BSPED2023 Poster Presentations Diabetes 3 (12 abstracts)
1Great Ormond Street Hospital, London, UK; 2William Harvey Research Institute, London, UK; 3University College London Hospital, London, UK
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.
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 |
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