Original Paper
HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2014;82:355–363 DOI: 10.1159/000364807
Received: March 6, 2014 Accepted: May 23, 2014 Published online: October 15, 2014
Efficacy and Safety of Growth Hormone Treatment in Children with Hypochondroplasia: Comparison with an Historical Cohort Graziella Pinto a Valérie Cormier-Daire b, e Martine Le Merrer b Dinane Samara-Boustani a Geneviève Baujat b Laurence Fresneau f Magali Viaud a Jean Claude Souberbielle c Jean Claude Pineau d Michel Polak a, e a
Pediatric Endocrinology, Gynecology and Diabetes, Centre des Maladies Endocriniennes Rares de la Croissance, Medical Genetics Department, Rare Bone Dysplasia Center, c Physiology Laboratory, Hôpital Universitaire Necker-Enfants Malades, d CNRS UPR 2147, and e Université Paris Descartes, Paris, and f Merck Serono s.a.s., Lyon, France
b
Abstract Background/Aims: Hypochondroplasia (HCH) is a skeletal dysplasia characterized by disproportionate short stature. The aims of the study are to evaluate efficacy and safety of recombinant human growth hormone (r-hGH) therapy in HCH children, when compared with a historical cohort of untreated HCH children. Methods: Nineteen HCH patients with an initial height standard deviation score (SDS) ≤–2 and a mean age of 9.3 ± 3.1 years were treated with a mean r-hGH dose of 0.053 mg/kg/day over 3 years. Growth charts were derived from the historical cohort (n = 40). Results: Height gain in the treated population was +0.62 ± 0.81 SDS greater than in the general population, and +1.39 ± 0.9 SDS greater than in the historical untreated HCH cohort (mean gain of 7.4 ± 6.6 cm gain). A negative correlation between height gain and age at treatment initiation was reported (p = 0.04). There was no significant difference in response between patients with fibroblast growth factor receptor 3 mutations and those without. No treatment-related serious adverse
© 2014 S. Karger AG, Basel 1663–2818/14/0826–0355$39.50/0 E-Mail [email protected] www.karger.com/hrp
events were reported. Conclusions: r-hGH treatment is well tolerated and effective in improving growth in HCH patients, particularly when started early. The treatment effect varies greatly and must be evaluated for each patient during treatment to determine the value of continued therapy. © 2014 S. Karger AG, Basel
Introduction
Hypochondroplasia (HCH; OMIM146000) is an autosomal dominant skeletal dysplasia with a heterogeneous phenotype [1–3]. In the most severe cases, patients have disproportionate severe short stature, micromelia, short broad hands and feet, lumbar hyperlordosis, and macrocephaly. Mild cases have moderate disproportionate short stature (until puberty), which is often misdiagnosed as idiopathic short stature. Failure of the puberty growth spurt compromises adult height, with Maroteaux and Falzon [2] reporting mean adult heights of 146.1 ± 4.9 cm (range: 138– 153) in boys and 137.6 ± 6.3 cm (range: 128–147) in girls.
Clinical Trial Registration No.: NCT01111019.
Michel Polak, MD, PhD and Graziella Pinto, MD Pediatric Endocrinology, Gynecology and Diabetes Hôpital Necker Enfants Malades, 149 rue de Sèvres FR–75015 Paris (France) E-Mail graziella.pinto @ nck.aphp.fr
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Key Words Hypochondroplasia · Growth hormone treatment · Skeletal dysplasia · Growth curve
HCH is largely caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene located at 4p16.3 [4]. Although the tyrosine kinase receptor FGFR3 is expressed in brain, lung and cartilage, its major physiological function is thought to be in the negative regulation of cartilage growth, restricting the length of long bones via inhibition of chondrocyte proliferation [5]. Gain-offunction mutations have been described in various skeletal dysplasias, including achondroplasia and HCH. Two recurrent mutations in exon 13 resulting in Asn540Lys account for approximately 50–70% of all HCH [4, 6]. Patients with the N540K mutation tend to have more severe short stature and disproportion than patients with other mutations [7, 8]. Nonetheless, gene mutations are not detected in all HCH patients. Recombinant human growth hormone (r-hGH) treatment in short children with others skeletal dysplasias, such as dyschondrosteosis, has given encouraging results: r-hGH has increased height velocity and height standard deviation score (SDS) to an equivalent extent in patients with a SHOX gene mutation and in those with Turner syndrome [9]. Studies with r-hGH are generally limited to the most commonly seen skeletal dysplasia, achondroplasia [10, 11]. Evaluations in HCH patients have been limited to a small number of patients, short treatment periods, and low r-hGH doses ranging from 0.02 to 0.047 mg/kg/day [12–21]. Results from the few studies performed show variable height gain, with mean height increases of +0.7 SD/2.6 years [16], +0.8 SD/3 years [20], and +1.4 SD/3 years [21]. As shown in previous r-hGH clinical studies, higher doses are needed in the absence of r-hGH deficiency. To date, no comparison studies including untreated HCH patients have been published. The aim of our study was to determine the efficacy and safety of r-hGH therapy in HCH children over a 3-year minimum period, compared with a historical cohort of untreated children. Final height in a subset of treated children was also assessed.
Patients To be eligible, patients had to have an HCH diagnosis based on clinical and specific skeletal abnormalities from X-rays showing no change or decreased interpedicular distance from the first to the fifth lumbar vertebra (radiologic criteria almost constant) and/or anteroposterior shortening of the lumbar pedicles and/or short broad femoral necks, confirmed by two experienced physicians (Bone Dysplasia Center of Necker Enfants-Malades Hospital); genetic analysis for FGFR3 gene mutation; chronological age ≥3 years; height for chronological age ≤–2 SDS, and bone age +2 SDS, r-hGH was reduced by 20% of the initial dose. The primary objective was to evaluate the efficacy of r-hGH by following the height (SDS) evolution in HCH children treated with 0.057 mg/kg/day when compared with a historical cohort of untreated HCH children. Treatment response according to the genotype FGFR3 was also described. The study was prolonged for 2 years beyond the 3-year period, and then until patients reached near final height with relevant inclusion/exclusion criteria and with patients/parents providing additional consent. The study was carried out in accordance with the Declaration of Helsinki, ICH Good Clinical Practice and local regulations. The study was approved by the French Independent Ethics Committee, CCP IDF II. Written informed consent was obtained from the parents or legal guardians, and when possible, written assent was also collected from the child. Genetic Analyses for FGFR3 Gene Defects Genetic analysis was performed before study inclusion. Blood samples were collected after appropriate informed consent, and genomic DNA was extracted from lymphocytes using standard procedures. A set of intronic primers was designed based on the genomic sequence of the human FGFR3 gene (accession No. AY 768549) and used to amplify exons 2–19 (primer sequences and PCR conditions available on request). PCR products were directly sequenced using the Big Dye Sequencing Kit (Applied Biosystems, Foster City, Calif., USA) on an ABI 3100 automatic DNA sequencer.
