Longitudinal growth results from multifactorial and complex processes that take place in the context of different genetic traits and environmental influences. The definition of GHD in children is difficult and remains arbitrary, in view of the fact that there is a continuity between absent and normal GH secretion during childhood.The most frequent genetic causes of isolated GH deficiency are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3 and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFκB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. 
TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in approximately 3% of short children, and also rasopathies (e.g. Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, copy number variants and imprinting disorders.

References

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