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The Treatment of Growth Disorders in Childhood and Adolescence
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Longitudinal growth in childhood is a complex process that is influenced by a variety of genetic, hormonal and environmental factors (1, e1, e2). Growth is assessed by comparing the development of a child�s height with data from suitable population-specific percentile curves. Current percentiles for the height development of children and adolescents in Germany are based on data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS); these can be found on the homepage of the Robert Koch Institute. The range of genetic expectations and the child�s body proportions are also important for assessing height (eBox 1). Prolonged deviations in growth rate can lead to either short stature or tall stature. Short stature is defined as height below the 3rd percentile, tall stature as height above the 97th percentile (2, 3); thus, by definition, 3% of all children are abnormally tall and another 3% are abnormally short. Endocrine or osseous causes are rare, and nearly all of the approximately 650 different diseases that cause short stature are rare. The growth rate can also be assessed with pertinent percentile charts and should be calculated over a period of at least 6 months. Deviations of growth rate can reflect normal processes such as constitutional early or late development but can also result from a wide range of diseases. Any abnormalities should prompt a presentation to a pediatric endocrinologist (4). An illustration of the endocrine regulation of longitudinal growth, with potential targets for pharmacological intervention, is provided in Figure 1, and a list of differential diagnoses of growth disorders in Figures 2 and 3 (e3).
Learning objectives
This article should enable readers to:
- gain an overview of the indications for the medical and surgical treatment of various diseases associated with growth disorders;
- know the possibilities and limitations of medical and surgical treatment of specific forms of short stature;
- be informed about the indications and risks of treatment for excessively tall stature.
The options for the treatment of growth disorders have expanded in recent years. In general, treatment consists either of hormone replacement therapy for patients with hormone deficiency, or of drugs or surgery that will affect longitudinal growth in order to achieve an adult height in the desired range. If drugs or surgery are used, the goals of treatment, its intended medical and psychosocial benefits, and its risks should be discussed beforehand in detail with the patients and their families, not only to prevent unrealistic expectations, but also to account properly for changing social attitudes towards below- or above-average height.
Methods
In this review, we address the currently approved and potentially emerging treatment options for children and adolescents with growth disorders from a pediatric endocrinological perspective. The review is based on current German (2, 3, 5) and international guidelines, and on expert recommendations (4). A selective PubMed search was also conducted for German- and English-language articles and reviews on the differential diagnosis and treatment of growth disorders. We searched for combinations of �short stature,� �tall stature,� �growth disorder,� �management,� �treatment,� and �therapy.�
The most clinically helpful works are cited directly, and further literature is listed in eReferences.
Reduced longitudinal growth and short stature
Treatment with recombinant human growth hormone (rhGH)
The first growth hormone (GH) for therapeutic purposes was extracted from cadaveric pituitary glands; its use in humans was first described in 1958 (6). Reports of the occurrence of Creutzfeldt-Jacob disease after treatment with human growth hormone led to a moratorium on this form of treatment starting in 1985 (7). Some pituitary extracts were contaminated with prions, and their use resulted in deaths in many locations around the world (e4). Recombinant human growth hormone (rhGH) became available a short time later and enabled the affected patients to resume treatment soon after its obligatory interruption; rhGH has been prescribable in Germany since 1987.
The recombinantly produced proteohormone rhGH (recombinant human growth hormone) has the same structure as the hormone released by the pituitary gland. It is administered once per day before bedtime with the aid of a device for subcutaneous injection (dose for GH deficiency: 25�35 �g/kg). The evening administration is intended to mimic the physiologically high, pulsatile release of growth hormone during sleep. Six different rhGH preparations and one biosimilar can now be prescribed in Germany. The dose of rhGH is mainly determined by the weight of the patient. The safety and efficacy of rhGH are additional matters of importance (4). The efficacy of rhGH therapy is assessed on the basis of the growth rate achieved, the change in height, and the serum level of insulin-like growth factor-1 (IGF-1). In children of short stature with growth hormone deficiency, growth is greatly accelerated under rhGH therapy (catch-up growth). Growth is fastest in the first year of treatment and slows down thereafter, returning to the growth rate of normal children within a few years. At the same time, there is a normalization of body composition, with an increase in muscle mass and strength and a decrease in fat mass. A key factor for safety is that the IGF-1 level should stay within the physiological reference range (4). rhGH therapy should be continued until the end of growth (growth rate < 2 cm/year); in adolescents with severe growth hormone deficiency, it can be continued further. In adulthood, severe growth hormone deficiency causes dyslipidemia, increasing fat mass, decreasing muscle and bone mass, and a decline in physical performance. These changes can be counteracted by the continuation of rhGH therapy (8).
