Article Figures & Data
Figures
- Fig 1.
A and B, Midsagittal T1-weighted images (T1WIs) in patients 1 and 3 show flattening of the ventral pons, thinning of the isthmus (arrowhead, A), dysmorphism of the dorsal upper pons (caplike) bulging (long arrows) and protruding in the fourth ventricle (B). The vermis is hypoplastic in A. C and D, Midsagittal T2WIs in patients 2 and 4 show the same findings as in A and B, with slightly different patterns (beaklike shape in D) (long arrow). In both cases, the vermis is hypoplastic and dysplastic and the CC is hypoplastic. The CC is dysmorphic in patient 3 (B) and thin in patient 4 (D). E and F, Midsagittal T1- and T2WIs for patients 5 and 6 show the tegmental cap with hypoplastic (E and F) and dysplastic (E) vermis. F, Fourth ventricle is slightly enlarged. The CC is hypoplastic in E and dysmorphic in F.
- Fig 2.
Patient 1: A and B, Coronal T1-weighted images and axial T2-weighted images (T2WIs) show the “molar tooth” appearance of the elongated SCPs running laterally (arrows) and the dorsal band crossing the midline and likely joining the MCPs (arrowheads). C, Axial T2WI at the level of the MCPs, which appear small (white arrows). D, Axial T2WI at the level of middle pons. A “horizontal cleft” is visible, outlined by black arrowheads. The black star indicates the fourth ventricle. Note the small size of cerebellar hemispheres (CH) and the hypoplastic vermis (V).
- Fig 3.
Patient 3: A and B, Color FA cross-sectional images show elongation of the SCP (green).The white star indicates the fourth ventricle. Descending long tracts (corticospinal and corticopontine) appear in blue. The ventral and middle transverse pontine fibers are missing; the SCP decussation is not visible. B, The ectopic bundle of fibers appears in red at the dorsal aspect of the pons and seems not to connect the MCPs visible laterally. C, Coronal FA image shows the elongated SCPs running laterally (arrows); the dorsal band (arrowheads) crossing the midline may join either the SCPs vertically or the MCPs horizontally. D and E, 3D projections of tractography. In the control (D), ventral transverse fibers are clearly seen (black arrow) and the MCPs are of normal size (arrowheads). In patient 3 (E), long descending tracts and the MCPs appear smaller (arrowheads). The ectopic dorsal pontine fibers are visible (long arrow) and are not seen to definitely connect the MCP (arrowheads).
- Fig 4.
Hypotheses to explain the aberrant dorsal position of transverse pontine fibers. A, Normal development. 1) Pontine gray neurons are produced from progenitors in the rhombic lip (blue circles). 2) Newly generated neurons migrate toward the ventral midline (yellow), the “anterior extramural migratory stream” of Altman and Bayer.25 3) Axonal growth cones cross the ventral midline, leaving most neuronal cell bodies uncrossed.26 4) Cell bodies migrate toward the ventricle along radial glia.27 5) Axonal growth cones migrate into the MCP (pink). The transverse pontine fibers are sandwiched between the concurrently growing corticospinal tract (CST) and central tegmental tract (CTT). B, Hypothesis 1: Decreased ventral migration (step 2) leaves the pontine gray neurons scattered along the lateral pontine surface. Axonal growth cones cross the midline directly toward the contralateral MCP. C, Hypothesis 2: Increased radial migration (step 4) deposits pontine neurons near the ventricular surface of the pontine tegmentum. D, Hypothesis 3: Normal migration of pontine neurons. Note abnormal axon guidance away from the ventral surface, followed by midline crossing and attraction toward the MCP.
Tables
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Sex M M M F F F Parent consanguinity No No No NA No No Family history Autosomal dominant retinitis pigmentosa (father, paternal aunt, paternal grand- father) No significant history NA NA No neurologic or developmental disorders, mother with hypothyroidism No neurologic or developmental disorders, sister with interrupted aortic arch, 2nd cousin with VSD Siblings Twin brother, normal Female sibling, normal NA NA NA None Pregnancy Twin pregnancy (monozygotic with single placenta) Singleton pregnancy NA NA Singleton pregnancy Singleton pregnancy, IUGR Antenatal Imaging US at 20 w: cerebellar hypoplasia US at 18 w: cerebellar hypoplasia; at 21w: scoliosis with 2 hemivertebrae NA NA NA NA Delivery Elective cesarian birth at 38 w Elective cesarian birth at 37w NA Normal, delayed cry Cesarean birth for maternal hypertension at 38 w Cesarean birth for fetal distress at 34 w Birth W/L/HC 2580 g/47 cm/33 cm 2450 g/NA/31.8 cm 2512 g/47.2 cm/31.9 cm Low weight 2850 g/NA/32.5 cm 1493 g/NA/NA Cranial nerve involvement Bilateral V palsies, bilateral facial weakness (VII), bilateral sensorineural hearing loss (VIII) diagnosed at 18 m Partial V palsy, possible VI palsy; lower facial weakness, profound high frequency sensorineural hearing loss, VII and VIII palsies Moderate left hearing loss (VIII) Bilateral partial V palsies, bilateral VII palsies, bilateral VIII palsies Bilateral severe sensorineural hearing loss Bilateral severe sensorineural hearing loss, bilateral absence of the vestibular nerves on MRI, bilateral VII palsy, bilateral V Ocular abnormalities Oculomotor apraxia, no nystagmus; corneal ulcers Poor visual fixing, apparent