- Clinical Study
- Open Access
IGF-I and IGF Binding Protein-3 Generation Tests and Response to Growth Hormone in Children with Silver-Russell Syndrome
© Beserra et al. 2010
Received: 24 August 2010
Accepted: 5 October 2010
Published: 10 October 2010
Objectives. To evaluate, in children with Silver-Russell Syndrome, the response to the IGF-I and IGFBP-3 generation test and compare results to the growth response after 6 months of rhGH. Methods. Eight children (6 males), with a mean age of years and height SDS of received rhGH for 6 months. IGF-I and IGFBP-3 were analyzed before and after 4 doses of rhGH. Results. The mean growth velocity (GV) before treatment was cm/year. GV increased after rhGH in five children to a mean GV of cm/year. Six children had normal basal IGF-I levels and two low levels. After 4 doses of rhGH, the IGF-I levels were normal in seven. There was no correlation between the growth response and the IGF-I generation test. Conclusions. Children with SRS have normal IGF-I generation test. There is no correlation between the generation test and the growth velocity after 6 months of rhGH.
Silver-Russell syndrome (SRS) was first described in 1953 by Silver et al. and in 1954 by Russell . Ten percent of the cases are due to maternal chromosome 7 disomy (mUPD7) suggesting a genomic "imprinting" [3, 4]. In 2005 Gicquel et al.  identified an epimutation (loss of methylation) of the central telomeric imprinting center region 1 (ICR1) on chromosome 11p15 in various patients with typical SRS clinical characteristics. Other authors subsequently confirmed the presence of these mutations with a high frequency (20–63.8%) in patients with SRS . This region is associated with the regulation of many genes, such as tumor suppressor genes (H19) and the IGF-2 gene. Hypermethylation in this region is associated with Beckwith-Wiedemann syndrome characterized by excessive growth and/or asymmetry. Hypomethylation in the H19/IGF2 region could lead to asymmetry and fetal growth retardation as seen in SRS . SRS and Beckwith-Wiedemann syndrome are currently considered two diseases caused by opposite epigenetic alteration in the same chromosomal region (11p15) thus leading to different growth disorders [8–10]. This epigenetic defect can be involved in syndromic intrauterine growth retardation [5, 11]. The diagnosis is clinical and requires at least 3 of the following criteria: (1) birth weight 2 SDS or more below the mean for gestational age (GA), (2) short stature (height more than 2 SDS below the mean for children of the same age and gender) at the time of the diagnosis, (3) characteristic appearance (triangular face, small mandible, low ear implantation, down turned corners of the mouth, proeminent forehead), (4) clinodactyly of the 5th finger, and (5) body asymmetry . The incidence of SRS is 1 in 50.000 to 100.000 newborns , and it can be as high as 1 : 3000 with a male predominance . SRS diagnosis although easily recognizable in extreme cases can be difficult in more subtle situations, especially in the absence of body asymmetry. In their review of the published data, Netchine et al.  recently proposed a clinical scoring system for diagnosis in those cases where the patient was born SGA. They suggested that the patient must also have at least three of the five following criteria: postnatal growth retardation, relative macrocephaly, body asymmetry, prominent forehead, and feeding difficulties, with a body mass index (BMI) < −2SD during infancy and early childhood. The latter criterion was included because it is particularly severe and frequent in these children. They also stated that the scoring system is highly predictive of a molecular defect in the diagnosis as 63.8% of patients here classified as SRS under this scoring present 11p15 ICR1 epimutation (loss of methylation).
Many of these children do not present a postnatal catch-up growth and show persistent short stature. The growth in the first three years of life is slow, and from this point on it remains parallel to the curve but below the third percentile . Puberty may occur earlier than normal, and the growth spurt can be smaller [16, 17]. The cumulative result of this growth deficiency is short stature with an average adult height of cm for males and cm for females, between 3.6 and 4.0 SD [15, 18].
