Case Report: Aicardi-Goutières Syndrome Type 6 and Dyschromatosis Symmetrica Hereditaria With Congenital Heart Disease and Mitral Valve Calcification – Phenotypic Variants Caused by Adenosine Deaminase Acting on the RNA 1 Gene Homozygous Mutations

Abstract

Dyschromatosis symmetrica hereditaria (DSH), characterized by a mixture of hyper- and hypopigmented macules on the skin, is a rare pigmentary dermatosis of autosomal dominant inheritance. The pathogenic gene is adenosine deaminase acting on the RNA 1 gene (ADAR1), mutations in this gene also lead to Aicardi-Goutières syndrome type 6 (AGS 6), a rare hereditary encephalopathy with isolated spastic paraplegia. The pathomechanism of the ADAR1 gene mutations inducing DSH has not been clarified yet. We report the first case of DSH combined with AGS caused by the homozygous mutation of the ADAR1 gene in China (c.1622T > A) and reviewed the relevant literature. AGS 6 could occur in both men and women, and start in infancy. The main characteristics are growth retardation, skin depigmentation, intracranial calcification, and cerebral white matter lesions. In the current paper, the proband also had patent ductus arteriosus (PDA), ventricular septal defect (VSD), and mitral valve calcification, which are new symptoms that have not been reported in other cases. Additionally, we also aim to discuss the possible molecular mechanisms underlying the clinical heterogeneity caused by ADAR1 gene mutations.

Dyschromatosis symmetrica hereditaria: A clue to early diagnosis of Aicardi–Goutières syndrome

“…Lesions arise in infancy or early childhood and tend to increase in number until adolescence. Concurrent presentation of DSH and AGS 6 has been previously described with compound heterozygous and homozygous ADAR mutations 1–3 . Our case reports on a patient with de novo, heterozygous ADAR variants associated with DSH and AGS 6.…”

“…Concurrent presentation of DSH and AGS 6 has been previously described with compound heterozygous and homozygous ADAR mutations. [1][2][3] Our case reports on a patient with de novo, heterozygous ADAR variants associated with DSH and AGS 6. However, we cannot exclude the possibility of another unknown mutated allele in the non-coding region of ADAR is responsible for the present findings.…”

Aicardi–Goutières syndrome: A monogenic type I interferonopathy

“…29 Dyschromatosis symmetrica hereditaria (DSH), a rare autosomal dominant hereditary pigmented skin disorder, may arise in patients with AGS6 type. 30 AGS also has clinical manifestations of liver, kidney and other organs. [31][32][33][34][35] These suggest that we should consider AGS when the aforementioned 'atypical' phenotypes appear.…”

“…Alburaiky et al found a phenotypic association between Opsoclonus‐myoclonus syndrome and AGS 29 . Dyschromatosis symmetrica hereditaria (DSH), a rare autosomal dominant hereditary pigmented skin disorder, may arise in patients with AGS6 type 30 . AGS also has clinical manifestations of liver, kidney and other organs 31–35 .…”

Adenosine deaminase acting on RNA 1 (ADAR1) as crucial regulators in cardiovascular diseases: structures, pathogenesis, and potential therapeutic approach

“…Liu et al reported the first Chinese case of dyschromatosis symmetrica hereditaria with Aicardi-Goutières syndrome caused by A homozygous mutation of the ADAR1 gene (c.1622T>A). In cardiac terms, the patient had significant cardiac involvement, patent ductus arteriosus, VSD, and symptoms of progressive heart failure ( Liu et al, 2022 ). It may be related to the mutation site located in the protein domain of ADAR1 gene ( Liu et al, 2022 ).…”