Effects of Letrozole on Precocious Puberty Due to McCune Albright Syndrome

Girls ages 1 - 8 years with the McCune-Albright syndrome (MAS) and girls with other conditions characterized by precocious puberty due to estrogen hypersecretion from ovarian cysts will be eligible for this pilot study. Patients who have previously enrolled in Protocol 98-D-0145 (Screening and natural history of patients with polyostotic fibrous dysplasia and the McCune-Albright Syndrome) will also be eligible. Patients will be treated with letrozole, a potent, nonsteroidal aromatase inhibitor, to suppress their elevated serum estrogen levels. We will confirm the safety and efficacy of letrozole, and study its effectiveness in controlling the elevated sex steroid levels, and the advanced rates of linear growth, bone maturation, and pubertal progression in these patients. We will also study the effect of decreased estrogen levels on the status of their polyostotic fibrous dysplasia by measuring serum and urine values for bone biomarkers, including calcium, phosphate, organic amino acids, and vitamin D metabolites, which are known to be abnormal in many patients with MAS. Patients will act as their own controls. We will compare serum and urine parameters of pubertal progression and bone biomarkers before, during, and after discontinuation of letrozole. This trial will be carried out in parallel with in-vitro and in-vivo laboratory studies using an animal model of fibrous dysplasia. In this model, osteogenic precursor cells from patient bone biopsies will be cultured in a hydroxyapatite/tricalcium phosphate matrix and transplanted into immunocompromised mice. We anticipate that our laboratory findings will complement the care of our patients, resulting in more effective treatment for the precocious puberty and the bone disease in children with MAS. Because our initial studies have indicated that letrozole is effective in treating precocious puberty in MAS patients, this protocol also enrolls girls who have a related condition, gonadotropin-independent precocious puberty without the bone disease polyostotic fibrous dysplasia. We also believe that this study complements the recent FDA and NIH mandates that children be included in the evaluation of pharmaceutical products and in federally funded clinical research studies.