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Authors; Anusree Subramonian, and Jennifer Horton.
Turner syndrome (TS) is a chromosomal abnormality in female individuals in which the X chromosome is partially or completely absent. TS occurs due to the deletion or nonfunctioning of 1 of the X chromosomes in the female embryo.1 It affects approximately 1 in 2,500 female live births.2 Also known as congenital ovarian hypoplasia syndrome;3 TS presents as a spectrum of clinical features affecting multiple organ systems. Primarily TS is associated with premature ovarian failure resulting in absent or delayed puberty and infertility.3 The most common feature of TS is growth failure resulting in short stature, often noticeable by age 5.1 Children with TS are typically born with a birth length and weight in the low normal range. However, the growth rate in the early years for those with TS is slower than their peers without TS and decreases severely around puberty. Without treatment, their average adult height is around 20 cm shorter than people without TS.2 Other than the shorter stature, the characteristic facial features of TS include hypertelorism (increased distance between the eyes), webbed neck, high arched palate, and low-set ears. TS is also associated with a higher risk of cardiovascular malformations (e.g., coarctation of the aorta, bicuspid aortic arch), endocrine and metabolic dysfunction (e.g., thyroiditis, glucose intolerance, diabetes, dyslipidemia), musculoskeletal features (e.g., scoliosis, Madelung’s deformity, low bone mineral density), and other gastrointestinal and renal impairments.4 TS can be suspected in utero (during prenatal ultrasounds) or at birth based on clinical features. Diagnosis is confirmed with karyotype testing.1 Later in childhood or adolescence, a patient can present with short stature, delayed onset of puberty or an absence of menstrual periods. The mainstay of management of TS is growth promotion using growth hormone (GH) with or without oxandrolone, estrogen replacement, and managing the spectrum of clinical and metabolic concerns.4
Short stature in TS is due to the haploinsufficiency of the SHOX gene located in the X chromosome.5 The SHOX deficiency also causes the various musculoskeletal and craniofacial impairments associated with TS. While there is no true GH deficiency in TS, patients benefit from GH therapy.2
GH is a peptide hormone naturally produced by the anterior pituitary gland and induces linear growth in children.5 Synthetic or recombinant human GH, somatropin, has been used to treat short stature in children and adults due to various causes. Somatropin products approved in Canada for promoting growth in children with TS are Genotropin, Humatrope, Nutropin, Omnitrope,6 and Saizen.7 A 2014 CADTH reimbursement review of Genotropin found that treatment with somatropin results in greater and rapid height gain, and final height in children with TS whose epiphyses have not closed.7 The Canadian Drug Expert Committee (CDEC) recommended listing Genotropin in this population.7
Evidence-based guidelines regarding best practices could help inform policy decisions regarding reimbursement criteria for somatropin in children with TS. The purpose of the current report is to summarize the evidence-based guidelines regarding the use of GH therapy in children with TS.
What are the evidence-based guidelines regarding the use of growth hormone therapy for children with Turner syndrome?
An information specialist conducted a literature search on key resources, including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, and a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were human growth hormone and Turner Syndrome. CADTH-developed search filters were applied to limit retrieval to guidelines. The search was completed on June 13, 2023 and limited to English-language documents published since January 1, 2013.
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Selection Criteria.
Articles were excluded if they did not meet the selection criteria outlined in Table 1, were duplicate publications or were published before 2013.
Guidelines with unclear methodology but relevant to the research question were excluded from the main report, but their characteristics and findings are presented in Appendix 5.
The included publications were critically appraised by 1 reviewer using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument8 for guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
A total of 154 citations were identified in the literature search. Following screening of titles and abstracts, 130 citations were excluded, and 24 potentially relevant reports from the electronic search were retrieved for full-text review. One potentially relevant publication was retrieved from the grey literature search or via handsearching for a full-text review. Of these potentially relevant articles, 24 publications were excluded for various reasons, and 1 evidence-based guideline9 met the inclusion criteria and was included in this report. Appendix 1 presents the PRISMA10 flow chart of the study selection.
