Recombinant growth hormone therapy in a girl with costello syndrome: a 4-year observation
© Blachowska et al. 2015
Received: 4 August 2015
Accepted: 10 December 2015
Published: 26 January 2016
Costello syndrome is a rare syndrome of multiple congenital anomalies. The typical clinical traits include dysmorphic craniofacial features, skin hyperpigmentation and excess, feeding difficulties leading to severe postnatal growth retardation, short stature, joint hypermobility, and delayed psychomotor development. Additionally, Costello syndrome may present with an increased incidence of congenital heart disease, hypertrophic cardiomyopathy, and increased risk of both benign and malignant tumors. Furthermore, cases of patients with endocrine disorders such as adrenal insufficiency and endogenous growth hormone deficiency have also been documented.
We present a patient with Costello syndrome who has been successfully treated with recombinant human growth hormone (rhGH) for almost 4 years.
The possibility of growth hormone (GH) treatment can be considered in cases of documented GH deficiency in patients with Costello syndrome, but only under close oncologic and cardiologic supervision.
KeywordsCostello syndrome Growth hormone deficiency Hypertrophic cardiomyopathy Malignancy HRAS gene
Costello syndrome (CS, OMIM #218040) is caused by heterozygous germline mutations in the proto-oncogene HRAS that cause dysfunction of the Ras-MAPK signaling pathway. To date, 15 mutations in HRAS have been identified. The birth prevalence of this disease is estimated at 1:1,230,000 to 1:300,000 [1–4]. Clinically, CS is characterized by polyhydramnios, high birth weight, postnatal growth retardation, relative macrocephaly, coarse facial features, loose skin, especially of the hands and feet, hyperpigmentation, hypertrophic cardiomyopathy, atrial arrhythmias, papillomata, developmental delay or mental retardation, and predisposition to malignancies. In the newborn and neonatal periods, the presence of suggestive facies and severe feeding difficulties leading to failure to thrive and hypoglycemia help make the correct diagnosis [5–7]. Furthermore, cases of Costello syndrome patients with endocrine disorders such as adrenal insufficiency and endogenous growth hormone deficiency have also been documented in the literature [8–11]. Due to the complex nature of the discussed syndrome, patients require multidisciplinary care (provided by cardiologists, speech therapists, gastroenterologists, orthopedic surgeons) along with early stimulation and developmental support. Because of the short stature and growth hormone deficiency in this condition, growth hormone therapy is often considered. For decades there has been great debate on the anticipated risk of carcinogenesis and cardiomyopathy weighted against the potential benefits resulting from recombinant human growth hormone (rhGH) therapy. To date, there are no conclusive data showing a negative role of rhGH therapy in the development of these diseases.
Here we report a six-year-old patient with Costello syndrome, who has been successfully treated with rhGH for 42 months.
AM, was born at 40 weeks gestation by caesarean section (due to large fetal mass) as the first baby of healthy and nonconsanguineous parents with a birth weight of 4270 g (>97 c), length of 55 cm (50 c) and head circumference of 38 cm (>97c). Her Apgar score was 7/7/8 points. The pregnancy was complicated by polyhydramnios and impaired glucose tolerance in the mother.
In the neonatal period, generalized edema, hypoglycemia, and hypocalcaemia were observed. Transthoracic echocardiography revealed thickened muscles of both ventricles and septum, although follow-up cardiac examinations revealed no evidence of cardiomyopathy.
Symptoms in consecutive months of life
Lack of appetite
Vomiting, spitting up
Delayed speech development
Coarse facial features
Excessive joint laxity
Achilles tendon contractures
>3 years of life
The treatment of gastroesophageal reflux, which involved proton pump inhibitors and prokinetic agents, was ineffective. During eight months, her weight gain had been only 1000 g. At the age of nine months the patient weighed 5300 g (SD: −4.92). Due to persistent feeding difficulties she was referred for surgical treatment and Nissen fundoplication was performed at the age of 11 months. The improvement after abovementioned procedure was very brief, with feeding difficulties quickly reoccurring. Due to lack of improvement after pharmacological treatment, and persistent signs of gastroesophageal reflux in performed endoscopy our patient was qualified for second operation. Finally the decision about surgical treatment was abandoned due to slow spontaneous improvement in feeding and apetite after the patient was 3 years old.
Growth hormone secretion in nocturnal and stimulation tests
Nocturnal GH excretion [ng/ml]
GH after L-dopa [ng/ml]
GH after clonidine [ng/ml]
At the age of 3 years and 9 months the girl was qualified for growth hormone therapy, following careful considerations of the risks and benefits and discussion of the issue with the child’s parents.
