Pontocerebellar Hypoplasia Type 4

A severe, genetic form of pontocerebellar hypoplasia (PCH) characterized by delayed neocortical maturation with underdeveloped cerebral hemispheres and pontocerebellar hypoplasia and a severely affected vermis. Clinically, the disorder manifests with prenatal onset of polyhydramnios and contractures followed by hypertonia, severe clonus, primary hypoventilation leading to an early postnatal death.

Epidemiology

Pontocerebellar hypoplasia type 4 (PCH4) has been reported in 10 families to date.

Clinical description

PCH4 is characterized prenatally by polyhydramnios. Neonates present with microcephaly, central apnea requiring respiratory support, dysmorphism (sloping forehead, midface hypoplasia, micrognathia), congenital arthrogryposis (50%), severe clonus, and hypertonia. Weaning from mechanical ventilation is difficult and usually fails. Survival beyond the neonatal period is rare.

Etiology

PCH4 is caused by a compound heterozygosity for p.A307S plus non-sense or splice site mutations in the TSEN54 gene (17q25.1).

Diagnostic methods

MRI (usually performed at autopsy) demonstrates microcephaly due to delayed neocortical maturation with underdeveloped cerebral hemispheres, increased volume of extracerebral cerebrospinal fluid, wide midline cava, pontocerebellar hypoplasia with large denuded areas without folia of the cerebellar hemispheric cortex and a severely affected vermis. Genetic testing is recommended to confirm the diagnosis.

Differential diagnosis

Other types of PCH at the severe end of the spectrum should be considered, such as severe forms of PCH1 or SLC25A46-related PCH.

Antenatal diagnosis

In families in which the causal mutation is detected, prenatal genetic testing or pre-implantation genetic diagnosis should be offered. In general, prenatal detection of PCH by ultrasound is unreliable, since cerebellar abnormalities are often not detected at time of the routine screening for structural abnormalities at 20 weeks of gestation.

Genetic counseling

PCH4 is inherited in an autosomal recessive manner. Genetic counseling is recommended for families of individuals with PCH4. For parents of an affected individual, there is a 25% recurrence risk of having another affected child.

Management and treatment

Treatment is symptomatic in PCH.

Prognosis

Survival beyond the neonatal period is rare in PCH4.