Pontocerebellar hypoplasia type 1 with a milder phenotype in a two-year-old girl.

The rare association of pontocerebellar hypoplasia with anterior horn cell involvement has been classified as pontocerebellar hypoplasia type 1. Its classic phenotype is usually severe. However, the pontocerebellar hypoplasia type 1 may have wider variability in clinical and radiological features. There may be a genetic heterogeneity as well. We described here a young girl with relatively milder clinical phenotype with cerebellar atrophy with absent pontine involvement, further adding to the clinical phenotype.

Introduction

The rare association of pontocerebellar hypoplasia with anterior horn cell involvement has been classified as pontocerebellar hypoplasia type 1.[1] Its genetic basis was largely unknown until recently.[234] The classic phenotype is severe with intra-uterine abnormalities, neonatal feeding and breathing difficulties, contractures, and early death. Milder phenotypes have been rarely reported.[567] We describe a young Indian girl who was diagnosed as pontocerebellar hypoplasia type 1.

Case Report

A 2-year-old girl presented with delayed milestones and floppiness. She was the second child of a non-consanguineous couple with no perinatal or antenatal complications. She had global developmental delay. She achieved head control at 8 months of age but did not achieve independent sitting. She had palmar grasp with transfer of objects. She recognized her parents, responded to her name, and spoke monosyllables. She had no neuroregression. There was no history of seizures, difficulty in feeding or breathing, or recurrent chest infections. There was no vision or hearing impairment. The family history was unremarkable.

Examination revealed an undernourished, alert infant. Her head circumference was normal. There were no neurocutaneous features, facial dysmorphism, spinal deformity, or contractures. She had no bulbar dysfunction but had horizontal nystagmus and tongue fasciculations. There was global hypotonia with absent muscle stretch reflexes and poor antigravity movements. There were no ptosis, facial weakness, extra-pyramidal movements, or cerebellar signs. The fundoscopy was normal. The rest of the systemic examination was unremarkable.

Her initial investigations revealed normal hemogram, serum electrolytes, liver, renal, and thyroid function tests, and total creatine kinase (50 IU/L). The nerve conduction study was normal. Needle electromyography was performed in the right vastus lateralis and deltoid muscles. It revealed a neurogenic pattern of involvement with normal insertional activity, frequent fibrillations and positive sharp waves, and very few motor unit action potentials (MUAPs), which were large, and polyphasic and reduced recruitment.

The child did not show any deletion of exon 7 of the survival-motor-neuron (SMN1) gene. The muscle biopsy from the left vastus lateralis muscle showed variation in fiber size, fiber type grouping, and hypertrophied type 1 fibers suggestive of spinal muscular atrophy. There was no evidence of mitochondrial cytopathy in the biopsied muscle. The isoelectric focusing of transferrins was normal.

Magnetic resonance imaging of the brain showed cerebellar atrophy [Figure 1]. A diagnosis of pontocerebellar hypoplasia type 1 was made in view of paralytic hypotonia, cerebellar atrophy on neuroimaging, and clinical, electrophysiological, and pathological evidence of anterior horn cell involvement. Genetic testing could not be done. The nutritional and physical rehabilitation was initiated, and genetic counseling was done.

Figure 1

Neuroimaging in the child with pontocerebellar hypoplasia type 1. T1-weighted axial (a) and T2-weighted axial (b) and sagittal (c) magnetic resonance images of the brain show prominent cerebellar folia consistent with cerebellar atrophy. Also note the prominent clava (c)

Discussion

The pontocerebellar hypoplasias are characterized by normal initial patterning followed by prenatal onset of degeneration of the hindbrain structures with progressive atrophy postnatally.[1] Parisi et al. had suggested the use of term ‘pontocerebellar atrophies’ for this group of disorders.[8]

In 1993, Barth et al. classified pontocerebellar hypoplasias into two subtypes based on the presence of anterior horn cell involvement.[1] In the last two decades, the classification has been extended up to 7 subtypes.[910] The pontocerebellar or cerebellar hypoplasia associated with anterior horn cell involvement has been classically described as pontocerebellar hypoplasia type 1.[1] The first description of this case was reported in 1961.[11]

The classic phenotype is severe with death in early infancy. The cases with later onset and relatively milder phenotypes have been reported. Four girls with pontocerebellar hypoplasias type 1 with milder phenotype with onset at around 3 years of age were described by Wilmshurst et al.[12] They had an additional feature of dystonia. All the described cases achieved ambulation with aids. A 12-years-old Indian boy was also reported with slowly progressive cerebellar ataxia who could still walk with support. He had marked atrophy of the vermis with minimal pontine involvement.[7]

Rudnik-Schoneborn et al. described an infantile onset with life span up to 2 to 4 years in 3 out of 6 families with pontocerebellar hypoplasias type.[5] These cases with milder phenotypes had isolated cerebellar atrophy without pontine involvement.[513] Our patient also had a relatively milder phenotype as compared to the classical descriptions. Her neuroimaging also revealed cerebellar atrophy without pontine involvement. A late-onset variant of pontocerebellar hypoplasias type 1 with milder phenotype was also described by Lev et al.[6]

The gene defects involved in pontocerebellar hypoplasias type 1 were largely unknown until recently. The mutations in the Exosome Component 3 (EXOSC3) gene were found in 30%-40% of patients with pontocerebellar hypoplasias type 1.[4] The mutations have also been reported in the vaccinia-related kinase 1 gene (VRK1)[2] and tRNA-splicing endonuclease (TSEN) 54 (TSEN54) gene.[3] Rudnik-Schoneborn et al. described the variability in the clinical phenotype among families with pontocerebellar hypoplasias type 1 with EXOSC3 gene mutations. The homozygous c. 395A > C mutations in EXOSC3 were found to be associated with relative sparing of the brainstem and survival beyond early childhood.[4]

The clinico-radiological differentials of pontocerebellar hypoplasia include congenital disorders of glycosylation (CDG), mitochondrial disorders, progressive cerebello-cerebral atrophy, infantile cerebral and cerebellar atrophy, phosphoserine aminotransferase deficiency, and the progressive cerebellar atrophy-encephalopathy-hypsarrhythmia-edema-optic atrophy syndrome (PEHO syndrome).[9] Associated cortical dysplasia may point towards lissencephaly syndromes and dystroglycanopathies. A meticulous evaluation may help in ruling out these entities.

Thus, pontocerebellar hypoplasias type 1 may have wider variability in clinical and radiological features. There may be a genetic heterogeneity as well, and further genetic discoveries may help in better understanding of the pathological process involving the cerebellum, brainstem, and spinal cord. We described here a young girl with relatively milder clinical phenotype with cerebellar atrophy with absent pontine involvement, further expanding the spectrum of this disorder.