Introduction: PCSK1/3 gene mutations are known as a cause for congenital diarrhea and various endocrinopathies. Pubertal development in these patients was not fully characterized and studied. This study aimed to characterize the pubertal development in a family reported to carry 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 . Central hypothyroidism diagnosed at age 2 years required replacement therapy. Poor growth rate with low GH response in 2 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 and 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.