Historical Cohort An historical cohort was identified from patients followed by pediatricians at the Bone Dysplasia Center of Necker EnfantsMalades Hospital. It was composed of 40 patients (22 boys, 18 girls) with HCH, and with height and weight data available from 3 years of age until final height. Growth charts were modeled after these data and height SDS were calculated. A model to predict the growth and final height of patients without growth hormone (GH) therapy was designed.
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Horm Res Paediatr 2014;82:355–363 DOI: 10.1159/000364807
Clinical, Biological and Radiological Assessments Standing height, sitting height and head circumference were measured and the sitting height-to-height ratio was calculated to evaluate body proportions. BMI was calculated at baseline and every 3 months. GH/IGF-1 status was evaluated at baseline. Stimulated GH concentrations were measured after the administration of glucagon (13 patients), ornithine (4 patients) or arginine-insulin (1 patient) with an immunochemiluminescent kit calibrated against the 98/574 reference standard (r-hGH Access, Beckman, Saska, Minn., USA). Serum IGF-1 was determined every 6 months
Pinto et al.
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Patients and Methods
GH Therapy in HCH
Color version available online
160 150
Height (cm)
140 130 120 110 100 Untreated r-hGH treated at 3 years Sempé 3rd
90 80
2
4
6
8
10 12 Age (years)
160
14
16
18
20
Girls
150 140 130 120 110 100 Untreated r-hGH treated at 3 years Sempé 3rd
90 80
2
4
6
8
10 12 Age (years)
14
16
18
20
Fig. 1. Comparison of height prediction model from untreated
HCH patients, with r-hGH treated patients at 3 years and with the general population (Sempé values at 3rd percentile) for boys and girls.
Results
Height Evolution in an Historical Cohort Growth charts were derived from 4- to 18-year-old boys and girls in the historical HCH cohort. Heights SDS were calculated and are presented in figure 1 and table 1. During childhood, mean heights in the HCH patient curve were between –2 and –3 SD of the general population (as published by Sempé). From 14 years of age on, mean heights in the HCH patient curve were below –3 SD, confirming the loss of the normal height spurt at puHorm Res Paediatr 2014;82:355–363 DOI: 10.1159/000364807
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Statistical Analysis Curves were constructed using data from the historical cohort, classifying individual height values according to chronological age, providing a mean height and ±2 SD. Use of the modeling curve on average height allowed determination of a linear relationship between the natural logarithm, Ln (stature), and age where height is expressed in cm and age in months; for boys, stature (cm) = 10^(0.07 t0.365 + 1.674), and for girls, stature (cm) = 10^(0.0697 t0.365 + 1.67). The coefficient of determination r2 = 0.999 and the standard error of estimate = 0.003, which is relatively low, allowing precise adjustment of mean values. Anthropometric parameter values (standing height, sitting height, head circumference and BMI) were converted to SDS adjusted for age and sex from standard anthropometric data in the French general population, published by Sempé et al. [27]. Standing height and BMI were also expressed in SDS in comparison with the historical cohort [28]. The sitting height-to-height ratio was expressed as SDS using data from the Dutch general population, published by Fredriks et al. [29]. Data are presented as means ± SD. Student’s t test was used to compare values at study completion to baseline values for anthropometric parameters, bone area mineral density, and biochemical markers. p < 0.05 was considered significant. Statistical tests were performed using Statistica software (Version 6; Statsoft, Tulsa, Okla., USA).
Boys
170
Height (cm)
using an immunoradiometric assay (IGF I RIA CT; Cis Bio International, Gif-sur-Yvette, France) and expressed as a Z-score according to reference standards published by Bussières et al. [23]. Serum osteocalcin (bone formation marker) and serum CTX (bone resorption marker) were measured by immunochemiluminescent assays on an automated platform (Elecsys; Roche Diagnostics, Meylan, France). Bone X-rays were performed annually with anterior radiographs of the spine, pelvis and lower legs to detect scoliosis and deformations, and of the left hand/wrist to determine bone age according to the methods described by Greulich and Pyle [24]. Lean body mass, percent fat mass and lumbar spine bone area mineral density measured at the lumbar spine (L1–L4) were determined annually by dual-energy X-ray absorptiometry using a Hologic QDR 4500W machine (Hologic Inc., Bedford, Mass., USA). Bone area mineral density values were converted to age- and sex-specific Z-scores. Blood chemistry, hematology, liver enzymes, fasting lipids (cholesterol, HDL cholesterol, triglycerides), glycemia, HbA1C, free T4, thyroid-stimulating hormone, estradiol, total testosterone, dehydroepiandrosterone sulfate, calcium and phosphate were evaluated at baseline and every 6 months. Oral glucose tolerance tests (1.75 g/kg body weight) were performed at baseline and yearly. Impaired glucose tolerance was defined as a fasting glucose level >5.5 mmol/l or a 2-hour glucose level between 7.7 and 11.0 mmol/l, and diabetes as a level >11 mmol/l. The homeostasis model assessment index of insulin resistance (HOMA-IR) was computed as glycemia (mmol/l) × insulinemia (mIU/l)/22.5 [25]. Fasting hyperinsulinemia was defined as >15 mIU/l [26]. Insulin resistance was defined as HOMA-IR >3.16 [25]. Insulin was determined using a radioimmunometric sandwich assay, Bi-Insulin IRMA (Cis Bio International). Glucose and lipids were measured using colorimetric methods (Hitachi 977, Hitachi Ltd., Tokyo, Japan), and HbA1C was measured using high-performance liquid chromatography (Tosoh Bioscience, Tokyo, Japan).
