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Case Reports
. 2008 May 15;146A(10):1235-40.
doi: 10.1002/ajmg.a.32262.

The clinical spectrum of homozygous HOXA1 mutations

Thomas M Bosley  1 , Ibrahim A Alorainy, Mustafa A Salih, Hesham M Aldhalaan, Khaled K Abu-Amero, Darren T Oystreck, Max A Tischfield, Elizabeth C Engle, Robert P Erickson
Affiliations
Case Reports

The clinical spectrum of homozygous HOXA1 mutations

Thomas M Bosley et al. Am J Med Genet A. .

Abstract

We describe nine previously unreported individuals from six families who have homozygous mutations of HOXA1 and either the Bosley-Salih-Alorainy syndrome (BSAS) or the Athabascan brainstem dysgenesis syndrome (ABDS). Congenital heart disease was present in four BSAS patients, two of whom had neither deafness nor horizontal gaze restriction, thus raising the possibility that cardiovascular malformations might be a clinically isolated, or relatively isolated, manifestation of homozygous HOXA1 mutations. Two ABDS probands had relatively mild mental retardation. These individuals blur the clinical distinctions between the BSAS and ABDS HOXA1 variants and broaden the phenotype and genotype of the homozygous HOXA1 mutation clinical spectrum.

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Figures

Figure 1
Figure 1. Ocular motility
Images A, D, and G are right gaze; images B, E, and H are primary gaze; and images C, F, and I are left gaze. Figures A, B, and C show Patient A1 with total horizontal gaze palsy, while Figures D, E, and F show Patient C1 with bilateral DRS type 3, and Figures G, H, and I are Patient C4 with entirely normal ocular motility. All of these patients had full vertical gaze OU. This montage illustrates the spectrum of horizontal gaze with homozygous HOXA1 mutations, from complete horizontal gaze restriction (top row) to DRS type 3 OU (middle row) to full motility (bottom row).
Figure 2
Figure 2. Neuroimaging
(A) Axial T2-weighted image of Patient B1 at the level of the lateral ventricles showing reduced amount of the periventricular white matter adjacent to the frontal horns and atria of the lateral ventricles secondary to hypoxic-ischemic injury. (B) Axial steady state free precession (SSFP) images of Patient C1 at the level of the temporal bone showing hypoplastic cochlea (solid arrow) and hypoplasia of the vestibule and semicircular canals (open arrow). (C) Axial SSFP images of Patient C1 at the level of the pons where the abducens cranial nerves should be visible. Both 6th cranial nerves are absent.
See this image and copyright information in PMC

References

    1. Tischfield MA, Bosley TM, Salih MA, et al. Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet. 2005;37:1035–1037. - PubMed
    1. Chisaka O, Musci TS, Capecchi MR. Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6. Nature. 1992;355:516–520. - PubMed
    1. Lufkin T, Dierich A, LeMeur M, et al. Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell. 1991;66:1105–1119. - PubMed
    1. Bosley TM, Salih MA, Alorainy IA, et al. Clinical charactization of the HOXA1 Syndrome BSAS variant. Neurology. 2007 in press. - PMC - PubMed
    1. Holve S, Friedman B, Hoyme HE, et al. Athabascan brainstem dysgenesis syndrome. Am J Med Genet A. 2003;120:169–173. - PubMed

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