SHORT STATURE ASSOCIATED WITH HIGH CIRCULATING INSULIN-LIKE-GROWTH-FACTOR (IGF)-BINDING PROTEIN-1 AND LOW CIRCULATING IGF-II - EFFECT OF GROWTH-HORMONE THERAPY

We report a case of short stature associated with high circulating lev els of insulin-like growth factor (IGF)-binding protein-1 (IGFBP-10 an d low levels of IGF-II responsive to pharmacological treatment with GH . Our patient suffered severe growth failure from birth (2.06 So below the mean for normal full-term boys, and 5.2 and 7.3 so below the mean at 5 and 10 months). Studies carried out before referral to our pedia tric unit included normal 46,XY karyotype and normal encephalic imagin g. Other endocrine and metabolic alterations and other systemic diseas es were excluded.,At 1.7 yr of age (length, 6.1 so; weight, 4.6 So; he ad circumference, 1.4 So below the mean, respectively) the patient was referred to our pediatric unit. The baseline GH concentration was 31 mu g/L: and the peak after an arginine load was 59.6 mu g/L. In the sa me samples GH bioactivity was nearly superimposable (RIA/Nb2 bioactivi ty ratio = 0.9). Fasting insulin and glucose concentrations were 7.4 m u U/mL and 65 mg/dL, respectively, both normally responsive to an oral glucose load. GPI insensitivity was excluded by a basal IGF-I concent ration 164 ng/mL) in the normal range for 0- to 5-yr-old boys and its increase after 2 IU/day hGH administration for 4 days. IGFBP-3 (0.5 mu g/mL) was slightly reduced, whereas IGFBP-1 (2218 and 1515 ng/mL in t wo different basal samples) was well above the normal values for age a nd was suppressible by GH (maximum suppression, -77% at 84 h) and gluc ose load (maximum suppression, -46% at 150 min). The basal IGF-II conc entration was below the normal range (86 ng/mL), whereas IGFBP-3 was n or-mal (258 ng/mL). Analysis of the promoter region of IGFBP-1 and IGF -II failed to find major alterations. Neutral gel filtration of serum showed that almost all IGF-I activity was in the 35- to 45-kDa complex , coincident with IGFBP-1 peak, while the 150-kDa complex was absent, although the acid-labile subunit was normally represented. At 2.86 yr (height, 65.8 cm; height so score, -7.3; height velocity So score, -5) the patient underwent treatment with 7 IU/week human GH; after 4 mont hs, the patient's height was 68.5 cm (height So score, -6.9) correspon ding to a growth velocity of 8.3 cm/yr 10.3 height velocity SD score). IGFBP-1 was reduced (216 ng/mL), although still in the high range, wh ereas IGF-I (71 ng/mL), IGFBP-3 (0.62 mu g/mL), and IGF-II(111 ng/mL) were only slightly increased. The IGF-I profile showed activity in the 150-kDa region. In conclusion, we speculate that the increased IGFBP- 1 values found in this patient produce 1)inhibition of IGF-I biologica l activity and, therefore, a resistance to IGF-I not due to a receptor defect for this hormone; 2) inhibition of formation of the circulatin g 150-kDa ternary complex and, therefore, an accelerated clearance rat e of IGF peptides; 3) inhibition of the feedback action on GH, leading to increased GH levels, which could suggest the diagnosis of GH insen sitivity syndrome; and 4) inhibition of body growth.