rhGH Safety and Efficacy Update
Growth hormone (GH) has been used to treat patients with GH deficiency (GHD) since 1960 when it was originally extracted from cadaveric pituitary glands [1]. In 1985, several cases of Creutzfeldt-Jakob disease were identified and attributed to pituitary-derived GH. Later that year, recombinant human GH (rhGH) was approved by the US Food and Drug Administration (FDA). The availability of an unlimited supply of rhGH improved access to therapy for children with GHD and the frequency of dosing increased from 3 times each week to 6 or 7 days each week [2]. The increased supply of rhGH allowed investigation into treatment of multiple conditions associated with short stature not associated with GHD leading to FDA approval for treatment of children with growth failure associated with chronic renal insufficiency (1993), Turner syndrome (TS; 1996), Prader-Willi Syndrome (PWS; 2000), small for gestational age (SGA) without adequate catch-up growth (2001), idiopathic short stature (ISS; 2003), short stature homeobox (SHOX) deficiency (2006), and Noonan syndrome (NS, 2007). In addition, rhGH therapy was FDA approved for acquired immune deficiency syndrome (AIDS) wasting (1996), adult GHD (1996), and short bowel syndrome (2003) (Table 1). Guidelines for the use of GH therapy have been reported previously by the American Association of Clinical Endocrinologists (AACE), Growth Hormone Research Society (GRS), and The Lawson Wilkins Pediatric Endocrinology Society (LWPES) [2,4].
GH registries have been an invaluable resource for determining the safety and efficacy of GH. These registries were originally mandated by the FDA in 1985 because rhGH was the first product approved in the United States derived from recombinant DNA technology. The FDA required Genentech to conduct a 5-year phase IV postmarketing safety study. However, the National Cooperative Growth Study (NCGS) was extended as a phase IV postmarketing safety and efficacy study until 2010 [5]. Other GH registries include GHMonitorSM (Serono) and the ongoing international registries American Norditropin Studies: Web Enabled Research (ANSWER; Novo Nordisk), Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS, Eli Lilly), and Pfizer International Growth Study (formerly Kabi International Growth Study [KIGS]) as well as national and pharmaceutical registries in many individual countries. Some countries continue to mandate safety and efficacy registries for children receiving GH therapy. The cumulative safety and efficacy data from these multiple studies involves more than 120,000 children treated for nearly half a million patient years. Numerous publications from these studies have educated the pediatric and adult endocrinology community about the safety and efficacy of GH therapy in children and adults.
GH registries have been, and continue to be, primarily conducted through entry of data relating to patient care without requiring adherence to specific practice guidelines. Thus, the data collected reflect the variation in clinical practice among the investigators who participate in the trial. Attempts have been made to use the registries to provide evidence to guide clinical practice [6] and to compare practice patterns with reported knowledge, attitudes, and beliefs [7]. However, one major weakness of these registries is the vast amount of data that are not entered by the participating sites. Although the study sites are compensated for the time required for data entry, because of the volume of data and work involved the number of fields required for payment were limited to high-priority items. Therefore, items not required for payment are less likely to be recorded. However, the sheer volume of these registries overcomes these limitations to some degree.
This article focuses on efficacy data for FDA-approved indications for promoting linear growth in children and available safety data related to rhGH treatment of all conditions in children. Effects that can occur after rhGH therapy is completed, or in individuals who continue rhGH therapy into adulthood, are also addressed.
Efficacy
Since rhGH became available, numerous clinical trials have been performed to show its efficacy in improving linear growth, quality of life, body composition, and bone mineral density [8–11]. Prospective, phase III clinical trials showing efficacy and safety have formed the basis of FDA approval for the numerous indications described earlier. Although small clinical trials have also shown efficacy in numerous other conditions associated with growth failure, including inflammatory bowel disease, chronic steroid use, cystic fibrosis, skeletal dysplasias, hypophosphatemic rickets, and juvenile rheumatoid arthritis, rhGH has not been FDA approved for these conditions. Phase IV postmarketing surveillance and efficacy studies (ie, registries) have also provided significant efficacy and safety information regarding FDA-approved indications and numerous other conditions treated with rhGH.
