Clinical characterization of the HOXA1 syndrome BSAS variant

Patients.

Nine affected individuals from five families were examined in neuro-ophthalmology clinics of the King Khaled Eye Specialist Hospital and the King Faisal Specialist Hospital and Research Centre and in the Pediatric Neurology Clinic of the King Khalid University Hospital in Riyadh, Saudi Arabia. The genetic features of eight of the individuals (Patients 1 through 8) were reported previously,¹ while Patient 9 was the child of an unrelated consanguineous family. She was genotyped more recently, using the same primer sequences and PCR conditions detailed previously, and was found to have the same homozygous HOXA1 guanine insertion (I75-I76insG) founder mutation as other reported Saudi individuals. All families signed informed consent at the appropriate institution.

Clinical evaluation.

All patients had complete neurologic, neuro-ophthalmologic, and orthoptic examinations, including videotaping of eye movements in eight individuals. Ocular motility and alignment was evaluated in all positions of gaze. Fusional status was evaluated using a variety of binocular vision tests including the Worth 4 Dot test, Titmus stereo-acuity test, Bagolini striated lenses, and ability to overcome base-out prism with convergence. Best-corrected visual acuity was assessed with methods appropriate for age and cognitive ability. All patients had dilated funduscopic examinations.

Neuropsychological evaluation.

Eight members of four Saudi families were seen by a neuropsychologist (M.N.), seven of whom were evaluated with the Vineland Adaptive Behavior (VAB) scale. VAB was administered by an experienced native neuropsychological technician trained in its use, and scoring for age equivalency was done independently by the neuropsychologist. All children other than the youngest (Patient 9) had repeated neurodevelopmental evaluations over several years (M.A.S.), and Diagnostic and Statistical Manual of Mental Disorders (DSM)-4 criteria for autism were applied separately by a neuropsychologist and a pediatrician. Patient 3 was also evaluated with the Childhood Autism Rating Scale (CARS).

Neuroimaging.

Six affected individuals had MR images of the brain or neck. Standard brain MR pulse sequences were acquired in five patients using a 1.5 Tesla GE Signa scanner (GE Medical Systems, Waukesha, WI) or 1.5 Tesla Siemens Magneton Vision (Siemens Medical Systems, Germany) including sagittal T1-weighted spin echo (350 to 500/10 to 15/1 [TR/TE/NEX]), coronal fluid-attenuated inversion recovery (8,800/130, inversion time, 2,200 msec), and axial dual echo (3,500/119 and 17). MR images were obtained in one patient on a 3.0 Tesla Siemens Magneton Allegra scanner (Siemens Medical Systems) including sagittal T1-weighted (624/7), axial fluid-attenuated inversion recovery (8,000/80, inversion time 2400 msec), and axial MP-RAGE (2,500/4.4, 1 mm thickness) through the brain, and axial 3D FT constructive interference in steady-state of the inner ear and cerebellopontine angle (11/5.6, 1 mm thickness).

MR angiogram (MRA) of the head was obtained in five patients using time-of-flight (TOF) sequence and of the neck in four of them using TOF or phase contrast sequence. One patient had CT of the brain (7 mm slice thickness), and five had CT of the temporal bone (1 mm slice thickness). Volume data from CT were used for reconstruction of coronal petrous bone images.

Clinical and neuropsychological observations.

Patient numbers for Patients 1 through 8 correspond to Supplementary Table 1 Online of Tischfield et al.,¹ while Patient 9 was proven more recently to have the same Saudi BSAS mutation. Table 1 includes basic demographics and certain general characteristics of these nine affected individuals (three male and six female, aged 3 to 20 years), while table E-1 (on the Neurology Web site at www.neurology.org) summarizes the developmental and cognitive characteristics of these patients, including the VAB scale.

Eight patients were deaf and mute while one had normal hearing and speech development. Eight had a variety of behavioral (sleep disturbance, grimacing) and somatic (affecting face, ear, gastrointestinal tract, genitourinary system, and feet) abnormalities. Two deaf patients with speech abnormalities (Patients 1 and 9) and the one patient with normal hearing (Patient 8) had grossly normal neurodevelopmental histories and examinations except for ocular motility. Six patients had developmental motor delay by report (two on examination when young), typically not walking until the age of 3 years. No patient had scoliosis, inappropriately small stature, or cervical spine malformation, but as a group they had a somewhat large cranial circumference. Three families reported a total of seven miscarriages.

