Understanding Growth Failure in Costello Syndrome: Increased Resting Energy Expenditure
Chiara Leoni, MD1, Roberta Onesimo, MD1, Valentina Giorgio, MD2, Antonella Diamanti, MD3, Daniela Giorgio, RD1, Lucilla Martini, MD1, Aurora Rossodivita, MD1, Marco Tartaglia, PhD4, and Giuseppe Zampino, MD1
Costello syndrome is a rare multisystem disorder caused by mutations in the proto-oncogene HRAS. Failure to thrive is one of its cardinal clinical features. This study documents that individuals with Costello syndrome have increased resting energy expenditure. We speculate this could be one of the potential mechanisms causing failure to thrive. (J Pediatr 2016;170:322-4).
Costello syndrome (OMIM# 218040) is a rare developmental disorder caused by germline activating mutations in the proto-oncogene HRAS,1,2 which encodes amember of the RAS subfamily of small monomeric GTPases controlling several intracellular signaling pathways with roles in cell proliferation, differentiation, and survival. Clinically, Costello syndrome3 is recognizable by a distinctive facies, reduced postnatal growth, intellectual disability, and cardiac and musculoskeletal anomalies. The growth phenotype presents with severe failure to thrive and swallowing / sucking difficulties after birth, followed by a mild improvement in gaining weight usually occurring after the third year of life.3 Most infants require nasogastric or gastrostomy tube feeds because of the severe feeding difficulties.3 During childhood, individuals are able to take oral feeds, yet they continue to have growth failure.
Herein we report the results of a case/control study evaluating the energy balance in Costello syndrome to further investigate the mechanisms underlying failure to thrive.
Growth hormone replacement therapy in Costello syndrome
1st Department of Pediatrics, Aristotle University, Thessaloniki, Greece
Costello syndrome (CS) is considered an overgrowth disorder given the macrosomia that is present at birth. However, shortly after birth the weight drops dramatically and the patients are usually referred for failure to thrive. Subsequently, affected patients develop the distinctive coarse facial appearance and are at risk for cardiac anomalies and solid tumor malignancies. Various endocrine disorders, although not very often, have been reported in patients with CS, including growth hormone deficiency, hypoglycemia, ACTH deficiency, cryptorchidism and hypothyroidism. We report a case of Costello syndrome with hypothyroidism, cryptorchidism and growth hormone deficiency andwe evaluate the long-termsafety and efficacy of growth hormone replacement therapy.The index patient is a paradigm of successful and safe treatment with growth hormone for almost 7 years. Since patients with CS are at increased risk for cardiac myopathy and tumor development they deserve closemonitoring during treatment.
Costello Syndrome and Hyperinsulinemic Hypoglycemia
Saji Alexander,1 Dina Ramadan,2 Haya Alkhayyat,1 Ibrahim Al-Sharkawi,2 K.C. Aboo Backer,2 Fatma El-Sabban,3 and Khalid Hussain1*
1 London Centre for Pediatric Endocrinology and Metabolism, Great Ormond Street, Hospital for Children NHS Trust, London, and The Institute of Child Health, London, United kingdom
2 Endocrine Unit, Paediatric Department, Sabah Hospital, Kuwait
3 Neonatal Department, Maternity Hospital, Kuwait
Costello syndrome is characterized by mental retardation, loose skin, coarse facies, skeletal abnormalities, cardiovascular abnormalities (congenital heart defects, cardiomyopathy, rhythm disturbances), and predisposition to neoplasia. Endocrine abnormalities including growth hormone deficiency, adrenal insufficiency, glucose intolerance, parathyroid adenoma with hyperprolactinemia and hypoglycemia have been described. Hypoglycemia has been documented due to growth hormone and cortisol deficiency.
Wereport on two patients with Costello syndrome and persistent hyperinsulinemic hypoglycemia and review the endocrine manifestations of Costello syndrome. Both patients required diazoxide therapy to stop the unregulated insulin secretion and maintain normoglycemia. The mechanism of persistent hyperinsulinism in patients with Costello syndrome is unclear.