GH treatment was approved in the United States in 2001 to be used in children with intrauterine growth retardation (IUGR) (including SRS) who did not present a catch-up growth until 2-3 years of age  and in Europe in 2003 after the age of 4 years. The initial age, the dose used, and the height deficit related to the parents height at the beginning of the treatment are predictor factors of the growth response [20–24]. These results were independent of the GH status [23, 25–30]. Boguszewisk et al.  described abnormalities in the 24-hour spontaneous GH secretion and lower levels of IGF-I and IGFBP-3 demonstrating that although these children do not present classical GH deficiency (GHD), their growth hormone secretion is frequently abnormal. Even though the majority of these children achieve a normal adult height when treatment is initiated early and is long lasting, the response to rhGH therapy is heterogeneous.
Previous studies suggest that the IGF generation test can be useful in the diagnosis of GH insensitivity syndrome and in predicting their response to rhGH therapy. We raise the question if in some cases of SRS the growth hormone insensitivity could be influencing adult height and response to rhGH.
The objectives of our study were to compare the growth response after six months of rhGH to the response to the IGF-I and IGFBP-3 generation test.
All SRS patients followed at the Instituto de Puericultura e Pediatria Martagão Gesteira, the pediatric hospital of the Universidade Federal do Rio de Janeiro, were evaluated. The inclusion criteria were children clinically diagnosed with SRS, older than 2 years, prepubertal, with a height more than 2 SD below the mean, bone age (BA) below 10 years, with a minimum of 6 months of follow-up to calculate growth velocity (GV), and never treated with rhGH. Children with poor compliance with the regular visits or showing other conditions that could affect growth, like hypothyroidism, were excluded.
This study was approved by the ethics committee of the Universidade Federal do Rio de Janeiro. Informed consent and child assent were obtained from parents or legal guardians and from the patients.
The diagnosis of SRS was established by an expert geneticist based on the presence of at least 3 of the following clinical criteria: (1) short stature; (2) weight and/or height at birth below 2 SDS for gestational age ; (3) characteristic facial features;  clinodactyly of the fifth digit; (5) body asymmetry.
In order to exclude the presence of other possible conditions that could affect growth or the IGF-I and IGFBP-3 generation, a set of laboratories tests were performed in all patients—complete blood count, erythrocyte sedimentation rate, electrolytes, liver and kidney function tests, lipid profile, urine analysis, free thyroxine, and thyroid-stimulating hormone. Magnetic resonance imaging (MRI) scan or computed tomography (CT) of the brain and of the pituitary gland and abdominal ultrasound were performed in all children. All female patients had a karyotype to exclude Turner syndrome.
Serum samples were collected before the initiation of rhGH and after 4 doses (in the morning of the fifth day). Immediately after collection, samples were centrifuged, divided, and frozen at −20°C. The IGF-I and IGFBP-3 analyses were performed at the same time. Serum levels of IGF-I were analyzed by an IRMA assay (DSL, Webster, TX) with an intra-assay coefficient of variation of 3.4% and interassay coefficient of variation of 8.2%. The limit of detection is 0,8 ng/dL in a dilution of 1 : 30. Serum levels of IGFBP-3 were analyzed by an IRMA assay (DSL, Webster, TX) with an intra- and interassay coefficient of variation of 1.8% and 8.9%, respectively. The limit of detection is 0.0005 mg/L.
Following the protocol described by Blum et al. , a basal blood sample was collected, and all children received subcutaneous rhGH (0.05 mg/kg/day) daily for 4 doses. In the morning of the fifth day, another blood sample was collected. An increment of 15 ng/mL for IGF-I (IGF-I Δ) and of 0.4 mg/L for IGFBP-3 (IGFBP-3 Δ) was considered a positive response to the generation test. After the generation test, all patients continue to receive rhGH (same dose) for 6 months. Anthropometrical data collected at the beginning of the generation tests and after 6 months of rhGH therapy were used to calculate the growth velocity.
Pre-and posttreatment bone age (BA) radiograph was done and evaluated by Greulich-Pyle  method.
3.2. Gestational and Delivery History
The gestational age varied from 36 to 40 weeks with a mean ± SD of . Just two children were born at less than 37 weeks of gestation. The mean birth weight (±SD) was 1953.8 g (±464.1). Six of the patients were born with a weight more than 2 SD below the mean. The mean birth length (±SD) was 41.88 cm (±3.27), and all of them had the birth length more than 2 SD below the mean for gestational age. There was no uniform history of teratogenic conditions.