Selected auxological parameters of the patient during rhGH treatment
Age [years and months]
Body height [cm]
Body height SDS
Growth rate [cm/year]
Body weight [kg]
Body weight SDS
Bone age [years and months]
3 years and 2 months
3 years 9 months (start of rhGH treatment)
4 years 5 months
4 years 8 months
4 years 2 months
5 years 2 months
5 years 6 months
5 years – 5 years 9 months
6 years 1 month
6 years 8 months
7 years 10 months
7 years 2 months
During the treatment, progression of the abnormalities within the ligaments of the ankles and hip joints (right club foot, left plano-valgus foot, shortening of the Achilles tendon, dislocation of the right hip) was observed. At the age of 5 years and 6 months, surgical correction of both feet was necessary due to further progression of mobility impairment, and plasty of the hip joint was performed in the following year. At present, the patient is recovering after the last intervention.
Currently, after 42 months of rhGH treatment, the girl has grown 30.3 cm, reaching a body height above the 3rd percentile (115 cm; SD: −1.61), her weight gain has been 10.4 kg. Her current weight is 20.3 kg (10–25 percentile; SD: −1.28). So far, no serious adverse events have been observed. The patient tolerates daily injections of growth hormone well, she receives comprehensive speech therapy and rehabilitation, and attends kindergarten. Her parents have observed a significant improvement in her psychomotor development, especially with respect to speech.
Costello syndrome was first described in 1977 by Jack Costello, a New Zealand pediatrician, in two unrelated children who presented similar phenotypic characteristics. The molecular etiology of this syndrome (germline mutations in the HRAS gene) was identified in 2005 . Among many dysfunctions associated with this condition, impaired growth is one of the most challenging clinical problems [8, 12, 13]. The average final height in Costello syndrome patients, without growth-stimulating therapy, reaches about 138 cm (118–148 cm) . The pathogenesis of short stature associated with this condition has been studied in recent decades. The first cases diagnosed with partial/total endogenous growth hormone deficiency and treated with rhGH were described in the 1990s [9–11]. To date, there are few studies in the scientific literature that assess the safety and efficacy of rhGH therapy in individual patients [14, 15]. As the syndrome is extremely rare, evaluating a larger group of patients iseems to be a very difficult task. Increased incidence of cancer and increased risk of development of hypertrophic cardiomyopathy are serious clinical problems that should be taken into account when considering treatment with rhGH [1, 7, 8, 15]. Gripp et al.  estimated that the risk of developing tumors in patients with Costello syndrome reaches 17 %, most of which are rhabdomyosarcoma, neuroblastoma, papilloma, and bladder cancer. Interestingly, the p.G12A mutation detected in our patient is the main mutation associated with the higher risk of cancer in CS, which correlates with an up to 57 % risk in affected patients (2, 3). However, no occurrence of malignancy has been noted in the patient so far. Growth hormones promote cell divisions, which may generate a potential hazard. However, existing research in this area has given inconclusive results [14, 15]. Stein et al.  presented long-term observations involving three patients with endogenous growth hormone deficiency successfully treated with rhGH with no severe adverse events. On the other hand, cases of patients with unsatisfactory response to rhGH therapy  and complications during the treatment have also been documented. There are reports describing a case of a 16-year-old girl diagnosed with bladder cancer after 7 years of rhGH therapy , a 26-month-old boy diagnosed with rhabdomyosarcoma after one year of treatment , and progression of hypertrophic cardiomyopathy in a 6-year-old boy treated with rhGH . However, in all of these cases it is difficult to assess whether the administration of growth hormone actually influenced the development of these diseases and to what extent.
During 3.5 years of follow-up, we have observed accelerated growth in our rhGH-treated patient, and no serious health complications have yet occurred. In infancy the girl was diagnosed with supraventricular arrhythmias and hypertrophic cardiomyopathy, which was not confirmed in subsequent echocardiography. However, because of the risk of recurrence she remains under the systematic control of a cardiologist. The observed motor-system problems, resulting from the excessive ligamentous laxity associated with Costello syndrome, were already present before the initiation of growth hormone therapy. It seems that their progression was associated with significant growth acceleration resulting from GH supply, but the impact of rhGH therapy alone is difficult to assess.
The available data, based on a small number of reported cases of Costello syndrome treated with recombinant growth hormone, do not allow drawing general conclusions. The very good response to the treatment, demonstrated in our case, improved her body height prognosis and eliminated the disability related to extreme short stature. The 3.5-year observation revealed no serious side effects. However, reports of the otherauthors regarding the development and progression of cancer and hypertrophic cardiomyopathy in children with Costello syndrome treated with rhGH indicate that these patients require special oncologic and cardiologic supervision.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Harvey rat sarcoma viral oncogene homolog
Mitogen-activated protein kinases
Recombinant human growth hormone
The research was partially supported by the National Science Center Project UMO-2011/03/N/NZ2/00516 and MNiSW Project PB 0056/B/P01/2008/35.