Patients 3 and 5 met DSM-4 criteria for autistic spectrum disorder by examination, family report, and VAB scores. Patient 3, who was institutionalized, scored 42 on CARS examination, falling in the moderate/severe autistic range. Both children exhibited profound linguistic delay with virtually nonexistent nonverbal communication skills, impaired social functioning, lack of eye contact, stereotypic hand movements, tactile avoidance, and obsessional features, such as compulsively arranging pictures and objects in the environment and persistent preoccupation with bright or shiny parts of objects. They had no reciprocal play, and their interests were narrow. Self-care skills were uniformly poor. Families of both autistic individuals reported sleep disturbance, although the older individual had improved with age. Patient 7 also had autistic features with stereotyped movements, excessive shyness, and complete lack of language; however, she had nonverbal communication and socialized in a fashion typical of a deaf child her age.

Ocular motility.

All patients had a moderately severe or complete limitation of adduction and abduction bilaterally with full vertical gaze, as detailed in table 2 and illustrated in figure 1. Six patients (Patients 1, 2, 4, 6, 8, and 9) had globe retraction and palpebral fissure narrowing on adduction bilaterally diagnostic of DRS type 3 (figure 1, A through F). Patient 7 had retraction documented only unilaterally; however, horizontal motility restriction was present bilaterally, and her older sister had unequivocal globe retraction bilaterally. Globe retraction and fissure narrowing was not observed in either eye of Patients 3 and 5 (figure 1, G through I). These patients had severe restriction of horizontal eye movement, and autism interfered with their ability to cooperate with the examination. Both patients had at least one BSAS-affected sibling with obvious DRS type 3 bilaterally. Bilateral globe retraction was readily apparent upon convergence in the three patients with strong convergence (Patients 4, 8, and 9).

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Figure 1 Variability of ocular alignment and motility

Images A, D, and G are right gaze, while images B, E, and H are in primary position, and images C, F, and I are left gaze. Top row (A, B, and C) are of Patient 4 who had a primary position esotropia with no anomalous head position when fixing with the right eye. This patient was unable to abduct either eye beyond the midline but demonstrated modest adduction bilaterally with globe retraction and fissure narrowing of the adducting eye. Middle row (D, E, and F) are of Patient 8 who was orthotropic in primary position but adopted a small face turn left to maintain comfortable binocular fixation. He had no eye movements to the left but modest symmetric movement of both eyes into right gaze. Bottom row (G, H, and I) are of Patient 5, who was orthotropic in primary position and had severely limited eye movements bilaterally with only minimal adduction the right eye. No abnormal head posture was present in primary position but she used a face turn to view objects to the right or left.

Five patients (Patients 3, 5, 7 through 9) were orthotropic in primary position at distance (figure 1, E and H), while four (Patients 1, 2, 4, and 6) had an esotropia in primary position (figure 1B). Patient 6 had an accommodative element to her esotropia, and she was the only patient who underwent strabismus surgery to correct the horizontal deviation. Two patients had low amplitude nystagmus that was horizontal pendular in one (Patient 5) and vertical pendular in another (Patient 6). Three patients (Patients 2, 4, and 6) developed a vertical deviation on attempted horizontal gaze.

Afferent functioning.

Seven patients had normal visual acuity, ocular fundi, pupillary function, and visual fields. Patient 2 had 20/80 acuity bilaterally, possibly because of age and ability to cooperate. Three patients (Patients 6, 7, and 8) demonstrated fusion. Patient 6 had a monofixation syndrome with a tiny residual manifest deviation following early strabismus surgery, while Patient 7 had no manifest deviation in primary position, and Patient 8 required a small left face turn to maintain binocular alignment (figure 1E).

Neuroimaging.

Table 3 details results of neuroimaging studies. No imaged patient had gross congenital brain anomalies or evidence of ischemia. Orbits and extraocular muscles appeared normal in all studies (figure E-1, A and B). Brainstem and 4th ventricle were normally developed (figure E-1, C and D), as were supratentorial structures. Patient 8 had a 3 Tesla scan with thin MR sections through the caudal pons. These images were degraded by a pulsation artifact anterior to the pons, but the exiting abducens cranial nerve (CN) could not be identified bilaterally (figure E-1, E through G) despite routine identification of these nerves on control images. Scout views of five of the six patients undergoing head CT allowed gross evaluation of the cervical spine, all of which appeared normal.