3.3. Target Height
The fathers' heights ranged from 165 to 189 cm (−1.72 to 1.85 SDS) with a mean height of cm and a mean height SDS of . The mothers' heights ranged from 156 cm to 171 cm, and the range of maternal heights SDS was −1.29 to 0.55 with a mean height SDS of . One of the patients was adopted, and no family information was available.
3.4. Growth Velocity (GV), Height SD Score and Bone Age Pre- and Posttreatment
After 6 months of treatment with rhGH, four patients had a delta GH below 3 cm/year Figure 1. The other 4 patients doubled their GV. Considering the height SDS, it improved for at least 0.5 SD in half of the patients while the other half had no change. The mean posttreatment growth velocity (GV2) was cm/year, and the mean height SDS after 6 months of treatment was .
The greatest Δ IGF-I was observed in patient 1, and this did not reflect the change in growth velocity as his growth velocity remained unaltered with rhGH therapy.
3.7. Laboratories Parameters and Adverse Events
There were no adverse events during rhGH therapy. Lower limb asymmetry did not change during treatment.
The number of patients in this study reflects the low incidence of SRS (3).
Among the facial characteristics, the small triangular face with small mandible and prominent forehead (relative macrocephaly) was evident in all children. Wollmann et al.  analyzed data of 386 published patients and reported that the small triangular facies is the most common characteristic, present in 79% of patients.
Corporal asymmetry was detected in 1/3 of the patients. The literature shows that body asymmetry has a frequency between 33% to 51% [12, 15, 18]. This range can be partially justified by the difficulty in detecting and quantifying the asymmetry, especially in children with less manifested phenotypes .
All patients had clinodactyly of the 5th finger similarly to the published data (68%). One child had café au lait spots. The published prevalence is around 19% .
Concerning birth data, 6 children were born with low weight and all of them with their length more than 2SD below the mean, similarly to published data .
Not all children with SRS respond well to rhGH therapy. At the moment, most centers will administer rhGH and evaluate the change in growth velocity after 6–12 months to decide whether to continue or discontinue treatment. In this study, we investigated if the short term (4 doses-5 days) IGF-I and IGFBP-3 generation tests could predict the growth response to 6 months of treatment with rhGH.
In this study the basal serum IGF-I was low in two children (25%) while normal for the others (75%). Most studies evaluating the growth response to rhGH in children with SRS include them in studies investigating children with intrauterine growth retardation (IUGR). Our data are in contrast to Boguszewski's et al. , who had shown IGF-I and IGFBP-3 low levels in prepubertal children with IUGR. In the studies by Thieriot-Prevost et al.  and Boguszewski et al. , serum IGF-I levels increased in children who had catch-up growth during the first year of life, but not in children without this catch-up growth. This statement is not confirmed in the findings here since serum levels of IGF-I increased in all children, independently of the change in growth velocity.
The used rhGH dose for the generation test was based on the one used for children born SGA, since the SRS is the extreme of IUGR. Buckway et al.  used 0.025 and 0.05 mg/kg/day dose and observed little advantage of larger rhGH dose. Blair et al.  did test in idiopathic short stature (ISS) children using a standard dose (0.033 mg/kg/day) and low dose (0.011 mg/kg/day) observing a better result with the higher dose. From Stanhope et al.  and Albertsson-Wikland et al.  studies was selected the use of a dose of 0.05 mg/kg/day as they postulated that the presence of some resistance to GH action by children with SRS. The test duration time was based in the literature, where the majority was carried through in 4 days. Buckway et al.  and Jorge et al.  found no advantage in more than 4-day test, as there is no significant difference in the increment and no evidence that children with GHD or GHIS would show a normal reply on more prolonged test.
In the present study serum levels of IGF-I increased more than 15 ng/mL in all children after rhGH, demonstrating a non-GH resistant response. Regarding serum levels of IGFBP-3, half of the patients did not increase serum levels by more than 0.4 mg/L, "failing" the generation test. When we correlated the growth response to the generation tests results, there were no correlations, indicating that we cannot use the short-term biochemical response to rhGH therapy to predict the 6-month growth response.
