Female newborn. Pregnancy with few checkups and normal prenatal ultrasound findings. Uncomplicated term delivery with Apgar score of 7/8. The patient required resuscitation with positive pressure ventilation in the delivery room. The physical examination revealed generalised severe hypotonia with very reduced deep tendon reflexes, shallow breathing, arthrogryposis with contractures in hands and elbows, genu recurvatum in the right lower extremity and fracture at the epiphyseal-metaphyseal junction in the distal third of the femur. The facial phenotype was not dysmorphic, save for the features resulting from hypotonia. Anthropometric measurements at birth: weight, 2330g (5th–10th percentile); length, 44.5cm (<3rd percentile); head circumference, 32.5cm (10th–25th percentile). The patient needed mechanical ventilation due to progressive respiratory failure and placement of a nasogastric tube for enteral nutrition due to inefficient sucking and swallowing. Peripheral hypotonia was suspected, leading to performance of electromyography (EMG), which revealed a clear neuropathic pattern. The karyotype was 46, XX. The results of single-gene testing of the SMN1 gene were normal, ruling out spinal muscular atrophy type 1. The unexpected finding of hypoplasia of the pons, vermis and cerebellar hemispheres in magnetic resonance imaging (MRI) of the head, along with ventriculomegaly with normal intracranial pressure, guided the diagnosis of PCH type 1, which was subsequently confirmed by molecular testing, which identified a homozygous missense mutation in exon 1 of the EXOSC gene (c.92G>C). The patient died at age 4 months of complications of aspiration pneumonia.

Male. Uncomplicated delivery at 39 weeks’ gestation, with normal findings in prenatal ultrasound examinations. Apgar score of 8/9. The patient did not need resuscitation in the delivery room. Anthropometric measurements at birth: weight, 2560g (<5th percentile); length, 46.7cm (10th–25th percentile); head circumference, 32.5cm (<5th percentile). The clinical presentation was similar to that of his deceased sister, requiring mechanical ventilation and enteral feeding through a nasogastric tube. The karyotype was 46, XY. Head MRI revealed hypoplasia of the pons and cerebellum, compatible with the diagnosis of PCH type 1 (Fig. 1). The patient died at age 4½ months due to cardiorespiratory failure. The findings of the postmortem histopathological examination (spinal cord and muscle) were consistent with spinal muscular atrophy, with gliosis and a reduced number of Purkinje cells in the granular layer in the cerebellum. Molecular testing detected the same homozygous mutation (c.92G>C) in the EXOSC3 gene, confirming the clinical diagnosis. Both parents were heterozygous carriers of the mutation.

Figure 1.

Brain MRI.

(0.05MB).

Pontocerebellar hypoplasia type 1 (OMIM# 606489) manifests in the neonatal period with severe hypotonia, absent or reduced deep tendon reflexes, contractures and very weak sucking requiring the use of nasogastric feeding to ensure adequate nutrition. It is associated with a high incidence of aspiration pneumonia, whose complications are usually the cause of early death. Table 1 summarises the clinical criteria for the diagnosis of PCH type 1. The prognosis is highly uncertain, and symptomatic treatment and support measures are the only options currently available. Survival varies, with ranging from infancy to adolescence,4 and there are no biological or genetic markers that allow reliable prognostication. Most sporadic cases of PCH had initially been associated with mutations in various genes (TSEN54, RARS2 and VRK) until the identification of the EXOSC35 gene, of which mutations have been detected in 50% of the cases studied. The EXOSC3 gene encodes a component of the human exosome, a protein complex involved in RNA processing. Its discovery provided evidence than changes in the exosome can cause disease in humans.5 The c.92G>C mutation in the EXOSC3 gene has been identified in some cases of PCH1 reported in the literature, especially in the Czech Romani population, and associated with the most severe form of disease.6

We ought to mention that the EXOSC3 gene is not included in many of the gene panels designed for the assessment of PCH, which should be taken into account in the investigation of these patients given the large size of the Romani population in Spain.