Table 1. Mean height and SD in boys and girls with untreated HCH (historical cohort) and predicted heights of r-hGH-treated boys and
Untreated boy’s and girl’s height1, cm
r-hGH-treated boy’s and girl’s predicted height2, cm
mean values
SD
mean at 1 year
mean at 2 years
mean at 3 years
Boys 4/48 5/60 6/72 7/84 8/96 9/108 10/120 11/132 12/144 13/156 14/168 15/180 16/192 17/204 18/216
92 97 102 106 111 115 119 123 127 131 134 138 142 145 149
2.9 3.2 3.4 3.6 3.8 4.2 4.8 4.8 5.0 5.3 5.9 6.0 5.9 5.6 5.5
93.8 99.3 104.3 109.1 113.7 118.2 122.8 126.7 130.7 134.7 138.9 142.6 146.1 149.4 152.8
95.0 100.7 105.8 110.7 115.3 120.0 124.8 128.8 132.9 137.0 141.4 145.2 148.7 151.8 155.2
95.6 101.3 106.5 111.4 116.0 120.8 125.7 129.7 133.8 138.0 142.6 146.3 149.8 152.9 156.2
Girls 4/48 5/60 6/72 7/84 8/96 9/108 10/120 11/132 12/144 13/156 14/168 15/180 16/192 17/204 18/216
90 96 100 105 109 113 118 121 125 129 133 136 137 137 137
2.9 3.2 3.4 3.6 3.8 4.2 4.8 4.8 5.0 5.3 5.9 6.0 5.9 5.6 5.5
92.7 98.1 103.1 107.8 112.3 116.7 121.2 125.1 129.0 133.0 137.1 140.7 141.2 141.3 141.5
93.9 99.5 104.5 109.3 113.9 118.5 123.3 127.2 131.2 135.3 139.6 143.3 144.0 144.1 144.1
94.5 100.1 105.2 110.0 114.6 119.3 124.2 128.1 132.1 136.3 140.7 144.4 145.2 145.3 145.3
Age, years/months
Example 1: a girl with an initial height of 123 cm at 11 years had a height SDS_HCH of 123–121/4.8 = +0.41; at 13 years of age, after 2 years of r-hGH her height was 140 cm. With a gain of +4.7 cm vs. mean height of treated girls over 2 years (135.3 cm), she is considered to be a good responder. Example 2: a girl with an initial height of 121 cm at 11 years had a height SDS_ HCH = 0; after 2 years of r-hGH her height was 131 cm, so a
gain of –4.3 cm vs. mean height of treated girls – she is considered to be a bad responder. 1 Height of an HCH patient can be expressed in SDS in comparison of historical cohort of HCH (SDS_HCH) using data from the first three columns. 2 r-hGHtreated boys’ and girls’ predicted height were calculated using the above formula.
berty. Patient heights were expressed in SDS using data from untreated HCH patients (SDS_HCH) presented in table 1.
the beginning of the study, 6 patients had begun puberty (3 girls and 1 boy were Tanner 2, 1 girl and 1 boy were Tanner 3). These pubertal patients, except one boy, did not increase more growth velocity despite puberty. Mean growth velocity was 4.7 cm (range 3.5–6 cm). During rhGH therapy, 3 additional girls reached breast stage 2 at the mean age, and 3 boys reached Tanner 2 at the mean age. One boy had advanced puberty (Tanner 2 at 9.3
Patient Characteristics Nineteen HCH patients (11 females, 8 males) with initial height ≤–2 SDS were included in the study at a mean (SD) age of 9.0 ± 3.1 years (range: 3.4–14.7; table 2). At 358
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girls for 1, 2 and 3 years
n = 19 Female/male Familial form FGFR3 mutation Age, years Tanner I/II/III Height1 (SDS) BMI1 (SDS) Height2 (SDS_HCH) BMI2 (SDS_HCH) Upper segment3 (SDS) Head circumference1 (SDS) % Total fat mass4 (SDS) Bone age5, years BMD4 (SDS)
11/8 7 14 9.3±3.1 (3.4–14.7) 13/4/2 –2.80±0.83 1.50±1.22 0.39±0.90 –0.68±0.9 –0.90±1.14 1.88±1.37 1.13 7.9±3.5 (1.5–13) –1.90
Values are given as n or means ± SD (range). 1 Versus Sempé cohort values [27]. 2 Versus values of an untreated historical cohort of HCH patients. 3 Versus reference published by Fredriks et al. [29]. 4 Body composition and lumbar spine mineralometry evaluated by dual X-ray absorptiometry. 5 According to Greulich-Pyle method [24].
years) with an advanced bone age of 1 year before initiation of r-hGH therapy. He was treated with a gonadotropin-releasing hormone agonist during the last 9 months of the study. FGFR3 mutations were present in 14 patients, the N540K mutation in 10 patients, and E360K, K650Q, R200C and S64L mutations in 1 patient each. GH stimulation tests were normal except for 3 patients whose r-hGH peak was 3.16) was identified in 4 patients (21%), 3 of whom had begun puberty. No patients had glucose intolerance and mean HbA1C remained in the normal range. 360
Horm Res Paediatr 2014;82:355–363 DOI: 10.1159/000364807
Safety All but one patient reported at least one adverse event; however, the majority of adverse events were common childhood illnesses expected in children (upper respiratory infection, otitis, gastroenteritis, bronchitis and viral meningitis) with minor safety issues. Three patients had scoliosis with mild spine deviation (+3 SDS) had a cerebral MRI excluding hydrocephaly secondary to a narrowing of the foramen magnum. No patients discontinued r-hGH therapy.
Discussion
After 3 years of r-hGH therapy in HCH children, a modest but significant height gain was reported when compared with the French general reference population [27] (mean +0.62 ± 0.81 SDS, p < 0.05). The value of this study is gained from a comparison of these results with HCH patients not treated with r-hGH. Growth charts of the historical cohort confirm that the growth retardation of untreated HCH patients worsens during puberty; mean height was between –2 and –3 SDS in prepubertal patients and became +2SDS with a GH dose of 0.04 mg/kg/ day. Treatment was well tolerated; the majority of adverse events, such as respiratory infections, are either common to childhood or unrelated to the treatment. Some adverse events could be related to GH treatment, such as orthopedic events; however, these events also occur in untreated patients with HCH and it is difficult to assess the effect of r-hGH itself. Among the 4 patients with initial genu varum, only one worsened and required corrective surgery. The scoliosis present in 3 patients was very moderate, and did not require therapy. In our study, body disproportion increased moderately
1 Glasgow JF, Nevin NC, Thomas PS: Hypochondroplasia. Arch Dis Child 1978; 53: 868– 872. 2 Maroteaux P, Falzon P: Hypochondroplasie. Revue de 80 cas. Arch Fr Pediatr 1988;45:105– 109. 3 Prinster C, Carrera P, Del Maschio M, Weber G, Maghnie M, Vigone MC, Mora S, Tonini G, Rigon F, Beluffi G, Severi F, Chiumello G, Ferrari M: Comparison of clinical-radiological findings in hypochondroplasia. Am J Med Genet 1998;75:109–112. 4 Bellus GA, McIntosh I, Smith EA, Aylsworh AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA: A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet 1995;10:357–359. 5 Foldynova-Trantirkova S, Wilcox WR, Krejci P: Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum Mutat 2012;33:29–41. 6 Bonaventure J, Rousseau F, Legeai-Mallet L, Le Merrer M, Munnich A, Maroteaux P: Common mutations in the fibroblast growth factor receptor 3 (FGFR3) gene account for achondroplasia, hypochondroplasia and thanatophoric dwarfism. Am J Med Genet 1996;63:148–154. 7 Grigelioniene G, Eklöf O, Laurencikas E, Ollars B, Hertel NT, Dumanski JP, Hägenas L: Asn540Lys mutation in fibroblast growth factor 3 and phenotype in hypochondroplasia. Acta Paediatr 2000;89:1072–1076. 8 Rousseau F, Bonaventure J, Legeai-Mallet L, Schmidt H, Weissenbach J, Maroteaux P, Munnich A, Le Merrer M: Clinical and genetic heterogeneity of hypochondroplasia. J Med Genet 1996;33:749–752. 9 Blum WF, Judith LR, Zimmermann AG, Quigley CA, Child CJ, Kalifa G, Deal C, Drop SLS, Rappold G, Cutler GB: GH treatment to final height produces similar height gains in patients with SHOX deficiency and Turner syndrome: results of a multicenter trial. J Clin Endocrinol Metab 2013; 98:E1383– E1392. 10 Tanaka H, Kubo T, Yamate T, Ono T, Kanzaki S, Seino Y: Effect of growth hormone therapy in children with achondroplasia: growth pattern, hypothalamic-pituitary function and genotype. Eur J Endocrinol 1998; 138:275–280. 11 Hertel NT, Eklöf O, Ivarsson S, Aronson S, Westphal O, Sipilä I, Kaitila I, Bland J, Veimo D, Müller J, Mohnike K, Neumeyer L, Ritzen M, Hägenas L: Growth hormone treatment in 35 prepubertal children with achondroplasia: a five-year dose-response trial. Acta Paediatr 2005;94:1402–1410. 12 Appan S, Laurent S, Chapman M, Hindmarsh PC, Brook CG: Growth and growth hormone therapy in hypochondroplasia. Acta Paediatr Scand 1990;79:796–803.
