Prohormone convertase 1/3 deficiency can be associated with diabetes mellitus in childhood

Rachel Varughese; Sasha Howard; Gary Butler; Mehul Dattani

doi:10.1530/endoabs.95.P102

Prohormone convertase 1/3 (PC1/3) deficiency is rare, caused by homozygous or compound heterozygous mutations in the PCSK1 gene. PCSK1 encodes a serine protease important in cleavage of several proneuropeptides and prohormones. Despite a variety of known endocrine associations, paediatric diabetes mellitus is rare, described only once before. Previous understanding was that biological activity of elevated proinsulin (<5% of the activity of insulin) confers protection from diabetes mellitus in childhood, and that diabetes emerges in adulthood through B-cell exhaustion. We present two cases of PC1/3 deficiency with diabetes mellitus onset in childhood. The endocrine manifestations were very similar across the two and are summarised in Table 1.Patient 1Patient 1 was born at term to consanguineous parents (first cousins). Severe malabsorption from week1 required TPN until 7 months old. At 8.5years, he had marked acanthosis, and an OGTT revealed impaired glucose tolerance, with elevated fasting insulin (54.1 mU/L=390 pmol/L) and peak glucose 9.7 mmol/L. Insulin therapy led to hypoglycaemia, so management focussed on metformin/dietary changes. Exome sequencing revealed a novel homozygous PCSK1 nonsense mutation (p.R391*) in the catalytic domain.Patient 2 Patient 2 was born at term to ‘distantly related’ parents. Significant diarrhoea from week 2 required TPN until 7 months old. He developed diabetes mellitus at 11.5years. Insulin therapy prompted recurrent hypoglycaemias leading to challenging glycaemic control, unsuccessful metformin trial and eventual cautious insulin reintroduction.

Table 1
	Patient 1	Patient 2
Hypothyroidism	Yes-1.5y	Yes-5y
Hypogonadotrophic-hypogonadism	Yes	Yes
Hyperphagia	Yes-4y	Yes-3y
Obesity	Yes-4y-persisted	Yes-5y-resolved in adolescence
Diabetes insipidus	Partial-5y	Partial-4y
Growth hormone deficiency	Yes-8y-GH commenced, coinciding with diabetes mellitus	Yes-7y-treatment delayed due to good height velocity, and then poor glycaemic control
Cortisol deficiency	Yes-6y	Yes-7.5y
MRI Pituitary	Small anterior pituitary, decreased posterior pituitary signal	Normal anterior pituitary, absent posterior pituitary
Final height	−0.485	−1.42
Current weight z-score	+4.39	+0.16

Key Learning:

Diabetes mellitus in childhood is possible in PC1/3 deficiency, warranting assessment in known cases
Diabetes phenotype in both included:
1. A mixed picture of insulin insensitivity and insulin deficiency
2. Recurrent hypoglycaemic episodes with insulin (suggesting preservation of insulin sensitivity)
3. Swinging hypo-/hyperglycaemia (theorised to be related to delayed effects of proinsulin, which has a five-fold longer half-life than insulin).

Endocrine Abstracts

P102