Biosynthetic GH is officially approved for short SGA children by the Food and Drug Administration in USA since 2001, the European Agency for the Evaluation of Medicinal Products since 2003 and in Japan since 2008. The criteria at which GH treatment can be started are somewhat different between Europe, USA, and Japan. Short children with a dysmorphic syndrome, except those with Silver– Russell syndrome, tend to show poor growth to GH.
The registered starting dose of GH is 0.033 mg/ kg/ day (~1 mg/ m2/ day) in Europe and Japan, while in the USA the recommended dose ranges from 0.033 to 0.067 ug/ kg/ day (~1– 2 mg/ m2/ day).
Effect on Growth and Adult Height
GH treatment effectively induces catch- up growth and improves adult height in most short children born SGA. A systematic review reported that the mean height gain was on average 1.25 SDS.
The growth response to GH is, however, highly variable, which is probably associated with multiple gene variants. Prediction models could explain 52% of the variability of the growth response in the first year and 40% of adult height, but it is impossible to reliably predict the individual growth response both before and during treatment. The growth response to GH treatment does not differ between those born preterm or term.
No difference in adult height SDS was found between children treated with a GH dose of 0.033 mg/ kg/ day and 0.067 mg/ kg/ day [73], while the higher GH dose led to an average serum IGF- I of +2 SDS. For that reason, it is recommended to treat short SGA children with a GH dose of 0.033 mg/ kg/ day, and to sonly increase the GH dose when the growth response is unsatisfactory and other causes of a poor growth response are ruled out [2] . High serum IGF- I levels >2 SDS during GH treatment with 0.033 mg/ kg/ day might be due to a heterozygous IGF1R defect. Consideration should be given to undertaking genetic testing for this diagnosis. These children re quire a higher GH dose to obtain an acceptable growth response, and an elevated serum IGF- I on GH treatment may be accepted due to their partial IGF- I insensitivity. Persistently high serum IGF- I levels are also found in short SGA children with syndromes like Bloom and Fanconi, which may not have been identified due to lack of clear dysmorphic features. Again, genetic testing would be helpful to achieve a specific diagnosis. If such a syndrome is identi fied, then GH should be discontinued. Children with SRS (15p11) can also show high IGF- I levels, likely due to a relative IGF- I resist ance, but until this has become clear, it is recommended to lower the GH dose. GH dosing based on IGF- I titration results in a poorer growth response than treatment based on a fixed GH dose, and is therefore not recommended [79]. Adult height is greater when treatment is started at least 2 years before the onset of puberty [74]. However, some short SGA children come to medical attention when they have just started puberty. When their predicted adult height is < - 2.5 SDS at onset of puberty, their adult height can improve by combined treatment of GH and 2 years of a GnRHa.
Effect on Pubertal Development
On average, GH- treated SGA children start puberty at a similar age as the normal population, although some start relatively early. GH treatment has no influence on the onset and progression of puberty compared to AGA controls, regardless of GH dose (0.033 vs. 0.067 mg/ kg/ day).
Effect on Metabolism, Insulin Sensitivity, and cardiovascular Health
GH has lipolytic, anabolic, and insulin- antagonistic effects and leads in short SGA children to an increase in lean body mass and decrease in fat mass. Short SGA children have reduced insulin sensitivity before the start of GH treatment, a further reduction in insulin sensitivity with a compensatory increase in insulin secretion during GH, but a complete normalization after cessation of GH. Assessment of the impact of long- term GH treatment in large study groups has shown that none of the GH- treated SGA- born subjects developed β- cell dysfunction or type 2 DM.
Blood pressure and cholesterol levels decline during GH treatment, and become significantly lower than in untreated SGA children. The few studies reporting on the carotid intima media thickness (cIMT) in GH- treated SGA children showed no effect of GH treatment.
Treatment with combined GH/ GnRHa in SGA children results in similar body composition, insulin sensitivity, β- cell function, blood pressure, and lipid levels at adult height as those treated with GH only.
Effect on Bone Mineral Density
During long- term GH treatment, the total- body BMD improves from – 1.00 SDS to – 0.44 SDS, and lumbar- spine BMD corrected for height, from – 0.48 SDS to – 0.14 SDS.
Effect on cognitive Functioning and Health- Related Quality of Life
Short SGA children have on average lower cognitive functioning. One study showed that long- term GH treatment improved performance IQ and attention while the estimated total IQ scores significantly increased by 5– 10 points, to the same range as the normal population.
Long- term GH treatment improves health- related quality of life (HRQoL) in short SGA children.
Safety
Since the early nineties, multiple large cohort studies in short children born SGA have been conducted, showing that GH treatment is well tolerated, and that serious adverse effects are uncommon.
Diagnosing syndromes can be challenging, particularly when children have mild symptoms, but identifying the genetic aetiology is important for health prognosis, genetic counselling, and treatment. GH treatment is contraindicated in several conditions, such as chromosomal breakage syndromes and DNA repair disorders.
Monitoring During GH Treatment
Height, weight, and Tanner pubertal stage should be monitored regularly. It is recommended to determine the serum IGF- I level 3 to 6 months after the start of treatment, to evaluate whether the GH dose requires adjustment and/ or further evaluation. Thereafter, it is advised to determine the serum IGF- I level annually. When IGF- I levels remain high even with a relatively low GH dose, one should consider performing IGF1R mutational analysis, and to examine for the presence of a possible underlying dysmorphic syndrome like Bloom syndrome. As serum- free T4 levels decrease to levels just below the norm in 14% of GH- treated SGA children but thyroid- stimulating hormone (TSH) levels remained normal, it is recommended to annually assess serum- free T4 and TSH.
As bone maturation in short children born SGA is highly variable and unreliable for growth prediction, radiological investigations are not very informative. Since SGA birth is associated with a higher risk of the metabolic syndrome, one could argue that metabolic syndrome parameters should be checked annually. On the other hand, many studies have shown that GH has very limited effects on cardiometabolic parameters during treatment and several years thereafter. For that reason, it is recommended to only monitor blood pressure, BMI, abdominal waist circumference, fasting glucose, and lipid levels. Periodical measurement of fasting insulin is not recommended for clinical care because of the absence of criteria to differentiate normal from abnormal. However, additional monitoring and testing should be performed when indicated (e.g. in the case of a positive family history for DM or cardiometabolic diseases).