One interesting patient to discuss is patient 8: she had the lowest prestudy serum levels of IGF-I and IGFBP-3 (10 ng/mL and 1.44 mg/L, resp.) and the second lowest prestudy growth velocity (4.5 cm/year). When we look at her response to 4 days of rhGH, her serum levels of IGF-I went to 96 ng/mL, and serum levels of IGFBP-3 went to 5.7 mg/L. After 6 months of rhGH, she had the highest annualized growth velocity (16 cm/year). These results suggest that she could have GHD. The generation test was carried through with no previous evaluation of GH deficiency since SGA born children can show normal response to GH stimulation tests even when they produce less GH than children with a birth weight adequate for gestational age (AGA) or with short stature [45–47].
Based on the results of our study, where not only there was no correlation between the generation tests and the growth response to rhGH therapy but also some of the more robust responses to one of the tests were associated with some of the poorer responses to the other test, and vice versa, we do not believe that increasing the number of patients or increasing the length of follow-up would increase the predictability of the test.
- Silver HK, Kiyasu W, George J, Deamer WC: Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins. Pediatrics. 1953, 12: 368-376.PubMedGoogle Scholar
- Russell A: A syndrome of intra-uterine dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples). Proceedings of the Royal Society of Medicine. 1954, 47 (12): 1040-1044.PubMedGoogle Scholar
- Kotzot D, Balmer D, Baumer A, Chrzanowska K, Hamel BCJ, Ilyina H, Krajewska-Walasek M, Lurie IW, Otten BJ, Schoenle E, Tariverdian G, Schinzel A: Maternal uniparental disomy 7—review and further delineation of the phenotype. European Journal of Pediatrics. 2000, 159 (4): 247-256. 10.1007/s004310050064.View ArticlePubMedGoogle Scholar
- Yoshihashi H, Maeyama K, Kosaki R, Ogata T, Tsukahara M, Goto Y-I, Hata J-I, Matsuo N, Smith RJ, Kosaki K: Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome. American Journal of Human Genetics. 2000, 67 (2): 476-482. 10.1086/302997.PubMed CentralView ArticlePubMedGoogle Scholar
- Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, Danton F, Thibaud N, Le Merrer M, Burglen L, Bertrand A-M, Netchine I, Le Bouc Y: Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nature Genetics. 2005, 37 (9): 1003-1007. 10.1038/ng1629.View ArticlePubMedGoogle Scholar
- Schönherr N, Meyer E, Eggermann K, Ranke MB, Wollmann HA, Eggermann T: (Epi)mutations in 11p15 significantly contribute to Silver-Russell syndrome: but are they generally involved in growth retardation?. European Journal of Medical Genetics. 2006, 49 (5): 414-418. 10.1016/j.ejmg.2006.03.001.View ArticlePubMedGoogle Scholar
- Bliek J, Terhal P, Van Den Bogaard M-J, Maas S, Hamel B, Salieb-Beugelaar G, Simon M, Letteboer T, Van Der Smagt J, Kroes H, Mannens M: Hypomethylation of the H19 gene causes not only silver-russell syndrome (SRS) but also isolated asymmetry or an SRS-like phenotype. American Journal of Human Genetics. 2006, 78 (4): 604-614. 10.1086/502981.PubMed CentralView ArticlePubMedGoogle Scholar
- Eggermann T, Schönherr N, Meyer E, Obermann C, Mavany M, Eggermann K, Ranke MB, Wollmann HA: Epigenetic mutations in 11p15 in Silver-Russell syndrome are restricted to the telomeric imprinting domain. Journal of Medical Genetics. 2006, 43 (7): 615-616. 10.1136/jmg.2005.038687.PubMed CentralView ArticlePubMedGoogle Scholar
- Schönherr N, Meyer E, Roos A, Schmidt A, Wollmann HA, Eggermann T: The centromeric 11p15 imprinting centre is also involved in Silver-Russell syndrome. Journal of Medical Genetics. 2007, 44 (1): 59-63. 10.1136/jmg.2006.044370.PubMed CentralView ArticlePubMedGoogle Scholar