The skull base was normal only in Patient 8, who had normal inner ear anatomy (figure 2A) and normal hearing, while the eight patients with sensorineural deafness had malformations involving the inner ear and petrous bone. Four patients (Patients 4 through 7) had the common cavity deformity (CCD) replacing cochlea, semicircular canals, and vestibule bilaterally (figure 2, B through D) and two (Patients 1 and 3) had CCD on one side and complete absence of inner ear structures on the other side (figure 2E). Carotid canals were absent bilaterally in Patient 5 and unilaterally in Patients 4 and 6 (figure 2B). Internal auditory canal (IAC) was absent or severely narrowed in the six patients with inner ear malformation (figure 2E). The combination of profound inner ear maldevelopment with absent carotid canal sometimes yielded the appearance of a small petrous bone with patulous Meckel's caves (figure 2F).

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Figure 2 Variability of skull base neuroimaging

(A) High resolution axial constructive interference in steady-state MR image of the inner ear and low brainstem of Patient 8 demonstrating normal inner ear structures and normal lower cranial nerves. (B, C) Axial CT (B) and T2-weighted MR images (C) at the level of the inner ear of Patient 6 demonstrating bilateral common cavity deformity (black arrow in B and white arrows in C). The medial part of the left carotid canal is absent (double arrows in B) while the right one is present. (D) Axial CT of the petrous bone of Patient 3 showing common cavity deformity of the left inner ear (open arrow) with normal stapes (double arrows) and lack of development of the oval window opposite to the footplate of stapes (solid arrow). (E) Reconstructed coronal CT image of the petrous bone of Patient 3 showing the common cavity deformity of the left inner ear (open arrow) and severe stenosis of the left internal auditory canal (black arrow). Inner ear structures on the right side are absent. (F) Coronal T2-weighted MR image of Patient 7 showing patulous Meckle's caves (arrows).

All six patients with MR angiography or MR imaging had abnormalities of the internal carotid arteries. The left internal carotid artery (ICA) was hypoplastic in Patients 1 and 8 (figure 3A) and absent in Patients 4, 6, and 7 (figure 3B) where the left common carotid artery terminated into the external carotid artery. Four patients (Patients 1, 6, 7, and 8) with hypoplastic or absent left ICAs had a right common carotid artery bifurcation quite low in the neck, at about the C7 level (figure 3C). All six patients with ICA anomalies had an enlarged posterior communicating artery on the side of an absent or hypoplastic ICA (figure 3, B, D, and E). The ICAs were absent bilaterally in Patient 5, who had blood supply to the brain only through an enlarged vertebrobasilar system (figure 3, D and E). The intracranial portion of the left vertebral artery was duplicated in Patient 5 (figure 3F), while Patient 1 had duplication of the proximal half of the left vertebral artery.

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Figure 3 Variability of MR angiography

(A) Coronal T2-weighted MR image of Patient 8 demonstrating hypoplasia of the cavernous (white arrow) and supraclinoid (black arrow) portions of the left internal carotid artery. The cavernous and supraclinoid portions of the right internal carotid artery have normal caliber. (B) MR angiogram of the brain of Patient 6 showing absence of the left internal carotid artery and hypoplasia of the cavernous portion of the right internal carotid artery (black arrow). Vertebral and basilar arteries (white arrow) have larger caliber than the right internal carotid artery. (C) MR angiogram of the neck of Patient 6 demonstrating absence of the left internal carotid artery with the common carotid artery ending as a continuation of external carotid artery (white arrows). The right common carotid artery has a bifurcation (black arrow) at about the level of the C7 vertebra, while normal bifurcation of common carotid artery is about the level of C4. (D, E) Anterior (D) and lateral (E) projections of the MR angiogram of the brain of Patient 5 demonstrating absence of both internal carotid arteries and enlargement of the basilar (arrow) and posterior communicating arteries, which supply both the anterior and posterior cerebral circulations. (F) MR angiogram of the brain of Patient 5 showing duplication of the intracranial portion of the left vertebral artery (arrows).