CEDIE   05498
CENTRO DE INVESTIGACIONES ENDOCRINOLOGICAS "DR. CESAR BERGADA"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
New Insights on the Insulin-like Growth Factor Deficiency
Autor/es:
HORACIO DOMENÉ
Lugar:
San Pablo, Brasil
Reunión:
Congreso; 8vo Congreso Paulista de Endocrinologia y Metabologia; 2009
Institución organizadora:
Sociedade Brasileira de Endocrinologia y Metabologia
Resumen:
Insensitivity to GH (GHI) is characterized by low IGF-I levels associated to normal or elevated GH levels and lack of IGF-I response upon GH treatment. Molecular defects in at least 4 different genes have been characterized in  patients presenting GHI, also called severe primary IGF-I deficiency: GHR, STAT5b, IGF1, and IGFALS (the genes encoding for the GH receptor, the signal transducer and activator of transcription type 5b, the IGF-I and the acid labile subunit, ALS). The first description of GH insensitivity (GHI) was reported in 1966 by Laron et al. in two siblings with the classical clinical appearance of GH deficiency, but presenting elevated levels of GH. It was not until 1989 that the molecular basis  was characterized in patients with this condition presenting a partial deletion of GHR gene. Since then, more than 150 patients have been characterized, most of which carry point mutations in the GHR gene. Frequently the molecular defect affects the extracellular domain of the receptor resulting in abnormal GH binding and low to undetectable GHBP levels. Other GHR gene mutations may result in defects in receptor dimerization, cell membrane anchorage, or transduction of the signal. In 1996, the first patient presenting a partial IGF1 gene deletion was described in a 15-year-old boy with severe intrauterine growth retardation, postnatal growth failure, sensorineural deafness, mental retardation, microcephaly and delayed puberty. Marked insulin-resistance was also present, likely related to the abnormally high GH levels and a functional GHR. Three additional patients with IGF1 gene mutations have been reported, all showing pre- and postnatal growth failure and mental retardation and two with sensorineural hearing loss. Interestingly, high levels of IGF-I were reported in a 55-year-old patient, indicating that the V44M-IGF-I mutant is inactive and unable to bind type 1 IGF receptor.       The STATs (signal transducers and activators of transcription) family include seven members that are activated by multiple growth factors and cytokines. Although GH activates four members of this family, STAT-5b is the key mediator of GH promoting actions. In 2003 a homozygous mutation in STAT5b gene was described in a 16 year old girl with severe post natal growth retardation and IGF-I deficiency. The patient had a history of recurrent pulmonary infections and lymphocytic interstitial pneumonia, presenting immunodeficiency characterized by a defect in T cell immunity. Since STAT5b is also required in the signaling of several cytokines such us interleukine-2 and ã-interpheron it seems likely that the growth failure and the immune defect are both due to its inactivation. At least seven patients with STAT5b deficiency have been reported and they all present severe growth failure, complete GH insensitivity and moderate to severe immunodeficiency.   In 2004, we described a 17-year-old boy with delayed onset of puberty, slow pubertal progress with marked IGF-I and IGFBP-3 levels that remain unchanged after GH stimulation. He presented an inactivating mutation in the IGFALS gene encoding the acid labile subunit (ALS), a key factor for stabilizing IGF-I in the circulation. So far, at least 17 patients have been described with ALS deficiency. In these patients, whereas circulating levels of IGF-I are dramatically decreased, local production appears to be preserved. Circulating IGF-II, IGFBP-1, -2, and -3 levels are also reduced, with the greatest reduction observed for IGFBP-3. Insulin resistance, characterized by normal glucose levels, hyperinsulinemia and low levels of IGFBP-1, were common findings. Commonly, height SDS before puberty was between -2 and -3. Adult height SDS was higher than prepubertal height, but still 1.0 SD lower than the midparental height SDS. Interestingly, despite a profound circulating IGF-I deficiency, there is only a mild impact on postnatal growth. The local expression of IGF-I, under the control of normal and/or increased GH levels, could be responsible for the preservation of linear growth near normal limits. These recent studies have revealed novel molecular mechanisms of GH insensitivity/primary IGF-I deficiency beyond the GH receptor gene. In addition, they have also underlined the importance of several players of the GH-IGF axis  in the complex system that promotes human growth.