Costello Syndrome

Rare congenital disorder with multiple anomalies including: characteristic dysmorphic craniofacial features, musculoskeletal abnormalities, neurocognitive delay, and high prevalence of cancer. Germline mutations in H-Ras protein can cause Costello syndrome. Costello syndrome shows early phenotypic overlap with other disorders that involve MAP KINASE SIGNALING SYSTEM (e.g., NOONAN SYNDROME and cardiofaciocutaneous syndrome).

Also Known As:

Networked: 78 relevant articles (2 outcomes, 5 trials/studies)

Relationship Network

Disease Context: Research Results

Related Diseases

1.	Hypothyroidism
2.	Cryptorchidism (Undescended Testes)
3.	Acne Vulgaris
4.	Acanthosis Nigricans
5.	LEOPARD Syndrome (Syndrome, LEOPARD)

Experts

1.	Gripp, Karen W: 9 articles (03/2012 - 07/2004)
2.	Rauen, Katherine A: 6 articles (05/2015 - 01/2006)
3.	Zenker, Martin: 6 articles (01/2014 - 03/2007)
4.	Hinek, Aleksander: 5 articles (08/2012 - 01/2004)
5.	Niemeyer, Charlotte M: 4 articles (11/2014 - 03/2007)
6.	Lin, Angela E: 4 articles (03/2012 - 02/2005)
7.	Sol-Church, Katia: 4 articles (12/2009 - 08/2006)
8.	Stabley, Deborah L: 4 articles (12/2009 - 08/2006)
9.	Nicholson, Linda: 4 articles (03/2008 - 07/2004)
10.	Bunda, Severa: 3 articles (10/2011 - 09/2010)

Drugs and Biologics

Drugs and Important Biological Agents (IBA) related to Costello Syndrome:

