Costello Syndrome

Overview

Costello Syndrome is a rare congenital disorder with multiple anomalies; characterised by dysmorphic craniofacial features, musculoskeletal abnormalities, neurocognitive delay, and increased risk of cancers; particularly rhabdomyosarcoma, with occasional reports of other cancers including neuroblastoma and childhood onset bladder carcinoma.

Literature Analysis

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  • Phenotype
  • Noonan Syndrome
  • Developmental Disabilities
  • Adolescents
  • Dwarfism
  • Craniofacial Abnormalities
  • Cardiomyopathy, Hypertrophic
  • Differential Diagnosis
  • MAP Kinase Signaling System
  • Germ-Line Mutation
  • Risk Factors
  • HRAS
  • Proto-Oncogene Proteins p21(ras)
  • Infant
  • Costello Syndrome
  • Failure to Thrive
  • Childhood Cancer
  • Multiple Abnormalities
  • Paranasal Sinus and Nasal Cavity Cancer
  • Signal Transduction
  • Facies
  • Congenital Heart Defects
  • Growth Disorders
  • Intellectual Disability
  • Genetic Predisposition
  • Rhabdomyosarcoma
  • Mutation
  • LEOPARD Syndrome
  • Musculoskeletal Abnormalities
  • Genotype
  • Ectodermal Dysplasia
  • Mitogen-Activated Protein Kinases
  • Skin Abnormalities
  • Bladder Cancer
  • Newborns
  • RAS Genes
  • Face
  • raf Kinases
  • Neurofibromatosis 1
  • Papilloma
  • Young Adult
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (1)

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GeneLocationAliasesNotesTopicPapers
HRAS 11p15.5 CTLO, HAMSV, HRAS1, RASH1, p21ras, C-H-RAS, H-RASIDX, C-BAS/HAS, C-HA-RAS1 -HRAS germline mutation in Costello Syndrome
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Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Useful Links (3 links)

Publications

Publications related to Costello Syndrome and cancer.
Kratz CP, Franke L, Peters H, et al.
Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes.
Br J Cancer. 2015; 112(8):1392-7 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
BACKGROUND: Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown.
METHODS: We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry.
RESULTS: We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4.
CONCLUSIONS: These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.

Anichini C, Lotti F, Longini M, et al.
Antioxidant strategies in genetic syndromes with high neoplastic risk in infant age.
Tumori. 2014 Nov-Dec; 100(6):590-9 [PubMed] Related Publications
Oxidative stress plays a key role in carcinogenesis. Oxidative damage to cell components can lead to the initiation, promotion and progression of cancer. Oxidative stress is also a distinctive sign in several genetic disorders characterized by a cancer predisposition such as ataxia-telangiectasia, Fanconi anemia, Down syndrome, Beckwith-Wiedemann syndrome and Costello syndrome. Taking into account the link between oxidative stress and cancer, the capacity of antioxidant agents to prevent or delay neoplastic development has been tested in various studies, both in vitro and in vivo, with interesting and promising results. In recent years, research has been conducted into the molecular mechanisms linking oxidative stress to the pathogenesis of the genetic syndromes we consider in this review, with the resulting identification of possible new therapeutic targets. The aim of this review is to focus on the oxidative mechanisms intervening in carcinogenesis in cancer-prone genetic disorders and to analyze the current status and future prospects of antioxidants.

Bezniakow N, Gos M, Obersztyn E
The RASopathies as an example of RAS/MAPK pathway disturbances - clinical presentation and molecular pathogenesis of selected syndromes.
Dev Period Med. 2014 Jul-Sep; 18(3):285-96 [PubMed] Related Publications
The RASopathies are a class of developmental syndromes. Each of them exhibits distinctive phenotypic features, although there are numerous overlapping clinical manifestations that include: dysmorphic craniofacial features, congenital cardiac defects, skin abnormalities, varying degrees of intellectual disability and increased risk of malignancies. These disorders include: Noonan syndrome, Costello syndrome, LEOPARD syndrome, cardio-facio-cutaneous syndrome (CFC), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Legius syndrome and neurofibromatosis type 1 (NF1). The RASopathies are associated with the presence of germline mutation in genes encoding specific proteins of the RAS/mitogen - activated protein kinase (MAPK) pathway that plays a crucial role in embryonic and postnatal development. In this review, we present the clinical and molecular features of selected syndromes from the RASopathies group.