GH Therapy in HCH
13 Bridges NA, Hindmarsh PC, Brook CGD: Growth of children with hypochondroplasia treated with growth hormone for up to three years. Horm Res 1991;36(suppl 1):56–60. 14 Hagenäs L, Ritzen EM, Eklof O, et al: Two year results on growth hormone treatment in prepubertal children with achondroplasia and hypochondroplasia – a dose study. Horm Res 1996;46(suppl 2):A106. 15 Hägenas L, Hertel T: 2003 Skeletal dysplasia, growth hormone treatment and body proportion: comparison with other syndromic and non-syndromic short children. Horm Res 2003;60(suppl 3):65–70. 16 Key L, Gross AJ: Response to growth hormone in children with chondrodysplasia. J Pediatr 1996;128:S14–S17. 17 Mullis PE, Patel MS, Brickell PM, Hindmarsh PC, Brook CG: Growth characteristics and response to growth hormone therapy in patients with hypochondroplasia: genetic linkage of the insulin-like growth factor I gene at chromosome 12q23 to the disease in a subgroup of these patients. Clin Endocrinol (Oxf) 1991;34:265–274. 18 Ramaswani U, Hindmarsh PC, Brook CG: Growth hormone therapy in hypochondroplasia. Acta Paediatr Suppl 1999; 428: 116– 117. 19 Sohat M, Tick D, Barakat S, Bu X, Melmed S, Rimoin DL: Short-term recombinant human growth hormone treatment increases growth rate in achondroplasia. J Clin Endocrinol Metab 1996;81:4033–4037. 20 Burren CP, Werther GA: Skeletal dysplasias: response to growth hormone therapy. J Pediatr Endocrinol Metab 1996;9:31–40. 21 Tanaka N, Katsumata N, Horikawa R, Tanaka T: The comparison of the effects of short-term growth hormone treatment in patients with achondroplasia and with hypochondroplasia. Endocr J 2003;50:69–75. 22 Chatelain P, Colle M, Nako JP, Le Luyer B, Wagner K, Berlier P, Tauber M: Optimization of growth hormone dosing in children born small for gestational age: an open-label, randomized study of children during the fourth year of therapy. Horm Res Paediatr 2012; 77: 156–163. 23 Bussières L, Souberbielle JC, Pinto G, Adan L, Noel M, Brauner R: The use of insulin-like growth factor 1 reference values for the diagnosis of growth hormone deficiency in prepubertal children. Clin Endocrinol (Oxf) 2000; 52:735–739. 24 Greulich WW, Pyle S: Radiographic Atlas of Skeletal Development of the Hand and Wrist, ed 2. Palo Alto, Stanford University Press California, 1959. 25 Wallace TM, Matthews DR: The assessment of insulin resistance in man. Diabet Med 2002;19:527–534. 26 Keskin M, Kurtoglu S, Kendirci M, Atabek ME, Yazici C: Homeostasis model assessment is more reliable than the fasting glucose/insu-
27 28
29
30
31
32
33
34
35
36
lin ratio and quantitative insulin sensitivity check index for assessing insulin resistance among obese children and adolescents. Pediatrics 2005;115:e500–e503. Sempé M, Pedron G, Roy-Pernot MP: Auxologie méthodes et séquences. Paris, Théraplix, 1979. Rolland-Cachera MF, Cole TJ, Sempé M, Tichet J, Rossignol C, Charraud A: Body mass index variations: centiles from birth to 87 years. Eur J Clin Nutr 1991;45:13–21. Fredriks AM, van Buuren S, van Heel WJ, Dijkman-Neerincx RH, Verloove-Vanhorick SP, Wit JM: Nationwide age references for sitting height, leg length, and sitting height/ height ratio, and their diagnostic value for disproportionate growth disorders. Arch Dis Child 2005;90:807–812. Blum WF, Cao D, Hesse V, Fricke-Otto S, Ross JL, Jones C, Quiqley CA, Binder G: Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome. Horm Res 2009;71:167–172. Stephure DK; Canadian Growth Hormone Advisory Committee: Impact of growth hormone supplementation on adult height in turner syndrome: results of the Canadian randomized controlled trial. J Clin Endocrinol Metab 2005;90:3360–3366. Rothenbuhler A, Linglart A, Piquard C, Bougnères P: A pilot study of discontinuous, insulin-like growth factor 1-dosing growth hormone treatment in young children with FGFGR3 N540K-mutated hypochondroplasia. J Pediatr 2012;160:849–853. Cohen P, Weng W, Rogol AD, Rosenfeld RG, Kappelgaard AM, Germak J: Dose-sparing and safety-enhancing effects of an IGF-Ibased dosing regimen in short children treated with growth hormone in a 2-year randomized controlled trial: therapeutic and pharmacoeconomic considerations. Clin Endocrinol 2014;81:71–76. Alatzoglou KS, Hindmarsh PC, Brain C, Torpiano J, Dattani MT: Acanthosis nigricans and insulin sensitivity in patients with achondroplasia and hypochondroplasia due to FGFR3 mutations. J Clin Endocrinol Metab 2009;94:3959–3963. Sas TC, de Muinck Keizer-Schrama SM, Stijnen T, Aanstoot HJ, Drop SL: 2000 carbohydrate metabolism during long-term growth hormone (GH) treatment and after discontinuation of GH treatment in girls with Turner syndrome participating in a randomized dose-response study. Dutch Advisory Group on Growth Hormone. J Clin Endocrinol Metab 2000;85:769–775. Prodam F, Savastio S, Genoni G, Babu D, Giordano M, Ricotti R, Aimaretti G, Bona G, Bellone S: Effects of growth hormone (GH) therapy withdrawal on glucose metabolism in not confirmed GH deficient adolescents at final height. PLoS One 2014;9:e87157.