Pediatric GHD
rhGH was first approved for the treatment of childhood-onset GHD on October 18, 1985. The efficacy of GHD depends on several variables including cause, rhGH dose, and dosing schedule. Children with organic causes of GHD, including congenital panhypopituitarism, multiple pituitary hormone deficiency, and suprasellar tumors, tend to be more sensitive to rhGH and grow well in response to lower doses. However, the growth response in children with idiopathic GHD (IGHD) is more variable and may be predicted by the results of the GH stimulation tests [9]. GHD is diagnosed in children using auxologic features (short stature and/or poor growth velocity), radiologic investigations (bone age, magnetic resonance imaging of brain with focus on pituitary), and biochemical testing (insulin-like growth factor [IGF]-1, IGFBP-3, and GH stimulation testing). Peak GH responses of less than 10 ng/mL to two separate secretory stimuli have been considered the cutoff for abnormally low GH secretion and support a diagnosis of GHD. Because of the variability and lack of reproducibility of GH stimulation tests (GHSTs), a trial of GH therapy has been suggested as part of the diagnostic evaluation of a child who otherwise fits the criteria for GHD but has normal response to GHST. The recommended rhGH dose for children with GHD in the United States is 0.175 to 0.35 mg/kg/wk with 0.3 mg/kg/wk being used most commonly [2–4,6]. Because of the GH sensitivity of children with GHD, at some point in the dose curve, increasing the dosage does not translate into improvement in growth response (Fig. 1) [12]. Adjustment of rhGH dosing (0.4–0.7 mg/kg/wk) during puberty in an attempt to match the normal increase in GH secretion during puberty has also been shown to improve growth velocity during puberty [13]. A stepwise increase in rhGH dose with pubertal stages has been shown to improve near-adult height by 3.6 cm (or +0.49 mean height standard deviation score [SDS]) compared with age-matched historical controls [14].
Fig. 1 First-year response to rhGH therapy.
(From Keni J, Cohen P, Keni J, et al. Optimizing growth hormone dosing in children with idiopathic short stature. Horm Res 2009;71 Suppl 1:71; with permission.)
The use of serum IGF-1 values to adjust rhGH dosing has been debated since the reliable assays for IGF-1 (formerly Somatomedin C) became available [15]. The impact of this treatment paradigm was shown in a clinical trial in which weight-based dosing of rhGH was compared with dosing of rhGH to target an IGF-1 value at the mean (0 SDS) or top of the normal range for age (+2 SDS) [16]. Children in the weight-based dosing arm of the study grew similarly to those titrated to an IGF-1 at 0 SDS. However, children whose rhGH doses were titrated to IGF-1 levels at +2 SDS grew significantly better than either other group. An important finding in this study was that the spectrum of rhGH doses that children required to achieve a particular target was highly variable. The weight-based arm was treated with 0.28 mg/kg/wk, whereas the 0 SDS target arm received an average of 0.23 mg/kg/wk and the GHD subjects in the +2 SDS target arm received an average of 0.46 mg/kg/wk. Children with GHD also showed better growth response to treatment in all 3 arms. In a 2006 survey of pediatric endocrinologists, 72% reported that they routinely monitor IGF-1 values in children receiving rhGH [7]. Demonstration of the use of IGF-based dosing in clinical practice was done by reviewing NCGS that which showed that 41% of children with GHD had IGF-1 values entered into the registry between 2000 and 2005 [7]. However, the long-term efficacy of IGF-based dosing has not been tested. In addition, the safety of the higher doses of rhGH required in some children to achieve a serum IGF-1 target of +2 SDS is unclear [17].
Short-term growth responses to rhGH in GHD have been reported in multiple articles [8–11]. The growth velocity (GV) seen in the first 12 months is characteristically the highest GV seen during therapy, with subsequent years remaining at more than the pretreatment values. In mathematical growth predication models, growth in children with the first-year growth response has been shown to be inversely correlated with age and height deficit, but positively correlated with body weight, birth weight, and GH dose [18]. A recent analysis of data from the NCGS provides expected growth responses to rhGH in prepubertal children for the first year of therapy (Fig. 2A–D). This analysis also shows that responsiveness to rhGH decreases with age [6].