Long-term studies in children with GH deficiency have demonstrated the efficacy of rhGH and the achievement of an adult height that is on average 3�4 cm less than the familial target height (9, e5). The treatment of GH deficiency is less successful if catch-up growth cannot be completed before puberty, if the treatment is started late, if the diagnosis is in doubt, or if adherence is deficient. The side effect profile is favorable (e6); the rare serious side effects include pseudotumor cerebri (1 : 1116 patients) and epiphysiolysis of the femoral head (1 : 898 patients [e7]). The European long-term study SAGhE (Safety and Appropriateness of Growth hormone treatments in Europe), which followed up patients for as long as 30 years after the end of rhGH therapy, found no increased overall mortality compared to the normal population (10). rhGH therapy was also extended to other short stature disorders after it became available without restriction in 1987. rhGH has since been approved for growth promotion in girls with Ullrich-Turner syndrome and children with severe short stature after hypotrophy at birth (small for gestational age, SGA), Prader-Willi syndrome, SHOX deficiency (a genetic growth disorder related to Ullrich-Turner syndrome), Noonan syndrome, and chronic renal failure. Its efficacy for these indications is lower than for GH deficiency, and the recommended dose is 50�100% higher. Selected indications are listed in the Table.
Treatment with long-acting growth hormone (LAGH)
Long-acting growth hormone preparations (LAGH) have been approved and available for use in Germany since early 2022. Clinical testing in randomized controlled trials (RCT) with a treatment duration of 12 months demonstrated their non-inferiority to conventional rhGH ([19], Table). LAGH only need to be injected once a week. Clinical experience with these new drugs is limited, particularly with regard to their long-term safety and efficacy. The data available to date have not revealed any relevant differences in the side-effect profiles of long-acting and daily injected rhGH (e8). Unlike conventional rhGH, LAGH does not produce a stable IGF-1 serum concentration, but rather one that fluctuates over the course of the week. The resulting weekly cycle of IGF-1 concentration is non-physiological, and as a result the evaluation of IGF-1 measurements during treatment depends on their timing in relation to the administration of the drug. In view of the different pharmacology and the lack of long-term experience with these new drugs, LAGH should only be prescribed after the patient and/or his/her parents or guardians have been thoroughly informed and have explicitly chosen this form of treatment.
Treatment with recombinant human insulin-like growth factor-1 (mecasermin)
In 1966, Zvi Laron described a group of patients of short stature who had the low IGF-1 levels characteristic of GH deficiency despite relatively high GH serum levels (20). Subsequent analysis revealed that they had a defective GH receptor (e9). Mutations were later found in genes of the post-GH-receptor signaling cascade as well. All of these mutations are subsumed under the term severe GH insensitivity (GHIS) (e10). Recombinant human IGF-1 (mecasermin) was approved in the EU in 2007 by the European Medicines Agency (EMA) as an orphan drug for the treatment of patients with so-called severe primary IGF-1 deficiency (21). Treatment with recombinant human insulin-like growth factor-1 (rhIGF-1) improves adult height, but not to the same extent as GH administration to treat GH deficiency (e5). rhIGF-1 replacement optimizes adult height by compensating for the deficient formation of endogenous IGF-1 that is due to the missing activation of GH receptors by GH. Further IGF-1-independent signaling pathways are also stimulated by GH, and thus rhIGF-1 cannot fully compensate for the interruption of GH-dependent signaling. The long-term studies carried out to date on patients with severe GHIS have shown a cumulative increase in height by approximately two standard deviations (21, 22), but only by approximately one standard deviation in patients with milder forms (23). This means that the adult height of treated patients often remains below normal despite treatment.
The main adverse effect of rhIGF-1 is hypoglycemia (18%). Thus, patients should always eat before a mecasermin injection to avoid hypoglycemia. Other reported complications include local reactions, enlargement of lymphoid tissue, the transient development of acromegalic facial features, and a slightly increased likelihood of intracranial hypertension with congestive papilledema and headache (23).