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References
HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2014;82:355–363 DOI: 10.1159/000364807
Received: March 6, 2014 Accepted: May 23, 2014 Published online: October 15, 2014
Efficacy and Safety of Growth Hormone Treatment in Children with Hypochondroplasia: Comparison with an Historical Cohort Graziella Pinto a Valérie Cormier-Daire b, e Martine Le Merrer b Dinane Samara-Boustani a Geneviève Baujat b Laurence Fresneau f Magali Viaud a Jean Claude Souberbielle c Jean Claude Pineau d Michel Polak a, e a
Pediatric Endocrinology, Gynecology and Diabetes, Centre des Maladies Endocriniennes Rares de la Croissance, Medical Genetics Department, Rare Bone Dysplasia Center, c Physiology Laboratory, Hôpital Universitaire Necker-Enfants Malades, d CNRS UPR 2147, and e Université Paris Descartes, Paris, and f Merck Serono s.a.s., Lyon, France
b
Abstract Background/Aims: Hypochondroplasia (HCH) is a skeletal dysplasia characterized by disproportionate short stature. The aims of the study are to evaluate efficacy and safety of recombinant human growth hormone (r-hGH) therapy in HCH children, when compared with a historical cohort of untreated HCH children. Methods: Nineteen HCH patients with an initial height standard deviation score (SDS) ≤–2 and a mean age of 9.3 ± 3.1 years were treated with a mean r-hGH dose of 0.053 mg/kg/day over 3 years. Growth charts were derived from the historical cohort (n = 40). Results: Height gain in the treated population was +0.62 ± 0.81 SDS greater than in the general population, and +1.39 ± 0.9 SDS greater than in the historical untreated HCH cohort (mean gain of 7.4 ± 6.6 cm gain). A negative correlation between height gain and age at treatment initiation was reported (p = 0.04). There was no significant difference in response between patients with fibroblast growth factor receptor 3 mutations and those without. No treatment-related serious adverse
© 2014 S. Karger AG, Basel 1663–2818/14/0826–0355$39.50/0 E-Mail [email protected] www.karger.com/hrp
events were reported. Conclusions: r-hGH treatment is well tolerated and effective in improving growth in HCH patients, particularly when started early. The treatment effect varies greatly and must be evaluated for each patient during treatment to determine the value of continued therapy. © 2014 S. Karger AG, Basel
Introduction
Hypochondroplasia (HCH; OMIM146000) is an autosomal dominant skeletal dysplasia with a heterogeneous phenotype [1–3]. In the most severe cases, patients have disproportionate severe short stature, micromelia, short broad hands and feet, lumbar hyperlordosis, and macrocephaly. Mild cases have moderate disproportionate short stature (until puberty), which is often misdiagnosed as idiopathic short stature. Failure of the puberty growth spurt compromises adult height, with Maroteaux and Falzon [2] reporting mean adult heights of 146.1 ± 4.9 cm (range: 138– 153) in boys and 137.6 ± 6.3 cm (range: 128–147) in girls.
Clinical Trial Registration No.: NCT01111019.
Michel Polak, MD, PhD and Graziella Pinto, MD Pediatric Endocrinology, Gynecology and Diabetes Hôpital Necker Enfants Malades, 149 rue de Sèvres FR–75015 Paris (France) E-Mail graziella.pinto @ nck.aphp.fr
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Key Words Hypochondroplasia · Growth hormone treatment · Skeletal dysplasia · Growth curve
HCH is largely caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene located at 4p16.3 [4]. Although the tyrosine kinase receptor FGFR3 is expressed in brain, lung and cartilage, its major physiological function is thought to be in the negative regulation of cartilage growth, restricting the length of long bones via inhibition of chondrocyte proliferation [5]. Gain-offunction mutations have been described in various skeletal dysplasias, including achondroplasia and HCH. Two recurrent mutations in exon 13 resulting in Asn540Lys account for approximately 50–70% of all HCH [4, 6]. Patients with the N540K mutation tend to have more severe short stature and disproportion than patients with other mutations [7, 8]. Nonetheless, gene mutations are not detected in all HCH patients. Recombinant human growth hormone (r-hGH) treatment in short children with others skeletal dysplasias, such as dyschondrosteosis, has given encouraging results: r-hGH has increased height velocity and height standard deviation score (SDS) to an equivalent extent in patients with a SHOX gene mutation and in those with Turner syndrome [9]. Studies with r-hGH are generally limited to the most commonly seen skeletal dysplasia, achondroplasia [10, 11]. Evaluations in HCH patients have been limited to a small number of patients, short treatment periods, and low r-hGH doses ranging from 0.02 to 0.047 mg/kg/day [12–21]. Results from the few studies performed show variable height gain, with mean height increases of +0.7 SD/2.6 years [16], +0.8 SD/3 years [20], and +1.4 SD/3 years [21]. As shown in previous r-hGH clinical studies, higher doses are needed in the absence of r-hGH deficiency. To date, no comparison studies including untreated HCH patients have been published. The aim of our study was to determine the efficacy and safety of r-hGH therapy in HCH children over a 3-year minimum period, compared with a historical cohort of untreated children. Final height in a subset of treated children was also assessed.
Patients To be eligible, patients had to have an HCH diagnosis based on clinical and specific skeletal abnormalities from X-rays showing no change or decreased interpedicular distance from the first to the fifth lumbar vertebra (radiologic criteria almost constant) and/or anteroposterior shortening of the lumbar pedicles and/or short broad femoral necks, confirmed by two experienced physicians (Bone Dysplasia Center of Necker Enfants-Malades Hospital); genetic analysis for FGFR3 gene mutation; chronological age ≥3 years; height for chronological age ≤–2 SDS, and bone age +2 SDS, r-hGH was reduced by 20% of the initial dose. The primary objective was to evaluate the efficacy of r-hGH by following the height (SDS) evolution in HCH children treated with 0.057 mg/kg/day when compared with a historical cohort of untreated HCH children. Treatment response according to the genotype FGFR3 was also described. The study was prolonged for 2 years beyond the 3-year period, and then until patients reached near final height with relevant inclusion/exclusion criteria and with patients/parents providing additional consent. The study was carried out in accordance with the Declaration of Helsinki, ICH Good Clinical Practice and local regulations. The study was approved by the French Independent Ethics Committee, CCP IDF II. Written informed consent was obtained from the parents or legal guardians, and when possible, written assent was also collected from the child. Genetic Analyses for FGFR3 Gene Defects Genetic analysis was performed before study inclusion. Blood samples were collected after appropriate informed consent, and genomic DNA was extracted from lymphocytes using standard procedures. A set of intronic primers was designed based on the genomic sequence of the human FGFR3 gene (accession No. AY 768549) and used to amplify exons 2–19 (primer sequences and PCR conditions available on request). PCR products were directly sequenced using the Big Dye Sequencing Kit (Applied Biosystems, Foster City, Calif., USA) on an ABI 3100 automatic DNA sequencer.
