Editorial
HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2014;82:353–354 DOI: 10.1159/000369169
Published online: December 16, 2014
Growth Hormone Treatment in Patients with Hypochondroplasia Molly O. Regelmann Robert Rapaport Division of Pediatric Endocrinology and Diabetes, Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai, New York, N.Y., USA
© 2014 S. Karger AG, Basel 1663–2818/14/0826–0353$39.50/0 E-Mail [email protected] www.karger.com/hrp
plasia with developmental delay and acanthosis nigricans, achondroplasia, and HCH [4]. The most commonly found genotype for patients meeting clinical and radiographic criteria for HCH is the N540K mutation in the FGFR3 gene on chromosome 4p16.3. Adult heights for patients with the clinical diagnosis of HCH have been reported to vary widely: from 145 to 165 cm in males and from 133 to 151 cm in females [5]. The broad spectrum of adult height lost may be attributable to varying degrees of penetrance even among children with the same FGFR3 genotype [6, 7]. Reports of the benefits of recombinant human growth hormone (hGH) treatment in children with skeletal dysplasias are mixed. In children with achondroplasia, there may be transient improvement in height velocity without improvement in adult height. Thus, the use of hGH to treat achondroplasia is not routinely recommended [4]. For children with HCH, there are no reports of placebocontrolled trials that have evaluated the use of hGH treatment to adult height. Previous reports of patients with HCH suggested an improvement in height velocity when treated with hGH, particularly at the time of the pubertal growth spurt [5, 8]. A report of 6 children with the N540K mutation of the FGFR3 gene treated with growth hormone also showed improvement in height velocity and trunk/leg disproportion; however, the study lacked control patients for comparison and the patients were not followed up to adult heights [9]. Prof. Robert Rapaport, MD Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai One Gustave L. Levy Place, Box 1616 New York, NY 10029 (USA) E-Mail robert.rapaport @ mountsinai.org
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In children evaluated for short stature or growth failure, subtle skeletal dysplasias may be difficult to identify, particularly before puberty when skeletal disproportions are less obvious. Children with mild forms of skeletal dysplasias, including hypochondroplasia (HCH), may be mislabeled as having ‘growth failure of unknown etiology’, otherwise known as ‘idiopathic short stature’ [1]. Patients with HCH have also been labeled as ‘small for gestational age’ or having ‘familial short stature’ [2]. Stimulation testing has occasionally been performed in patients with HCH and some have been diagnosed with growth hormone deficiency that was not reproduced on subsequent testing [3]. Correctly identifying children with skeletal dysplasias is important to establish appropriate treatment regimens as well as manage expectations for short-term growth and adult height. The diagnosis of HCH can be established by clinical, radiographic, and genetic testing. Clinically, children with HCH may have short stature, an increased upper-to-lower segment ratio, short arm spans, and macrocephaly. Radiographic abnormalities include decreased interpedicular distances between lumbar vertebrae L1 and L5 and short lumbar pedicles in the absence of other gross radiographic abnormalities. FGFR3 mutations have been reported in subjects with skeletal dysplasias. The phenotype of affected individuals varies according to the FGFR3 mutation and ranges from thanatophoric dysplasia to severe achondro-
In this issue of Hormone Research in Paediatrics, Pinto et al. [10] report the natural history of growth in 40 untreated children with HCH and use this cohort as the control for a group of children with HCH treated with hGH. Even though not genotyped and limited in number, the untreated patients form a valuable, previously unavailable group of patients with HCH who may be used, as was done in the paper, as historical controls. The mean adult height reached in the control group was 137 ± 5.5 cm for girls and 149 ± 5.5 cm for boys. The 19 patients treated with hGH had an overall good response with improvement in height and height velocity. At the initiation of treatment, they ranged in age from 3.4 to 14.7 years (mean: 9.0 ± 3.1), and 6 were already pubertal. The height velocity on treatment increased from a baseline of 5.1 ± 0.3 to 8.1 ± 1.9 cm/year in the first year. During the second year, the height velocity trended down to 6.2 ± 1.7 cm/year, and by the