Frederico S Regateiro1, Serkan Belkaya2, Nélson Neves3, Sandra Ferreira4, Paula Silvestre5, Sónia Lemos6, Margarida Venâncio7, Jean-Laurent Casanova8, Isabel Gonçalves4, Emmanuelle Jouanguy9, Luísa Diogo10. 1. Serviço de Pediatria Médica, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal; Instituto de Imunologia, Faculdade de Medicina, Universidade de Coimbra, Portugal. Electronic address: regateiro@gmail.com. 2. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA. 3. Serviço de Pediatria Médica, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal. 4. Unidade de Hepatologia e Transplantação Hepática Pediátrica, Hospital Pediátrico, CHUC, Coimbra, Portugal. 5. Serviço de Pediatria, Hospital Amato Lusitano, Castelo Branco, Portugal. 6. Consulta de Imunodeficiências Primárias, Hospital Pediátrico, CHUC, Coimbra, Portugal. 7. Serviço de Pediatria Ambulatória, Hospital Pediátrico, CHUC, Coimbra, Portugal. 8. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Descartes University, Imagine Institute, Paris, France; Pediatric Hematology - Immunology Unit, Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute, The Rockefeller University, New York, USA. 9. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; Paris Descartes University, Imagine Institute, Paris, France. 10. Centro de Desenvolvimento da Criança, Hospital Pediátrico, CHUC, Coimbra, Portugal; Serviço de Bioquímica, Faculdade de Medicina, Universidade de Coimbra, Portugal.
Abstract
BACKGROUND: Acute liver failure (ALF) in children can be life-threatening. Although many causes are known, ALF remains unexplained in about half of the cases. Recently, bi-allelic mutations in NBAS were reported to underlie recurrent episodes of elevated liver transaminases (ELT) and ALF in the context of diverse extrahepatic phenotypes. METHODS AND RESULTS: We here describe two sisters, born to non-consanguineous Portuguese parents, who had short stature and presented with recurrent episodes of severe ELT triggered by febrile respiratory viral infections since early childhood. Patient 1 had mild facial dysmorphism and died during the second ELT crisis at 3-11/12 years of age. Patient 2, currently 9 years old, had multiple episodes of ELT (>30), twice with ALF, often accompanied by extensive urticaria and facial angioedema. Whole-exome and Sanger sequencing revealed that both patients carried previously undescribed compound heterozygous mutations of NBAS (NM_015909.3): c.680A > C (p.His227Pro), affecting an evolutionarily conserved residue, and c.1749G > A (p.Trp583*), causing a premature stop codon. Both mutations are predicted to be highly damaging. The parents and two younger siblings are healthy and heterozygous for one or another mutant allele. CONCLUSION: The multiplex kindred reported herein expands the genotypic and phenotypic spectrum of this recently described clinical syndrome due to autosomal recessive NBAS deficiency.
BACKGROUND:Acute liver failure (ALF) in children can be life-threatening. Although many causes are known, ALF remains unexplained in about half of the cases. Recently, bi-allelic mutations in NBAS were reported to underlie recurrent episodes of elevated liver transaminases (ELT) and ALF in the context of diverse extrahepatic phenotypes. METHODS AND RESULTS: We here describe two sisters, born to non-consanguineous Portuguese parents, who had short stature and presented with recurrent episodes of severe ELT triggered by febrile respiratory viral infections since early childhood. Patient 1 had mild facial dysmorphism and died during the second ELT crisis at 3-11/12 years of age. Patient 2, currently 9 years old, had multiple episodes of ELT (>30), twice with ALF, often accompanied by extensive urticaria and facial angioedema. Whole-exome and Sanger sequencing revealed that both patients carried previously undescribed compound heterozygous mutations of NBAS (NM_015909.3): c.680A > C (p.His227Pro), affecting an evolutionarily conserved residue, and c.1749G > A (p.Trp583*), causing a premature stop codon. Both mutations are predicted to be highly damaging. The parents and two younger siblings are healthy and heterozygous for one or another mutant allele. CONCLUSION: The multiplex kindred reported herein expands the genotypic and phenotypic spectrum of this recently described clinical syndrome due to autosomal recessive NBAS deficiency.
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