Historical Cohort An historical cohort was identified from patients followed by pediatricians at the Bone Dysplasia Center of Necker EnfantsMalades Hospital. It was composed of 40 patients (22 boys, 18 girls) with HCH, and with height and weight data available from 3 years of age until final height. Growth charts were modeled after these data and height SDS were calculated. A model to predict the growth and final height of patients without growth hormone (GH) therapy was designed.
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Clinical, Biological and Radiological Assessments Standing height, sitting height and head circumference were measured and the sitting height-to-height ratio was calculated to evaluate body proportions. BMI was calculated at baseline and every 3 months. GH/IGF-1 status was evaluated at baseline. Stimulated GH concentrations were measured after the administration of glucagon (13 patients), ornithine (4 patients) or arginine-insulin (1 patient) with an immunochemiluminescent kit calibrated against the 98/574 reference standard (r-hGH Access, Beckman, Saska, Minn., USA). Serum IGF-1 was determined every 6 months
Pinto et al.
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Patients and Methods
GH Therapy in HCH
Color version available online
160 150
Height (cm)
140 130 120 110 100 Untreated r-hGH treated at 3 years Sempé 3rd
90 80
2
4
6
8
10 12 Age (years)
160
14
16
18
20
Girls
150 140 130 120 110 100 Untreated r-hGH treated at 3 years Sempé 3rd
90 80
2
4
6
8
10 12 Age (years)
14
16
18
20
Fig. 1. Comparison of height prediction model from untreated
HCH patients, with r-hGH treated patients at 3 years and with the general population (Sempé values at 3rd percentile) for boys and girls.
Results
Height Evolution in an Historical Cohort Growth charts were derived from 4- to 18-year-old boys and girls in the historical HCH cohort. Heights SDS were calculated and are presented in figure 1 and table 1. During childhood, mean heights in the HCH patient curve were between –2 and –3 SD of the general population (as published by Sempé). From 14 years of age on, mean heights in the HCH patient curve were below –3 SD, confirming the loss of the normal height spurt at puHorm Res Paediatr 2014;82:355–363 DOI: 10.1159/000364807
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Statistical Analysis Curves were constructed using data from the historical cohort, classifying individual height values according to chronological age, providing a mean height and ±2 SD. Use of the modeling curve on average height allowed determination of a linear relationship between the natural logarithm, Ln (stature), and age where height is expressed in cm and age in months; for boys, stature (cm) = 10^(0.07 t0.365 + 1.674), and for girls, stature (cm) = 10^(0.0697 t0.365 + 1.67). The coefficient of determination r2 = 0.999 and the standard error of estimate = 0.003, which is relatively low, allowing precise adjustment of mean values. Anthropometric parameter values (standing height, sitting height, head circumference and BMI) were converted to SDS adjusted for age and sex from standard anthropometric data in the French general population, published by Sempé et al. [27]. Standing height and BMI were also expressed in SDS in comparison with the historical cohort [28]. The sitting height-to-height ratio was expressed as SDS using data from the Dutch general population, published by Fredriks et al. [29]. Data are presented as means ± SD. Student’s t test was used to compare values at study completion to baseline values for anthropometric parameters, bone area mineral density, and biochemical markers. p < 0.05 was considered significant. Statistical tests were performed using Statistica software (Version 6; Statsoft, Tulsa, Okla., USA).
Boys
170
Height (cm)
using an immunoradiometric assay (IGF I RIA CT; Cis Bio International, Gif-sur-Yvette, France) and expressed as a Z-score according to reference standards published by Bussières et al. [23]. Serum osteocalcin (bone formation marker) and serum CTX (bone resorption marker) were measured by immunochemiluminescent assays on an automated platform (Elecsys; Roche Diagnostics, Meylan, France). Bone X-rays were performed annually with anterior radiographs of the spine, pelvis and lower legs to detect scoliosis and deformations, and of the left hand/wrist to determine bone age according to the methods described by Greulich and Pyle [24]. Lean body mass, percent fat mass and lumbar spine bone area mineral density measured at the lumbar spine (L1–L4) were determined annually by dual-energy X-ray absorptiometry using a Hologic QDR 4500W machine (Hologic Inc., Bedford, Mass., USA). Bone area mineral density values were converted to age- and sex-specific Z-scores. Blood chemistry, hematology, liver enzymes, fasting lipids (cholesterol, HDL cholesterol, triglycerides), glycemia, HbA1C, free T4, thyroid-stimulating hormone, estradiol, total testosterone, dehydroepiandrosterone sulfate, calcium and phosphate were evaluated at baseline and every 6 months. Oral glucose tolerance tests (1.75 g/kg body weight) were performed at baseline and yearly. Impaired glucose tolerance was defined as a fasting glucose level >5.5 mmol/l or a 2-hour glucose level between 7.7 and 11.0 mmol/l, and diabetes as a level >11 mmol/l. The homeostasis model assessment index of insulin resistance (HOMA-IR) was computed as glycemia (mmol/l) × insulinemia (mIU/l)/22.5 [25]. Fasting hyperinsulinemia was defined as >15 mIU/l [26]. Insulin resistance was defined as HOMA-IR >3.16 [25]. Insulin was determined using a radioimmunometric sandwich assay, Bi-Insulin IRMA (Cis Bio International). Glucose and lipids were measured using colorimetric methods (Hitachi 977, Hitachi Ltd., Tokyo, Japan), and HbA1C was measured using high-performance liquid chromatography (Tosoh Bioscience, Tokyo, Japan).
