ESPE Abstracts

Background: Proprotein convertase subtilisin/kexin types 1 and 2 (PCSK1 and PCSK2) are expressed in neuroendocrine tissues where they cleave a subset of inactive prohormones into biologically active hormones, including pro-opiomelanocortin (POMC), proTRH, proinsulin, proglucagon, and proGnRH. Congenital deficiency of PCSK1 is a very rare syndrome causing malabsorptive diarrhea contrasting with severe early-onset obesity and hypopituitarism. We described here a new case of congenital PCSK1 deficiency.

Case presentation: The male proband was born in 2008 at 41 weeks of amenorrhea from consanguineous parents of Turkish origin, after an uneventful pregnancy. He presented macrosomia at birth (weight 4580 g and height 55 cm). Moderate dysmorphic features were noticed: macroglossia, bilateral clinodactyly of fourth and fifth toes, frontal bossing, mid-facial hypoplasia, depressed nasal bridge, and micropenis. He developed severe malabsorptive diarrhea with pancreatic exocrine insufficiency and recurrent hypoglycaemia immediately after birth. Nocturnal parenteral nutrition was necessary during 3 years. Endocrine investigations confirmed isolated GH deficiency at 2 months. Multiple pituitary hormone deficiency was diagnosed by the age of 3, including diabetes insipidus, central hypothyroidism, and hypocortisolism. Pituitary MRI was normal. He developed severe early-onset obesity and eating disorders with a BMI of 28 kg/m² at 6½ years. In view of the combination of chronic diarrhoea, rapid weight gain, and hypopituitarism, the possibility of PCSK1 deficiency was entertained. Fasting plasma insulin was normal (2.7 μU/ml; n 5–25) but proinsulin was very increased (300 pmol/l; n 3.3–28). Exome sequencing found a variant in PSK1 corresponding to a homozygous stop codon. In hg19, coordinates of isoform NM_000439 were chr5: 95757609-95757609; exon 5; c.C595T p.R199X. Considering the precocity of the stop codon, we expect for a haploinsufficiency of PCSK1, as already described mutations.

Conclusion: We described a rare case of neonatal malabsorptive diarrhoea associated with panhypopituitarism and severe obesity caused by a new homozygous mutation in PCSK1.