We also found a perspective document from the Growth Hormone Research Society (GRS).11 It was not considered an evidence-based guideline but provided content relevant to the research question. The characteristics and relevant recommendations from this publication are presented in Appendix 5. Additional references of potential interest are provided in Appendix 6.
We included 1 evidence-based guideline, namely the clinical practice guideline9 from the 2016 Cincinnati International Turner Syndrome Meeting, in this report. It provides recommendations regarding various care areas for people with TS such as, diagnosis and genetics, growth and puberty, reproductive care and pregnancy, transition from pediatric to adult care, other health concerns, and health surveillance. Relevant to the current report, we have summarized the recommendations related to GH therapy in the sections below.
Additional details regarding the characteristics of included publications are provided in Appendix 2.
The clinical practice guideline9 published in 2017, was initiated by the European Society of Endocrinology (Europe) and the Pediatric Endocrine Society (US), collaborating with several other professional societies from Europe and the US. The guideline development working group consisted of endocrinologists and clinicians from other specialties, along with an epidemiologist, and a clinical psychologist. A patient advocate was also involved in the meetings.
Recommendations were developed and finalized through 2 working group meetings. The working group identified 4 clinical questions, with separate inclusion criteria and outcomes of interest. They conducted systematic literature searches for these questions and used the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework to evaluate the evidence and formulate the recommendations. Factors such as quality of evidence, a risk-benefit profile, and values and preferences such as patient perspectives and implementation feasibility were considered in this process. Other recommendations were based on the majority consensus of the working group. The strength of each recommendation was indicated in the verbiage: “recommend” and “suggest” for strong and weak recommendations, respectively. The quality of evidence for each recommendation was ranked from strong to very low, following the GRADE format.
The clinical question from this guideline relevant to the current report was “what is the effect of growth-promoting treatment in TS?”9. A systematic literature search and formal GRADE assessment was conducted for this question. Randomized controlled trials published since 1990, which examined the effectiveness of GH therapy with or without oxandrolone were searched for. Thus, 24 publications were included, in which 12 were about GH therapy. Characteristics of these included studies were reported in the publication.
The guideline9 was developed for the US and European countries.
The target population of this guideline are children, adolescents, and adults with TS. The population relevant to the current report are children (< 18 years of age) with TS.9
The intended users of the guideline are health care providers of individuals with TS, including primary care and specialized care (e.g., endocrinologists, fertility specialists, geneticists).9
The guideline provided recommendations regarding various interventions for diagnosing and caring for individuals with TS.9 The intervention relevant to the current report was GH therapy with or without concomitant treatment with oxandrolone and estrogen.
The relevant outcomes considered in the guidelines related to growth-promoting treatments were height, quality of life, mortality, cardiovascular adverse effects, and masculinization.9
In this section, we have provided a summary of methodological strengths and limitations of the included guideline.9 Additional details are provided in Appendix 3.
The scope and purpose of the included guideline were clearly described. The objective of the guideline and the health questions covered were clear. The target population and the intended users of the guideline were clear from the publication. The guideline development working group included clinicians from various relevant specialties, a psychologist, and an epidemiologist. While patient partners were not directly involved in guideline development, patient advocacy group members participated in the working group meetings and reviewed the draft.
Recommendations were either based on evidence identified through systematic searches or based on expert opinion. Systematic literature searches were conducted for 4 specific clinical questions considered by the working group. Study inclusion criteria and outcomes of interest for each of these questions were reported. For these questions, evidence was evaluated using the GRADE framework, and recommendations were evidence based. Multiple electronic databases were searched. Since the search methods, such as search strategy, were not reported, we could not ascertain whether the searches were robust and could capture all relevant literature. Study selection (as a flow chart) and characteristics of included studies were reported with adequate details. The strength and limitations of the evidence base were described. However, many of the other recommendations provided in the guideline were based on the expertise and opinion of the working group and developed through consensus. Supporting evidence was not provided for all of them, and it was unclear whether systematic searches were conducted to identify evidence.