Normative Growth Charts for Individuals With Costello Syndrome
Mary R. Sammon,1 Dan Doyle,2 Elizabeth Hopkins,3 Katia Sol-Church,4 Deborah L. Stabley,4 John McGready,5 Kerry Schulze,6 Yewande Alade,7 Julie Hoover-Fong,7 and Karen W. Gripp3*
1 Division of General Pediatrics, A. I. duPont Hospital for Children, Wilmington, Delaware
2 Division of Endocrinology, A. I. duPont Hospital for Children, Wilmington, Delaware
3 Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware
4 Department of Biomedical Research, Nemours’ Children’s Clinic, Wilmington, Delaware
5 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
6 Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
7 Greenberg Center for Skeletal Dysplasias, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland
Costello syndrome is a rare condition due to heterozygous germline mutations in the proto-oncogene HRAS. It affects multiple organ systems and includes severe failure-to-thrive, short stature, and macrocephaly. The goal of this study was to develop Costello syndrome-specific growth curves.
We collected height, weight, and head circumference (OFC) measurements from 94 individuals (45 males and 49 females). Their HRAS mutation spectrum reflects previously published cohorts, with p.G12S in 77.7%. Participants received medical care, therefore our data does not reflect natural history per se, but rather growth with nutritional support. Due to limited cohort size, we analyzed data from males and females together. Weight-for-age data included 417 separate measurements from 80 individuals age 0–36 months, and 585 measurements from 82 individuals for age 0–10 years. Height-for-age data were derived from 391 measurements from 77 individuals age 0–36 months, and 591 measurements from 90 individuals age 0–10 years.
Measurements obtained after growth hormone exposure in 15 individuals were excluded in this analysis. The OFC curve was derived from 221 measurements from 55 individuals age 0–36 months. Centiles (5th, 50th, and 95th) were estimated across the age continuum for each growth parameter, and compared to gender-specific curves for average stature individuals. The resulting curves demonstrate very slow weight gain in the first 2 years. Short stature is seen inmany, but after age 4 years the 95th centile for height falls within the low normal range for average stature children. Head circumference curves largely overlap those for average stature, reflecting relative macrocephaly.
Growth Hormone Deficiency in Costello Syndrome
Robert I. Stein,1 Laurent Legault,2 Denis Daneman,3 Rosanna Weksberg,4 and Jill Hamilton3*
1 Department of Paediatrics, Division of Endocrinology, Children’s Hospital of Western Ontario and University of Western Ontario, London, Canada
2 Department of Paediatrics, Division of Endocrinology, Montreal Children’s Hospital and McGill University, Montreal, Canada
3 Department of Paediatrics, Division of Endocrinology, The Hospital for Sick Children and University of Toronto, Toronto, Canada
4 Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto,Toronto, Canada
We report on three patients with Costello syndrome and isolated growth hormone (GH) deficiency treated with biosynthetic GH. To our knowledge, these are the only patients with Costello syndrome who have been successfully treated for GH deficiency. We review the pathophysiology of Costello syndromeandhighlight the recent recommendations of tumor screening and cardiac surveillance in this population, of particular relevance to those receiving GH therapy.
Costello syndrome is a growth deficiency syndrome that was first described in the 1970s [Costello, 1971, 1977]. It is a rare disorder characterized by short stature; mental retardation; distinctive coarse facies; redundant skin on the neck, palms, and soles; nasal papillomata; and musculoskeletal abnormalities (see Fig. 1). These patients are at risk for cardiac anomalies, including malformations, hypertrophic cardiomyopathy, rhythm disturbances [Lin et al., 2002]; and solid tumor malignancies including neuroblastoma, rhabdomyosarcoma, and bladder carcinoma [Gripp et al., 2002].
The characteristic growth pattern in this condition is one of increased birth weight and macrocephaly, followed by postnatal growth retardation and failure to thrive [Zampino et al., 1993]. Young children with Costello syndrome often require placement of enteral feeding tubes due to poor oral motor coordination. In time, weight gain improves but there is a persistence of linear growth deficiency [Zampino et al., 1993].
Adults with Costello syndrome have significant short stature reaching a mean final height of 138 cm (range 118–148 cm) [van Eeghen et al., 1999]. The etiology of the growth failure has not been extensively investigated. We report on two new cases of Costello syndrome with growth hormone (GH) deficiency treated with GH and present long-term follow-up data on a previously reported patient [Legault et al., 2001].