1.	Growth Hormone (Somatotropin)IBA 12/01/2014 - "Growth hormone replacement therapy in Costello syndrome." 08/30/2004 - "We report on three patients with Costello syndrome and isolated growth hormone (GH) deficiency treated with biosynthetic GH. " 08/30/2004 - "Growth hormone deficiency in Costello syndrome." 08/30/2004 - "We describe an 18-month-old boy with Costello syndrome (CS) with proven partial growth hormone (GH) deficiency and hypoglycemic episodes. " 07/01/2003 - "Thus, although osteofibrous dysplasia in Costello syndrome has not been reported before, growth hormone therapy should be used under close supervision in children with this syndrome."
2.	Isotretinoin (Accutane)FDA LinkGeneric 01/01/2015 - "We present this case as a successful treatment option by using oral isotretinoin for the treatment of acanthosis nigricans in Costello syndrome patients. " 01/01/2015 - "Costello syndrome with severe nodulocystic acne: unexpected significant improvement of acanthosis nigricans after oral isotretinoin treatment."
3.	Chondroitin Sulfates (Chondroitin Sulfate)IBA 02/15/2005 - "Most peculiar was the finding that the bulk of the chondroitin sulfate accumulated in these Costello syndrome hearts is a chondroitin-6-sulfate. " 02/15/2005 - "We propose that an imbalance in sulfation of chondroitin sulfate molecules and subsequent accumulation of chondroitin-6-sulfate in cardiomyocytes contribute to the development of the hypertrophic cardiomyopathy of Costello syndrome." 02/15/2005 - "Myocardial storage of chondroitin sulfate-containing moieties in Costello syndrome patients with severe hypertrophic cardiomyopathy." 08/01/2012 - "Our recent observation that heart tissue from patients with Costello syndrome showed a loss of the glycosaminoglycan chondroitin-4-sulfate (C4S) inspired our present study aimed to explore a functional involvement of the chondroitin sulfate (CS) biosynthesis gene Carbohydrate sulfotransferase 11/Chondroitin-4-sulfotransferase-1 (CHST11/C4ST-1), as well as an impaired chondroitin sulfation balance, as a downstream mediator of oncogenic HRAS in Costello syndrome. " 02/15/2005 - "Previous studies with cultured fibroblasts from individuals with Costello syndrome demonstrate excessive accumulation of chondroitin sulfate-bearing proteoglycans, associated with both impaired formation of elastic fibers and an unusually high rate of cellular proliferation. "
4.	Protein Kinases (Protein Kinase)IBA 03/01/2012 - "Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations." 10/01/2011 - "Costello syndrome is a rare association of symptoms caused by de novo germline mutations of the HRAS oncogene interfering in the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. " 05/15/2011 - "Cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (CS) are two of the more rare RASopathies caused by altered signal transduction of the Ras/mitogen-activated protein kinase (MAPK) pathway. " 12/01/2009 - "Costello syndrome is a rare rasopathy caused by germline mutations in the oncogene HRAS resulting in increased signal transduction through the Ras/mitogen-activated protein kinase pathway. " 12/01/2007 - "Costello syndrome is caused by heterozygous de-novo point mutations in HRAS, resulting in increased activation of the mitogen-activated protein kinase pathway. "
5.	Proteoglycans (Proteoglycan)IBA 05/06/2015 - "Human iPSCs derived from patients with Costello syndrome differentiated to astroglia more rapidly in vitro than those derived from wild-type cell lines with normal HRAS, exhibited hyperplasia, and also generated an abundance of extracellular matrix remodeling factors and proteoglycans. " 02/15/2005 - "Previous studies with cultured fibroblasts from individuals with Costello syndrome demonstrate excessive accumulation of chondroitin sulfate-bearing proteoglycans, associated with both impaired formation of elastic fibers and an unusually high rate of cellular proliferation. " 05/06/2015 - "Acute treatment with a farnesyl transferase inhibitor and knockdown of the transcription factor SNAI2 reduced expression of several proteoglycans in Costello syndrome iPSC-derived astrocytes. " 03/01/2000 - "Because the normal association between EBP and tropoelastin can be disrupted on contact with galactosugar-bearing moieties, and the fibroblasts from patients with Costello syndrome revealed an unusual accumulation of chondroitin sulfate-bearing proteoglycans (CD44 and biglycan), we postulate that a chondroitin sulfate may be responsible for shedding EBP from Costello cells and in turn for their impaired elastogenesis. " 08/08/2008 - "Comprehensive expression analysis revealed remarkable up-regulation of several cytokines and chemokines including Gro family proteins, interleukin-1beta (IL-1beta), IL-8 and MCP-1 but down-regulation of extracellular matrix components including collagens and proteoglycans of skin fibroblasts derived from a Japanese Costello syndrome patient characterized by significantly reduced tropoelastin mRNA, impaired elastogenesis and enhanced cell proliferation. "
