A novel mutation of PCSK1 responsible for PC1/3 deficiency in two siblings

Abstract

Proprotein convertase 1 (PCSK1, PC1/3) deficiency is an uncommon cause of neonatal malabsorptive diarrhoea associated with endocrinopathies that are due to the disrupted processing of a large number of prohormones, including proinsulin. To date, only 26 cases have been reported. Herein, we describe two siblings with typical features including severe congenital diarrhoea, central diabetes insipidus, growth hormone deficiency, and hypoadrenalism. Next generation sequencing found a homozygous missense mutation in exon 5 of PCSK1 gene, c.500A>C (p.Asp167Ala), located within the catalytic domain. Both patients presented a high level of proinsulin. In the first years of life they required parenteral nutrition and hormone replacement therapy. The patients, aged 3 and 1.5 years, experienced several infectious episodes associated with septic shocks. While the mechanism underlying intestinal failure remains poorly investigated, parenteral nutrition is essential in order to ensure normal growth in early childhood.

Keywords: Congenital chronic diarrhoea; Monogenic disorders; PCSK1; TNGS.