Giannoulatou E, McVean G, Taylor IB, et al.
Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline.
Proc Natl Acad Sci U S A. 2013; 110(50):20152-7 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
The RAS proto-oncogene Harvey rat sarcoma viral oncogene homolog (HRAS) encodes a small GTPase that transduces signals from cell surface receptors to intracellular effectors to control cellular behavior. Although somatic HRAS mutations have been described in many cancers, germline mutations cause Costello syndrome (CS), a congenital disorder associated with predisposition to malignancy. Based on the epidemiology of CS and the occurrence of HRAS mutations in spermatocytic seminoma, we proposed that activating HRAS mutations become enriched in sperm through a process akin to tumorigenesis, termed selfish spermatogonial selection. To test this hypothesis, we quantified the levels, in blood and sperm samples, of HRAS mutations at the p.G12 codon and compared the results to changes at the p.A11 codon, at which activating mutations do not occur. The data strongly support the role of selection in determining HRAS mutation levels in sperm, and hence the occurrence of CS, but we also found differences from the mutation pattern in tumorigenesis. First, the relative prevalence of mutations in sperm correlates weakly with their in vitro activating properties and occurrence in cancers. Second, specific tandem base substitutions (predominantly GC>TT/AA) occur in sperm but not in cancers; genomewide analysis showed that this same mutation is also overrepresented in constitutional pathogenic and polymorphic variants, suggesting a heightened vulnerability to these mutations in the germline. We developed a statistical model to show how both intrinsic mutation rate and selfish selection contribute to the mutational burden borne by the paternal germline.

Beukers W, Hercegovac A, Zwarthoff EC
HRAS mutations in bladder cancer at an early age and the possible association with the Costello Syndrome.
Eur J Hum Genet. 2014; 22(6):837-9 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
Bladder tumours of patients <20 years have a low incidence of genetic aberrations typically found in tumours in older patients. In this study, we investigated oncogene mutations in patients with bladder cancer (BC) <20 years and compared them to older age groups. Interestingly, we observed a relatively high number of HRAS mutations in tumour from young patients. These mutations were also highly uncommon in BCs of older patients, ie, p.(Gly12Ser) and p.(Gly12Ala). Germline mutations in the HRAS gene, especially p.(Gly12Ser/Ala), cause Costello Syndrome (CS), a severe congenital disorder. Indeed, one of the patients had been diagnosed with CS. We hypothesized that some of the other patients might be mosaic for the HRAS mutation and therefore could express some of the clinical features of CS, like tumour predisposition. Hence, we isolated DNA from microdissected stroma and analysed it for HRAS mutations. In the CS patient and in patient X, the mutation was also highly expressed in normal stroma. We conclude that patient X is possibly mosaic for the HRAS mutation. These results suggest that mosaicism for oncogenic HRAS mutations may increase the risk for developing BC at a young age.

Cizmarova M, Kostalova L, Pribilincova Z, et al.
Rasopathies - dysmorphic syndromes with short stature and risk of malignancy.
Endocr Regul. 2013; 47(4):217-22 [PubMed] Related Publications
OBJECTIVES: The term ´Rasopathies´ represents a group of five neurodevelopmental syndromes (Noonan, LEOPARD, Costello, Cardio-facio-cutaneous, and Neurofibromatose-Noonan syndrome) caused by germline mutation in genes encoding proteins involved in RAS/MAPK (rat sarcoma/mitogen-activated protein kinase) signaling pathway. The RAS/MAPK signaling pathway participates in regulation of cell determination, proliferation, differentiation, migration, and senescence and dysregulation of this pathway can lead to the risk of tumorigenesis. In this review, we aim to summarize the current clinical and molecular genetic knowledge on Rasopathies with special attention for the risk of cancer. We propose also clinical and therapeutic approach for patients with malignancy.
METHODS: We are reviewing the clinical and molecular basis of Rasopathies based on recent studies, clinical examination, and molecular diagnostics (mutation analysis of causal genes for Rasopathies) in Slovak pediatric patients.
RESULTS: Some clinical features, such as short stature, a specific facial dysmorphology and cardiac abnormalities are common to all of Rasopathy syndromes. However, there are unique signs by which the syndromes can differ from each other, especially multiple lentigo in LEOPARD syndrome, increased risk of malignancy in Costello syndrome, dry hyperkeratotic skin in patients with cardio-facio-cutaneous syndrome, and neurofibromas and cafe-au-lait spots in neurofibromatosis-Noonan syndrome.
CONCLUSION: Despite the overlapping clinical features, Rasopathy syndromes exhibit unique fenotypical features and the precise molecular diagnostics may lead to confirmation of each syndrome. The molecular diagnostics may allow the detection of pathogenic mutation associated with tumorigenesis.

