A Study of the Genetic Basis of Response to Growth Hormone Treatment in Children With Idiopathic Short Stature

Inclusion Criteria:

• Signed consent/parental consent and patient assent for minor children obtainedbefore any study-related activities (study-related activities are any procedurerelated to recording of data according to the protocol).

• Patient has been diagnosed with Idiopathic Short Stature (ISS) and received at least 1 year of GH therapy.

• Patient was prepubertal at initiation of and throughout first year of GH therapy, asdetermined by the treating physician and patient medical records.

• Patient had no prior exposure to growth promoting therapy prior to initiation of GHtherapy, including but not limited to growth hormone, IGF-I and ghrelin analogues.

• Age at initiation of GH therapy:

• Boys: Age above or equal to 3 years and below 11.0 years.

• Girls: Age above or equal to 3 years and below 10.0 years.

• Impaired height prior to initiation of GH therapy defined as at least 2 standarddeviations below the mean height for chronological age and sex according to localgrowth reference charts. In the absence of local reference charts, the standards ofCentres for Disease Control and Prevention should be used.

• GH deficiency has been excluded via GH stimulation test (cut point of 7 nanogramsper milliliter [ng/ml]) or other clinical and biochemical criteria according tolocal clinical practice.

• Patient fits within one of the following response groups:

• Change in Height Standard Deviation Score (SDS) after approximately the firstyear (+/- 2 months) of GH therapy greater than (>) 1.0.

• Change in Height SDS after approximately the first year (+/- 2 months) of GHtherapy less than (<) 0.4.

Exclusion Criteria:

• Previous participation in this study. Participation is defined as having giveninformed consent in this study.

• Mental incapacity, unwillingness or language barriers precluding adequateunderstanding, cooperation or informed consent.

• Receipt of any investigational medicinal product within 3 months before or duringthe first year of GH therapy that could influence response to GH therapy.

• Concomitant illness within 3 months before or during the first year of GH therapythat could (positively or negatively) influence the first year of GH therapy.Exception: Attention Deficit Hyperactive Disorder and its treatment can be includedbut should be recorded.

• Children with suspected or confirmed growth hormone deficiency according to localpractice.

• Concomitant use of medication including gonadotropin-releasing hormone (GnRH)analogues, aromatase inhibitors, sex steroids, glucocorticoids or any othermedication that can influence response to GH therapy. Exception: Attention DeficitHyperactive Disorder and its treatment can be included but should be recorded.

• Any known or suspected clinically significant abnormality likely to affect growth orthe ability to evaluate growth with standing height measurements, such as but notlimited to:

• Significant spinal abnormalities including but not limited to scoliosis,kyphosis and spina bifida variants.

• Any other disorder that can cause short stature such as, but not limited to,psychiatric disorders, nutritional disorders, chronic systemic illness, chronicrespiratory conditions (e.g. asthma), and chronic renal disease.

• Turner Syndrome (including mosaicism).

• Noonan Syndrome.

• Born small for gestational age (defined as birth length below -2 SDS OR birthweight below -2 SDS OR both) (according to national standards).

• Extreme prematurity, defined as gestational age less than 32 weeks.

• Syndromic short stature defined by the presence of significant dysmorphicfeatures and/OR major malformations, Laron syndrome, Prader-Willi syndrome,Russell-Silver syndrome.

• Significant developmental delays, autism spectrum or intellectual deficit ofany degree.

• Skeletal dysplasia.

• Magnetic resonance imaging (MRI) result confirming pituitary structuralabnormalities.

• Poor adherence to GH therapy or interruption of it for any time during thefirst year of therapy, as judged by the treating physician.