- Netchine I, Rossignol S, Dufourg M-N, Azzi S, Rousseau A, Perin L, Houang M, Steunou V, Esteva B, Thibaud N, Demay M-CR, Danton F, Petriczko E, Bertrand A-M, Heinrichs C, Carel J-C, Loeuille G-A, Pinto G, Jacquemont M-L, Gicquel C, Cabrol S, Le Bouc Y: Brief report: 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. Journal of Clinical Endocrinology and Metabolism. 2007, 92 (8): 3148-3154. 10.1210/jc.2007-0354.View ArticlePubMedGoogle Scholar
- Binder G, Seidel A-K, Weber K, Haase M, Wollmann HA, Ranke MB, Eggermann T: IGF-II serum levels are normal in children with Silver-Russell syndrome who frequently carry epimutations at the IGF2 locus. Journal of Clinical Endocrinology and Metabolism. 2006, 91 (11): 4709-4712. 10.1210/jc.2006-1127.View ArticlePubMedGoogle Scholar
- Price SM, Stanhope R, Garrett C, Preece MA, Trembath RC: The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria. Journal of Medical Genetics. 1999, 36 (11): 837-842.PubMed CentralPubMedGoogle Scholar
- Stanhope R, Albanese A, Azcona C: Growth hormone treatment of Russell-Silver syndrome. Hormone Research. 1998, 49 (supplement 2): 37-40. 10.1159/000053086.View ArticleGoogle Scholar
- Moore GE, Abu-Amero S, Wakeling E, Hitchins M, Monk D, Stanier P, PM: The search for the gene for Silver-Russell syndrome. Acta Paediatrica. 1999, 88 (433, supplement): 42-48. 10.1111/j.1651-2227.1999.tb14402.x.View ArticlePubMedGoogle Scholar
- Tanner JM, Lejarraga H, Cameron N: The natural history of the Silver Russell syndrome: a longitudinal study of thirty nine cases. Pediatric Research. 1975, 9 (8): 611-623. 10.1203/00006450-197508000-00001.View ArticlePubMedGoogle Scholar
- Davies PSW, Valley R, Preece MA: Adolescent growth and pubertal progression in the Silver-Russell syndrome. Archives of Disease in Childhood. 1988, 63 (2): 130-135. 10.1136/adc.63.2.130.PubMed CentralView ArticlePubMedGoogle Scholar
- Ibáñez L, Ferrer A, Marcos MV, Hierro FR, de Zegher F: Early puberty: rapid progression and reduced final height in girls with low birth weight. Pediatrics. 2000, 106 (5): E72-10.1542/peds.106.5.e72.View ArticlePubMedGoogle Scholar
- Wollmann HA, Kirchner T, Enders H, Preece MA, Ranke MB: Growth and symptoms in Silver-Russell syndrome: review on the basis of 386 patients. European Journal of Pediatrics. 1995, 154 (12): 958-968. 10.1007/BF01958638.View ArticlePubMedGoogle Scholar
- Lee PA, Chernausek SD, Hokken-Koelega ACS, Czernichow P: International small for gestational age advisory board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics. 2003, 111 (6): 1253-1261. 10.1542/peds.111.6.1253.View ArticlePubMedGoogle Scholar
- Boguszewski M, Albertsson-Wikland K, Aronsson S, Gustafsson J, Hagenäs L, Westgren U, Westphal O, Lipsanen-Nyman M, Sipilä I, Gellert P, Müller J, Madsen B: Growth hormone treatment of short children born small-for-gestational-age: the Nordic Multicentre Trial. Acta Paediatrica. 1998, 87 (3): 257-263. 10.1111/j.1651-2227.1998.tb01434.x.View ArticlePubMedGoogle Scholar
- Boguszewisk M, Jansson C, Rosberg S, Albertsson-Wikland K: Changes in serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 levels during growth hormone treatment in prepubertal short children born small for gestational age. Journal of Clinical Endocrinology and Metabolism. 1996, 81 (11): 3902-3908. 10.1210/jc.81.11.3902.Google Scholar
- Fjellestad-Paulsen A, Czernichow P, Brauner R, Bost M, Colle M, Lebouc JY, Lecornu M, Leheup B, Limal JM, Raux MC, Toublanc JE, Rappaport R: Three-year data from a comparative study with recombinant human growth hormone in the treatment of short stature in young children with intrauterine growth retardation. Acta Paediatrica. 1998, 87 (5): 511-517. 10.1111/j.1651-2227.1998.tb01495.x.View ArticlePubMedGoogle Scholar