One clinical question from the guideline (“What is the effect of growth-promoting treatment in TS?”)9 was relevant to the current report . A systematic literature search of multiple databases was conducted to identify evidence for this question. Of the 9 recommendations from the guideline related to GH therapy, 3 were based on formal GRADE assessments. The authors discussed some evidence related to 2 of the recommendations, and supporting evidence was not reported for 4 of the relevant recommendations. It was unclear whether this was due to a lack of evidence or a limited literature search. The recommendations based on expert opinion were not identifiable from the evidence-based recommendations. Thus, even though systematic searches were conducted for the relevant research question, the limitations around reporting methodology made interpretation challenging.
The recommendation statements were specific, unambiguous, and easily identifiable. The strength of each recommendation and the quality of supporting evidence were given clearly. However, the reason why a specific recommendation was rated as strong versus weak was unclear. Similarly, while the quality of evidence (ranging from strong to very low quality) was provided, details of evidence such as the number of relevant studies, and findings from them were not always clear. Authors reported that quality of evidence, risk-benefit profile, and values and preferences were considered while formulating the recommendations.
Experts reviewed the draft guideline before publication. Feedback received from external review and from professional societies were addressed appropriately and were made available with the publication. A procedure for updating the guidelines was not provided. There was no advice and/or tools to help implement the recommendations, as well as to audit or monitor adherence to recommendations. The guideline did not discuss the potential resource implications of applying the recommendations.
Lastly, the guideline likely had editorial independence. Potential conflicts of interest of the working group members were reported and available for review. It is unlikely that the funding body influenced the contents of the guideline.
We have summarized the relevant recommendations along with the supporting evidence (if available) from the clinical practice guideline from the 2016 Cincinnati International Turner Syndrome Meeting9 in this section. Appendix 4 presents the detailed recommendation statements, supporting evidence, and authors’ comments.
The Cincinnati International Turner Syndrome Meeting9 guidelines recommend initiating GH therapy early at 4 to 6 years of age (preferably before 12 to 13 years) if,
Strong recommendation based on moderate quality evidence from 14 randomized controlled trials.9 The supporting evidence demonstrated that with GH therapy, a height gain of 1 cm per year can be expected (10 studies). High doses at younger ages can result in height gains of up to 15 to 17 cm than their predicted adult height without GH (2 studies). The authors noted that the main limitations of evidence were high heterogeneity, lack of adequate blinding, high loss to follow-up, and unclear outcome definitions.
The guideline authors provided some comments regarding the discontinuation of GH therapy but did not provide formal recommendations. Treatment can be continued until a desired height is achieved or when there is no more growth potential remaining, as evidenced by bone age greater than 14 years and a height velocity of less than 2 cm per year (evidence unclear). After completion of puberty, treatment can be discontinued as there is no physiological rationale for continuing (evidence unclear).
Recommended GH dose:
Strong recommendation based on strong evidence.9 However, details of the supporting evidence were unclear from the publication.
Authors noted that higher doses are only warranted if the height prognosis is very poor. However, further details on the factors that might indicate a ‘very poor’ prognosis were unclear. Potential risks and benefits of treatment should be discussed with the patient when giving higher doses.
The guidelines provided recommendations for regular height measurements and IGF-I monitoring to assess treatment response, and to adjust GH dose.
Strong recommendation based on moderate quality evidence.9 However, details of the supporting evidence were unclear from the publication.
Strong recommendation based on low-quality evidence.9 However, details of the supporting evidence were unclear from the publication.
Weak recommendation based on very low-quality evidence.9 However, details of the supporting evidence were unclear from the publication.