Fig. 2 First-year growth responses to daily rhGH. First-year growth responses to daily GH expressed as height velocity (HV) at age of treatment onset (x-axis) in naive, prepubertal girls and boys with IGHD (A, B), organic GHD (OGHD) (C, D), and ISS (E, F), and girls with TS (G). Data given for mean and mean ± 1 SD.
(From Bakker B, Frane J, Anhalt H, et al. Height velocity targets from the National Cooperative Growth Study for first-year growth hormone responses in short children. J Clin Endocrinol Metab 2008;93(2):355; with permission.)
Efficacy may also be termed lack of failure. However, growth parameters for failure to respond to rhGH therapy have not been well established. Criteria that have been used include a doubling of the pretreatment growth velocity, 2 cm/y faster than pretreatment GV, and 50% faster than pretreatment GV. It has been proposed that the children whose GV is greater than −1 SDS on the Bakker charts are showing an adequate response to therapy. The relationship of the early growth response to rhGH therapy has been shown to correlate with final adult height [19].
Determination of long-term growth response to rhGH using near-adult height has been done for 2 large GH registries [19,20]. In the NCGS, height improved in children with IGHD from −2.7 (± 0.7) SDS to −1.4 (± 1.0) SDS [20]. Enrollment height and GHST response were significant predictors for Δ height SDS in this cohort. In KIGS, median height SDS at the start of treatment were −2.4 (IGHD) and −2.9 (MPHD) for white boys and −2.6 (IGHD) and −3.4 (MPHD) for girls, respectively. With rhGH treatment, height improved to −0.8 (IGHD) and −0.7 (MPHD) for white boys and −1.0 (IGHD) and −1.1 (MPHD) for girls, respectively [19] The first-year increase in height SDS and prepubertal height gain was highly correlated with total height gain.
Chronic renal insufficiency before transplantation
Children with chronic renal insufficiency (CRI) frequently have growth failure that, if untreated, leads to adult short stature. Growth failure in CRI is multifactorial, with GH resistance playing a major role [21]. Before consideration of rhGH therapy, management of modifiable factors that may impair growth in CRI (eg, malnutrition, acidosis, metabolic bone disease, and/or the iatrogenic impact of therapies for CRI) needs to be optimized. rhGH therapy for children with growth failure (height <−1.88 SDS) in the setting of CRI before renal transplant was approved in 1993. GH treatment is recommended at a dosage of 0.35 mg/kg/wk, divided into 6 or 7 doses [2,22]. Treatment with rhGH is effective and has been shown to improve final adult height [22,24]. A recent analysis of data from the NCGS provides expected growth responses to rhGH in prepubertal children with CRI for the first year of therapy (Fig. 3) [25]. To maximize response to rhGH therapy in CRI, it is important that continued attention is paid to the management of modifiable factors that may impair growth. Long-term rhGH treatment of children with CRI showed improvement of height from −2.6 to −0.7 SDS after 5 years [26]. Final adult height was analyzed in a study of 38 children with CRI, showing that rhGH therapy led to improvement from a height of −3.1 ± 1.2 to −1.6 ± 1.2 SDS [23]. A group of 50 age-matched controls with CRI without growth failure at baseline did not receive rhGH therapy and had worsening of their height in the same time period, with a loss of 0.5 SDS [23]. Analysis of adult height in 49 patients with baseline height SDS between −2 and −3 revealed that 65% had an adult height of more than −2 SDS [27].
Fig. 3 First-year growth responses to daily rhGH in CRI. First-year growth response (fitted curves) expressed in HV for prepubertal children with chronic kidney disease during rhGH treatment compared with pretreatment HV for the same children.
(From Mahan JD, Warady BA, Frane J, et al. First-year response to rhGH therapy in children with CKD: a National Cooperative Growth Study report. Pediatr Nephrol 2010;25(6):1128; with permission.)