The technical and language assistance was provided by Proper Medical Writing Sp. z o.o., Warsaw, Poland.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Gripp KW, Lin AE. Costello Syndrome. GeneReviews® University of Washington, Initial Posting: August 29, 2006; Last Update: January 12, 2012.
- Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, et al. Germline mutations in HRAS proto-oncogen cause Costello syndrome. Nat Genet. 2005;37:1038–40.View ArticlePubMedGoogle Scholar
- Kerr B, Delrue M-A, Sigaudy S, Perveen R, Marche M, Burgelin I, et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006;43:401–5. doi:10.1136/jmg.2005.040352.PubMed CentralView ArticlePubMedGoogle Scholar
- Pelc M, Ciara E, Krajewska-Walasek M. Zespół Costello jako przykład rzadkich zaburzeń funkcji szlaku sygnalnego Ras-MAPK: obraz kliniczny i diagnostyka molekularna choroby. Pediatr Pol. 2012;87:19–32.View ArticleGoogle Scholar
- Gripp KW, Scott CI, Nicholson L, McDonald-McGinn DM, Ozeran JD, Jones MC, et al. Five additional Costello syndrome patients with rhabdomyosarcoma: proposal for a tumor screening protocol. Am J Med Genet. 2002;108:80–7.View ArticlePubMedGoogle Scholar
- Kerr B, Eden B, Dandamudi R, Shannon N, Quarrell O, Emmerson A, et al. Costello syndrome: two cases with embryonal rhabdomyosarcoma. J Med Genet. 1998;35:1036–9.PubMed CentralView ArticlePubMedGoogle Scholar
- van Eeghen AM, van Gelderen I, Hennekam RCM. Costello syndrome: report and review. Am J Med Genet. 1999;82:187–93.View ArticlePubMedGoogle Scholar
- Gregersen N, Viljoen D. Costello syndrome with growth hormone deficiency and hypoglycemia: a new report and review of the endocrine associations. Am J Med Genet Part A. 2004;129A:171–5.View ArticlePubMedGoogle Scholar
- Okamoto N, Chiyo H, Imai K, Otani K, Futagi Y. A Japanese patient with the Costello syndrome. Hum Genet. 1994;93:605–6.View ArticlePubMedGoogle Scholar
- Schimke RN, Donaldson D, Moore W. Growth hormone deficiency in Costello syndrome. Proc Greenwood Genet Ctr. 1996;15:195.Google Scholar
- Yetkin I, Ayvaz G, Arslan M, Yilmaz M, Cakir N. A case of Costello syndrome with endocrine features. Ann Genet. 1998;41:157–60.PubMedGoogle Scholar
- Legault L, Gagnon C, Lapointe N. Growth hormone deficiency in Costello syndrome: a possible explanation for the short stature. J Pediatr. 2001;138:151–2.View ArticlePubMedGoogle Scholar
- Stein RI, Legault L, Daneman D, Weksberg R, Hamilton J. Growth Hormone Deficiency in Costello Syndrome. Am J Med Genet Part A. 2004;129A:166–70.View ArticlePubMedGoogle Scholar
- Kerr B, Einaudi MA, Clayton P, Gladman G, Eden T, Saunier P, et al. Is growth hormone treatment beneficial or harmful in Costello syndrome? J Med Genet. 2003;40, e74.PubMed CentralView ArticlePubMedGoogle Scholar
- Rauen KA, Hefner E, Carrillo K, Taylor J, Messier L, Aoki Y, et al. Molecular Aspects, Clinical Aspects and Possible Treatment Modalities for Costello Syndrome: Proceedings From the 1st International Costello Syndrome Research Symposium 2007. Am J Med Genet Part A. 2008;146A:1205–17.View ArticlePubMedGoogle Scholar
- Gripp KW, Scott CI, Nicholson L, Figueroa TE. Second case of bladder carcinoma in a patient with Costello syndrome. Am J Med Genet. 2000;90:256–9.View ArticlePubMedGoogle Scholar
- Kobayashi D, Cook AL, Williams DA. Progressively worsening hypertrophic cardiomyopathy in a child with newly diagnosed Costello syndrome while receiving growth hormone therapy. Cardiol Young. 2010;20:459–61. doi:10.1017/S1047951110000260.EpubMar22.View ArticlePubMedGoogle Scholar