Clinical Description
EXOSC3-related pontocerebellar hypoplasia (PCH) is characterized at birth by skeletal muscle weakness manifest as hypotonia (sometimes with congenital joint contractures) and poor feeding. In children with prolonged survival, spasticity, dystonia, and seizures become evident. Respiratory insufficiency and swallowing difficulties are common. Intellectual disability is severe.
To date, 51 individuals (in 36 families) with EXOSC3-related PCH have been described [Wan et al 2012, Biancheri et al 2013, Rudnik-Schöneborn et al 2013, Schwabova et al 2013, Zanni et al 2013, Eggens et al 2014]. In children with the pontocerebellar hypoplasia type 1 (PCH1) phenotype who have identifiable EXOSC3 pathogenic variants, neonatal death, delayed nerve conduction velocities (NCVs), and congenital respiratory and feeding difficulties occur less frequently than in those without identifiable EXOSC3 pathogenic variants [Rudnik-Schöneborn et al 2014].
Pregnancy is unremarkable in the majority. Fetal akinesia resulting in prenatal-onset joint contractures and polyhydramnios may occur in 1%-2% of cases.
Birth weight and length are normal; birth head circumference varies from normal to small. Hypotonia, the most common initial finding, is present at birth in most infants and not evident until age three to six months in the remainder.
Motor milestones are delayed or not achieved at all. Unsupported sitting and walking, observed in only a few children with prolonged survival, are often lost as the disease progresses. Speech is usually absent, but may be limited to short sentences in a few.
In relatively older individuals, central motor (pyramidal or extrapyramidal) and signs of peripheral motor involvement may coexist.
Infections and respiratory failure due to muscle weakness are among the reported causes of death. In most severe cases, respiratory problems start soon after birth. In the majority of children onset of respiratory failure begins within the first year of life. In rare cases, onset is during childhood [Rudnik-Schöneborn et al 2013].
Joint contractures can be present at birth in the most severe cases, or can develop after a few years. Unsupported crawling, sitting, or walking is reported in a few [Zanni et al 2013]; however, these abilities are often lost when disease progresses. In individuals who are able to sit or stand upright, scoliosis can arise due to muscle weakness.
Some infants can be bottle fed or breast fed in the first weeks of life [Eggens et al 2014]. Although on occasion infants are able to eat without aid [Zanni et al 2013], swallowing insufficiency in the majority necessitates tube feeding. Age of onset varies from birth to a few years of age [Rudnik-Schöneborn et al 2013].
Vision is hard to assess in young children. Many are unable to fix and follow, and many show strabismus and/or nystagmus. Possibly, the nystagmus in some children results from early-onset visual impairment, but clear evidence is lacking.
Seizures are mainly reported in individuals who survive beyond infancy [Rudnik-Schöneborn et al 2013, Eggens et al 2014]. A few instances of infantile spasms (West syndrome) are described. Around 25% of those with prolonged survival develop spasticity or epileptic seizures.
Age of death ranges from a few weeks of age to adolescence and can be correlated with certain pathogenic variants (see Genotype-Phenotype Correlations).