Effects of Letrozole on Precocious Puberty Due to McCune Albright Syndrome
Condition: McCune Albright Syndrome; Polyostotic Fibrous Dysplasia; Precocious Puberty
MeSH terms: Fibrous Dysplasia of Bone; Fibrous Dysplasia, Polyostotic; Puberty, Precocious; Syndrome
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will test the safety and effectiveness of letrozole in treating precocious (early)
      puberty in girls with McCune-Albright syndrome (MAS). The physical changes of puberty, such
      as breast enlargement, menstruation and growth spurt, as well as the emotional changes of
      this developmental stage, usually begin in girls between the ages of 8 and 14. Girls with
      MAS, however, often begin puberty before age 7. In MAS, large ovarian cysts produce high
      levels of estrogens (female hormones) that cause the changes of puberty. Children with MAS
      also have polyostotic fibrous dysplasia (PFD), a disease of bones that, depending on what
      parts of the skeleton are affected, can lead to broken bones or disfigurement of the head,
      face, arms and legs, or can cause pressure on nerves and blood vessels. Many children with
      MAS have cafe-au-lait spots (increased pigmentation) on areas of their skin as well.

      Letrozole is an estrogen-lowering drug that has been approved for treating women with breast
      and other cancers. Although the drug has not been tested or approved for use in children,
      some pediatric specialists have given it to girls with precocious puberty and MAS and found
      that it improves their condition without harmful side effects. This study will examine
      whether letrozole can lower estrogen in girls with MAS and arrest puberty. It will also study
      the drug's effects on substances involved in bone growth, including calcium, phosphate and
      amino acids.

      Girls 1 to 8 years old with MAS may be eligible for this study. Patients who were enrolled in
      NIH protocol 98-D-0145 (Screening and Natural History of Patients with Polyostotic Fibrous
      Dysplasia and the McCune-Albright syndrome) are also eligible. Participants will be admitted
      to the hospital for 2 to 3 days every 3 months for 15 months, for a total of 6 visits. They
      will undergo a complete history and physical examination and routine blood and urine tests
      every visit, as well as evaluations of their general health, growth and bone development,
      endocrine system (hormone-secreting glands) status and PFD status. A hand X-ray will be taken
      at the first visit and every 6 months to measure bone age advance. The children will begin
      taking letrozole at the second visit and continue the drug for 6 months. They will be
      evaluated after 3 months and 6 months on the drug (visits 3 and 4), and again after 3 months
      and 6 months after stopping treatment (visits 5 and 6).

      Parents of children who weigh more than 18 kilograms (about 40 pounds) may be asked if extra
      blood may be drawn after 3 months (visit 3) and 6 months (visit 4) of treatment to measure
      letrozole levels. The blood will be drawn before the morning dose and at 0.5, 1, 1.5, 2, 3,
      4, 6, 8, and 24 hours after the dose through an indwelling needle placed in the vein for 8 to
      24 hours.

      Parents will keep a record of all episodes of menstrual bleeding and any other symptoms or
      complaints. Children who respond well to therapy (decreased menses, slowed breast
      development, slowed growth and bone age advance) will be offered another 12 months of
      letrozole treatment.
    

Detailed description: 
      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.
    

Intervention name(s): Letrozole
Intervention type(s): Drug
Intervention MeSH terms: Letrozole
Primary purpose: Treatment
Keywords: Precocious Puberty; Polyostotic; Fibrous Dysplasia; PFD; McCune-Albright Syndrome (MAS)