6.	TropoelastinIBA 08/08/2008 - "Tropoelastin regulates chemokine expression in fibroblasts in Costello syndrome." 08/01/2006 - "Significant decrease in tropoelastin gene expression in fibroblasts from a Japanese Costello syndrome patient with impaired elastogenesis and enhanced proliferation." 08/01/2006 - "In this study we demonstrated a significant decrease in the expression of tropoelastin mRNA in fibroblasts derived from a Japanese Costello syndrome patient with impaired elastogenesis and enhanced proliferation. " 03/01/2000 - "Using immunohistochemistry and metabolic labeling with [3H]-valine, we have established that cultured skin fibroblasts obtained from patients with Costello syndrome did not assemble elastic fibers, despite an adequate synthesis of tropoelastin and normal deposition of the microfibrillar scaffold. " 03/01/2000 - "Because the normal association between EBP and tropoelastin can be disrupted on contact with galactosugar-bearing moieties, and the fibroblasts from patients with Costello syndrome revealed an unusual accumulation of chondroitin sulfate-bearing proteoglycans (CD44 and biglycan), we postulate that a chondroitin sulfate may be responsible for shedding EBP from Costello cells and in turn for their impaired elastogenesis. "
7.	Messenger RNA (mRNA)IBA 08/01/2012 - "Here we demonstrate a loss of C4S, as well as a reduction in C4ST-1 mRNA and protein expression, in primary fibroblasts from Costello syndrome patients. " 08/01/2006 - "In this study we demonstrated a significant decrease in the expression of tropoelastin mRNA in fibroblasts derived from a Japanese Costello syndrome patient with impaired elastogenesis and enhanced proliferation. " 08/08/2008 - "Comprehensive expression analysis revealed remarkable up-regulation of several cytokines and chemokines including Gro family proteins, interleukin-1beta (IL-1beta), IL-8 and MCP-1 but down-regulation of extracellular matrix components including collagens and proteoglycans of skin fibroblasts derived from a Japanese Costello syndrome patient characterized by significantly reduced tropoelastin mRNA, impaired elastogenesis and enhanced cell proliferation. "
8.	MicroRNAs (MicroRNA)IBA 01/01/2015 - "Previously selected miRNAs, were further analyzed in developed cell lines containing H-Ras protein mutants, that included the G12S Costello Syndrome mutant, with PCR Real-Time Taq Man miRNA Assays primers. " 01/01/2015 - "This study describes how p19 affects the RNA world and shows that: i) miR-342, miR-206, miR-330, miR-138 and miR-99b are upregulated by p19 but not by p19W164A mutant; ii) anti-miR-206 can restore the G2 phase in the presence of p19; iii) p19 and p21Q61L regulate their own alternative splicing; iv) miR-206 and miR-138 are differentially regulated by p19 and p21 H-Ras and v) P19G12S Costello mutants show a clear upregulation of miR-374, miR-126, miR-342, miR-330, miR-335 and let-7. These results allow us to conclude that the H-Ras G12S mutation plays an important role in miRNA expression and open up a new line of study to understand the consequences of this mutation on Costello syndrome. " 01/01/2015 - "Our aim is to better understand the role of p19 and p21 H-Ras proteins in the cancer and Costello Syndrome development, concerning the miRNAs expression. " 01/01/2015 - "The role of p19 and p21 H-Ras proteins and mutants in miRNA expression in cancer and a Costello syndrome cell model."
9.	RNA (Ribonucleic Acid)IBA 01/01/2015 - "This study describes how p19 affects the RNA world and shows that: i) miR-342, miR-206, miR-330, miR-138 and miR-99b are upregulated by p19 but not by p19W164A mutant; ii) anti-miR-206 can restore the G2 phase in the presence of p19; iii) p19 and p21Q61L regulate their own alternative splicing; iv) miR-206 and miR-138 are differentially regulated by p19 and p21 H-Ras and v) P19G12S Costello mutants show a clear upregulation of miR-374, miR-126, miR-342, miR-330, miR-335 and let-7. These results allow us to conclude that the H-Ras G12S mutation plays an important role in miRNA expression and open up a new line of study to understand the consequences of this mutation on Costello syndrome. "
10.	HormonesIBA 01/01/2009 - "In recent years, germline mutations that affect components of the RAS-MAPK (mitogen-activated protein kinase) pathway were shown to be involved in the pathogenesis of NS and four rare syndromes with clinical features overlapping with NS: Leopard syndrome, cardio-facio-cutaneous syndrome, Costello syndrome and neurofibromatosis type 1. Several hormones act through receptors that stimulate the RAS-MAPK pathway, and therefore, NS and related disorders represent a remarkable opportunity to study the implication of the RAS-MAPK pathway in different endocrine systems. "

Therapies and Procedures

1.	Tonsillectomy 03/01/2003 - "The authors present a 2-year old child with Costello syndrome who required anaesthesia for direct laryngoscopy, rigid bronchoscopy, bilateral pressure equalization tubes and tonsillectomy. "
2.	Enema (Enemas) 01/01/2009 - "We report the case of a 13-year-old boy with Costello syndrome and chronic constipation who received phosphate-containing Fleet-pediatric enemas at regular intervals. "
3.	Anesthesia 06/01/2008 - "Anesthetic considerations in the child with Costello syndrome: risks of cardiac arrest upon induction of anesthesia."