Situs Inversus in an Infant With Hypomandibular Faciocranial Syndrome: Clinical Overlap With the Agnathia-Otocephaly...

There have been three previously reported cases of hypomandibular faciocranial syndrome (HFS), which is characterized by dysgnathia (an absent or hypoplastic mandible), a protruding lower face, microstomia, normally positioned ears, and craniosynostosis. The dysgnathia and oro-pharyngo-laryngeal abnormalities in HFS are virtually identical to those found in the agnathia-otocephaly complex (AOC), of which severe forms can include holoprosencephaly (HPE), synotia-melotia, and situs abnormalities, but not craniosynostosis. We report an infant with HFS who also presented with situs inversus totalis, which supports its pathogenic overlap with the AOC. The infant showed severe craniofacial asymmetry due to a complex craniosynostosis, microstomia, a hypoplastic tongue, and severe micrognathia, as well as situs inversus totalis. Exome sequencing did not identify any potentially causal variants. It has been noted that dysgnathia is most commonly associated with four distinctive anomalies: synotia-melotia, HPE, situs abnormalities, or craniosynostosis. Through a four-way Venn diagram, we identified eight predictable subsets of patients with dysgnathia that cover all possible phenotypic overlaps that may occur among patients with AOC. Using this approach, we identified that HFS should be conceptualized as a form of dysgnathia (or AOC) that is distinguishable by a distinctive presence of craniosynostosis and an absence of anomalies in the brain and ears, along with the situs abnormalities observed in this case.