Table 1. Mean height and SD in boys and girls with untreated HCH (historical cohort) and predicted heights of r-hGH-treated boys and
Untreated boy’s and girl’s height1, cm
r-hGH-treated boy’s and girl’s predicted height2, cm
mean values
SD
mean at 1 year
mean at 2 years
mean at 3 years
Boys 4/48 5/60 6/72 7/84 8/96 9/108 10/120 11/132 12/144 13/156 14/168 15/180 16/192 17/204 18/216
92 97 102 106 111 115 119 123 127 131 134 138 142 145 149
2.9 3.2 3.4 3.6 3.8 4.2 4.8 4.8 5.0 5.3 5.9 6.0 5.9 5.6 5.5
93.8 99.3 104.3 109.1 113.7 118.2 122.8 126.7 130.7 134.7 138.9 142.6 146.1 149.4 152.8
95.0 100.7 105.8 110.7 115.3 120.0 124.8 128.8 132.9 137.0 141.4 145.2 148.7 151.8 155.2
95.6 101.3 106.5 111.4 116.0 120.8 125.7 129.7 133.8 138.0 142.6 146.3 149.8 152.9 156.2
Girls 4/48 5/60 6/72 7/84 8/96 9/108 10/120 11/132 12/144 13/156 14/168 15/180 16/192 17/204 18/216
90 96 100 105 109 113 118 121 125 129 133 136 137 137 137
2.9 3.2 3.4 3.6 3.8 4.2 4.8 4.8 5.0 5.3 5.9 6.0 5.9 5.6 5.5
92.7 98.1 103.1 107.8 112.3 116.7 121.2 125.1 129.0 133.0 137.1 140.7 141.2 141.3 141.5
93.9 99.5 104.5 109.3 113.9 118.5 123.3 127.2 131.2 135.3 139.6 143.3 144.0 144.1 144.1
94.5 100.1 105.2 110.0 114.6 119.3 124.2 128.1 132.1 136.3 140.7 144.4 145.2 145.3 145.3
Age, years/months
Example 1: a girl with an initial height of 123 cm at 11 years had a height SDS_HCH of 123–121/4.8 = +0.41; at 13 years of age, after 2 years of r-hGH her height was 140 cm. With a gain of +4.7 cm vs. mean height of treated girls over 2 years (135.3 cm), she is considered to be a good responder. Example 2: a girl with an initial height of 121 cm at 11 years had a height SDS_ HCH = 0; after 2 years of r-hGH her height was 131 cm, so a
gain of –4.3 cm vs. mean height of treated girls – she is considered to be a bad responder. 1 Height of an HCH patient can be expressed in SDS in comparison of historical cohort of HCH (SDS_HCH) using data from the first three columns. 2 r-hGHtreated boys’ and girls’ predicted height were calculated using the above formula.
berty. Patient heights were expressed in SDS using data from untreated HCH patients (SDS_HCH) presented in table 1.
the beginning of the study, 6 patients had begun puberty (3 girls and 1 boy were Tanner 2, 1 girl and 1 boy were Tanner 3). These pubertal patients, except one boy, did not increase more growth velocity despite puberty. Mean growth velocity was 4.7 cm (range 3.5–6 cm). During rhGH therapy, 3 additional girls reached breast stage 2 at the mean age, and 3 boys reached Tanner 2 at the mean age. One boy had advanced puberty (Tanner 2 at 9.3
Patient Characteristics Nineteen HCH patients (11 females, 8 males) with initial height ≤–2 SDS were included in the study at a mean (SD) age of 9.0 ± 3.1 years (range: 3.4–14.7; table 2). At 358
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girls for 1, 2 and 3 years
n = 19 Female/male Familial form FGFR3 mutation Age, years Tanner I/II/III Height1 (SDS) BMI1 (SDS) Height2 (SDS_HCH) BMI2 (SDS_HCH) Upper segment3 (SDS) Head circumference1 (SDS) % Total fat mass4 (SDS) Bone age5, years BMD4 (SDS)
11/8 7 14 9.3±3.1 (3.4–14.7) 13/4/2 –2.80±0.83 1.50±1.22 0.39±0.90 –0.68±0.9 –0.90±1.14 1.88±1.37 1.13 7.9±3.5 (1.5–13) –1.90
Values are given as n or means ± SD (range). 1 Versus Sempé cohort values [27]. 2 Versus values of an untreated historical cohort of HCH patients. 3 Versus reference published by Fredriks et al. [29]. 4 Body composition and lumbar spine mineralometry evaluated by dual X-ray absorptiometry. 5 According to Greulich-Pyle method [24].
years) with an advanced bone age of 1 year before initiation of r-hGH therapy. He was treated with a gonadotropin-releasing hormone agonist during the last 9 months of the study. FGFR3 mutations were present in 14 patients, the N540K mutation in 10 patients, and E360K, K650Q, R200C and S64L mutations in 1 patient each. GH stimulation tests were normal except for 3 patients whose r-hGH peak was 3.16) was identified in 4 patients (21%), 3 of whom had begun puberty. No patients had glucose intolerance and mean HbA1C remained in the normal range. 360
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Safety All but one patient reported at least one adverse event; however, the majority of adverse events were common childhood illnesses expected in children (upper respiratory infection, otitis, gastroenteritis, bronchitis and viral meningitis) with minor safety issues. Three patients had scoliosis with mild spine deviation (+3 SDS) had a cerebral MRI excluding hydrocephaly secondary to a narrowing of the foramen magnum. No patients discontinued r-hGH therapy.
Discussion
After 3 years of r-hGH therapy in HCH children, a modest but significant height gain was reported when compared with the French general reference population [27] (mean +0.62 ± 0.81 SDS, p < 0.05). The value of this study is gained from a comparison of these results with HCH patients not treated with r-hGH. Growth charts of the historical cohort confirm that the growth retardation of untreated HCH patients worsens during puberty; mean height was between –2 and –3 SDS in prepubertal patients and became +2SDS with a GH dose of 0.04 mg/kg/ day. Treatment was well tolerated; the majority of adverse events, such as respiratory infections, are either common to childhood or unrelated to the treatment. Some adverse events could be related to GH treatment, such as orthopedic events; however, these events also occur in untreated patients with HCH and it is difficult to assess the effect of r-hGH itself. Among the 4 patients with initial genu varum, only one worsened and required corrective surgery. The scoliosis present in 3 patients was very moderate, and did not require therapy. In our study, body disproportion increased moderately
1 Glasgow JF, Nevin NC, Thomas PS: Hypochondroplasia. Arch Dis Child 1978; 53: 868– 872. 2 Maroteaux P, Falzon P: Hypochondroplasie. Revue de 80 cas. Arch Fr Pediatr 1988;45:105– 109. 3 Prinster C, Carrera P, Del Maschio M, Weber G, Maghnie M, Vigone MC, Mora S, Tonini G, Rigon F, Beluffi G, Severi F, Chiumello G, Ferrari M: Comparison of clinical-radiological findings in hypochondroplasia. Am J Med Genet 1998;75:109–112. 4 Bellus GA, McIntosh I, Smith EA, Aylsworh AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA: A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet 1995;10:357–359. 5 Foldynova-Trantirkova S, Wilcox WR, Krejci P: Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum Mutat 2012;33:29–41. 6 Bonaventure J, Rousseau F, Legeai-Mallet L, Le Merrer M, Munnich A, Maroteaux P: Common mutations in the fibroblast growth factor receptor 3 (FGFR3) gene account for achondroplasia, hypochondroplasia and thanatophoric dwarfism. Am J Med Genet 1996;63:148–154. 7 Grigelioniene G, Eklöf O, Laurencikas E, Ollars B, Hertel NT, Dumanski JP, Hägenas L: Asn540Lys mutation in fibroblast growth factor 3 and phenotype in hypochondroplasia. Acta Paediatr 2000;89:1072–1076. 8 Rousseau F, Bonaventure J, Legeai-Mallet L, Schmidt H, Weissenbach J, Maroteaux P, Munnich A, Le Merrer M: Clinical and genetic heterogeneity of hypochondroplasia. J Med Genet 1996;33:749–752. 9 Blum WF, Judith LR, Zimmermann AG, Quigley CA, Child CJ, Kalifa G, Deal C, Drop SLS, Rappold G, Cutler GB: GH treatment to final height produces similar height gains in patients with SHOX deficiency and Turner syndrome: results of a multicenter trial. J Clin Endocrinol Metab 2013; 98:E1383– E1392. 10 Tanaka H, Kubo T, Yamate T, Ono T, Kanzaki S, Seino Y: Effect of growth hormone therapy in children with achondroplasia: growth pattern, hypothalamic-pituitary function and genotype. Eur J Endocrinol 1998; 138:275–280. 11 Hertel NT, Eklöf O, Ivarsson S, Aronson S, Westphal O, Sipilä I, Kaitila I, Bland J, Veimo D, Müller J, Mohnike K, Neumeyer L, Ritzen M, Hägenas L: Growth hormone treatment in 35 prepubertal children with achondroplasia: a five-year dose-response trial. Acta Paediatr 2005;94:1402–1410. 12 Appan S, Laurent S, Chapman M, Hindmarsh PC, Brook CG: Growth and growth hormone therapy in hypochondroplasia. Acta Paediatr Scand 1990;79:796–803.
