Pseudo-Torch Syndrome 1

A number sign (#) is used with this entry because of evidence that pseudo-Torch syndrome-1 (PTORCH1) is caused by homozygous or compound heterozygous mutation in the gene encoding occludin (OCLN; 602876) on chromosome 5q13.

Description

Pseudo-TORCH syndrome-1 is an autosomal recessive neurologic disorder with characteristic clinical and neuroradiologic features that mimic intrauterine TORCH infection in the absence of evidence of infection. Affected individuals have congenital microcephaly, intracranial calcifications, severe developmental delay, simplified gyration and polymicrogyria, and severe developmental delay (Reardon et al., 1994; O'Driscoll et al., 2010).

Crow et al. (2000, 2003) called attention to the phenotypic overlap of pseudo-TORCH syndrome and Aicardi-Goutieres syndrome (AGS; 225750), and even suggested that some cases may represent the same disorder. Congenital microcephaly, thrombocytopenia, hepatic dysfunction, and hepatosplenomegaly are usually associated with pseudo-TORCH syndrome and not with AGS, but some patients with AGS have shown these features.

Genetic Heterogeneity of Pseudo-TORCH Syndrome

See also PTORCH2 (617397), caused by mutation in the USP18 gene (607057) on chromosome 22q11.

Clinical Features

Ishitsu et al. (1985) described 2 brothers, aged 49 and 17 months, with microcephaly, severe mental retardation, quadriplegia, and calcification of the cerebral white matter. Congenital toxoplasmosis was excluded by the negative serology in the mother and sons, by the absence of chorioretinopathy, and by the different character of the cerebral calcification. They suggested that this was a previously undescribed genetic disorder, either autosomal or X-linked recessive. The parents were not related.

Baraitser et al. (1983) reported 2 infant sibs born with congenital microcephaly who developed seizures, hypertonia, and spasticity. There was severe developmental delay, and imaging studies showed intracranial calcifications in the white matter and thalamus. There was no evidence of intrauterine infection. Postmortem examination was not performed.

Burn et al. (1986) reported 2 sibs, born of consanguineous Turkish/Cypriot parents, with a disorder resembling intrauterine infection. Both patients were born with microcephaly, jaundice, hepatomegaly, and corneal clouding. Both were jittery in the first hours of life and were found to have thrombocytopenia and petechiae. Brain imaging showed intracranial periventricular calcification. There was no evidence of intrauterine infection. Both infants died at ages 30 and 50 days, respectively. Postmortem examination showed enlarged ventricles, lissencephaly, polymicrogyria, and severely disorganized cortex. There was massive calcification throughout the brain. The basal ganglia, thalamus, hippocampus, and amygdala were shrunken and calcified with severe neuronal loss and gliosis. Calcification was also present in the cerebellum and brainstem. Burn et al. (1986) commented that the disorder in these sibs was distinct from Aicardi-Goutieres syndrome.

Reardon et al. (1994) presented data on 10 patients from 5 families with a combination of microcephaly, intracranial calcification, and a clinical course resembling congenital TORCH infection. The parents were first cousins in 1 family. Hepatomegaly, abnormal liver function tests, petechial rash, and thrombocytopenia were present in some of the affected persons. The optic fundi were normal in all cases in which they were examined. Reardon et al. (1994) compared these cases with those reported by Baraitser et al. (1983), Ishitsu et al. (1985), and Burn et al. (1986). Based on their observations, Reardon et al. (1994) suggested that this entity can be characterized by microcephaly from birth, seizures, periventricular calcification, and sometimes hepatosplenomegaly, platelet dysfunction, and purpura which clinically mimics TORCH infection. The entity was considered to be distinct from the Aicardi-Goutieres syndrome.

Monastiri et al. (1997) reported 2 sibs, born of consanguineous parents, with congenital microcephaly, profound growth retardation, and periventricular calcifications. Variable features included thrombocytopenia, anemia, corneal clouding, spasticity, seizures, and hepatosplenomegaly. Both died in infancy. One sib had dysmorphic features, including microphthalmia, hypertelorism, micrognathia, and micropenis, and left ventricular hypertrophic cardiomyopathy. The other sib had no dysmorphic features.

Slee et al. (1999) presented 2 sisters with congenital microcephaly, developmental delay, marked microphthalmia, congenital cataracts, cerebral and cerebellar hypoplasia, and extensive intracranial periventricular calcification. No evidence of intrauterine infection was found. Slee et al. (1999) suggested that the sibs they reported represented a more severe form of pseudo-TORCH syndrome or a previously undescribed entity. Microcephaly with chorioretinopathy (251270) has changes reminiscent of those seen with fetal intrauterine infection, particularly toxoplasmosis; hence, the designation pseudotoxoplasmosis syndrome.

Briggs et al. (2008) reported 5 patients, including 2 sib pairs, with a distinct pattern of band-like intracranial calcifications, profound developmental delay, postnatal microcephaly, and simplified gyration or polymicrogyria. Two sibs were born of consanguineous Turkish parents. The disorder resembled pseudo-TORCH syndrome, except that none of the patients had thrombocytopenia, hepatosplenomegaly, or congenital microcephaly. Other features included seizures and spastic quadriparesis with hypotonia. Calcification was present in the basal ganglia, thalami, and pons, and formed a ribbon in the posterior frontal, perisylvian, anterior temporal and anterior parietal areas. Some patients had a slightly hypoplastic cerebellum. Mutation in known AGS genes was excluded in 1 patient. In addition, the 2 Turkish sibs had possible evidence of early postnatal cytomegalovirus infection. Although the same group (Crow et al. (2000, 2003)) had previously suggested that some cases of pseudo-TORCH syndrome may represent Aicardi-Goutieres syndrome, Briggs et al. (2008) noted that the umbrella term 'pseudo-TORCH syndrome' remains a useful designation in cases in which the disorder is clearly not Aicardi-Goutieres syndrome, as in their report.

