Lower-eyelid colobomas (gaps) and other eye anomalies require evaluation and ongoing care by an ophthalmologist to protect the cornea and prevent scarring.

• Cleft lip or palate and other facial differences are managed through specialized referrals to a craniofacial or cleft palate team for reconstructive or supportive therapy.

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• Psychological support or therapy may be helpful for coping with facial dysmorphism.

• Hearing and Audiology:

• Regular audiological assessments are essential.

• Sensorineural hearing loss is treated on an individualized basis, commonly utilizing hearing aids or other assistive listening devices.

• Cardiology Evaluation:

• A full cardiology assessment, including cardiac imaging, is performed to check for congenital heart defects, which are then managed routinely with appropriate follow-up care.

• Genetic Counseling:

• Because the condition is inherited in an autosomal recessive pattern (associated with variants in TXNL4A), genetic counseling is recommended for affected families to discuss recurrence risks and carrier testing.

Type of Doctor Department : Otolaryngologist