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Decreased sensitivity to insulin‐like growth factor I as a cause of growth failure in Turner's syndrome?

Short stature combined with a broad-chested and compact appearance is the most frequent clinical feature of patients with Turner’s syndrome [1,2]. Intrauterine growth retardation is usually mild with birth length approximately 1 SD below normal. Post-natal growth rates are reduced even during infancy and childhood in patients with Turner’s syndrome. Finally, the lack of pubertal growth spurt contributes to the greatly reduced average adult height of approximately 144 cm [1–3]. It has been speculated for decades that peripheral endorgan resistance to growth-promoting factors, such as the insulin-like growth factors (IGFs), might be partially responsible for the growth failure in Turner’s syndrome [3,4]. However, because of the lack of availability of target tissues or cells, such as bone, cartilage and connective tissue, it has been difficult to prove or disprove this attractive hypothesis. Other factors adding to the overall growth failure seen in many Turner’s syndrome patients are steroid hormone deficiency as a result of ovarian failure even before puberty and, in a small number of patients, the impact of chronic disease caused by cardiac or renal anomalies and recurrent infectious complications (Table 1). Growth hormone (GH) is ubiquitously used to treat growth failure in Turner’s syndrome [2,5]. However, while in some patients responses to GH treatment are well documented, in others very little or no effect of GH treatment upon growth and especially final height is evidenced. Despite this, GH therapy is the recommended standard treatment for growth failure in Turner’s syndrome. Hochberget al. [4], in this issue of theEuropean Journal of Clinical Investigation , show an IGF-I subresponsiveness in Turner’s syndrome patients by using their well-established techniques to study lymphoblast and monocyte/macrophage function. They found a more than 50% reduction in IGF-I-stimulated low-density lipoprotein (LDL) degradationin vitro. In addition, and most importantly, both growth hormone and IGF-I failed to elicit T-cell proliferation in autologous mixed lymphocyte cultures from Turner’s syndrome patients but were capable of greatly enhancing the proliferation of normal human lymphoblasts. Since both IGF-I receptors [6] and GH receptors [7] have been found on immune cells, these cells might indeed serve as a model for further study of the biological effects of GH and IGF-I in health and disease. As stated by Hochberg et al. [4], their findings on IGF-I refractoriness in peripheral immune cells might partly reflect some of the molecular mechanisms by which insulin resistance and hyperlipidaemia are caused in Turner’s syndrome. However, it remains largely unclear whether or not growth failure, the most common and very devastating feature of the syndrome, might be caused or aggravated by partial IGF-I and/or GH resistance in bone and cartilage. In this respect, studies in immune cells, such as that by Hochberget al.,might not contribute too much to our knowledge of a putative IGF-I signalling defect in growth failure: the signalling cascades in lymphoblasts might differ greatly from those in bone or cartilage. In addition, normal [8] and low [9] GH secretion, as well as normal IGF-I levels [5], have been found in patients with Turner’s syndrome. This is surprising if one assumes peripheral unor subresponsiveness to the GH/IGF system: in patients with defects in the growth hormone receptor signalling pathway, one usually finds elevated GH levels as an attempt of the hormonal system to counter-regulate target unresponsiveness [10–12]. In addition, IGF-I binding to fibroblasts from a small number of Turner’s syndrome patients was normal, as mentioned by Hochberget al. [4]. These data suggest that IGF-I resistance seems not to be among the most prominent factors causing growth failure in Turner’s syndrome. In contrast, it might be interesting to note that connective tissue molecules and substrates, such as biglycan [13], are currently being investigated as to their putative role in stunted growth in disorders like Turner’s syndrome. In addition, paediatric osteologists have begun to dissect the molecular basis of human bone formation during childhood in both health and disease [14]. As long as the cause and underlying mechanisms of growth failure in girls with Turner’s syndrome remain European Journal of Clinical Investigation (1997)27, 548–549