Aromatase Inhibitor in Bone Maturation, Children With Silver Russell or Prader-Willi Syndrome
Aromatase Inhibitor in Bone Maturation, Children With Silver Russell or Prader-Willi Syndrome
There is currently no drug with pediatric marketing authorization capable of limiting the
 advance in bone maturation of children with aggressive adrenarche. Estrogens are the
 principal actors involved in bone maturation and premature epiphyseal fusion. Aromatase
 inhibitors, used for the treatment of hormone-dependent cancers, block the transformation of
 androgens into estrogens. Third generation inhibitors, of which Anastrozole is one, appear to
 be well tolerated in children and are sometimes used within the framework of clinical trials
 to limit bone maturation and improve prognosis with respect to final size, notably in
 children treated with growth hormone (GH) due to a GH deficit. Nevertheless, the data
 reported are based on small sample sizes and do not include children with pathological
 adrenarche.
Silver-Russell syndrome (SRS), which occurs secondary to an imprinting disorder due to the
 anomalous methylation of chromosome 11 or due to a uniparental disomy of chromosome 7, is a
 rare syndrome (ORPHA813, OMIM 180860) characterized by growth retardation with an
 intrauterine onset, a normal head circumference, small postnatal size and major feeding
 difficulties. Starting at a very young age, the rapid aging of bone can occur even in the
 absence of central puberty, in association with the production of androgens by the adrenal
 glands (adrenarche). This advanced bone maturation can compromise final size, even when the
 child receives growth hormone (GH) treatment for several years.

 Prader-Willi syndrome (PWS) is also a rare disease (ORPHA739, OMIM 176270), occurring
 secondary to an imprinting disorder due to an anomaly in chromosome 15 (paternal deletion or
 maternal disomy). These children also present feeding difficulties during the first few years
 of life, as well as small size. They are frequently treated with GH, and their bone age can
 increase during the course of adrenarche, as in certain patients with SRS.
Inclusion Criteria:

 -  Patients with genetically proven SRS or PWS, under treatment with GH in the usual
 context of the disease, presenting with adrenarche (defined either by DHEAS levels as
 a function of age or by the appearance of pubic hair) associated with a bone age at
 least 6 months greater than chronological age and in the absence of the onset of
 central puberty (LH peak ≤ LH peak in prepubertal patients, according to the standards
 of the laboratory performing the GnRH stimulation test for LH and FSH, and dating back
 to less than 3 months).

 -  Patients with medical coverage.

 -  The lower age limit for inclusion is 5 years and the upper age limit is 10 complete
 years for girls and 12 complete years for boys.

 -  The maximum body-mass index (BMI) Z-score for inclusion is +4

 -  Patients should be capable of swallowing pills of the same size as the experimental
 drug.

 Exclusion Criteria:

 -  Renal insufficiency (creatinine clearance, calculated according to the Schwartz
 formula, lower than 70ml/min/l, 73 m²),

 -  Hepatic insufficiency (prothrombin ratio < 50% and factor V < 50%),

 -  Hepatic cytolysis (liver transaminases levels greater than twice the normal level for
 age), cholestasis (gamma-glutamyl transferase (GGT) levels greater than twice the
 normal level for age),

 -  Contraindication to one of the components of Anastrozole or the placebo.

 -  Patients with scoliosis requiring surgery.