Treatment with vosoritide
The cause of achondroplasia is a gain-of-function mutation of the growth-regulating fibroblast growth factor receptor 3 gene (FGFR3 gene). This activating mutation leads to impaired enchondral ossification. The affected individuals have syndromic short stature with rhizomelic (i.e., proximally shortened) limbs and macrocephaly (mean adult height: 132 cm in men, 124 cm in women). Other skeletal anomalies may be present as well. Vosoritide was approved in late 2021 as a drug for the treatment of short stature in children with achondroplasia aged 2 years and above (for its mechanism of action, see the eFigure). Daily injections increase the annual growth rate by around 1.5 cm/year (24, 25, e11, e12). Data on the adult height of treated patients are not yet available. The available safety data have not yet shown any serious side effects; common adverse events include circulatory dysregulation (12% vs. 5% with placebo), dizziness and vomiting (27% vs. 20% with placebo) and local reactions at the injection site (73% vs. 48% with placebo). It also remains unclear whether the favorable changes in the spine that have been seen in the animal model will be reproduced in vosoritide-treated children with achondroplasia. Further sustained-release C-natriuretic peptide (CNP) analogs (e13), drugs with a different point of attack, and so-called long-acting preparations are being developed but have not yet been clinically tested e14).
Treatment with gonadotropin-releasing hormone analogs to suppress puberty
The onset of puberty marks the beginning of the end of growth. With the aid of monthly subcutaneous injections of gonadotropin-releasing-hormone analog (GnRHa) depot preparations, the secretion of gonadotropins from the pituitary gland can be inhibited and gonadal activity reversibly suppressed. This form of treatment has few side effects. The efficacy of GnRHa in the treatment of central precocious puberty is undisputed (e15), but two controlled studies of GnRHa for the treatment of other conditions have shown no more than a marginal effect of GnRHa on adult height (26, e16). This result is probably explained by the fact that the pubertal growth rate is negatively correlated with the age of onset of puberty. Therefore, monotherapy with GnRHa to promote growth is not recommended. The recommendation is different if GnRHa is given in combination with growth hormone. An average gain in adult height of 6�9 cm has been described in children with growth hormone deficiency who were not treated with GH until late in puberty and were given GnRHa in addition (e17).
Treatment with aromatase inhibitors to suppress estradiol production
The senescence of the growth plate and its ultimate bony closure is effectuated by estradiol in both sexes. Inhibition of the last enzymatic step in estradiol production, the aromatization of testosterone, is therefore a promising pharmacological approach for prolonging the duration of body growth. A third-generation aromatase inhibitor (letrozole) has been used in boys with constitutionally delayed growth and puberty, and in boys with idiopathic short stature, in two different randomized and controlled trials (27, 28). The preliminary findings were positive, showing slowed bone maturation and increased residual growth, but no such effect was seen in the long-term outcome: in a follow-up study on idiopathic short stature, the patients treated with the drug became no taller in adulthood than the controls (e18). this form of treatment should thus still be considered experimental. Aromatase inhibitors are not approved for the treatment of short stature in Germany.
Treatment with oxandrolone
Oxandrolone is a synthetic anabolic steroid with a markedly lower virilizing effect than testosterone; unlike testosterone, it cannot be aromatized. Its use to treat idiopathic short stature has been found not just to accelerate growth, but also to accelerate bone maturation as well, so that it is not expected to increase adult height. Interestingly, however, three placebo-controlled studies have shown that girls with Ullrich-Turner syndrome who are treated with growth hormone become taller as adults if they are also given low doses of oxandrolone from the age of 8 to 10 onward (29). Mild virilization symptoms, such as deepening of the voice, occurred in 18.6% of girls who were so treated (e19). Oxandrolone is now only available in the USA and has not been approved for the treatment of short stature in Germany.
Surgery for short stature
Various surgical procedures have already been used for surgical limb lengthening. At first, the surgical lengthening of short limbs was mainly based on the ring-fixator method developed by Ilizarov. In recent years, internal implantable systems, so-called lengthening or distraction intramedullary nails, have come into increasing use (e20). Surgical limb lengthening has been performed mainly in patients with skeletal dysplasias such as achondroplasia. Depending on the underlying disease, mean height increases of 27 cm (12�40 cm) (e21) or 11�30 cm (e22) have been reported. These invasive procedures carry a risk of postoperative leg axis malalignment, infection, or functional impairment of the operated limb. Limb lengthening should be performed with highly restricted indications in children and adolescents.
