This comprehensive phenotypic description of patients with genetically defined BSAS expands the original brief report1
and complements the description of ABDS that was published prior to identification of the underlying HOXA1
BSAS is characterized by variable DRS type 3 bilaterally, deafness with malformation of the inner ear, and abnormal development of cerebral vasculature. When patients are young or uncooperative or when individuals have atypical features such as severely restricted horizontal ocular motility or normal hearing, these HOXA1
syndromes may be difficult to distinguish phenotypically from autosomal recessive horizontal gaze palsy and progressive scoliosis (HGPPS; OMIM 607313). Table E-2
compares BSAS with ABDS and HGPPS,5,6
emphasizing genetic, clinical, and neuroimaging features important to the diagnosis.
The BSAS phenotype is variable among these nine patients. Horizontal ocular motility, globe retraction, and convergence were different between eyes and individuals. One patient had normal hearing with normal inner ear anatomy, while eight were deaf with a severe abnormality of cochlear and semicircular canal development. All studied patients had abnormalities of cerebral vasculature, but each had a unique constellation of abnormalities. Patients had a spectrum of somatic defects, most commonly involving external ears or extremities. Delayed motor development could be explained by the lack of a vestibular system rather than by a generalized brain disturbance in most patients. However, two were unequivocally autistic and a third had a number of autistic features, implying an abnormality extending beyond the brainstem. Some of the variability between patients could be interpreted as a severity gradient, from relatively mild involvement (e.g., Patient 8 with modest ocular motility, normal hearing, only left ICA hypoplasia, and normal cognition) to more severe disease (e.g., Patient 5 with no observed horizontal eye movement, deafness and CCD bilaterally, absent ICA bilaterally, and autism).
These patients with BSAS are distinct among patients with inherited DRS7-12
because they have bilateral DRS with limitations of both adduction and abduction. DRS is now understood as a neurogenic problem in which an abnormal abducens nerve results in a denervated lateral rectus muscle that is aberrantly innervated by the inferior division of the oculomotor nerve that also innervates the ipsilateral medial rectus muscle.13
This innervation pattern is believed to precipitate co-contraction of lateral and medial recti, causing the globe retraction and fissure narrowing on adduction and convergence that define DRS.14,15
Abducens nucleus interneurons are spared in unilateral DRS type 1,13,16
where the contralateral eye moves normally, but their status is uncertain in bilateral DRS type 3.
Given that the abducens cranial nerve is absent in the Hoxa1
and probably also in one patient reported here, it seems likely that both BSAS and ABDS patients have partial or complete absence of the abducens nucleus and nerve bilaterally. Differences in residual adduction and the presence of mild abduction in two patients imply variable depletion of abducens motoneurons and interneurons. Similarly, variable dysinnervation of the lateral rectus by branches of the oculomotor nerve may explain differences in globe retraction and fissure narrowing on both voluntary adduction and convergence.
Surprisingly, brain neuroimaging is relatively normal in BSAS. The brainstem has a normal contour, implying that loss of tissue volume is minimal compared to Hoxa1
mutations in the mouse, which cause loss of rhombomere 5 and a 40% reduction in the size of the ventral pons.18
Extraocular muscles appear normal at the resolution of available images, suggesting that the lateral rectus muscle received sufficient innervation for myofiber survival. The supratentorial brain also has a normal appearance despite autism in two patients with BSAS and mental retardation in all patients with ABDS. Only patients with ABDS severely affected by central hypoventilation were reported to have diffuse cortical atrophy, possibly secondary to recurrent hypoxia.4
Deafness is arguably the most important disability in patients with BSAS. The eight deaf patients with BSAS all had the common cavity deformity and underdeveloped petrous bones. Hoxa1
mice also have variable developmental abnormalities in the inner,17,19
and external ear2
even though Hoxa1
expression has not been reported in the otic vesicle. Inductive signals from the adjacent hindbrain neuroectoderm and notochord are necessary for otic vesicle patterning,20,21
and hindbrain defects associated with Hoxa1/
HOXA1 dysfunction may lead to inner ear malformations. Current patients with BSAS were enrolled primarily because of visual abnormalities, and the prevalence of HOXA1 abnormalities in deafness clinics is not yet known.
All six patients with BSAS studied appropriately had cerebrovascular malformations, and the majority of patients with ABDS had conotruncal heart defects.4
Carotid arteries and cardiac out-flow tract arise from symmetrically paired dorsal aortae, aortic arches, and the aortic sac, which appear in the third and fourth weeks of gestation.22 Hoxa1
is expressed in lateral plate and paraxial mesoderm as vasculogenesis commences in the mouse23
and could regulate aspects of angioblast migration or remodeling of primordial aortic arch vessels,24
a process dependent upon neural crest cells and lateral plate mesoderm.25,26
Vascular defects in these patients with BSAS were clinically silent but probably place patients at increased risk of cerebrovascular compromise.
Two patients with BSAS had autism spectrum disorder and another had autistic features. These observations are surprising because the CNS expression pattern of Hoxa1
in vertebrates has a rostral limit at the boundary of rhombomere 3 and 4 prior to neurogenesis27
and at the midbrain-forebrain boundary following neurogenesis.28
Loss of HOXA1
function might cause cortical and cerebellar abnormalities by disturbing development of serotonergic neurons in the brainstem1
that may modulate cerebral cortex columnar organization and cerebellar Purkinje cell arborization.29,30
syndrome implies that correct hindbrain development may be necessary for normal cognition and behavior, and studies of patients with BSAS and ABDS and mutant mice are necessary to determine how HOXA1
function regulates cognitive and behavioral maturation. Patients with BSAS had relatively large skulls, as reported previously in patients with a HOXA1
The constellation of congenital defects in BSAS is similar to abnormalities described in thalidomide exposure between 20 and 24 days post-fertilization.32,33
These thalidomide children sometimes manifest DRS, facial nerve palsy, deafness, external ear anomalies, other somatic abnormalities, autism, and mental retardation, suggesting that thalidomide may disrupt early rhombomere development,34
possibly by a direct effect on HOXA1
or downstream pathways.