third year of treatment, the mean height velocity was less than at baseline, i.e. 4.8 ± 2.2 cm/ year. The height SDS compared to the general population increased from –2.80 ± 0.83 to –2.18 ± 1.52. Inasmuch as the height velocity improved most, and almost exclusively, in the first year, it will be important to determine whether treatment beyond the first year has a significant additional impact on adult height. In the 7 treated patients who reached adult heights, the mean height compared to the average population was essentially the same (–3.1 SDS at baseline and –3.0 SDS adult height). However, compared to the untreated HCH historical control group, there was a height gain of +1.39 ± 0.9 SDS. The mean height gained from treatment was 7.4 ± 6.6 cm, with a range of –1.8 to 19 cm. The individ-
ual variability in response to treatment seemed to be unrelated to the FGFR3 genotype. Frequent adjustments to the hGH dose were needed to maintain IGF-1 levels within 2 SDS of normal. The authors did not report, and it may be of interest to note, whether or not the 3 (out of 18) patients who failed provocative growth hormone stimulation tests had different responses to treatment and whether stimulation testing would be of clinical use for determining initial doses of growth hormone. Safety concerns reported included 3 patients who developed mild scoliosis and 4 patients who had worsening of genu varum, with 1 patient requiring surgical intervention. Another patient had insulin resistance but normal glucose tolerance after 3 years of hGH; this patient had a K650Q mutation of the FGFR3 gene, which is known to be associated with insulin resistance and acanthosis nigricans [11]. Given the potential benefit in height in the treated versus untreated control subjects, it seems reasonable to consider treatment with hGH in some children with HCH. The factors that may modulate the response to hGH, such as growth hormone peak response to stimulation, genotype, puberty, sex, age at start of treatment, duration of treatment, and IGF-1 levels during treatment, remain unclear and require further elucidation. Additional studies are also needed to characterize growth patterns in more untreated patients with HCH and to establish the safety of hGH and its benefits to adult height, skeletal health, and body proportions. Collaborative, prospective studies involving multiple interested centers should be able to provide sufficient numbers of well-characterized and uniformly treated and monitored subjects to allow for a definitive management pathway for children with HCH.
References
354
5 Appan S, Laurent S, Chapman M, Hindmarsh PC, Brook CG: Growth and growth hormone therapy in hypochondroplasia. Acta Paediatr Scand 1990;79:796–803. 6 Ramaswami U, Rumsby G, Hindmarsh PC, Brook CG: Genotype and phenotype in hypochondroplasia. J Pediatr 1998;133:99–102. 7 Sobreiera N, McKusick VA: Hypochondroplasia; HCH (#146000). OMIM 7/14/29 (accessed June 14, 2014). 8 Ramaswami U, Hindmarsh PC, Brook CG: Growth hormone therapy in hypochondroplasia. Acta Paediatr Suppl 1999;88:116–117.
Horm Res Paediatr 2014;82:353–354 DOI: 10.1159/000369169
9 Rothenbuhler A, Linglart A, Piguard C, Bougneres P: A pilot study of discontinuous, insulin-like growth factor 1-dosing growth hormone treatment in young children with FGFR3 N540K-mutated hypochondroplasia. J Pediatr 2012;160:849–853. 10 Pinto G, Cormier-Daire V, Le Merrer M, Samara-Boustani D, Baujat G, Fresneau L, Viaud M, Souberbielle JC, Pineau JC, Polak M: Efficacy and safety of growth hormone treatment in children with hypochondroplasia: comparison with an historical cohort. Horm Res Paediatr 2014;82:355–363. 11 Leroy JG, Nuytinck L, Lambert J, Naeyaert JM, Mortier GR: Acanthosis nigricans in a child with mild osteochoncrodysplasia and K650Q mutation in the FGFR3 gene. Am J Med Genet A 2007;143A:3144–3149.
Regelmann/Rapaport
Downloaded by: Göteborgs Universitet 130.241.16.16 - 11/7/2017 9:40:25 PM
1 Graber E, Rapaport R: Growth and disorders of growth. Pediatr Ann 2012;41:e1–e9. 2 Flechtner I, Lambot-Juhan K, Teissier R, Colmenares A, Baujat G, Beltrand J, Ajaltouni Z, Pauwels C, Pinto G, Samara-Boustani D, Simon A, Thalassinos C: Unexplained high frequency of skeletal dysplasia in idiopathic short stature and small for gestational age patients. Eur J Endocrinol 2014;170:677–684. 3 Meyer MF, Menken KU, Zimny S, Hellmich B, Schatz H: Pitfall in diagnosing growth hormone deficiency in a hypochondroplastic patient with a delayed puberty. Exp Clin Endocrinol Diabetes 2003;111:177–181. 4 Horton WA, Hall JG, Hecht JT: Achondroplasia. Lancet 2007;370:162–172.
HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2014;82:353–354 DOI: 10.1159/000369169
Published online: December 16, 2014
Growth Hormone Treatment in Patients with Hypochondroplasia Molly O. Regelmann Robert Rapaport Division of Pediatric Endocrinology and Diabetes, Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai, New York, N.Y., USA
© 2014 S. Karger AG, Basel 1663–2818/14/0826–0353$39.50/0 E-Mail [email protected] www.karger.com/hrp
plasia with developmental delay and acanthosis nigricans, achondroplasia, and HCH [4]. The most commonly found genotype for patients meeting clinical and radiographic criteria for HCH is the N540K mutation in the FGFR3 gene on chromosome 4p16.3. Adult heights for patients with the clinical diagnosis of HCH have been reported to vary widely: from 145 to 165 cm in males and from 133 to 151 cm in females [5]. The broad spectrum of adult height lost may be attributable to varying degrees of penetrance even among children with the same FGFR3 genotype [6, 7]. Reports of the benefits of recombinant human growth hormone (hGH) treatment in children with skeletal dysplasias are mixed. In children with achondroplasia, there may be transient improvement in height velocity without improvement in adult height. Thus, the use of hGH to treat achondroplasia is not routinely recommended [4]. For children with HCH, there are no reports of placebocontrolled trials that have evaluated the use of hGH treatment to adult height. Previous reports of patients with HCH suggested an improvement in height velocity when treated with hGH, particularly at the time of the pubertal growth spurt [5, 8]. A report of 6 children with the N540K mutation of the FGFR3 gene treated with growth hormone also showed improvement in height velocity and trunk/leg disproportion; however, the study lacked control patients for comparison and the patients were not followed up to adult heights [9]. Prof. Robert Rapaport, MD Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai One Gustave L. Levy Place, Box 1616 New York, NY 10029 (USA) E-Mail robert.rapaport @ mountsinai.org
Downloaded by: Göteborgs Universitet 130.241.16.16 - 11/7/2017 9:40:25 PM
In children evaluated for short stature or growth failure, subtle skeletal dysplasias may be difficult to identify, particularly before puberty when skeletal disproportions are less obvious. Children with mild forms of skeletal dysplasias, including hypochondroplasia (HCH), may be mislabeled as having ‘growth failure of unknown etiology’, otherwise known as ‘idiopathic short stature’ [1]. Patients with HCH have also been labeled as ‘small for gestational age’ or having ‘familial short stature’ [2]. Stimulation testing has occasionally been performed in patients with HCH and some have been diagnosed with growth hormone deficiency that was not reproduced on subsequent testing [3]. Correctly identifying children with skeletal dysplasias is important to establish appropriate treatment regimens as well as manage expectations for short-term growth and adult height. The diagnosis of HCH can be established by clinical, radiographic, and genetic testing. Clinically, children with HCH may have short stature, an increased upper-to-lower segment ratio, short arm spans, and macrocephaly. Radiographic abnormalities include decreased interpedicular distances between lumbar vertebrae L1 and L5 and short lumbar pedicles in the absence of other gross radiographic abnormalities. FGFR3 mutations have been reported in subjects with skeletal dysplasias. The phenotype of affected individuals varies according to the FGFR3 mutation and ranges from thanatophoric dysplasia to severe achondro-
In this issue of Hormone Research in Paediatrics, Pinto et al. [10] report the natural history of growth in 40 untreated children with HCH and use this cohort as the control for a group of children with HCH treated with hGH. Even though not genotyped and limited in number, the untreated patients form a valuable, previously unavailable group of patients with HCH who may be used, as was done in the paper, as historical controls. The mean adult height reached in the control group was 137 ± 5.5 cm for girls and 149 ± 5.5 cm for boys. The 19 patients treated with hGH had an overall good response with improvement in height and height velocity. At the initiation of treatment, they ranged in age from 3.4 to 14.7 years (mean: 9.0 ± 3.1), and 6 were already pubertal. The height velocity on treatment increased from a baseline of 5.1 ± 0.3 to 8.1 ± 1.9 cm/year in the first year. During the second year, the height velocity trended down to 6.2 ± 1.7 cm/year, and by