Burn-Mckeown Syndrome

A number sign (#) is used with this entry because of evidence that Burn-McKeown syndrome (BMKS) is caused by homozygous or compound heterozygous mutation in the TXNL4A gene (611595) on chromosome 18q23.

Description

Burn-McKeown syndrome is a rare condition in which individuals with normal intellectual development exhibit the characteristic combination of choanal atresia, sensorineural deafness, cardiac defects, and typical craniofacial dysmorphism consisting of narrow palpebral fissures, coloboma of the lower eyelids, prominent nose with high nasal bridge, short philtrum, cleft lip and/or palate, and large and protruding ears (summary by Wieczorek et al., 2014).

Clinical Features

Burn et al. (1992) reported 5 children who presented with bilateral choanal atresia and a spectrum of additional malformations including cardiac defects, deafness, defects of the external ear, eyes and eye lids, and a characteristic dysmorphic appearance. All of the children had normal intelligence. In 1 family, consecutive male sibs had choanal atresia, inguinal hernia, and sensorineural hearing loss. In another family, 1 boy had choanal atresia, a secundum atrial septal defect, widely spaced eyes, and short palpebral fissures, and his brother had bilateral choanal atresia, a unilateral cleft lip with an intact palate, a ventricular septal defect that closed spontaneously, and micrognathia. The brothers in both families had normal 46,XY karyotypes. In an isolated case, a girl had bilateral choanal atresia, cleft lip, a broad nasal bridge, widely spaced eyes with short palpebral fissures, and relative deficiency of the lateral portion of the lower eyelids. She had a short nose, malar hypoplasia and micrognathia, but normal development. Her chromosome analysis was 46,XX,r(18)(p14q23) with normal parental karyotypes. Common features in all were choanal atresia, prominent ears, hypertelorism with short palpebral fissures, and abnormalities of the outer third of the lower eyelid.

Wieczorek et al. (2003) reported 2 German brothers with features resembling those in the patients of Burn et al. (1992). The brothers had normal intelligence, bilateral choanal atresia, and a characteristic pattern of facial dysmorphic features consisting of hypertelorism, lower lid coloboma, narrow palpebral fissures, prominent nasal bridge, small mouth with thin lips, and protruding ears. They also had additional features, including median cleft palate with oronasal fistula, preauricular tag, hypomimic face, and hypoplastic unilateral kidney. Although autosomal recessive inheritance had been suggested, Wieczorek et al. (2003) raised the possibility of X-linked inheritance because all reported patients, except for a female with an X-chromosome abnormality, were male.

Hing et al. (2006) described an autosomal recessive malformation syndrome in 4 related individuals from a geographically isolated Native Alaskan community who had facial defects similar to those of individuals with Treacher Collins syndrome (154500) or Miller syndrome (263750). Distinctive findings included malar and mandibular hypoplasia, lower eyelid coloboma, choanal atresia, orofacial clefting, and external ear malformation with preauricular tags. Intellect was normal. Profound mixed hearing loss was observed in affected adults. Variable extracranial findings included atrial septal defect, renal dysplasia, and imperforate anus, but no limb defects were observed. Three-dimensional CT imaging showed relative prominence of the zygoma, inferior orbital maxillary hypoplasia, and lateral orbital wall defects with an accessory superior bony projection off the zygoma lateral to the orbital rim. Although 2 of the patients had previously been diagnosed with Treacher Collins syndrome, Hing et al. (2006) noted that their features were more similar to those of Miller syndrome except for the absence of limb anomalies.

Wieczorek and Gillessen-Kaesbach (2006) reviewed the clinical features of the 4 patients described by Hing et al. (2006) and noted similarities to those of the 8 patients reported by Burn et al. (1992) and Wieczorek et al. (2003). Hing and Parisi (2006) acknowledged the overlapping clinical features of Burn-McKeown syndrome and what they designated 'oculootofacial dysplasia' (OOFD), and suggested that documentation by CT scan of the characteristic lateral orbital rim observed in OOFD in a patient with Burn-McKeown syndrome would provide further evidence of a common genetic mechanism. Opitz and Burn (2006) commented that the overlap of the dysmorphic appearance and major malformations made it 'highly likely' that these 2 syndromes represent the same entity.

Molecular Genetics

In affected individuals from 9 of 11 families with Burn-McKeown syndrome, Wieczorek et al. (2014) identified biallelic mutations in the TXNL4A gene. Affected members of 8 families, including 2 families originally reported by Burn et al. (1992) and the German family reported by Wieczorek et al. (2003), were compound heterozygous for a 34-bp deletion in the TXNL4A promoter (designated 'type 1;' 611595.0001) and another TXNL4A mutation (see, e.g., 611595.0002-611595.0005). In the Native Alaskan pedigree originally reported by Hing et al. (2006), affected individuals were homozygous for an overlapping but different 34-bp TXNL4A promoter deletion (designated 'type 2;' 611595.0006). Wieczorek et al. (2014) noted that the 2 probands in whom no mutations were detected in TXNL4A were clinically indistinguishable from mutation-positive patients.