Acrofacial Dysostosis, Cincinnati Type

A number sign (#) is used with this entry because of evidence that the Cincinnati type of acrofacial dysostosis (AFDCIN) is caused by heterozygous mutation in the POLR1A gene (616404) on chromosome 2p11.

Description

The Cincinnati type of acrofacial dysostosis is a ribosomopathy characterized by a spectrum of mandibulofacial dysostosis phenotypes, with or without extrafacial skeletal defects (Weaver et al., 2015).

Clinical Features

Weaver et al. (2015) studied 3 patients with acrofacial dysostosis, which they designated 'Cincinnati type.' The first patient was a 3-year-old Caucasian boy with multiple prenatally identified craniofacial anomalies, including severe micrognathia requiring tracheostomy at birth. Examination revealed downslanting palpebral fissures, severe bilateral lower eyelid clefts, inferiorly displaced orbits, an underdeveloped midface, and extreme micrognathia. He had bilateral anotia and severe conductive hearing loss as well as decreased head circumference and short stature that became more apparent with age. CT scan revealed hypoplasia of the zygomatic arches, maxilla, and mandible, with absent mandibular rami. In addition, the boy had congenital short, bowed femurs with metaphyseal flaring, dysplastic acetabula, and delayed or absent ossification of the capital femoral epiphyses. The second patient was a 6-year-old Brazilian girl, previously included by Wieczorek et al. (2014) in a study of Burn-McKeown patients (see 608572), who had craniofacial anomalies including short downslanting palpebral fissures, upper and lower eyelid clefts, absence of medial eyelashes, heminasal aplasia, large ears, and full lips. CT scan of the face showed hypoplastic zygomata and maxilla and bilateral choanal atresia, which was more severe on the left side. She also had microcephaly, but height and weight were within normal limits, and there were no limb anomalies. Her father had downslanting palpebral fissures and mild malar hypoplasia. The third patient was a 52-year-old German man who exhibited downslanting palpebral fissures, malar flattening, mild micrognathia, and low-set ears with unilateral dysplastic helix and accessory tragus. In addition, he had short, broad fingers and toes.

Molecular Genetics

In a 3-year-old boy with severe acrofacial dysostosis, who was negative for mutation in the Treacher Collins syndrome (154500)-associated gene TCOF1 (606847), Weaver et al. (2015) performed whole-exome sequencing and identified heterozygosity for a de novo missense mutation in the POLR1A gene (E593Q; 616404.0001). Sanger sequencing of POLR1A in 48 patients with mandibulofacial dysostosis of unknown genetic etiology revealed a heterozygous 1-bp deletion (616404.0002) in a 6-year-old Brazilian girl, who was known to be negative for mutation in the TCOF1, POLR1D (613715), POLR1C (610060), and TXNL4A (611595) genes; she inherited the POLR1A deletion from her mildly affected father. Weaver et al. (2015) also found a V1299F missense mutation in a mildly affected 52-year-old German man whose parents were not available for testing. Noting the disparate phenotypes of the 3 affected individuals, Weaver et al. (2015) suggested that the variable severity might correlate with the location or type of mutation or be caused by as yet unidentified genetic modifiers.