Growth failure may be due to genetic mutations, acquired disease and/or environmental deficiencies. Growth failure may result from a failure of hypothalamic GHRH production or release, from (genetic or sporadic) maldevelopment of the pituitary somatotropes, secondary to ongoing chronic illness, malnutrition, intrinsic abnormalities of cartilage and/or bone such as osteochondrodysplasias, and from genetic disorders affecting growth hormone production and responsiveness. Children without any identifiable cause of their growth failure are commonly labeled as having idiopathic short stature.
Genetic factors affecting growth include pituitary transcription factors (PROP1, POU1F1, HESX1, LHX3, and LHX4) as well as hormones (growth hormone-releasing hormone (GHRH), GH secretagogues (GHS), GH, insulin like growth factor-1 (IGF1), insulin like growth factor-2 (IGF2), insulin (INS)) and their receptors (GHRHR, GHSR, GHR, IGF1R, IGF2R and INSR) as well as transcription factors controlling GH signaling, including STAT1, STAT3, STAT5a, and STAT5b. Growth is also influenced by other factors such as sex steroids (estrogens and androgens), glucocorticoids and thyroid hormone.
Since the replacement of human pituitary-derived GH with recombinant human GH, much experience has been gained with the use of GH therapy. The Food and Drug Administration (FDA) had expanded GH use for the following conditions for children (80):
GH deficiency/insufficiency
Chronic renal insufficiency (pretransplantation)
Turner syndrome
Short stature from Prader-Willi Syndrome (PWS)
Children with a history of fetal growth restriction (SGA, IUGR) who have not caught up to a normal height range by age 2 years
Children with idiopathic short stature (ISS): height > 2.25 SD below the mean in height and unlikely to catch up in height.
FDA approved conditions for GH treatment for adults:
Adults with GH deficiency
Adults with AIDS wasting
Additionally, the efficacy of GH treatment has been investigated in children whose height has been compromised due to chronic illnesses such as Crohn’s disease, cystic fibrosis, glucocorticoid-induced suppression of growth in other disorders (asthma and juvenile idiopathic arthritis (JIA), also known as juvenile rheumatoid arthritis (JRA)), and adrenal steroid disorders such as congenital adrenal hyperplasia (CAH). Studies have shown both anabolic effects and improvement of growth velocity after GH treatment in children with glucocorticoid dependent Crohn’s disease (81-83). Improvement in linear growth has also been observed after GH treatment in children with cystic fibrosis and JIA (84-86). The same studies have shown significant improvement in weight gain and body composition, changes that have been variably correlated with improvement in life expectancy and quality of life.
The growth-suppressing effects of glucocorticoids, is also seen in children affected with CAH where high androgens limit the height potential. Most patients with CAH complete their growth prematurely and are ultimately short adults. Lin-Su et al., showed that GH in combination with LHRHa significantly improved their final adult height in children with CAH. (142).
Larger, long-term prospective studies are needed to determine the safety and efficacy of GH treatment in these populations of children.