The guideline did not include any specific formal recommendation statements regarding the adverse effects of GH therapy. Authors provided the following notes on the safety of treatment. They were supported by evidence as indicated in parentheses.
Concurrent treatment with oxandrolone is suggested by guideline authors:
Weak recommendation based on strong evidence.9 Supporting evidence showed that, compared to children who received GH only treatment, those who received concomitant treatment with GH and oxandrolone were 2 to 5 cm taller as adults (evidence from GRADE evaluation of 3 studies). Evidence from 6 studies suggests that concurrent treatment with oxandrolone is associated with a modest synergistic increase in growth (data not reported). Possible adverse effects are delayed breast development and dose-dependent virilization (e.g., clitoromegaly, hirsutism, acne, voice deepening). The main limitation of evidence as noted by the authors, was a high between-study heterogeneity. Therefore, a meta-analysis was not conducted.
This guideline9 also recommends against adding very-low-dose estrogen supplementation in the prepubertal years to further promote growth (Weak recommendation based on low-quality evidence9). One study found that concurrent treatment with GH and very-low-dose estrogen was associated with a modest synergistic increase in adult height, cognition, and normal timing of thelarche. However, due to the lack of any other evidence, the lack of long-term safety information, and the absence of optimized dosing strategy, the authors do not recommend concurrent treatment.
The guideline recommends regular clinical evaluation for scoliosis every 6 months while receiving GH therapy, and then annually until growth is completed (strong recommendation based on very low quality evidence).9
It also recommends coordinating GH therapy with orthopedic care if spine abnormalities are detected at the beginning or during treatment (strong recommendation based on very low quality evidence).9
The authors provided the following notes on the bone-related effects of GH therapy. They were supported by evidence as indicated in parentheses.
We identified 1 evidence-based guideline9 regarding the use of GH (somatropin) for TS. In previous sections, we have summarized the strengths and limitations of this guideline. The main limitation was that several recommendations were formulated through consensus from expert opinion of the working group based on limited available evidence. However, it was unclear whether the authors systematically searched for evidence (and found limited evidence) supporting them. Therefore, these recommendations should be interpreted with caution.
In Canada, somatropin products are approved for children with TS in whom the epiphyses are not closed.7 We did not identify any recommendations that specifically addressed treatment eligibility in relation to epiphyseal closure. We did not identify any recommendations related to outcomes such as laboratory cut-offs for treatment eligibility or for treatment discontinuation (e.g., criteria for discontinuation due to lack of treatment effect). The recommendations in the guideline were produced during a meeting in 2016; it is possible that new studies regarding the use of GH for children with TS have been published since. Therefore, the recommendations provided in the guideline may not reflect the current evidence landscape. Lastly, we did not identify any guidelines published in Canada regarding GH therapy for children and adolescents with TS. The applicability of the included guideline in Canadian settings is unclear.
We included 1 guideline from the 2016 Cincinnati International Turner Syndrome Meeting,9 that provided recommendations regarding GH therapy in children with TS. The guideline was developed for US and European countries. Recommendations were formulated either based on evidence found from systematic literature searches or from expert opinion and consensus. We also identified a perspective document from the GRS (2019),11 that discussed evaluation and treatment of short stature due to various causes in children. This publication was excluded because it was not an evidence-based guideline. The characteristics and relevant recommendations from this publication are summarized in Appendix 5.