inability to close the eyes, severe corneal drying and right corneal ulcer Absent corneal sensation bilaterally, vertical nystagmus, abnormal gaze-holding, smooth pursuit, saccades, no vestibular ocular reflexes Bilateral corneal opacities Unilateral corneal abrasion leading to corneal opacity, near-absent voluntary eye movements, esotropia requiring bilateral rectus muscle recession Decreased corneal sensation, impaired smooth pursuit but otherwise normal eye movements Swallowing Impaired Impaired Impaired Impaired Impaired Impaired Feeding Poor, nasogastric tube followed by gastrostomy at 5 m Feeding difficulties requiring nasogastric tube Feeding difficulties NA Gastrostomy at 4 m Feeding difficulties improved with age Cerebellar symptoms Ataxia Abnormal movements Head titubation, uncoordinated movements Ataxia Head titubation Ataxia Pyramidal symptoms NA Hypotonia Mild motor delay Normal tone and bulk, brisk reflexes Bilateral ankle clonus Mildly increased lower extremity tone, brisk reflexes Other neurologic or behavioral findings None Mildly dysmorphic features with low set and simple ears, a broad nasal root, a small upturned nose, hypoplastic alar nasae, a long smooth upper lip and mild retrognathia Bangs forehead on surfaces NA None Unknown Extracranial anomalies Thoracic scoliosis, numerous hemivertebrae Vertebral segmentation anomalies on the thoracic and lumbar spine, cocked first toe with a Y-shaped configuration of the second and third toes with minimal syndactyly, horseshoe configuration of the kidneys None Erythematous maculopapular skin rash over face, trunk, and limbs None Severe narrowing of the auditory canals, membranous VSD, submucous cleft palate, bilateral inguinal hernias, obstructive sleep apnea Global development Developmental delay noted from early infancy Failure to thrive NA NA Severe developmental delay Mild developmental delay: walks with a walker, uses many signs, some ability to read and type EEG PSG: recurrent central apneas, hypoventilation during REM sleep Seizures with clonic upper limb movements and facial twitching at 5 w responding to phenobarbital Excessive multifocal sharp waves, without sustained epileptiform activity NA Normal NA Blood examination Lysosomal enzymes, very-long-chain fatty acids; serum lactate and pyruvate, Transferrin isoforms and plasma amino acids, normal Total glycosaminoglycan level slightly elevated NA NA Normal transferrin, deficient glycoprotein testing, mildly elevated CK and liver transaminases Normal transferrin, deficient glycoprotein testing CSF examination Lactate and pyruvate slightly elevated Nonspecific elevation of amino acids NA NA NA NA Urine examination NA Organic and amino acid levels, normal NA NA Urine organic acids, plasma amino acids, normal Urine metabolic screen normal Karyotype 46XY 46XY NA NA 46XX, normal VCFS and subtelomeric FISH testing 46XX, normal VCFS and subtelomeric FISH testing Latest data NA Status epilepticus, hypoglycemia, metabolic acidosis, coagulopathy, and decreased pain response; died at 6 m from parainfluenza pneumonia 5 months old 6 months old Died at 2 years of age from unknown cause 10 years old Note:—NA indicates not available; w, weeks; m, months; W, weight; L, length; HC, head circumference; US, ultrasound; PSG, polysomnography; REM, rapid eye movement; VSD, ventricular septal defect; IUGR, inutero growth retardation; MRI, MR imaging; VCFS, velo-cardio facial syndrome; FISH, fluorescence in-situ hybridization; CK, creatine kinase.
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 DTI Findings in Patient 3 Cerebellar hemispheres Small Small Normal appearance Small Hypoplastic and dysplastic Small Vermis Moderately hypoplastic Hypoplastic and dysplastic Normal appearance Hypoplastic and dysplastic Hypoplastic and dysplastic Hypoplastic Fourth ventricle Slightly enlarged Slightly enlarged Normal, partially occupied by the cap Slightly enlarged Normal, partially occupied by the cap Slightly enlarged SCP Elongated Elongated Elongated Elongated Elongated Elongated Elongated, no decussation MCP Small Small Small Small Small Small Small, joined by the EDTB ICP Un Un Un Small Un Un Un Pons Hypoplastic, flattening of the ventral aspect, dorsal cap, “horizontal cleft” deformity Hypoplastic, flattening of the ventral aspect, dorsal cap, “horizontal cleft” deformity Hypoplastic, flattening of the ventral aspect, dorsal cap, “horizontal cleft” deformity Hypoplastic, flattening of the ventral aspect, dorsal cap, “horizontal cleft” deformity Hypoplastic, flattening of the ventral aspect, dorsal cap, “horizontal cleft” deformity Hypoplastic, flattening of the ventral aspect, dorsal cap, “horizontal cleft” deformity Ectopic dorsal transverse bundle or tegmental cap, descending long tracts located ventrally to the EDTB Pontine-mesencephalon junction (isthmus) Thin Thick Thick Thick Thick Thick Cerebrum Normal appearance Normal appearance Normal appearance Normal appearance Normal appearance Normal appearance Corpus callosum Dysmorphic Hypoplastic Thin Hypoplastic Hypoplastic Dysmorphic Note:—EDTB indicates ectopic dorsal transverse bundle; Un, unidentifiable; DTI, diffusion tensor imaging; SCP, superior cerebellar peduncles; MCP, middle cerebellar penduncles; ICP, inferior cerebellar peduncles.
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