- De Zegher F, Albertsson-Wikland K, Wollmann HA, Chatelain P, Chaussain J-L, Löfströ A, Jonsson B, Rosenfeld RG: Growth hormone treatment of short children born small for gestational age: growth responses with continuous and discontinuous regimens over 6 years. Journal of Clinical Endocrinology and Metabolism. 2000, 85 (8): 2816-2821. 10.1210/jc.85.8.2816.PubMedGoogle Scholar
- Sas TCJ, Gerver W-JM, De Bruin R, Mulder PGH, Cole TJ, De Waal W, Hokken-Koelega ACS: Body proportions during 6 years of GH treatment in children with short stature born small for gestational age participating in a randomised, double-blind, dose-response trial. Clinical Endocrinology. 2000, 53 (6): 675-681. 10.1046/j.1365-2265.2000.01155.x.View ArticlePubMedGoogle Scholar
- Albanese A, Stanhope R: GH treatment induces sustained catch-up growth in children with intrauterine growth retardation: 7-year results. Hormone Research. 1997, 48 (4): 173-177. 10.1159/000185509.View ArticlePubMedGoogle Scholar
- Azcona C, Albanese A, Bareille P, Stanhope R: Growth hormone treatment in growth hormone-sufficient and -insufficient children with intrauterine growth retardation/Russell-Silver Syndrome. Hormone Research. 1998, 50 (1): 22-27. 10.1159/000023196.View ArticlePubMedGoogle Scholar
- Azcona C, Stanhope R: Absence of catch-down growth in Russell-Silver syndrome after short-term growth hormone treatment. Hormone Research. 1999, 51 (1): 47-49. 10.1159/000023313.View ArticlePubMedGoogle Scholar
- Chatelain PG: Auxology and response to growth hormone treatment of patients with intrauterine growth retardation or Silver-Russell syndrome: analysis of data from the Kabi Pharmacia International Growth Study. Acta Paediatrica. 1993, 391, supplement: 79-81. 10.1111/j.1651-2227.1993.tb12935.x.View ArticleGoogle Scholar
- Rakover Y, Dietsch S, Ambler GR, Chock C, Thomsett M, Cowell CT: Growth hormone therapy in Silver Russell syndrome: 5 years experience of the Australian and New Zealand growth database (OZGROW). European Journal of Pediatrics. 1996, 155 (10): 851-857. 10.1007/BF02282833.View ArticlePubMedGoogle Scholar
- Ranke MB, Lindberg A: Growth hormone treatment of short children born small for gestation-al age or with Sliver-Russell syndrome: results from KIGS (Kabi Pharmacia International Growth Study), including the first report on final height. Acta Paediatrica. 1996, 18-26. 10.1111/j.1651-2227.1996.tb14288.x. supplement 417Google Scholar
- Boguszewski M, Rosberg S, Albertsson-Wikland K: Spontaneous 24-hour growth hormone profiles in prepubertal small for gestational age children. Journal of Clinical Endocrinology and Metabolism. 1995, 80 (9): 2599-2606. 10.1210/jc.80.9.2599.PubMedGoogle Scholar
- Usher R, McLean F: Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. The Journal of Pediatrics. 1969, 74 (6): 901-910. 10.1016/S0022-3476(69)80224-6.View ArticlePubMedGoogle Scholar
- Blum WF, Cotterill AM, Postel-Vinay MC, Ranke MB, Savage MO, Wilton P, Boulton J, Bramswig J, Caruso M, Chatelain P, Chaussain J, Despert F, Fraser N, Frisch H, Heinrich C, Heinrich U, Herrerea-Justiniano E, Hopp M, Kastrup K: Improvement of diagnostic criteria in growth hormone insensitivity syndrome: solutions and pitfalls. Acta Paediatrica. 1994, 83 (supplement 399): 117-124. 10.1111/j.1651-2227.1994.tb13303.x.View ArticleGoogle Scholar
- Greulich WW, Pyle SI: Radiographic Atlas Ok Skeletal Development of the Hand and Wrist. 1950, Stanford University Press, Stanford, Calif, USA, 1Google Scholar
- Saal HM, Pagon RA, Pepin MG: Reevaluation of Russell-Silver syndrome. Journal of Pediatrics. 1985, 107 (5): 733-737. 10.1016/S0022-3476(85)80402-9.View ArticlePubMedGoogle Scholar
