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.
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.
Oystreck et al. (2011) detailed the phenotypic similarity in five Saudi patients with genetically and pathologically different ocular motility abnormalities involving straight eyes. The first patient was a 47-year-old male with oculopharyngeal muscular dystrophy presented with complete bilateral ophthalmoparesis and ptosis covering the pupillary axis. He had substantial weakness and wasting of facial muscles, frontal balding, moderate proximal and distal muscle weakness, and nasal speech. The second patient was a 12-year-old boy with congenital myasthenic syndrome who developed bilateral ptosis and partial bilateral ophthalmoparesis at the age of 5 months. He had two older brothers affected with the same syndrome caused by a homozygous mutation in the CHRNE gene. A 7-year-old girl, five of her siblings, and their father were diagnosed with congenital fibrosis of the extraocular muscles type 3. The 7-year-old presented with congenital ptosis and restricted eye movements. At the age of 2 years she had bilateral ptosis repair. The 4th patient was an 11-year-old girl with Bosley-Salih-Alorainy syndrome who presented with anomalous horizontal eye movements and complete congenital deafness since birth. Her younger sister also had similar features, their parents were first cousins. The fifth patient was a 4-year-old-boy who presented with a completely absent horizontal gaze without globe retraction or lid fissure changes; he developed severe progressive scoliosis at the age of 2 years. His parents were first cousins. A homozygous mutation in the ROBO3 gene was found in the patient, confirming the diagnosis of HGPPS.