This study will evaluate the status of the growth hormone/ insulin-like growth factor-1 (GH/IGF-1) axis in relation to growth failure, body weight and composition and neuroprotection in children with Ataxia telangiectasia (AT).

Growth failure and GH/IgF-1 deficiency has been described in patients diagnosed with Ataxia telangiectasia (AT) [Boder et al.,1958]. This condition is a fatal inherited disease caused by a mutation of the ATM gene on chromosome 11 leading to chromosomal instability, immunodeficiency, cancer susceptibility and and endocrinological abnormalities. In this regard, several groups demonstrated a cross-linking of ATM with growth factor pathways. Participation of the ATM protein in insulin signaling through phosphorylation of eIF-4E-binding protein 1 has been postulated [Yang et al.,2000]. Peretz et al.[2001] described that expression of the insulin-like growth factor-I receptor is (IGF-I R) ATM dependent in a pathway regulating radiation response. In addition, Shahrabani-Gargir et al.[2004] found that the ATM gene controls IGF-I R gene expression in a DNA damage response pathway. Suzuki et al.[2004] described that IGF-I phosphorylates AMPK-alpha, a key regulator of cholesterol and fatty acid synthesis, acts in an ATM-dependent manner . We have recently demonstrated reduced levels of circulating Insulin-like growth factor-I (IGF-I) and its main binding protein 3 (IGFBP-3) in AT patients accompanied with decreased body mass index [Schubert et al.,2005]. Furthermore, apart from regulating somatic growth and metabolism, evidence suggests that the GH/IGF-I axis is involved in the regulation of brain growth, development and myelination. Moreover, GH and particularly IGF-1 have potential neuroprotective effects in different in vitro and in vivo experimental models. In addition we have recently shown that extracerebellar MRI-lesions in AT go along with deficiency of the GH/IGF-1 Axis, markedly reduced body weight, high ataxia scores and advanced age [Kieslich et al.,2009]. Supplementation with these growth hormones might overcome the progressive dystrophy and may have clinical benefits against the progression of neurodegeneration and immunodeficiency.

We found that supplementation with GH significantly increased longevity of Atm-deficient mice and improve T-cell immunity and locomotor behaviour [Schubert et al.,2009]. Surprisingly IGF-1 was not generated in the ATM deficient mice, indicating that the GH/IGF-1 signalling is impaired. Taken this into account a accurate diagnostic approach of the GH/IGF-1 axis is mandatory including a IGF-1 generation test before long term treatment either with GH or IGF-1 is justified in humans.

Inclusion Criteria:

• Have a diagnosis of AT
• Have no fusion of epiphyses/closed growth plates as determined by X-ray of left wrist and hand (special skeletal age film)
• Be between 3 years to 18 years old and have not completed puberty
• Consent to permit blood and/or tissue samples for storage
• Demonstrate growth failure: height below the 10th percentile for chronological age
• Have a primary care physician at home
• Demonstrate growth failure, defined as growth velocity (measured as linear growth) that is less than 5% to 10% of that expected for children of the same age group, over the past 12 months
• Willingness to remain hospitalized for several days
• Provide evidence of serum IGF-1 level performed within the preceding 6 months and the results fall below 25% range of normal limits for age

Exclusion Criteria:

• Have fusion of epiphyseal plates
• Be under the age of 3 years or have reached completion of puberty
• Have a serum IGF-1 level that is above the 25% range of normal limits for age
• Be above the 10th percentile height for chronological age
• Demonstrate any history of anaphylactic reaction or hypersensitivity to one of the GH formulation
• Have any active or suspected neoplasia
• Demonstrate signs of intracranial hypertension as evidenced by papilledema upon examination by fundoscopy
• Have any condition that, in the investigator's opinion, places the patient at undue risk by participating in the study
• Be unwilling to undergo testing or procedures associated with this protocol
• Have acute or chronic infections
• Have a hypersensitivity to one of the drugs: Clonidine hydrochlorid, Arginine hydrochlorid, Estradiol valerate, Somatropin
• Have a presence of bradycardia, cardiac arrhythmia, have symptoms of a sick sinus syndrome
• Suffer from depression
• Have acute or recurrent thrombosis
• Have acute liver diseases