Final adult height of children with idiopathic short stature: a multicenter study on GH therapy alone started during peri-puberty

Idiopathic short status (ISS) is defined as a condition in which the height of an individual is more than 2SD score (SDS) below the corresponding mean height for a given age, sex, and population group without evidence of systemic, endocrine, nutritional, or chromosomal abnormalities. Children with ISS have normal birth weight and are GH sufficient [1]. The incidence of ISS (including constitutional delay of growth and puberty and familial short stature) is about 23 in 1000 [1‐3]. In 2003, the US Food and Drug Administration approved growth hormone (GH) for the treatment of ISS patients (height < − 2.25 SD). The main purpose of GH therapy for ISS is to attain normal adult height and avoid daily life inconvenience and psychological problems caused by extreme or unacceptable short stature. However, few clinical studies have explored whether the final adult height (FAH) can reach the normal range after GH therapy. FAH is considered the golden indicator for evaluating the efficacy of GH therapy [4, 5]. However, the predicted FAH following a short period of treatment is dynamic and cannot reflect the actual FAH. Owing to the heterogeneity of the treated ISS populations and the individualization of treatment, only a few randomized trials with small sample sizes have observed ISS until FAH [6‐10]. A randomized study of FAH typically takes 8 years or more to complete and is often difficult to implement in clinical settings. Thus, most of the currently available studies only have small samples and are carried out in a single center. More studies are needed to confirm the efficacy of GH in the treatment of ISS.

In the clinical real world, many ISS children’s parents are willing to observe their children growth when they are young. As children grow older and become peri-puberty, more people come to see doctors. What is the effect of GH treatment alone in peri-puberty? Past literatures are not accurate. This is the first multicenter study in China on the efficacy of growth hormone alone in the treatment of elder children. In our current study, we followed up children with ISS diagnosed by the departments of pediatric endocrinology in seven tertiary hospitals in different regions of mainland China, and evaluated the efficacy of GH for ISS children until FAH.

This is the first observational multicenter study with FAH results in China on the efficacy of growth hormone alone for ISS. It was an observational study based on the clinical reality and reflected the real-world situation. In addition to the follow-up of FAH, the difference between FAH SDS and baseline height SDS and between FAH height SDS and TH SDS was also evaluated. It was found that a treatment course of 2 years or more had better efficacy. Even for over 10 years old ISS children, GH therapy could improve FAH if the treatment course was long enough.

Randomized controlled trials (RCTs) have been recognized as high-quality research evidence because of their rigorous grouping/screening criteria and standardized treatment. However, sometimes RCTs do not actually reflect the clinical reality because the efficacy of GH for ISS varies greatly and the GH treatment is highly individualized in the true clinical setting. Although real-world retrospective studies are feasible, their data are limited by the natural characteristics of the treated children. In the study of short stature, it is difficult to find a control group without treatment: in clinical practice, few children will adhere to the follow-up protocol if no GH treatment is applied. In the current study, patients who had received GH treatment for less than 3 months were included in the control group, which was based on the following consideration: although GH is effective for a patient, such efficacy within a short period (3 months) can be neglected for the FAH; thus, the result of a short treatment course of up to 3 months is similar to that of natural growth. Our data comprised real-world clinical data, which may be used as evidence for long-term treatment of GH for ISS.

As known, the efficacy of GH in the treatment of ISS remains controversial. In a variety of prospective/retrospective, randomized/non-randomized, and controlled/non-controlled trials, some researchers concluded that GH treatment improved ISS while others considered it ineffective. The efficacies in these studies varied dramatically [12‐18]. Some meta-analyses showed that GH-treated ISS patients might gain more FAH than untreated children, but were still shorter than the normal populations. In the meta-analysis performed by Deodati and Canfarani, three RCTs that followed the ISS patients until FAH were included, among which the average treatment course was 4.6–6.2 years [8]. In these three RCTs the treated group gained 0.79 SDS (4.7 cm) more height than the control group without GH treatment. In the largest trial, the height attainment was 0.8 SDS (5 cm) more in the treatment group than in the control group. In the study by Sotos and Tokar, the height attainment was 1.9 SDS in the treatment group and only 0.49 SDS in the untreated control group [3]. Wit et al. evaluated 239 children treated with GH, of whom only 50 were followed up until FAH. The FAH increased by 1.52–1.85 SDS compared with baseline height [10]. In our current study, the FAH of boys and girls increased by 1.16 SD and 1.36 SD compared with baseline height, which is basically consistent with results reported in the literature. Compared with the 6 m-2y group, the ≥2y group had significantly more FAH gain over the baseline height. Therefore, GH treatment for more than 2 years can achieve better efficacy in ISS patients.

Our study showed that 54.4% of boys and 78.7% of girls had a FAH SDS > −2SD after GH treatment. This result explains that GH therapy is effective even in peri-puberty children. Among the girls who had been treated with GH > 2 years, their FAH was higher than TH. This further confirmed that GH therapy could improve FAH and longer the better. For boys, FAH SDS was lower than TH SDS in all groups although they attained the normal height. It may be that boys need to improve their height longer than girls. In the GeNeSIS observation study by Pfäffle and colleagues, including United States, Germany and France data, shows that most children achieved near adult height (NAH) within the normal range (height SDS > − 2) after GH treatment [19]. The main population of our study is Chinese Han children. It shows that the same results as in Europe and America, the efficacy of growth hormone is similar.

The average age of boys and girls at baseline was 12.7 ± 1.87 years and 11.7 ± 11.7 years, with bone age of 11.7 ± 2.32 years and 10.1 ± 10.02 years, respectively. The relatively late initiation of treatment reflected the real-world situation. Multivariate linear regression model analysis showed that FAH is influenced positively by baseline height SDS in the boys and girls, whereas negatively by baseline bone age in girls, which was consistent with previous findings [1, 3, 8, 13, 20]. Many previous studies have demonstrated that the age when starting GH treatment is an important factor for its efficacy [1, 2, 6, 10, 20]. In this regard, our patients might have benefited more from GH therapy if the treatment had started earlier.

And we notice in this study, even in the control group, there is a spontaneous height gain of 1.16 SD. Economic factors need to be taken into account in the treatment of ISS. In China, growth hormone therapy for ISS is covered by families themselves. Whether to treatment or not, as well as the course of treatment, is decided by parents after weighing the family economic and height expectations.

This study had some limitations: Although it was a multi-center observation study, 344 of 475 cases entered the final analysis. It reflects “real-world” clinical practice and can be considered reliable, but which is not represented in random clinical trials. The sample is not big enough when stratification by treatment duration, if there is a larger sample in each subgroup, it will be better to validate our findings.

In summary, both girls and boys of ISS improved FAH by GH therapy even if treatments begin over 10 years old and majority of them reached TH. Some peri-puberty ISS will have a spontaneous height gain. We recommend the course of GH treatment more than 2 years for girls, and longer courses for boys.