Whether or not they decide to undergo surgery, patients with short stature should receive psychological support as needed. Patient organizations offer patient-parent seminars that address such topics as self-esteem, emphasizing personal strengths, and dealing with the limitations caused by short stature.
Growth acceleration and tall stature
Children or adolescents whose height is above the 97th percentile of their age group are, by definition, tall. The most common cause is a family history of tall stature. As a rule, such persons are already longer than their age group at birth and then grow at a normal to slightly above-average growth rate towards their genetic target height (30, e23). This situation differs from that of children or adolescents whose growth is pathologically accelerated, either transiently or permanently, resulting in a final height that outstrips their familial target range (e24).
The main causes of tall stature are shown in Figure 3 (e1). Although the prevalence of tall stature is as high as that of short stature (3% each), children/adolescents with tall stature are seen much less frequently in pediatric endocrinology (30).
The treatment of children and adolescents with tall stature
In most cases, tall stature is not due to a disease and requires no treatment. Treatment to reduce final height may be sought if the predicted adult height is more than 2.5 standard deviations above the population mean (examples in eBox 2) and the predicted adult height is considered unacceptable for psychosocial reasons (e25).
There is hardly any evidence, however, that tall adults have more social or emotional difficulties than adults of normal height. The question therefore arises what might ethically justify the treatment of adolescents because they are too tall. Disease-related tallness is treated in different ways depending on its cause; the causes include hormone excess, amongst others precocious (pseudo-)puberty (e26), hyperthyroidism (e27), and gigantism (e28). The presence of comorbidities may indicate that the individual�s tall stature is syndromic (30).
There is no consensus on when treatment to limit longitudinal growth is indicated. The decision to treat tall stature should therefore be made by the patient and his or her parents. The physician is responsible for providing detailed, individualized information (3). A schematic summary of how to proceed is given in Figure 4.
Treatment with sex steroids
Sex steroids have been used since the late 1950s to reduce the height of tall boys and girls, on the basis of the observation that patients with untreated precocious puberty have skeletal age acceleration and premature epiphyseal joint closure i (31). In girls, the treatment is carried out (after exclusion of a coagulopathy) with supraphysiological levels of sex steroids, supplemented by a progestin for 10�14 days per month for cycle regulation. If possible, combination therapy should be continued until adult height is reached (3). The average effect on height reduction is approximately 5 cm, depending on age at the start of treatment (3). Patients and their parents should be informed about side effects such as increased weight gain, an increased risk of thromboembolic events, galactorrhea, and ovarian cysts (e29, e30, e31). Several independent studies (32, 33, 34) have shown that high-dose estrogen therapy can impair long-term fertility by lowering the probability of conception. A higher percentage of women who were so treated remained childless despite a desire for children and underwent treatment for infertility, compared to a control group of women with tall stature who were not so treated (1.8 times the risk of not becoming pregnant within 12 months, and twice the risk of being treated for infertility) (32). Adolescent women with tall stature who were treated with very high doses of ethinylestradiol (250�1000 �g) had a slightly increased risk of melanoma compared to untreated women of tall stature (e32).
In analogy to therapy for tall girls, treatment with supraphysiologic doses of sex steroids can be considered for tall boys (testosterone enanthate). The average reduction of height by means of this therapy is 5 cm (35). Side effects of testosterone therapy include aggressive behavior, priapism, gynecomastia, and acne vulgaris (36, e33). Studies of fertility and sperm quality in men who had undergone high-dose testosterone therapy yielded normal findings (37). The risk of cancer in treated men has not yet been systematically investigated (38).
Epiphysiodesis of the growth plates adjacent to the knee joint
Bilateral epiphysiodesis of the growth plates adjacent to the knee was first published in the late 1990s as an alternative to pharmacologic treatment to limit excessive longitudinal growth (e34). This involves bilateral percutaneous epiphysiodesis of the distal end of femur and of the proximal ends of the tibia and fibula. The timing should be based on the growth prognosis, pubertal status, and desired size reduction (39). Benyi (2010) recommends surgery in girls before menarche and before a bone age of 12.5 years, and in boys before a bone age of 14 years. With this approach, a reduction of 33% of prospective residual growth was achieved (e35). Postoperative knee pain is reportedly a common complication; wound infection is less common (e36). A size reduction of about 5 cm has been reported with this procedure even in patients with an advanced bone age (40).