RhGH therapy following renal transplantation has been controversial and is not FDA approved despite multiple studies showing efficacy [28]. Despite a lack of FDA approval, analysis of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database has shown that the number of children receiving rhGH more than 5 years after transplantation is 9% of all patients and 14% of those whose height was less than −1.88 SDS 6 months after transplant [28]. In this population, there was a modest improvement in height of approximately +0.5 SDS following 5 years of rhGH use [28]. Analysis of NAPRTCS data shows that the final adult height in renal transplant recipients who received rhGH therapy (n = 71) compared with renal transplant recipients who did not receive rhGH therapy (n = 669) showed a height gain of +0.77 SDS (−1.83 ± 0.14 rhGH vs −2.60 ± 0.05, P<.001) [29].
Turner syndrome
Short stature is the most common clinical characteristic of TS. A significant proportion of the height deficit in girls with TS is caused by the presence of only a single copy of the SHOX gene (haploinsufficiency). The SHOX gene is a homeobox gene that regulates the growth of long bones. The SHOX gene is located in the pseudoautosomal region of both sex chromosomes and its actions are gene dose related [30]. Growth in children with TS is characterized by a slight intrauterine growth retardation (−1 SD), slow growth during infancy and childhood, and lack of pubertal growth spurt. More than half of girls with TS are at less than the fifth percentile by 2 years of age [31]. The average height of an adult woman with TS who has not received rhGH therapy is 143 cm, approximately 20 cm (8 inches) less than the average adult woman [32].
rhGH therapy was FDA approved in 1996 for treatment of short stature in TS, has been shown to significantly improve adult height in girls with TS, and may allow achievement of height in the normal adult female range [33–36]. Earlier diagnosis and initiation of GH treatment in children with TS should help patients to attain heights near the normal range at a younger age. Early initiation of rhGH therapy enables the children to start estrogen supplementation in a more age-appropriate manner [37]. According to the 2006 Turner Syndrome Consensus Study Group, puberty should not be delayed to promote statural growth because this approach undervalues the psychosocial importance of age-appropriate pubertal maturation [38]. Treatment with rhGH should commence when the child has experienced growth deceleration or is less than or equal to −2SD less than the target adult height based on midparental height. Earlier rhGH treatment of young patients with TS can abrogate the height loss compared with their peers [39]. If the rhGH is initiated later than 10 years, or in cases of extreme short stature, adjunct therapy with nonaromatizable androgens should be considered [40]. Therapy should be continued until final adult height is reached or the height achieved is acceptable [41]. Final height gains may be as high as 8 to 10 cm with or without delaying estrogen-replacement therapy [42–45]. A typical rhGH dose for treatment in children with TS is 0.35 mg/kg/wk [2,6] and is FDA approved up to 0.469 mg/kg/wk. Higher doses of rhGH may be associated with increased height gain [46], although the potential for adverse late effects has not been evaluated adequately. rhGH dose seems to be the most important predictor of height velocity in the first year of rhGH therapy, whereas, for height gain in years 2 to 4 of therapy, the velocity during the previous year is the most important predictor [46]. A recent analysis of data from the NCGS provides expected growth responses to rhGH in prepubertal children with TS for the first year of therapy (see Fig. 2G) [6].
The usefulness of monitoring IGF-1 levels during rhGH therapy in TS has not been well studied. In one study of 24 prepubertal children with TS, IGF-1 values were low at baseline, improved at 3 and 6 months after starting rhGH therapy, but returned to baseline at 12 months [47]. Although the IGF-1 response does not seem to have a clear relationship with rhGH dose [47] in girls with TS, rhGH-induced IGF-1 levels have been shown to correlate with the growth response [48]. In the largest randomized study of rhGH therapy for TS treated to near-final height, in which 232 children with TS received either 0.27 or 0.36 mg/kg/wk, baseline IGF-I concentrations were low normal and remained within 2 SDS of the mean during GH therapy in all but 2 subjects [34].
