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Growth Horm IGF Res. 2018 Feb;38:19-23. doi: 10.1016/j.ghir.2017.12.004. Epub 2017 Dec 12.

Genetic disorders of GH action pathway.

Author information

1
Centro de Investigaciones Endocrinológicas (CEDIE-CONICET), "Dr. César Bergadá", División de Endocrinología, Hospital de Niños R. Gutiérrez, Buenos Aires, Argentina. Electronic address: hdomene@cedie.org.ar.
2
Escuela de Medicina, Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Quito, Ecuador.

Abstract

While insensitivity to GH (GHI) is characterized by low IGF-I levels, normal or elevated GH levels, and lack of IGF-I response to GH treatment, IGF-I resistance is characterized by elevated IGF-I levels with normal/high GH levels. Several genetic defects are responsible for impairment of GH and IGF-I actions resulting in short stature that could affect intrauterine growth or be present in the postnatal period. The genetic defects affecting GH and/or IGF-I action can be divided into five different groups: GH insensitivity by defects affecting the GH receptor (GHR), the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1), the synthesis of insulin-like growth factors (IGF1, IGF2), the transport/bioavailability of IGFs (IGFALS, PAPPA2), and defects affecting IGF-I sensitivity (IGF1R). Complete GH insensitivity (GHI) was first reported by Zvi Laron and his colleagues in patients with classical appearance of GH deficiency, but presenting elevated levels of GH. The association of GH insensitivity with several clinical sings of immune-dysfunction and autoimmune dysregulation are characteristic of molecular defects in the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1). Gene mutations in the IGF1 and IGF2 genes have been described in patients presenting intrauterine growth retardation and postnatal short stature. Molecular defects have also been reported in the IGFALS gene, that encodes the acid-labile subunit (ALS), responsible to stabilize circulating IGF-I in ternary complexes, and more recently in the PAPPA2 gen that encodes the pregnancy-associated plasma protein-A2, a protease that specifically cleaves IGFBP-3 and IGFBP-5 regulating the accessibility of IGFs to their target tissues. Mutations in the IGF1R gene resulted in IGF-I insensitivity in patients with impaired intrauterine and postnatal growth. These 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.

KEYWORDS:

GH insensitivity; GH receptor; IGF-I insensitivity; IGF1; IGF1 receptor; IGFALS; Molecular defects of GH action; PAPPA2; STAT3; STAT5B

PMID:
29249625
DOI:
10.1016/j.ghir.2017.12.004
[Indexed for MEDLINE]

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