Recurrent elevated liver transaminases and acute liver failure in two siblings with novel bi-allelic mutations of NBAS.

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.