Short stature from prader-willi syndrome
RhGH treatment was FDA approved in 2000 for the treatment of growth failure in children with PWS. The FDA-approved dose is 0.24 mg/kg/wk with recommended rhGH dosing between 0.24 and 0.35 mg/kg/wk [4]. rhGH treatment in PWS has been proved to improve linear growth and increase muscle mass/body fat ratios [49,51]. Improved muscle tone and strength have also been clinically observed in children with PWS treated with rhGH [49,51]. GH therapy has also been shown to provide neurodevelopmental benefits in young children with PWS [51]. This finding suggests additional benefits of rhGH treatment of younger PWS children with growth failure and hypotonia. Near-adult height in PWS is also shown to be improved with rhGH therapy. In a study of 22 children with genetically-confirmed PWS treated with rhGH (0.30 mg/kg/wk) from age 6.9 to 18.1 years, the near-adult height for all children was within midparental height median −0.5 SDS (−1.4 to 0.7) and 0.9 SDS (0.1–1.9) for girls and boys, respectively [52]. Analysis of growth data in the Pfizer International Growth Study (KIGS) shows that two-thirds of children with PWS achieved a height within the normal range [52,53].
The impact of rhGH treatment on obesity in children with PWS is controversial, and stringent weight management techniques are necessary for all children with PWS regardless of rhGH treatment status. However, multiple studies with rhGH have shown overall improvement in body composition. KIGS data indicate that there is a decrease in body mass index (BMI) in the first year of GH therapy. BMI then tends to stabilize as a result of an increase in muscle mass and a decrease in fat mass associated with rhGH therapy [53]. Furthermore, at final adult height, body composition has been shown to be improved, but not normalized [52].
Small for gestational age
SGA (<−2 SD for birth weight and/or birth length) is defined at different gestational ages based on data from Usher and McLean [54]. The incidence of children born SGA in the United States has been estimated at 8.6% [55]. Eighty-five percent of children born SGA catch up to the normal curve by the age of 2 years, with most of them catching up by the age of 6 months [56,57]. Children who have not shown adequate catch-up growth by 2 years of age are unlikely to attain a normal adult height without rhGH therapy [56,58]. Children who are SGA have relative GH resistance, but rhGH therapy has been shown to improve final adult height and was FDA approved in 2001 [59,60]. Approved rhGH doses for treatment of SGA are up to 0.49 mg/kg/wk. Mathematic prediction models of the growth response of SGA children to rhGH show that rhGH dose is the most important predictor of the first-year growth response [61]. Age at start of therapy is negatively correlated with the first-year growth response [61]. Subsequent growth is dependent on the first-year response to rhGH therapy. Investigations comparing continuous and intermittent rhGH therapy in SGA children showed similar growth responses over time [59]. However, because of the degree of catch-down growth seen between therapy courses with intermittent therapy, continuous therapy has been adopted [62]. In a final height study of continuous rhGH therapy, 54 children started treatment with rhGH at 8.1 (±1.9) years at a dose of 0.23 or 0.46 mg/kg/wk. Final adult height was −1.1 (± 0.7) SDS in those who received 0.23 mg/kg/wk and −0.9 (±0.8) SDS in those who received 0.46 mg/kg/wk. rhGH treatment resulted in an adult height more than −2 SDS in 85% of the children after a mean rhGH treatment period of 7.8 (± 1.7) years [57].
Idiopathic short stature
Short stature is commonly defined as a height less than the third percentile (2 SD <the mean) compared with children of the same age and gender. Using this statistical definition, 1.8 million children (aged 5–14 years) in the United States have short stature at any given time [63]. The prevalence of short stature (<third percentile) and poor growth (GV<5 cm/y) has been predicted as 0.7% of children (420,000; 1:143) in a school-based study [64]. The rate of referral of children with short stature and poor growth has a major impact on the number of children prescribed GH. Estimates of the referral rate vary from 2.5% by records review (Adda Grimberg, personal communications, 2006) to 34% by hypothetical survey [65]. Assuming a 20% referral rate, 84,000 children could be expected to be evaluated at some point between the ages of 4 and 15 years. If 35% of children referred to a pediatric endocrinologist for short stature have a known pathologic condition that would respond to GH therapy [5,66], 65% of referrals (54,600 children) for short stature and poor growth to have no known cause for their growth failure. This value correlates well with data from the NCGS showing that 60.2% of children receiving GH therapy are in a combined category of IGHD and ISS [67].
By definition, ISS excludes known causes of short stature [68]. However, ISS most certainly includes a subset of children with GHD that have a normal response to GHST. The basis of the diagnosis can affect the interpretation of efficacy. For example, the cutoff for the GH peak is moved following GHST to diagnose GHD from less than 10 down to less than 7, less than 5, or less than 3, the spectrum of ISS and its response to rhGH therapy expands. Therefore, the ability to describe the cause of short stature in children with ISS is limited by the current diagnostic tools [69]. Many children with undiagnosed conditions that result in severe short stature respond to rhGH therapy [70,72].
