Growth hormone insensitivity (GHI): Post GH receptor molecular defects

HORACIO M. DOMENE

Bogotá

Simposio; Tackling growth disorders in clinical practice: from molecular insights to patient managements; 2013

Serono Symposia International Foundation

Growth Hormone Insensitivity (GHI): Post-GH Receptor Molecular Defects 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 5 different genes have been characterized in patients presenting GHI: GHR, STAT5b, IGF1, IGFALS and NFKBIA. While the first description of GH insensitivity (GHI) was reported in 1966 by Laron et al. in two siblings with 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. In 1996, the first post-receptor molecular defect was characterized in a patient with a partial IGF1 gene deletion presenting 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. Five additional patients with IGF1 gene mutations have been reported since, all showing pre- and postnatal growth failure and mental retardation and two with sensorineural hearing loss. The STATs (signal transducers and activators of transcription) family includes seven members that are activated by multiple growth factors and cytokines. STAT-5b is the key mediator of GH promoting actions. In 2003 a homozygous mutation in STAT5B gene was described in a girl with severe post natal growth retardation and GH insensitivity, recurrent pulmonary infections and lymphocytic interstitial pneumonia, associated to T-cell immunedysfunction. Since STAT5b is also required in the signaling of several cytokines, such as interleukine-2 and γ-interpheron, it seems likely that the growth failure and the immune defect are both due to the inactive STAT5b mutant protein. Nine other 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 boy with delayed onset of puberty with marked IGF-I and IGFBP-3 deficiencies that remained 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, about 30 patients have been described with complete ALS deficiency. Insulin resistance was usually present. The height before puberty ranged between -2 and -3 SDS. The moderate impact on postnatal growth despite the profound circulating IGF-I deficiency, could be explained by the preserved action of local expressed IGF-I, under the control of normal and/or increased GH levels. More recently, in 2010, two patients presenting ectodermal dysplasia, persistent T-cell lymphocitosis, a hyper IgM-like syndrome and growth retardation were described. These patients presented NFKBIA gene mutations, resulting in a I-kappa-B-alfa protein unable to be phosphorylated and removed via the ubiquitination pathway, impairing the activation of the NF-kappa-B complex and its translocation to the nucleus to activate transcription of specific genes. These patients presented both GH and IGF-I resistance. These studies have revealed novel molecular mechanisms of GH insensitivity 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.