However, whereas LH pulses are due to the pulsatile secretion of GnRH (19), GnRH secretion itself cannot be the sole causative factor of HFs because exogenous estrogen withdrawal in female patients with a genetic cause of hypogonadotrophic hypogonadism secondary to failure of the hypothalamic GnRH neurones to develop and migrate appropriately (Kallman syndrome) causes HFs (20). This evidence concerns the gene PLOD1 and Hand-foot syndrome.