- Marks LJ, Bergeson PS: The Silver Russell syndrome. American Journal of Diseases of Children. 1977, 131 (4): 447-451.View ArticlePubMedGoogle Scholar
- Thieriot-Prevost G, Boccara JF, Francoual C, Badoual J, Job JC: Serum insulin-like growth factor 1 and serum growth-promoting activity during the first postnatal year in infants with intrauterine growth retardation. Pediatric Research. 1988, 24 (3): 380-383. 10.1203/00006450-198809000-00020.View ArticlePubMedGoogle Scholar
- Boguszewski M, Jansson C, Rosberg S, Albertsson-Wikland K: Changes in serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 levels during growth hormone treatment in prepubertal short children born small for gestational age. Journal of Clinical Endocrinology and Metabolism. 1996, 81 (11): 3902-3908. 10.1210/jc.81.11.3902.PubMedGoogle Scholar
- Buckway CK, Guevara-Aguirre J, Pratt KL, Burren CP, Rosenfeld RG: The IGF-I generation test revisited: a marker of GH sensitivity. Journal of Clinical Endocrinology and Metabolism. 2001, 86 (11): 5176-5183. 10.1210/jc.86.11.5176.View ArticlePubMedGoogle Scholar
- Blair JC, Camacho-Hübner C, Miraki Moud F, Rosberg S, Burren C, Lim S, Clayton PE, Bjarnason R, Albertsson-Wikland K, Savage MO: Standard and low-dose IGF-I generation tests and spontaneous growth hormone secretion in children with idiopathic short stature. Clinical Endocrinology. 2004, 60 (2): 163-168. 10.1046/j.1365-2265.2004.01957.x.View ArticlePubMedGoogle Scholar
- Stanhope R, Ackland F, Hamill G, Clayton J, Jones J, Preece MA: Physiological growth hormone secretion and response to growth hormone treatment in children with short stature and intrauterine growth retardation. Acta Paediatrica Scandinavica. 1989, 78 (349, supplement): 47-52. 10.1111/j.1651-2227.1989.tb17168.x.View ArticleGoogle Scholar
- Albertsson-Wikland K, Boguszewski M, Karlberg J: Children born small-for-gestational age: postnatal growth and hormonal status. Hormone Research. 1998, 49 (supplement 2): 7-13. 10.1159/000053080.View ArticleGoogle Scholar
- Buckway CK, Selva KA, Pratt KL, Tjoeng E, Guevara-Aguirre J, Rosenfeld RG: Insulin-like growth factor binding protein-3 generation as a measure of GH sensitivity. Journal of Clinical Endocrinology and Metabolism. 2002, 87 (10): 4754-4765. 10.1210/jc.2002-020045.View ArticlePubMedGoogle Scholar
- Jorge AA, Souza SC, Arnhold IJ, Mendonca BB: Poor reproducibility of IGF-I and IGF binding protein-3 generation test in children with short stature and normal coding region of the GH receptor gene. Journal of Clinical Endocrinology and Metabolism. 2002, 87 (2): 469-472. 10.1210/jc.87.2.469.View ArticlePubMedGoogle Scholar
- de Waal WJ, Hokken-Koelega ACS, Stijnen T, de Muinck Keizer-Schrama SMPF, Drop SLS: Endogenous and stimulated GH secretion, urinary GH excretion, and plasma IGF-I and IGF-II levels in prepubertal children with short stature after intrauterine growth retardation. Clinical Endocrinology. 1994, 41 (5): 621-630. 10.1111/j.1365-2265.1994.tb01828.x.View ArticlePubMedGoogle Scholar
- De Zegher F, Francois I, Van Helvoirt M, Van Den Berghe G: Small as fetus and short as child: from endogenous to exogenous growth hormone. Journal of Clinical Endocrinology and Metabolism. 1997, 82 (7): 2021-2026. 10.1210/jc.82.7.2021.PubMedGoogle Scholar
- Cutfield WS, Hofman PL, Vickers M, Breier B, Blum WF, Robinson EM: IGFs and binding proteins in short children with intrauterine growth retardation. Journal of Clinical Endocrinology and Metabolism. 2002, 87 (1): 235-239. 10.1210/jc.87.1.235.View ArticlePubMedGoogle Scholar
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