Abstract
The second 360° European Meeting on Growth Hormone Disorders, held in Barcelona, Spain, in June 2017, included a session entitled Pragmatism vs. Curiosity in Genetic Diagnosis of Growth Disorders, which examined current concepts of genetics and growth in the clinical setting, in terms of both growth failure and overgrowth. For patients with short stature, multiple genes have been identified that result in GH deficiency, which may be isolated or associated with additional pituitary hormone deficiencies, or in growth hormone resistance, primary insulin-like growth factor (IGF) acid-labile subunit deficiency, IGF-I deficiency, IGF-II deficiency, IGF-I resistance, and primary PAPP-A2 deficiency. While genetic causes of short stature were previously thought to primarily be associated with the GH–IGF-I axis, it is now established that multiple genetic anomalies not associated with the GH–IGF-I axis can result in short stature. A number of genetic anomalies have also been shown to be associated with overgrowth, some of which involve the GH–IGF-I axis. In patients with overgrowth in combination with an intellectual disability, two predominant gene families, the epigenetic regulator genes, and PI3K/AKT pathway genes, have now been identified. Specific processes should be followed for decisions on which patients require genetic testing and which genes should be examined for anomalies. The decision to carry out genetic testing should be directed by the clinical process, not merely for research purposes. The intention of genetic testing should be to direct the clinical options for management of the growth disorder.
Highlights
Human linear growth continues from the embryonic stage through to adolescence and early adulthood
Normal skeletal growth and development depends on multiple factors and can be affected by numerous genetic anomalies, including many that are not associated with the growth hormone (GH)–insulin-like growth factor (IGF)-I axis
Abnormalities of IGF1 are rare in humans, with only about 9 cases reported [34, 35], both homozygous and heterozygous mutations, and heterozygous deletions have been identified in patients with short stature [9, 36, 37]; homozygous carriers generally have more severe growth failure than those with heterozygous defects
Summary
Human linear growth continues from the embryonic stage through to adolescence and early adulthood. Anomalies of the classic transcription factor genes cause very specific profiles of hormone deficiencies due to abnormal pituitary development; the most prevalent defects in patients with growth failure are in PROP1, which was reported in a literature analysis to occur in 6.7% of worldwide sporadic cases of combined pituitary hormone deficiency and 11.2% when familial cases were included [21].
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