Epiphysiodesis alters body proportions, but, since most tall people have relatively long lower limbs, the ratio of sitting height to total height after treatment is closer to the population average than before (e36).
Experimental treatment with somatostatin analogs
The first publications on the use of somatostatin analogs appeared at the beginning of the 1990s. Only a few therapeutic trials with small case numbers were published, and these showed only minor effects on the predicted adult height (e37). Bone age acceleration was generally not observed. Side effects such as cholelithiasis, transient diarrhea, and abdominal pain were described. After analyzing their experimental data, the authors did not recommend the use of somatostatin analogs to limit excessive growth.
Psychological support
Especially in adolescent girls, acceptance is a common problem when an above-average adult height is predicted. If major psychosocial stress results, the affected children and adolescents should be given psychological support to help them adapt and enable them to mobilize their personal resources to cope with stress (3).
Overview and perspectives
There is only a limited palette of medical and surgical treatment approaches. The decision process for or against treatment should involve a careful weighing of the current and predicted somatic and psychosocial limitations caused by whatever condition is producing the abnormal stature. The patients and their parents should be informed realistically and in detail about the benefits and risks of treatment.
Conflict of interest statement
Prof. W�lfle has received lecture honoraria, and compensation for serving on advisory boards and as a consultant, from Ascendis, BioMarin, Hexal/Sandoz, Novo Nordisk, and Pfizer Pharma.He is a paid advisory board member for Ascendis, BioMarin, Hexal/Sandoz and Novo Nordisk. He is member of the board of directors of the German Society for Pediatric and Adolescent Endocrinology and Diabetology (Deutsche Gesellschaft f�r p�diatrische und adoleszente Endokrinologie und Diabetologie, DGPAED) and of the German Association of People of Short Stature and their Families (Bundesverband kleinw�chsiger Menschen und ihrer Familien, BKMF).
Dr. Schnabel has received lecture honoraria, and compensation for serving on advisory boards and as a consultant, from Ascendis, BioMarin, Hexal/Sandoz, Kyowa Kirin, Novo Nordisk, Pfizer Pharma. He has received travel support from Novo Nordisk and Kyowa Kirin. He serves as a paid advisory member for Ascendis, BioMarin, Hexal/Sandoz, Kyowa Kirin, and Novo Nordisk. He has received funding for industry-sponsored clinical trials in the field of achondroplasia from Ascendis. He is member of the board of directors of the German Society for Pediatric and Adolescent Endocrinology and Diabetology (Deutsche Gesellschaft f�r p�diatrische und adoleszente Endokrinologie und Diabetologie, DGPAED)
Prof. Binder has received lecture honoraria, and compensation for serving on advisory boards and as a consultant, from Ferring, Ipsen, Lilly, Merck Serono, Novo Nordisk, Pfizer und Sandoz/Hexal. He has received travel support from Novo Nordisk and Pfizer. He serves as a paid advisory member for Ascendis, Merck Serono, Novo Nordisk, Pfizer, and Sandoz/Hexal. He has received funding from Novo Nordisk for a study of pharmocogenetics of growth hormone treatment.
Manuscript received on 28 February 2023, revised version accepted on 21 August 2023.
Translated from the original German by Ethan Taub, M.D.
Corresponding author
Prof. Dr. med. Joachim Woelfle
Kinder- und Jugendklinik der Friedrich-Alexander-Universit�t
Erlangen-N�rnberg
Loschgestr. 15
D-91054 Erlangen, Germany
joachim.woelfle@uk-erlangen.de
Cite this as:
Woelfle J, Schnabel D, Binder G: The treatment of growth disorders in childhood and adolescence. Dtsch Arztebl Int 2024; 121: 96�106. DOI: 10.3238/arztebl.m2023.0247
detail/174�021 (last accessed on 14 January 2023).
Centre for Chronic Sick Children, Paediatric Endocrinology, Charit�, University Medicine Berlin, Berlin: Dr. med. Dirk Schnabel
Pediatric Endocrinology, University Children�s Hospital, Universiy of Tuebingen, Tuebingen: Prof. Dr. med. Gerhard Binder
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