The IGF system plays a critical role in all phases of human growth, including intrauterine, childhood and pubertal. The importance of IGF-I for both in utero as well as postnatal human growth is highlighted by rare human homozygous IGF1 mutations, which are characterized by intrauterine growth retardation (IUGR), microcephaly, mental retardation and severe postnatal growth failure. Clinical conditions of IGF-I resistance due to mutations in the IGF-I receptor (IGFIR) similarly lead to IUGR and postnatal growth retardation. Postnatal regulation of IGF-I production is predominantly GH dependent. Defects in the GH-IGF-I axis, including mutations in the GHR, STAT5B and IGFALS genes, lead to postnatal IGF deficiency and GH insensitivity. Patients are of normal birth size but present with severe postnatal growth failure, despite normal or elevated levels of GH. Other phenotypic features - immune deficiency for STAT5B defects and insulin insensitivity for IGFALS defects - are of note. Mutations identified have been predominantly recessive. The identification and assessment of genetic defects in the GH-IGF axis has greatly enhanced our understanding of the critical importance of IGF-I in human linear growth. Continued evaluations will facilitate better diagnosis and management of children presenting with abnormal growth and development.
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