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Pontine tegmental cap dysplasia: neuropathological confirmation of a rare clinical/radiological syndrome

Pontine tegmental cap dysplasia (PTCD) is a recently described brainstem malformation [1] characterized by hypoplasia of the ventral pons with a dorsal cap overlying the pontine tegmentum and protruding into the fourth ventricle. Twenty-nine sporadic cases [1–14], have been reported with imaging studies: some include diffusion tensor imaging (DTI) and tractography, which reveal an aberrant transverse fibre bundle at the pontine tegmentum, in the absence of the normal transverse fibres in the ventral pons, suggesting that this disorder results from a failure of axon guidance [1]. Other features include vermal hypoplasia, abnormalities of the cerebellar peduncles and multiple cranial nerve deficits. The children present with mild to severe developmental delay, feeding disorders and impaired swallowing, horizontal gaze palsy, and ataxia. There is variable involvement of cranial nerves V VI VII and IX, while the VIIIth nerve is always affected. Extracranial abnormalities include vertebral anomalies and scoliosis which are most frequent, but cardiac malformations are significant, atrial septal defect (ASD) in 5/29 [1,5,9], aortic arch hypoplasia and tetralogy of Fallot each in 1 of 29 [11,14]. Currently there is no published neuropathology. We report a new case and correlate neuroimaging findings with detailed autopsy pathology. The study was conducted in compliance with local and federal human protection guidelines and institutional review board regulations. The male subject was born to an 18-year-old G2P0 mother. He had an uncomplicated spontaneous delivery at 35 1/7 weeks gestation and weighed 2,120 grams. An ultrasound performed at 20 weeks gestation revealed tetralogy of Fallot, ventricular septal defect (VSD), and bilateral club feet. Amniocentesis showed normal 46 XY karyotype and was negative for 22q11.2 deletion. At birth, he was limp, with no spontaneous respiratory effort; he was resuscitated with positive pressure ventilation and breathing resumed at 3 min of life. Examination was significant for mild facial dysmorphism including a broad nasal bridge and mild hypertelorism. There was a II/VI systolic ejection murmur. Neurological examination demonstrated bilateral ptosis, bilateral facial diplegia, no behavioural response to sound, and absent gag and suck. There were roving eye movements but no apparent blink to light or threat. Strength was grossly normal. There was moderately severe axial hypotonia. Reflexes were normal. Post-natal echocardiogram showed a large, malaligned VSD, right ventricular outflow obstruction, and mild pulmonary valve annular stenosis. Head ultrasound at birth was normal. Magnetic resonance imaging (MRI) of the brain at 1 week of life (Figure 1a) showed a Z-shaped configuration to the brainstem, hypoplastic cerebellum, and very small and narrow middle cerebellar peduncles (not shown). The VSD was repaired at 4 months of life. A gastrostomy tube was placed for oral feeding intolerance; Nissen fundoplication was performed due to gastroesophageal reflux. Supplemental oxygen via nasal cannula was required due to respiratory insufficiency characterized by intermittent and severe oxygen desaturations. The patient developed epilepsy at 9 months of life. A continuous video electroencephalogram (EEG) showed diffuse background slowing and beta activity with left central attenuation, with multiple brief, subclinical seizures. He was started on levetiracetam. Video EEG was repeated at 1 year of life because of depressed mental status. It showed subclinical status epilepticus, which resolved with administration of benzodiazepines; the patient was started on adjunctive clobazam. He failed a hearing test in the neonatal intensive care unit twice and then again as an outpatient, because of sensorineural hearing loss. At last follow up, at 26 months of age, he exhibited profound global developmental delay, could roll over front-to-back and back-to-front, but could not sit with or without support. There was continued head lag with pull to sit and he did not reach for objects of interest. He remained nonverbal, with some nonspecific vocalizations. He did not laugh or smile. He did not visually fix or follow. Repeat MRI performed at 1 year of age showed similar findings to before, consistent with PTCD (Figure 1b,c), although with development of generalized brain parenchymal volume loss involving both supraand infratentorial compartments. The internal auditory canals were severely stenotic