Abdel-Salam et al. (2008) reported a consanguineous family from Egypt in which 5 sibs had congenital microcephaly, growth retardation, and generalized tonic-clonic seizures. There were multiple structural brain anomalies, including cortical band-like calcification, calcifications of the basal ganglia and brainstem, polymicrogyria, loss of white matter, dysplastic ventricles, and hypogenesis of the corpus callosum and cerebellum. Some of the patients had dysmorphic facial features, such as anteverted nostrils, high-arched palate, low-set ears, and sloping forehead. Other features included nystagmus and spasticity. Three died within the first years of life, whereas 2 died within days after birth with high fever and status epilepticus. No abnormalities of the eyes were noted. The features overlapped those of pseudo-TORCH syndrome.

Abdel-Salam and Zaki (2009) presented a family in which 2 sibs had congenital microcephaly, refractory seizures, apneic spells, sterile pyrexia, intracranial calcifications, polymicrogyria, dysplastic ventricles, hypogenesis of the corpus callosum, and loss of white matter. Facial features included sloping forehead, bitemporal grooving, nystagmus, prominent anteverted nostrils, long philtrum, high-arched palate, and microretrognathia. There was truncal hypotonia, absent head control, and increased tone of arms and legs with hyperreflexia. The patients died at 15 and 16 months of age, respectively. The authors concluded that the phenotype was consistent with an autosomal recessive form of a congenital infection-like syndrome.

O'Driscoll et al. (2010) described 10 affected individuals from 6 families with BLCPMG. Three of the families had been previously reported by Briggs et al. (2008) and Abdel-Salam and Zaki (2009). All affected individuals were severely microcephalic, developed seizures within 4 months of birth, showed demonstrated minimal developmental progress, and had spastic tetraparesis. Four of 5 patients had increased cerebrospinal fluid (CSF) protein levels. Brain imaging showed bilateral symmetrical PMG in a perisylvian and temporal distribution, with severe loss of cerebral volume, simplified gyration, and wide sylvian fissures. Calcification was present bilaterally in the deep cortical gray matter with variable calcification in the pons, thalami, and globus pallidus. Postmortem analysis of 1 patient showed mineral deposits in the deep cerebral and cerebellar cortices, frequently surrounding small blood vessels. Calcification was noted in cells in close apposition to endothelia, which possibly represented pericytes or astrocytes. Blood vessels without associated calcification were also seen.

Clinical Variability

LeBlanc et al. (2013) reported 2 patients from a consanguineous Maritime Canadian family who had a complex phenotype comprising congenital microcephaly, intracranial primarily subcortical calcifications in the thalami, basal ganglia, and subcortical white matter, severely delayed psychomotor development, cortical visual impairment, early-onset seizures, and chronic renal dysfunction with small echogenic kidneys, consistent with cortical calcifications. One of the patients had no evidence of a neuronal migration defect, but the other had evidence of mild polymicrogyria. The patients had no independent motility, use of the hands, or speech. An extensive genetic workup, including homozygosity mapping, candidate gene sequencing, exome sequencing, multiplex ligation-dependent probe amplification, PCR analysis, and Sanger sequencing identified a homozygous genomic rearrangement involving the OCLN gene. The rearrangement was a deletion within exon 9, which is expressed in all 7 of the known OCLN isoforms. Genetic analysis was complicated by the presence of a pseudogene in this region; the patients were homozygous for the pseudogene, whereas normal controls were heterozygous for the OCLN gene and the pseudogene. Although some of the patients reported by O'Driscoll et al. (2010) had less severe renal impairment, LeBlanc et al. (2013) noted that extracranial phenotypes, particularly the severe renal impairment seen in their patients, have not consistently been reported in this disorder. Previously reported OCLN mutations have occurred in exons 3 to 6 or at the 5-6 intron splice site, and are thus not expressed in all isoforms. LeBlanc et al. (2013) suggested that the loss of peripheral OCLN in their patients with interruption of exon 9 may explain the unusual renal involvement.

Molecular Genetics

In 9 individuals from 6 families with autosomal recessive band-like calcification with simplified gyration and polymicrogyria (BLCPMG), O'Driscoll et al. (2010) identified homozygous or compound heterozygous mutations in the OCLN gene (see, e.g., 602876.0001-602876.0004). Several of the patients had previously been reported by Briggs et al. (2008) and Abdel-Salam and Zaki (2009). Microarray analysis identified homozygous deletions of copy number probes within exons 3 and 4 in affected individuals from 2 unrelated but consanguineous families from Egypt and Turkey, respectively. Five of 6 families had deletions or mutations affecting the Marvel domain, suggesting that the OCLN mutations result in a protein product that fails to locate to tight junctions in the cell membrane. O'Driscoll et al. (2010) noted that PMG occurs during a critical interval of fetal development and is believed to be mediated by vascular or ischemic insults. Patients lacking functional occludin may have a compromised blood-brain barrier (BBB) and may be vulnerable to tissue damage. In addition, the defect may interrupt signaling between cells. None of the patients had extracerebral abnormalities, suggesting redundancy in other tissues. The findings indicated that mutations in the OCLN gene can result in malformations of cortical development.