ESPE Abstracts

Introduction: PCSK1/3 gene mutations are known as a cause for congenital diarrhea and various endocrinopathies. Hypogonadotrophic hypogonadism and aberrant pubertal development due to pro-convertase dysfunction was not characterized yet. This study aimed to characterize the pubertal development in a family carrying the novel N309K mutation in the PCSK1 gene.

Methods and Results: We Identified 2 siblings who presented with severe congenital diarrhea followed by overweight and endocrinopathies during early childhood to have a novel homozygous N309K PCSK1 gene-mutation. The female developed severe congenital malabsorptive diarrhea and was kept on parenteral nutrition for 5 years. L-thyroxin replacement was administered for central hypothyroidism diagnosed at 2 years of age. Poor growth rate and low GH response in stimulation tests lead to GH therapy. Severe obesity was noticed since the age of 6 years with BMI −21.6. Pubertal development started late at 12 years with breast developing only up to Tanner stage 2. No menarche occurred by the age of 14 years. Basal and LHRH stimulated LH levels were low. Estradiol levels were undetected. Gradual replacement therapy with Estrogen at 14 years of age resulted in pubertal progression with secondary sexual signs, addition of progesterone achieved menarche and regular periods.

Conclusions: This case illustrates the crucial role of the prohormone convertase 1/3 PCSK in processing of LHRH, LH and FSH and enabling normal pubertal development in females. The novel homozygous N309K mutation causes severe obesity associated with hypogonadotrophic hypogonadism and primary amenorrhea that fully respond to hormonal replacement therapy.