RNASET2-deficient leukoencephalopathy mimicking congenital CMV infection and Aicardi-Goutieres syndrome: a case report with a novel pathogenic variant

Abstract

Background: Ribonucleases (RNases) are crucial for degradation of ribosomal RNA (rRNA). RNASET2 as a subtype of RNASEs is a 256 amino acid protein, encoded by RNASET2 gene located on chromosome six. Defective RNASET2 leads to RNASET2-deficient leukoencephalopathy, a rare autosomal recessive neurogenetic disorder with psychomotor delay as its main clinical symptom. The clinical findings can be similar to congenital cytomegalovirus (CMV) infection and Aicardi-Goutieres syndrome (AGS).

Methods: Herein, we presented a patient with motor delay, neurological regression, infrequent seizures and microcephaly at 5 months of age. Brain imaging showed white matter involvement, calcification and anterior temporal cysts. Basic metabolic tests, serum and urine CMV polymerase chain reaction (PCR) were requested. According to clinical and imaging findings, screening of RNASET2 and RMND1 genes were performed. The clinical data and magnetic resonance imaging (MRI) findings of previous reported individuals with RNASET2-deficient leukodystrophy were also reviewed and compared to the findings of our patient.

Results: Brain MRI findings were suggestive of RNASET2-deficient leukoencephalopathy, AGS and CMV infection. Basic metabolic tests were normal and CMV PCR was negative. Molecular study revealed a novel homozygous variant of c.233C > A; p.Ser78Ter in exon 4 of RNASET2 gene compatible with the diagnosis of RNASET2-deficient leukoencephalopathy.

Conclusions: RNASET2-deficiency is a possible diagnosis in an infant presented with a static leukoencephalopathy and white matter involvement without megalencephaly. Due to overlapping clinical and radiologic features of RNASET2-deficient leukoencephalopathy, AGS and congenital CMV infections, molecular study as an important and helpful diagnostic tool should be considered to avoid misdiagnosis.

Keywords: Aicardi-Goutieres syndrome; Congenital cytomegalovirus infection; Cystic leukoencephalopathy; RNASET2-deficienct leukoencephalopathy; Ribonuclease.

Fig. 1

Brain CT-scan at the level of basal ganglia reveals bilateral mildly low attenuated frontal deep white matter with tiny calcified foci in the basal ganglia, most probably along lenticulostriate branches. Persistent cavum septum pellucidum is seen (white arrow) (a). Brain MRI, axial and coronal SE T2-WI and axial FLAIR sequence, illustrates diffuse brain volume loss with secondary ex vacuo type ventriculomegaly. Diffuse abnormal white matter signal, high in T2 WI an FLAIR which is more marked in frontal and temporal lobes is noticeable (b–d). Left anterior temporal lobe and bilateral frontal lobes cystic changes at the white matter could be seen furthermore in FLAIR sequence (black arrow) (e, f). Brain MRI, axial SE T2-WI at the level of centrum semiovale shows diffuse abnormal high signal white matter (g). Brain MRI, axial SE T2-WI and FLAIR sequence, at the level of lower temporal lobes reveals diffuse abnormal high signal white matter in T2-WI with bilateral subcortical anterior temporal cysts confirmed in FLAIR sequence (h, i). Brain MRI, axial SE T1-WI at the level of septum pellucidum demonstrates bilateral abnormal faint low attenuated deep white matter at frontal lobes. Persistent cavum septum pellucidum and vergae are additional findings (j)

Fig. 2

Schematic presentation of RNASET2 gene and location of the reported mutations.1–9: exons; Red boxes: catalytic active sites (CAS I and CAS II) (a). Schematic presentation of RNASET2 protein. Green box: signal peptide; purple boxes: functional domains; white boxes: N- glycosilation site (b). Sequence chromatogram showing homozygote and heterozygote state of c.233C > A mutation in RNASET2 (NM_ 003730.4) in the parents and affected girl