GH Therapy in HCH
13 Bridges NA, Hindmarsh PC, Brook CGD: Growth of children with hypochondroplasia treated with growth hormone for up to three years. Horm Res 1991;36(suppl 1):56–60. 14 Hagenäs L, Ritzen EM, Eklof O, et al: Two year results on growth hormone treatment in prepubertal children with achondroplasia and hypochondroplasia – a dose study. Horm Res 1996;46(suppl 2):A106. 15 Hägenas L, Hertel T: 2003 Skeletal dysplasia, growth hormone treatment and body proportion: comparison with other syndromic and non-syndromic short children. Horm Res 2003;60(suppl 3):65–70. 16 Key L, Gross AJ: Response to growth hormone in children with chondrodysplasia. J Pediatr 1996;128:S14–S17. 17 Mullis PE, Patel MS, Brickell PM, Hindmarsh PC, Brook CG: Growth characteristics and response to growth hormone therapy in patients with hypochondroplasia: genetic linkage of the insulin-like growth factor I gene at chromosome 12q23 to the disease in a subgroup of these patients. Clin Endocrinol (Oxf) 1991;34:265–274. 18 Ramaswani U, Hindmarsh PC, Brook CG: Growth hormone therapy in hypochondroplasia. Acta Paediatr Suppl 1999; 428: 116– 117. 19 Sohat M, Tick D, Barakat S, Bu X, Melmed S, Rimoin DL: Short-term recombinant human growth hormone treatment increases growth rate in achondroplasia. J Clin Endocrinol Metab 1996;81:4033–4037. 20 Burren CP, Werther GA: Skeletal dysplasias: response to growth hormone therapy. J Pediatr Endocrinol Metab 1996;9:31–40. 21 Tanaka N, Katsumata N, Horikawa R, Tanaka T: The comparison of the effects of short-term growth hormone treatment in patients with achondroplasia and with hypochondroplasia. Endocr J 2003;50:69–75. 22 Chatelain P, Colle M, Nako JP, Le Luyer B, Wagner K, Berlier P, Tauber M: Optimization of growth hormone dosing in children born small for gestational age: an open-label, randomized study of children during the fourth year of therapy. Horm Res Paediatr 2012; 77: 156–163. 23 Bussières L, Souberbielle JC, Pinto G, Adan L, Noel M, Brauner R: The use of insulin-like growth factor 1 reference values for the diagnosis of growth hormone deficiency in prepubertal children. Clin Endocrinol (Oxf) 2000; 52:735–739. 24 Greulich WW, Pyle S: Radiographic Atlas of Skeletal Development of the Hand and Wrist, ed 2. Palo Alto, Stanford University Press California, 1959. 25 Wallace TM, Matthews DR: The assessment of insulin resistance in man. Diabet Med 2002;19:527–534. 26 Keskin M, Kurtoglu S, Kendirci M, Atabek ME, Yazici C: Homeostasis model assessment is more reliable than the fasting glucose/insu-
27 28
29
30
31
32
33
34
35
36
lin ratio and quantitative insulin sensitivity check index for assessing insulin resistance among obese children and adolescents. Pediatrics 2005;115:e500–e503. Sempé M, Pedron G, Roy-Pernot MP: Auxologie méthodes et séquences. Paris, Théraplix, 1979. Rolland-Cachera MF, Cole TJ, Sempé M, Tichet J, Rossignol C, Charraud A: Body mass index variations: centiles from birth to 87 years. Eur J Clin Nutr 1991;45:13–21. Fredriks AM, van Buuren S, van Heel WJ, Dijkman-Neerincx RH, Verloove-Vanhorick SP, Wit JM: Nationwide age references for sitting height, leg length, and sitting height/ height ratio, and their diagnostic value for disproportionate growth disorders. Arch Dis Child 2005;90:807–812. Blum WF, Cao D, Hesse V, Fricke-Otto S, Ross JL, Jones C, Quiqley CA, Binder G: Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome. Horm Res 2009;71:167–172. Stephure DK; Canadian Growth Hormone Advisory Committee: Impact of growth hormone supplementation on adult height in turner syndrome: results of the Canadian randomized controlled trial. J Clin Endocrinol Metab 2005;90:3360–3366. Rothenbuhler A, Linglart A, Piquard C, Bougnères P: A pilot study of discontinuous, insulin-like growth factor 1-dosing growth hormone treatment in young children with FGFGR3 N540K-mutated hypochondroplasia. J Pediatr 2012;160:849–853. Cohen P, Weng W, Rogol AD, Rosenfeld RG, Kappelgaard AM, Germak J: Dose-sparing and safety-enhancing effects of an IGF-Ibased dosing regimen in short children treated with growth hormone in a 2-year randomized controlled trial: therapeutic and pharmacoeconomic considerations. Clin Endocrinol 2014;81:71–76. Alatzoglou KS, Hindmarsh PC, Brain C, Torpiano J, Dattani MT: Acanthosis nigricans and insulin sensitivity in patients with achondroplasia and hypochondroplasia due to FGFR3 mutations. J Clin Endocrinol Metab 2009;94:3959–3963. Sas TC, de Muinck Keizer-Schrama SM, Stijnen T, Aanstoot HJ, Drop SL: 2000 carbohydrate metabolism during long-term growth hormone (GH) treatment and after discontinuation of GH treatment in girls with Turner syndrome participating in a randomized dose-response study. Dutch Advisory Group on Growth Hormone. J Clin Endocrinol Metab 2000;85:769–775. Prodam F, Savastio S, Genoni G, Babu D, Giordano M, Ricotti R, Aimaretti G, Bona G, Bellone S: Effects of growth hormone (GH) therapy withdrawal on glucose metabolism in not confirmed GH deficient adolescents at final height. PLoS One 2014;9:e87157.
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References
