Variation in Phenotypic Features of Two Siblings with PC1/3 Deficiency—Obesity and Hyperproinsulinemia

Background: Inactivating mutations in the PCSK1 gene encoding prohormone convertase 1/3 (PC1/3) are associated with failure to thrive (FTT) and diarrhea during infancy, a tendency toward childhood obesity, and the potential for development of endocrinopathies throughout life, including hyperproinsulinemia. We describe two siblings with the same inactivating compound heterozygous mutations (c.625G>A and c.473G>A) in PCSK1, but with phenotypes of differing severity affecting both body composition and glucose homeostasis.

Methods: After sequencing confirmed inactivating PCSK1 mutations, we assessed the siblings for resultant endocrinopathies of PC1/3 deficiency.

Results: The siblings, a 9y male (M) and an 11y female (F), had severe early onset FTT with diarrhea. Currently, M has extreme obesity (BMI=38.2 kg/m², >99%), diabetes insipidus, central hypothyroidism (FT4 0.7 ng/dL; TSH 4.9 mIU/L with little diurnal variation), and adrenal insufficiency (peak cortisol post-ACTH 10.8 ug/dL). After an overnight fast, glucose was 64 mg/dL and he had dramatic hyperproinsulinemia (5030 pmol/L, normal <8), far exceeding his fasting insulin concentration (360 pmol/L). Glucose tolerance was better than predicted for his degree of obesity (OGTT 2h glucose 79 mg/dL) and proinsulin remained markedly elevated during the OGTT (6610 pmol/L; normal <200).

F was in the 86^th percentile for BMI. She had central hypothyroidism (FT4 0.7 ng/dL; TSH 4.7 mIU/L with little diurnal variation) and diabetes insipidus, but had normal adrenal function (peak cortisol post-ACTH 20.3 ug/dL). F also had high fasting proinsulin (1340 pmol/L), out of proportion to fasting insulin (70 pmol/L) and glucose (87 mg/dL) and good glucose tolerance (OGTT 2h glucose 89 mg/dL).

Discussion: PC1/3 deficiency reduces processing of proinsulin to insulin and may thus predispose to fasting or post-prandial hypoglycemia. There is substantial heterogeneity in PC1/3 deficiency even within families.