Early‐life liver cirrhosis and variable clinical presentation in telomere disease

• Published in: Acta Paediatrica Vol. 111; no. 12; pp. 2416 - 2421
• Main Authors: Faingelernt, Yaniv, Nassar, Raouf, Ling, Galina, Kodman, Yona, Feuerstein, Tamar, Yerushalmi, Baruch
• Format: Journal Article
• Language: English
• Published: Norway Wiley Subscription Services, Inc 01.12.2022
• Subjects: bone marrow failure; Cell death; Child, Preschool; Children; Chromosomes; chronic recurrent multifocal osteomyelitis; Cirrhosis; Genotypes; Hepatocytes; hepatopulmonary syndrome; Humans; Liver cirrhosis; Liver Cirrhosis - genetics; Liver diseases; Mutation; Nucleotide sequence; Patients; Phenotype; Phenotypes; Senescence; Telomerase; Telomerase - genetics; Telomerase - metabolism; Telomere - genetics; telomere disease; Telomeres; bone marrow failure; chronic recurrent multifocal osteomyelitis; telomere disease; hepatopulmonary syndrome; liver cirrhosis
• ISSN: 0803-5253; 1651-2227
• DOI: 10.1111/apa.16539

Aim Telomeres are DNA sequences of tandem TTAGGG repeats that protect chromosome ends from degradation and instability. Constitutional loss‐of‐function telomerase mutations result in rapid telomere shortening, premature senescence and cell death. Liver cirrhosis is rare and has only been reported in adults. We present five family members of Bedouin‐Muslim origin, all of which carry the same mutation, and yet demonstrate an extremely variable phenotypical presentation, including liver cirrhosis during early childhood. Methods A multidisciplinary long‐term follow‐up of two healthy and three affected patients was analysed. The mutation (r.95G>C) was identified in all patients using Sanger sequencing. Telomere length samples were obtained and analysed. Results Clinical phenotypes were extremely variable, including age at first symptoms, organ involvement, disease severity and patient prognosis. The most prominent clinical phenotype is liver involvement, including end‐stage liver disease early in life, which affects three members of the family. Affected patients had markedly shorter telomeres. Conclusion We describe an unusual presentation of early liver failure in telomere disease patients. Little, if any, is known about the association between the genotype and phenotype among children with telomere disease and whether the mutation we have described (r.95G>C) is predisposed to early severe hepatic involvement.