HOXA1 mutations are not a common cause of Möbius syndrome

Abstract

The HOXA1-related syndromes result from autosomal recessive truncating mutations in the homeobox transcription factor, HOXA1. Limited horizontal gaze and sensorineural deafness are the most common features; affected individuals can also have facial weakness, mental retardation, autism, motor disabilities, central hypoventilation, carotid artery and/or conotruncal heart defects. Möbius syndrome is also phenotypically heterogeneous, with minimal diagnostic criteria of nonprogressive facial weakness and impaired ocular abduction; mental retardation, autism, motor disabilities, additional eye movements restrictions, hearing loss, hypoventilation, and craniofacial, lingual, and limb abnormalities also occur. We asked, given the phenotypic overlap between these syndromes and the variable expressivity of both disorders, whether individuals with Möbius syndrome might harbor mutations in HOXA1. Our results suggest that HOXA1 mutations are not a common cause of sporadic Möbius syndrome in the general population.HOXA1-related syndromes include the Bosley-Salih-Alorainy syndrome (BSAS) identified in Saudi Arabian and Turkish families and the Athabascan brainstem dysgenesis syndrome (ABDS) identified in Native American families. 1,2 Both result from autosomal recessive truncating mutations in the homeobox transcription factor, HOXA1. The HOXA1-related syndrome phenotype is variable. The most common features in affected individuals are limited horizontal gaze (diagnosed as Duane syndrome in BSAS and horizontal gaze palsy in ABDS patients) and sensorineural deafness; facial weakness, mental retardation, autism, motor disabilities, central hypoventilation, carotid artery and/or conotruncal heart defects also occur. 1,2 The minimal diagnostic criteria for Möbius syndrome, which is also phenotypically heterogeneous, are nonprogressive facial weakness and impaired ocular abduction. 3,4 Affected individuals can also have mental retardation, autism, motor disabilities, additional eye movements restrictions, hearing loss, hypoventilation, and craniofacial, lingual, and limb abnormalities. 3 Approximately 20% of reported individuals with the HOXA1-related syndromes have both facial weakness and horizontal gaze palsy and thus meet diagnostic Reprint requests: Elizabeth C. Engle, MD, CLS14075 Children's Hospital Boston 300, Longwood Ave., Boston, MA 02115 (Elizabeth.engle@childrens.harvard.edu). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. We asked whether, given the phenotypic overlap between these syndromes and the variable expressivity of both disorders, individuals with Möbius synd...

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“…Most individuals with BSAS and ABDS also have bilateral sensorineural hearing loss caused by an absent cochlea and rudimentary inner-ear development and absent or hypoplastic carotid arteries with a corresponding absence of the carotid canal through which the artery normally passes. Approximately 20% of patients with BSAS or ABDS have congenital facial palsy [ 5 ]. Some affected individuals also have intellectual disability, autism spectrum disorder, moderate-to-severe central hypoventilation, swallowing difficulties, vocal cord paresis, conotruncal heart defects, macrocephaly, and malformations of inner ear bones and/or petrous bones.…”