The Athabaskan brainstem dysgenesis syndrome (ABDS) is a recessive genetic disorder with the following features: horizontal gaze palsy, sensorineural deafness, central hypoventilation, and developmental delay. These features significantly overlap with another congenital syndrome; the Bosley-Salih-Alorainy syndrome (BSAS). The phenotype of the latter syndrome includes horizontal gaze abnormalities, deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries, and cardiac outflow tract, mental retardation and autism spectrum disorder.
Importantly, many cases with BSAS suffered certain characteristic features of ABDS and vice versa, making it difficult to distinguish between these two syndromic variants especially that they result from mutations in the same gene (HOXA1). ABDS was named so because it was first observed in native American tribes of Athabaskan descent. Diagnosis is usually based on the symptoms, upon which depends the management of individual cases.
The two syndromes, BSAS and ABDS, have the HOXA1 gene at the centre of their causality. HOXA1 functions to ensure the correct placement of hindbrain segments in the proper location along the anterior-posterior axis during development. Loss of function mutations in the HOXA1 gene were implicated in the two syndromes. A guanine insertion (c.175-176insG) in HOXA1 introducing a premature stop codon is commonly associated with BSAS, while ABDS is associated with a 76C>T transition in HOXA1 that introduces a stop codon in the place of an arginine residue (p.R26X).
Tischfield et al. (2005) reported on eight Saudis belonging to four consanguineous families, who were suffering from BSAS. Their symptoms included horizontal gaze abnormalities, deafness, facial weakness, hypoventilation, vascular malformations, mental retardation and autism spectrum disorder. In thin magnetic resonance sections through the caudal pons from one affected individual, exiting abducens cranial nerves could not be identified. The inner ear was imaged in seven of eight individuals with deafness; bilateral absence of the cochlea, semicircular canals, and vestibule (common cavity deformity) was found in five of them, and cochlear aplasia in two. Otherwise, the cerebrum, cerebellum, and brainstem appeared normal. Computed tomography imaging of the skull base was performed in three individuals with BSAS. One had bilateral absence and two had left-sided absence of the carotid canal, the foramen through which the internal carotid artery (ICA) normally enters the skull. In four individuals in whom magnetic resonance angiography (MRA) of both the head and neck were performed and in three individuals who underwent MRA of the head only, variable ICA malformations, ranging from unilateral hypoplasia to bilateral agenesis, were found. In all patients, Tischfield et al. (2005) identified a homozygous truncating mutation in the HOXA1 gene, which was predicted to cause a loss of HOXA1 function. The identification of a homozygous ~300 kb subregion in chromosome 7p15.2 that is haploidentical in these patients is strongly suggestive of a founder mutation in the Saudi Arabian population. In each family the parents did not show features of BSAS. The abovementioned eight patients along with an additional Saudi patient from a different consanguineous family were further characterized clinically by Bosley et al. (2007). All the patients had the same mutation, but exhibited a fair degree of clinical variability. Additionally, many cases with BSAS suffered horizontal gaze palsy, deafness, and congenital heart disease, making it difficult to distinguish them from ABDS patients. On the other hand, a number of ABDS patients had only mild cognitive problems that are more similar to BSAS. Therefore the two syndromes are classified as phenotypic variants of mutations affecting the HOXA1 gene. In a subsequent study, Bosley et al. (2008) highlighted another six Saudi individuals in whom homozygous mutations in the HOXA1 gene were found. One of these six patients harbored a novel loss of function HOXA1 mutation causing the typical BSAS clinical syndrome. These individuals came from three families, one of which had four patients. The latter family was described as an inbred extended family in which two brothers had married two sisters who were first cousins. Each of these individuals suffered a number of the signs and symptoms of BSAS. For instance, there was a proband from each of the three families and all of these probands suffered severe restriction of horizontal gaze and deafness bilaterally. Importantly, five of these BSAS patients had conotruncal or septal heart defects not previously reported in BSAS, such as tetralogy of Fallot and double outlet right ventricle. These clinical features blurred the distinction between BSAS and ABDS and broadened the clinical spectrum of homozygous HOXA1 mutations.
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