The use of rhGH in ISS has been the focus of both ethical and financial controversies. Multiple natural history studies report that children with ISS have short stature as adults. Hintz and colleagues [70] showed that GH treatment in children with ISS resulted in an increase in final height of 5 cm compared with predicted height. A larger increase (9 cm) was seen when the final height of treated patients was compared with historical controls. In the only randomized, placebo-controlled trial of rhGH therapy for 68 children with ISS to final height, adult height was greater in the rhGH-treated group (−1.81 ± 0.11 SDS) than in the placebo-treated group (−2.32 ± 0.17 SDS) by 0.51 SDS (3.7 cm) [71]. In a meta-analysis of 40 studies of GH therapy in ISS, the investigators concluded that adult height was increased by 4 to 6 cm in those treated with GH [73]. However, they estimated the cost of treatment at $35,000 per inch. In May, 2003, the FDA approved the use of rhGH at a dose of up to 0.37 mg/kg/wk in children with ISS who are less than −2.25 height SDS and who are unlikely to catch up in height. A subsequent final height trial with higher dose and more frequent administration showed improved height outcome. This study compared the adult height of 50 patients with ISS given daily injections of GH at dosages of 0.24 mg/kg/wk, 0.24 mg/kg/wk for the first year and 0.37 mg/kg/wk thereafter, or 0.37 mg/kg/wk [72]. Mean height SDS increased by 1.55, 1.52, and 1.85, respectively. Final heights were 7.2 cm and 5.4 cm more than pretreatment predicted final heights for the 0.37 mg/kg/wk and 0.24 mg/kg/wk dose groups, respectively [72]. In addition, in those children who received 0.24 mg/kg/wk, 71% of final height SDS values were within the normal range and in those who received 0.37 mg/kg/wk, 94% of final height SDS values (all but 1) were within the normal range.
Determination of long-term growth response to rhGH for children with ISS using near-adult height has been done for 2 large GH registries [20,74]. In the NCGS, height improved in children with ISS from −2.8 (±0.6) SDS to −1.6 (±1.0) SDS [20]. The Δ height SDS for ISS was similar to that seen for IGHD. However, enrollment height and GHST response were not significant predictors of growth response in ISS. In the Pfizer International Growth Study (formerly KIGS), height improved in children with ISS from −2.5 to −1.4 SDS [74]. Age at onset of rhGH therapy and first-year responsiveness are the strongest predictors of long-term growth response in ISS.
The use of serum IGF-1 values to adjust rhGH dosing in ISS is also controversial. The impact of this treatment paradigm in ISS was shown in a clinical trial in which weight-based dosing of rhGH was compared with dosing of rhGH to target an IGF-1 value at the mean (0 SDS) or top of the normal range for age (+2 SDS) [16]. Children in the weight-based dosing arm of the study grew similarly to those titrated to an IGF-1 at 0 SDS. However, children whose rhGH doses were titrated to IGF-1 levels at +2 SDS grew significantly better than either other group. An important finding in this study was that the spectrum of rhGH doses that children required to achieve a particular target was highly variable. The weight-based arm was treated with 0.28 mg/kg/wk, whereas the 0 SDS target arm received an average of 0.23 mg/kg/wk and the ISS subjects in the +2 SDS target arm received a much higher average of 0.83 mg/kg/wk. This finding indicates that ISS represents partial GH insensitivity. Children with ISS also showed a poorer growth response to treatment in all 3 arms compared with children with GHD: Δ height SDS was 2.04 (±0.17) for GHD and 1.33 (±0.09) for ISS groups in those with IGF-1 values targeted at +2 SDS and 1.41 (±0.13) for children with GHD, and 0.84 (±0.07) for those with ISS with IGF-1 values targeted at 0 SDS [75]. This result indicates that ISS also represents a state of partial IGF-1-insensitivity. Demonstration of the use of IGF-based dosing in clinical practice was done by evaluation of IGF-1 data entered into NCGS, which showed that, when children with ISS were growing poorly, the dose was more likely to be changed if an IGF-1 value was obtained [7]. However, the long-term efficacy of IGF-based dosing in ISS has not been tested. In addition, the safety of the higher doses of rhGH required in some children to achieve a serum IGF-1 target of +2 SDS is unclear [17].