the third year of treatment, the mean height velocity was less than at baseline, i.e. 4.8 ± 2.2 cm/ year. The height SDS compared to the general population increased from –2.80 ± 0.83 to –2.18 ± 1.52. Inasmuch as the height velocity improved most, and almost exclusively, in the first year, it will be important to determine whether treatment beyond the first year has a significant additional impact on adult height. In the 7 treated patients who reached adult heights, the mean height compared to the average population was essentially the same (–3.1 SDS at baseline and –3.0 SDS adult height). However, compared to the untreated HCH historical control group, there was a height gain of +1.39 ± 0.9 SDS. The mean height gained from treatment was 7.4 ± 6.6 cm, with a range of –1.8 to 19 cm. The individ-
ual variability in response to treatment seemed to be unrelated to the FGFR3 genotype. Frequent adjustments to the hGH dose were needed to maintain IGF-1 levels within 2 SDS of normal. The authors did not report, and it may be of interest to note, whether or not the 3 (out of 18) patients who failed provocative growth hormone stimulation tests had different responses to treatment and whether stimulation testing would be of clinical use for determining initial doses of growth hormone. Safety concerns reported included 3 patients who developed mild scoliosis and 4 patients who had worsening of genu varum, with 1 patient requiring surgical intervention. Another patient had insulin resistance but normal glucose tolerance after 3 years of hGH; this patient had a K650Q mutation of the FGFR3 gene, which is known to be associated with insulin resistance and acanthosis nigricans [11]. Given the potential benefit in height in the treated versus untreated control subjects, it seems reasonable to consider treatment with hGH in some children with HCH. The factors that may modulate the response to hGH, such as growth hormone peak response to stimulation, genotype, puberty, sex, age at start of treatment, duration of treatment, and IGF-1 levels during treatment, remain unclear and require further elucidation. Additional studies are also needed to characterize growth patterns in more untreated patients with HCH and to establish the safety of hGH and its benefits to adult height, skeletal health, and body proportions. Collaborative, prospective studies involving multiple interested centers should be able to provide sufficient numbers of well-characterized and uniformly treated and monitored subjects to allow for a definitive management pathway for children with HCH.
References
354
5 Appan S, Laurent S, Chapman M, Hindmarsh PC, Brook CG: Growth and growth hormone therapy in hypochondroplasia. Acta Paediatr Scand 1990;79:796–803. 6 Ramaswami U, Rumsby G, Hindmarsh PC, Brook CG: Genotype and phenotype in hypochondroplasia. J Pediatr 1998;133:99–102. 7 Sobreiera N, McKusick VA: Hypochondroplasia; HCH (#146000). OMIM 7/14/29 (accessed June 14, 2014). 8 Ramaswami U, Hindmarsh PC, Brook CG: Growth hormone therapy in hypochondroplasia. Acta Paediatr Suppl 1999;88:116–117.
Horm Res Paediatr 2014;82:353–354 DOI: 10.1159/000369169
9 Rothenbuhler A, Linglart A, Piguard C, Bougneres P: A pilot study of discontinuous, insulin-like growth factor 1-dosing growth hormone treatment in young children with FGFR3 N540K-mutated hypochondroplasia. J Pediatr 2012;160:849–853. 10 Pinto G, Cormier-Daire V, Le Merrer M, Samara-Boustani D, Baujat G, Fresneau L, Viaud M, Souberbielle JC, Pineau JC, Polak M: Efficacy and safety of growth hormone treatment in children with hypochondroplasia: comparison with an historical cohort. Horm Res Paediatr 2014;82:355–363. 11 Leroy JG, Nuytinck L, Lambert J, Naeyaert JM, Mortier GR: Acanthosis nigricans in a child with mild osteochoncrodysplasia and K650Q mutation in the FGFR3 gene. Am J Med Genet A 2007;143A:3144–3149.
Regelmann/Rapaport
Downloaded by: Göteborgs Universitet 130.241.16.16 - 11/7/2017 9:40:25 PM
1 Graber E, Rapaport R: Growth and disorders of growth. Pediatr Ann 2012;41:e1–e9. 2 Flechtner I, Lambot-Juhan K, Teissier R, Colmenares A, Baujat G, Beltrand J, Ajaltouni Z, Pauwels C, Pinto G, Samara-Boustani D, Simon A, Thalassinos C: Unexplained high frequency of skeletal dysplasia in idiopathic short stature and small for gestational age patients. Eur J Endocrinol 2014;170:677–684. 3 Meyer MF, Menken KU, Zimny S, Hellmich B, Schatz H: Pitfall in diagnosing growth hormone deficiency in a hypochondroplastic patient with a delayed puberty. Exp Clin Endocrinol Diabetes 2003;111:177–181. 4 Horton WA, Hall JG, Hecht JT: Achondroplasia. Lancet 2007;370:162–172.
