Pseudo-Torch Syndrome 2

A number sign (#) is used with this entry because of evidence that pseudo-TORCH syndrome-2 (PTORCH2) is caused by homozygous or compound heterozygous mutation in the USP18 gene (607057) on chromosome 22q11.

Description

Pseudo-TORCH syndrome-2 is an autosomal recessive multisystem disorder characterized by antenatal onset of intracranial hemorrhage, calcification, brain malformations, liver dysfunction, and often thrombocytopenia. Affected individuals tend to have respiratory insufficiency and seizures, and die in infancy. The phenotype resembles the sequelae of intrauterine infection, but there is no evidence of an infectious agent. The disorder results from inappropriate activation of the interferon (IFN) immunologic pathway (summary by Meuwissen et al., 2016).

For a discussion of genetic heterogeneity of PTORCH, see PTORCH1 (251290).

Clinical Features

Knoblauch et al. (2003) described 2 brothers, born to healthy nonconsanguineous parents of German origin, who showed features resembling congenital intrauterine infection-like syndrome. Both showed extensive intra- and extracranial calcifications, thrombocytopenia, a septum pellucidum cyst, 1-sided paresis of the diaphragm, metaphyseal changes on x-ray scans resembling those produced by intrauterine infection, and hepatosplenomegaly. They developed seizures within the first days of life and died from severe cerebral hemorrhage. Postmortem examination of 1 infant showed lack of gyration of the temporal lobes, diminished gyration at the parietal lobes, and pachygyria. One patient also had cerebellar hypoplasia. There was no indication of a metabolic disorder, especially in calcium metabolism. The authors thought that this disorder could be distinguished from Aicardi-Goutieres syndrome (see, e.g., AGS1, 225750). Meuwissen et al. (2016) reported follow-up of the patients reported by Knoblauch et al. (2003), noting that both sibs had thrombocytopenia and that one had dyserythropoiesis on bone marrow aspiration.

Meuwissen et al. (2016) reported 3 sibs, born of consanguineous Turkish parents, with PTORCH2. One patient presented antenatally with microcephaly, cortical destruction, and calcifications in the subcortical regions, basal ganglia, and periventricular regions. This pregnancy was terminated at 23 weeks' gestation. The other 2 sibs were born alive, but died at ages 7 and 17 days. They had severe intracerebral hemorrhages, enlarged lateral ventricles, respiratory failure requiring ventilation, and bradycardia, and they developed liver dysfunction, ascites, and lactic acidosis; one had severe thrombocytopenia with petechiae. Postmortem examination of 1 patient showed microencephaly, polymicrogyria reflecting defective neuronal migration, heterotopic neural cell clusters, necrosis, rarefaction, dystrophic calcifications, and induction of the brain innate immune system with astrocytes, microglia, and activation of the type 1 IFN pathway.

Inheritance

The transmission pattern of PTORCH2 in the families reported by Meuwissen et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 sibs, born of consanguineous Turkish parents, with PTORCH2, Meuwissen et al. (2016) identified a homozygous truncating mutation in the USP18 gene (Q218X; 607057.0001). The mutation, which was found by a combination of linkage analysis, whole-exome sequencing, and capillary DNA sequencing, segregated with the disorder in the family. Two German sibs with the disorder, previously reported by Knoblauch et al. (2003), were found to be compound heterozygous for the Q218X mutation and a cryptic 3-prime deletion of the USP18 gene (607057.0002). Haplotype analysis of the region containing the Q218X mutation suggested a common ancestor between the 2 families. Cells from patients in both families showed complete absence of the USP18 protein. Patient fibroblasts showed enhanced induction of IFN-stimulated transcripts after stimulation with alpha-IFN (IFNA1; 147660) compared to controls, and transduction of patient cells with wildtype USP18 rescued these effects at the mRNA and protein level. The findings indicated that the disorder results from an aberrant response to type I IFN, rather than an increase in expression of IFN itself. Accordingly, patient cells had normal IFNB1 (147640) mRNA and protein levels. The results also indicated that USP18-mediated regulation of the IFN response is crucial for normal development of the central nervous system.