SHOX deficiency
SHOX is produced by the short stature homeobox gene in the pseudoautosomal regions on the distal ends of the X and Y chromosomes. Absence of 1 copy (haploinsufficiency) of the shox gene, caused by absence of X chromosome material, is a significant component of short stature in TS. The shox gene encodes a transcription factor that is important in regulating the growth of long bones. SHOX deficiency (SHOX-D), through mutation or deletion of the shox gene, is present in most individuals (∼70%) with Leri-Weill dyschondrosteosis (LWD) and in a small, but significant, number (2%–15%) of children with ISS [76,78].
There is a single published, randomized trial of rhGH in short prepubertal children with a molecularly proved SHOX gene defect [30]. In this multinational study, children with SHOX-D with both ISS and LWD phenotypes were randomized to treatment with rhGH. A comparison group of prepubertal girls with TS also received rhGH therapy. After 1 year, children with SHOX-D receiving rhGH therapy (n = 27, 12 boys; 0.35 mg/kg/wk; 8.7 ± 0.3 cm/y) showed a significant improvement in growth compared with untreated controls (n = 25, 12 boys; 5.2 ± 0.2 cm/y, P<.0001). The 1-year growth response was also comparable with a group of rhGH-treated children with TS (n = 26; 0.35 μg/kg/wk; 8.9 ± 0.4 cm/y, P = .592). After 2 years, rhGH-treated SHOX-deficient children had grown 5.9 cm more and gained +0.9 height SDS more than untreated controls (P<.001) [30]. rhGH therapy for SHOX-D was FDA approved in 2006 at a dose of 0.35 mg/kg/wk. A retrospective analysis of rhGH therapy showed similar height gain at final height in individuals with SHOX-D (n = 14, + 1.1± 0.2 SDS) to those with TS (n = 157, + 1.2 ± 0.1 SDS, P = .708) [79]. However, individuals with SHOX-D showed a trend toward shorter final heights than those with TS (149.0 ± 6.7 vs 151.4 ± 5.1 cm, P = .109) and had a lower final adult height SDS (−2.2 ± 0.8 vs −1.7 ± 0.8, P = .016) [79]. Further studies are needed to provide additional near-adult height efficacy data in this condition.
Noonan syndrome
NS, characterized by hypertelorism, down-slanting palpebral fissures, low-set posteriorly rotated ears, small chin, short neck, short stature, chest deformities, and heart defects (especially valvular pulmonic stenosis), was first described in 1963 and has an estimated incidence of 1 in 1000 to 1 in 2500 live births [80]. Mutations in multiple different genes involved in intracellular signaling (PTPN11, K-Ras, SOS1, Raf1, B-Raf, SHOC2, and N-Ras) have been found to cause NS in 61% of cases [80]. Short stature during childhood, caused by postnatal growth failure, is seen in more than 50% of individuals with NS. In untreated individuals with NS, mean adult height at age 19 years has been reported as 162.5 (±5.4) cm in men and 152.7 (±5.7) cm in girls [81]. However, because of the delayed puberty common to NS, untreated final adult height of boys with NS in another cohort was 167.4 cm [82]. The adult height of untreated North American individuals with NS is less than the third percentile in 54.5% of women (<151 cm) and 38% of men (<163.2 cm) [80]. There is a genotype-phenotype correlation, with individuals with NS caused by SOS1 mutations more likely to have normal stature and individuals with PTPN11 mutations more likely to have short stature [83,84]. Reports of GH secretion vary in the incidence of GHD in NS [85]. However, IGF-1 deficiency is a frequent finding in individuals with NS [80,85,86].
rhGH was FDA approved for the treatment of short stature in NS in 2007 at a dose of up to 0.462 mg/kg/wk. Early studies of rhGH therapy in NS showed only mildly improved height SDS and GV with therapy [87]
