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A rare multiple congenital anomaly syndrome characterized by bilateral choanal atresia associated with characteristic cranio-facial dysmorphisms (hypertelorism with narrow palpebral fissures, coloboma of inferior eyelid with presence of eyelashes medial to the defect, prominent nasal bridge, thin lips, prominent ears), that can be accompanied by hearing loss, unilateral cleft lip, preauricular tags, cardiac septal defects and anomalies of the kidneys. Affected individuals have normal intelligence.
ORPHA:1200Classification level: Disorder
To date, approximately 20 families have been reported worldwide.
Affected individuals present with dysmorphic features from birth onwards. Bilateral choanal stenosis/atresia is potentially life threatening, and may present with respiratory distress at birth. Most patients have lower eyelid defects that can result in corneal exposure and drying. Hearing loss is frequently observed (70% of patients). Cleft lip/palate (approximately 60%) can be uni- or bilateral. Cardiac defects (approximately 30%) include persistent ductus arteriosus (PDA) and patent foramen ovale. Short stature is uncommon but when present is proportionate and mild. Intelligence is typically normal, although intellectual disability has been reported.
The disease is usually caused by a loss of function mutation in TXNL4A (18q23) on one allele and a promotor deletion of TXNL4A on the second allele. Only one family has been described with a homozygous promotor deletion. It is still unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. A few patients are associated with mutations in POLR1A (2p11.2).
Diagnosis is suspected on clinical presentation and confirmed by sequencing of the promotor and coding region of TXNL4A.
The features of this syndrome overlaps with those of the CHARGE and Treacher Collins syndromes.
Theoretically, prenatal diagnosis is possible if there is a positive family history. It is very unlikely that the diagnosis will be prenatally established without a positive family history.
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Intubation is required for neonates presenting with respiratory distress. Surgery is required for choanal atresia. Multidisciplinary referral for evaluation of the possible ophthalmological, audiological, maxillofacial and cardiac anomalies is required. Hearing loss, eye and cardiac defects are managed according to routine procedures. The facial dysmorphism might warrant psychological therapy.
Quality of life is reduced due to choanal atresia, hearing loss and facial dysmorphism. Life expectancy is not reduced.
- Clinical genetics review
- English (2016)