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Idiopathic short stature is a condition in which the height of the individual is more than 2 SD below the corresponding mean height for a given age, sex and population, in whom no identifiable disorder is present. It can be subcategorized into familial and non-familial ISS, and according to pubertal delay. It should be differentiated from dysmorphic syndromes, skeletal dysplasias, short stature secondary to a small birth size (small for gestational age, SGA), and systemic and endocrine diseases. ISS is the diagnostic group that remains after excluding known conditions in short children.

In the management of ISS auxological, biochemical, psychosocial and ethical elements have to be considered. In boys with constitutional delay of growth and puberty androgens are effective in increasing height and sexual characteristics, but adult height is unchanged. GH therapy is efficacious in increasing height velocity and adult height, but the inter-individual variation is considerable. The effect on psychosocial status is uncertain. Factors affecting final height gain include GH dose, height deficit in comparison to midparental height, age and first year height velocity. In case of a low predicted adult height at the onset of puberty, addition of a GnRH analogue can be considered. Although GH therapy appears safe, long-term monitoring is recommended.

Administration of insulin-like growth factor-I to patients with diabetes enhances insulin action and reduces the degree of hyperglycemia but it is associated with a high rate of adverse events. Infusion of the combination of rhIGFBP-3 (the principal binding protein for IGF-I in plasma) with rhIGF-I to patients with type I diabetes improved insulin sensitivity and was associated with a low incidence in side effects. In this study, 52 patients with insulin-treated type 2 diabetes received recombinant human IGF-I plus rhIGFBP-3 in one of four dosage regimens for 14 days. The four groups were: (1) continuous subcutaneous infusion of 2 mg/kg/day; (2) the same 2 mg/kg dose infused subcutaneously over 6 h between 2000 and 0200 h; (3) 1 mg/kg twice a day by bolus subcutaneous injection; (4) a single bedtime subcutaneous injection of 1 mg/kg. Across these four groups rhIGF-I/rhIGFBP-3 decreased insulin requirements between 54% and 82%. Fasting glucose decreased by 32-37%. Mean daily blood glucose (4 determinations per day) declined in all 4 groups (range 9-23% decrease). Frequent sampling for total IGF-I, free IGF-I and IGFBP-3 was performed on days 0,1,7,14 and 15. The peak total IGF-I values were increased to 4.0-4.8-fold at 16-24 h. For free IGF-I the increase varied between 7.1 and 8.2-fold and peak values were attained at 16-20 h after administration. Both the time to maximum concentration (Tmax) and the maximum free IGF-I levels (Cmax) on day 1 for all groups were substantially less than previously published studies, wherein lower doses of rhIGF-I were given without IGFBP-3. The improvement in glucose values and the degree of reduction in insulin requirement were the greatest in groups 2 and 3 and the patients in those groups had the highest free IGF-I levels. The frequency of side effects such as edema, jaw pain and arthralgias was 4% which is less than that has been reported in previous studies wherein IGF-I was administered without IGFBP-3. We conclude that rhIGF-I/rhIGFBP-3 significantly lowers insulin requirements yet improves glucose values and these changes may reflect improvement in insulin sensitivity. Coadministration of IGFBP-3 with IGF-I produces lower free IGF-I (Tmax and Cmax) levels compared to administration of IGF-I alone and is associated with relatively low incidence of side effects during 2 weeks of administration.

restriction, maxillary hypoplasia, prominent heels and a variable incidence of skeletal abnormalities such as slender long bones and relatively tall vertebrae. Affected patients have a relatively poor growth response to growth hormone therapy. Nonsense and missense mutations in the genes encoding Obscurin-like 1 (OBSL1) and Cullin7 (CUL7) are known to cause 3M syndrome. There are, however some patients with well-defined 3-M syndrome but no mutation identified in either OBSL1 or CUL7. Aim: To assess cell proliferation, apoptosis and intracellular signal transduction responses to growth hormone (GH) and insulin-like growth factor-1 (IGF-I) in three 3-M patient cell lines: OBSL1 and CUL7 mutants and a cell line with no mutations in either gene. Methods: Dermal fibroblast cell lines were established from 2 unaffected children as controls and 3 patients, one with a nonsense mutation in CUL7 (c.4191delC p.H1379HfsX11), one with a nonsense mutation in OBSL1 (c.1273insAp.T425NfsX40) and one with 3-M syndrome but no identified mutation. Cell proliferation was assessed using a WST8 assay over 3 days and by measuring EdU incorporation at 24 hours. Apoptosis was measured using an ELISA for cleaved caspase 3 (CC-3), an essential enzyme for cell death. To assess GH and IGF-I signal transduction, control and patient fibroblasts were stimulated with GH (200ng/ml) and IGF-I (100ng/ml) with lysates taken at 0, 5, 15 and 60 minutes and immunoblotted for activation of ERK1/2, STAT5b, IRS-1 and Akt. Results: Both the WST8 assay and EdU incorporation showed basal cell proliferation to be decreased across all 3-M cell lines in comparison to controls (p < 0.01 for WST8 assay (OBSL1 mutant 65%, CUL7 mutant 64% and unknown mutant 78% compared to controls on day 3) and p < 0.01 for EdU incorporation (OBSL1mutant 43%, CUL7 mutant 24% and unknown mutant 25%)). There was no significant difference in the levels of CC-3 between patients and controls (p = 0.425, OBSL1 mutant 123%, CUL7 mutant 106% and unknown mutant 107% compared to controls). Following IGF-I stimulation, all three 3-M cell lines displayed normal IRS1 activation, but two showed reduced Akt activation when compared to controls (CUL7 mutant p < 0.01, unknownmutant p =0.024). Following GH stimulation, Stat5b and ERK1/2 activation was normal in OBSL1 and CUL7 mutant cell lines. Conclusions: 3-M syndrome is associated with reduced cell proliferation across all three cell lines but normal rates of apoptosis, even though each cell line carries a mutation in a different gene. However, only two of the three cell lines had reduced Akt activation in response to IGF-I stimulation. This suggests that disruption to different ‘upstream’ molecular pathways may lead into a common ‘downstream’ pathway that generates a consistent 3-M phenotype.