PRECOCIOUS PUBERTY IN NEUROFIBROMATOSIS TYPE 1 (NF-1)

Abstract

Precocious puberty (PP) has been reported in children with NF-1, primarily in the presence of optic pathway tumors (OPT). We evaluated 201 children with NF-1, 157 of whom had CNS imaging; 31 had OPT. Of these, 19 were 2-10 yrs old. Four of these children had PP, while no child without an OPT had clinical PP. We conducted a prospective case control study to investigate the effect of OPT on the maturation of the hypothalamic-pituitary-gonadal axis in children with NF-1, and the association between NF-1 and PP in the absence of OPT. We enrolled 24 prepubertal children, 2-10 yrs old, with NF-1, 12 with OPT and 12 without OPT, matched for sex and age. We measured height, weight, parental heights, bone age, and the LH and FSH response to LHRH. A 6 cm difference in height was found between the group with OPT 117.4±3.9 (MEAN±SE) and without OPT 111.5±4.0, (p = 0.15). Height Z-scores were higher in children with OPT (0.12±0.39 vs −1.07±0.35, p=0.02). Bone age minus chronological age was also higher in the glioma group (0.08±0.37 yrs vs −0.65±0.35, p = 0.08). In response to injected LHRH 100μg, there was a greater rise in LH in the group with OPT (p=0.06). FSH responses were identicl. All 4 pubertal responses (peak LH>15mIU/ml) occurred in children with OPT (p<0.05). Three of these children had lesions confined to the intraorbital portion of the optic nerve. We conclude: 1) PP occurred in NF-1 only in the presence of OPT, 2) accelerated growth was present in the children with OPT, consistent with early puberty, 3) contrary to expectations, a pubertal response to LHRH was evident in children with tumors remote from the hypothalamus, and 4) we have identified a subpopulation who provide a unique opportunity to prospectively investigate the pathogenesis of PP.