Genetic Diagnosis of Growth Failure

This chapter focuses on genetic defects associated with growth disorder. It explores the genetic abnormalities of the growth hormone-insulin-like growth factor axis as well as the defects of growth hormone receptor (GHR). The disturbances in each of two hormonal systems may result in growth failure. Chronic hypothyroidism, either primary or secondary can lead to severe stunting of growth in children and growth hormone (GH) deficiency on either a hypothalamic or pituitary basis can result in dramatic postnatal growth failure. The genetic pathophysiology of growth failure involve mutations or deletions of GHR genes and nearly 70 mutations of GHR is reported including missense, nonsense, frameshift and splicing defects. Mutation of IGF1R genes results in dramatic intrauterine growth retardation in animal studies, but no homozygous mutations of IGF1R have been reported in humans. The diagnosis, genetic testing and interpretation, prenatal testing are further discussed. Since majority of the disorders described are transmitted in an autosomal recessive manner, it should be amenable to prenatal testing.