Differential Diagnosis
Key disorders to consider in the differential diagnosis of pontocerebellar hypoplasia type 1 (PCH1) include EXOSC8-, SLC25A46-, and VRK1-related PCH1, PCH2/4 (TSEN54-related PCH), spinal muscular atrophy type 1, PCH10, and PCH12 . PCH1. About 50% of individuals with PCH1 have pathogenic variants in EXOSC3 (i.e., EXOSC3-PCH). In children with EXOSC3-PCH, neonatal death, delayed nerve conduction velocities, and congenital respiratory and feeding difficulties occur less frequently than in those without identifiable EXOSC3 pathogenic variants . PCH2/4. Dyskinesias and seizures are common in PCH2, the most common type of PCH. PCH4 is a severe form of PCH2, often with congenital contractures and polyhydramnios. In children with EXOSC3-PCH, central motor findings (together with the typical brain MRI findings of cerebellar or pontocerebellar hypoplasia) may falsely suggest a diagnosis of PCH2. Compared to findings in EXOSC3-PCH, the findings in PCH2 are: • No abnormalities of the spinal cord (whereas in PCH1 anterior horn cells are involved); • Attenuation of the pons on brain MRI (whereas in PCH1 the pons can be unaffected). Table 2. Genes of Interest in the Differential Diagnosis of EXOSC3 Pontocerebellar Hypoplasia
Gene(s) | Phenotype/Disorder | MOI | Brain MRI Findings | Clinical Characteristics |
|---|
VRK1 | PCH11,2 | AR | Pontine atrophy may not be present in some individuals. | Lower motor neuron deficits due to loss of anterior horn cells; manifestations of peripheral denervation incl weakness muscle hypotonia from birth; Mixed central (spastic, dystonic) peripheral pareses may be present in those w/prolonged survival; some children w/PCH1 die at an early age.3 |
TSEN54 | TSEN54-PCH (PCH2, 4, 5) | AR | Severe pontocerebellar hypoplasia w/relative sparing of pons; Profound supratentorial atrophy in PCH4 | Generalized clonus, impaired swallowing, dystonia, chorea, progressive microcephaly in PCH2; PCH4 is a severe type of PCH2, w/congenital contractures polyhydramnios. SMN1 |
Spinal muscular atrophy type 1 | AR | Normal | Early-onset (birth-6 mos) disease is characterized by muscle weakness lack of motor development.; Cognitive function is normal.; EMG reveals denervation; muscle biopsy shows grouped atrophy. | — |
CLP1 | PCH10 (OMIM 615803) | AR | Mild cerebellar atrophy/hypoplasia | Very rare disorder characterized by DD, microcephaly, spasticity, axonal motor sensory neuropathy, abnormal muscle tone, seizures, motor neuron degeneration |
COASY | PCH12 (OMIM 618266) | AR | Prenatal-onset microcephaly; hypoplasia of cerebellum, brain stem, spinal cord | Severe prenatal-onset PCH, microcephaly, arthrogryposis w/hypoplasia of spinal cord brain stem, multiple congenital contractures, polyhydramnios, motor neuron degeneration Other disorders to consider ... |
Source: GeneReviews — "EXOSC3 Pontocerebellar Hypoplasia"
