Growth velocity increase in children with Turner syndrome treated with growth hormone following a brief therapy interruption

INTRODUCTION

Growth failure is a substantial feature of Turner syndrome (TS) and typically progresses from infancy to adulthood. The average height of untreated adult females varies between 143 and 146 cm depending on the population and is approximately 20 cm lower than in unaffected women [1, 2]. It is well known that early and proper treatment with growth hormone (GH) in children with TS is essential to increase growth velocity and improve their final height [1–5]. However, the response to this therapy is not as effective as it is observed in children with growth hormone deficiency (GHD) [4], due to the different pathophysiology of the two diseases. It has been found that short stature in TS is a consequence of haploinsufficiency of the SHOX gene [1, 2, 6]. As GH secretion seems to be normal, growth delay appears to be related to diminished tissue sensitivity to growth factors. Therefore, supraphysiological GH doses are used in the treatment of TS and have proven to accelerate growth [4, 7, 8]. The use of such high doses is believed to overcome the tissue resistance.
During the GH treatment in GHD children, usually at the beginning of the therapy, a catch-up growth phenomenon occurs, with growth velocity greater than appropriate for age and gender [9, 10]. It lasts for several months to a year. Similar observations were also made in patients with TS [11, 12].
In a previous study [13], it was found that in GHD children, re-introducing the treatment after the interruption during the GH therapy resulted in a significant increase in height velocity, even greater than during the primary catch-up growth at the very beginning of the therapy.
In this paper, we analyze growth velocity in 5 patients with TS, treated long term with GH, who had short interruptions in drug administration, followed by the re-introduction of treatment. The aim was to perform a preliminary assessment of the influence of such interruptions on the growth process.

MATERIAL AND METHODS

The retrospective analysis of clinical data revealed five patients of developmental age (6–14 years) with TS who were treated with recombinant human GH (rhGH) (Omnitrope, Sandoz) and experienced short therapy interruptions (12–90 days) due to non-medical reasons, related to temporary unavailability of the medication. All subjects were previously treated with GH at a dose range of 0.32–0.35 mg/kg/week for more than one year (3–11 years). Their growth velocities were compared to the group of 10 TS patients of similar age, who had no interruptions in the treatment and were continuously treated with GH. Also, the patients’ growth velocities during the treatment beginning (after the first 3 and 6 months) were collected. Included patients presented no additional medical conditions affecting growth. This analysis was performed in accordance with the World Medical Association Declaration of Helsinki regarding the ethical conduct of research. It was based on the research protocol approved by the Bioethical Committee of Poznan University of Medical Sciences (No. 318/16).

RESULTS

The average growth velocity after the treatment interruption increased 2-fold compared to the value during continuous therapy prior to the interruption. Also, the average growth velocity after the interruption was 1.3–1.5 ti­- mes greater compared to values observed in the period after the primary rhGH therapy introduction (catch-up growth after 3 and 6 months). Detailed data regarding growth velocities of patients with TS during the primary catch-up growth, continuous therapy, and after restarting the treatment are presented in Table I and Figure I.

DISCUSSION

According to the authors’ knowledge, there are no studies on the re-occurrence of the catch-up growth phenomenon in GH-treated girls with TS after interruptions during long-term therapy. Such cases occur sporadically and cannot be planned due to the fact that the treatment is, by definition, continuous. Nevertheless, in the past, some studies were conducted regarding the influence of planned intermittent therapies on growth in certain groups of GH-treated children. Research involving patients born small for gestational age suggests no negative effect of interruptions in GH administration on the achieved height [14]. Another study with GHD children showed no negative growth results of less frequent GH administration: three times vs. six times a week gave similar effects [15].
Earlier observations proved the re-occurrence of catch-up growth in patients with GHD who restarted GH therapy after a break [13]. Due to various mechanisms of growth failure, there were doubts about whether the catch-up effect would recur after a therapy interruption also in TS children and how significant it would be. Our present observations show similar results as in the GHD children. When the treatment was restarted, the TS patients’ growth velocity increased to greater values than during the previous continuous treatment. Furthermore, this was also even more pronounced than during the period of initial treatment introduction. Thus, it strongly suggests that the catch-up effect is not a single phenomenon during GH therapy also in TS children.
Numerous studies show that the main factors influencing the intensity of catch-up growth in GH-treated children are bone age delay, the degree of growth deficit, and the severity of GH deficiency [9, 16]. In presented cases of TS patients with therapy interruptions, due to former long-term GH treatment, the height deficiency must have been less pronounced than at the therapy’s very beginning, and the bone age delay could not be greater. Also, in TS the secretion of GH and IGF1 is preserved, so we should not consider the degree of their deficiency. In the picture presented above, this rapid growth response, stimulated by the GH administration, must be regulated by some other factors and mechanisms that still need to be clarified.

CONCLUSIONS

The analyzed data suggest that a single brief GH treatment interruption should not cause a major concern regarding the growth delay in children with TS. It seems that it could even temporarily accelerate the growth velocity, due to the re-occurrence of the “catch-up growth” phenomenon. However, increasing the size of the study group and further, prolonged observation of patients’ height after a break in the therapy would make it possible to conduct a broader analysis of long-term effects of such interruptions.

DISCLOSURE

The authors declare no conflict of interest.

REFERENCES