The included guideline9 strongly recommends early initiation of GH treatment (around 4 to 6 years of age) if the child with TS has evidence of growth failure. Recommended dose of GH is 40 mcg/kg/day to 50 mcg/kg/day and can be increased if adult height potential is considerably low (strong recommendation). GH therapy should be monitored by regular height measurement (strong recommendation) and monitoring of IGF-I levels (weak recommendation) to regulate dosage. Authors noted that GH therapy could be discontinued when a bone age greater than 14 years is attained, and when the height is not increasing by at least 2 cm per year. The authors noted that there is no physiological reason to continue GH therapy after puberty is completed. However, no specific recommendations were made regarding epiphyseal plate closure and treatment discontinuation. If oxandrolone is given concurrently, patients should be 10 or older. Concomitant treatment of GH with low-dose estrogen for growth promotion is not recommended. Lastly, children with TS receiving GH therapy should be evaluated regularly for scoliosis. While no recommendations specific to the safety of GH were made, authors noted that there is an increased risk of adverse events such as intracranial hypertension, slipped capital femoral epiphysis, scoliosis, and pancreatitis in children with TS compared to those receiving GH for other growth disorders. However, these statements should be interpreted cautiously since the supporting evidence is scant. The guideline was relatively well conducted, with the main limitation of basing several recommendations on expert opinion and consensus.
The GRS perspective document11 recommended starting GH therapy with a dose at the higher end of the range if TS was diagnosed late and noted that higher IGF-I levels (i.e., more than 2 SDs above the mean for age) may be needed for effective growth in some patients. These statements should be interpreted with caution as the supporting evidence was unclear. We did not conduct a critical appraisal of the publication.
Growth promotion is 1 of the main objectives in the care for children with TS.4 Guidelines help clinicians and other health care providers make evidence-based decisions in clinical care. The recommendations from the included guideline to initiate early GH therapy in children with TS, providing recommended dosage, as well as recommendations about concurrent treatment with oxandrolone, could inform policy decisions. However, the recommendations should be implemented in light of their limitations. For many of the recommendations from the included guideline,9 such as those related to recommendations about health surveillance for orthopedic comorbidities, and treatment monitoring, the supporting evidence was unclear from the publication. They did not make recommendations regarding treatment eligibility in relation to epiphyseal closure, or regarding IGF-I thresholds for treatment discontinuation The guideline included in this report was published in 2017.9 Several studies have since been published evaluating long-term effectiveness and safety of GH therapy in children with TS.4 Appendix 6 presents some of the comparative and real-world studies published in the recent years. A detailed review of the newer studies is beyond the scope of this report; however, the evidence appears to be mostly consistent with the supporting evidence from the guideline. Future guidelines could focus on evidence regarding treatment eligibility in relation to epiphyseal closure, treatment duration, and criteria for discontinuation of treatment to inform precise recommendations on these aspects of GH therapy in children with TS.
growth hormone
Grading of Recommendations, Assessment, Development, and Evaluations
insulin-like growth factor – I
Turner syndrome
Contributors: Elizabeth Carson, Farhana Shivji
Selection of Included Studies.
Characteristics of Included Guideline From the 2016 Cincinnati International Turner Syndrome Meeting, Gravholt et al.(2017).
Note this appendix has not been copy-edited.
Strengths and Limitations of the Guideline From the 2016 Cincinnati International Turner Syndrome Meeting, Gravholt et al.(2017) Using AGREE II.
Summary of Recommendations of the Guideline From the 2016 Cincinnati International Turner Syndrome Meeting, Gravholt et al. (2017).
Note that this appendix has not been copy-edited.
Characteristics of Other Guideline (GRS Perspective, 2019).
This publication was a report from the workshop conducted by Growth Hormone Research Society International to discuss the evaluation and treatment of short stature in children. It provides recommendations based on expert opinion regarding GH treatment in children with TS. Since the recommendations provided were not evidence-based, this publication was excluded from the main report. The characteristics of the publication are summarized in Table 5.
For indications other than growth hormone deficiency the authors suggested a higher dose than for GHD. They recommend starting GH at approved dose ranges, and to use prediction models to optimize the dosage.
In case of late diagnosis of TS, the authors recommend starting rhGH on a dose at the higher end of the approved range. (Specific doses NR).
IGF monitoring: In some children with TS, IGF-I levels + 2SD is maybe needed for effective growth.
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