Aytekin S, Alyamac G
Two new cases with Costello syndrome.
Dermatol Online J. 2013; 19(8):19267 [PubMed] Related Publications
Costello syndrome (CS) was described in 1977 by Costello who reported two unrelated children with a new syndrome comprising short stature, redundant skin of the neck, palms, soles, and fingers, curly hair, papillomata around the mouth and nares, and mental retardation. Several additional cases have been reported since then. Herein we report two patients with Costello syndrome; one of these patients had associated mesenteric cyst.

Stevenson DA, Allen S, Tidyman WE, et al.
Peripheral muscle weakness in RASopathies.
Muscle Nerve. 2012; 46(3):394-9 [PubMed] Related Publications
INTRODUCTION: RASopathies are a group of genetic conditions due to alterations of the Ras/MAPK pathway. Neurocutaneous findings are hallmark features of the RASopathies, but musculoskeletal abnormalities are also frequent. The objective was to evaluate handgrip strength in the RASopathies.
METHODS: Individuals with RASopathies (e.g., Noonan syndrome, Costello syndrome, cardio-facio-cutaneous [CFC] syndrome, and neurofibromatosis type 1 [NF1]) and healthy controls were evaluated. Two methods of handgrip strength were tested: GRIP-D Takei Hand Grip Dynamometer and the Martin vigorimeter. A general linear model was fitted to compare average strength among the groups, controlling for confounders such as age, gender, height, and weight.
RESULTS: Takei dynamometer: handgrip strength was decreased in each of the syndromes compared with controls. Decreased handgrip strength compared with sibling controls was also seen with the Martin vigorimeter (P < 0.0001).
CONCLUSIONS: Handgrip strength is decreased in the RASopathies. The etiology of the reduced muscle force is unknown, but likely multifactorial.

Shen Z, Hoffman JD, Hao F, Pier E
More than just skin deep: faciocutaneous clues to genetic syndromes with malignancies.
Oncologist. 2012; 17(7):930-6 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
Genetic syndromes with dermatologic findings and multisystemic involvement (e.g., visceral cancer predisposition) are underrecognized. Patients may have incomplete penetrance and variable expressivity; some patients may solely exhibit subtle skin signs, which create a diagnostic challenge for physicians. Interdisciplinary diagnostic knowledge is required for the early diagnosis and monitoring of patients with these syndromes. Cutaneous changes in the face-one of the most highly exposed areas-can be easily noticed by patients themselves, their families and friends, and physicians; these changes may serve as early indicators of genetic syndromes with malignancies. In this article, we present examples of genetic syndromes with malignancies for which a thorough faciocutaneous examination is helpful in establishing a diagnosis. These examples include lentiginosis-related syndromes (e.g., Peutz-Jeghers syndrome, Carney complex), photosensitivity-related syndromes (Bloom syndrome, Rothmund-Thomson syndrome), and hamartoma-related syndromes (Cowden syndrome, multiple endocrine neoplasia syndrome, tuberous sclerosis complex, Gardner syndrome, Muir-Torre syndrome). The characteristics of these faciocutaneous clues are summarized and discussed. Objective evaluation of these faciocutaneous clues in combination with other clinical information (e.g., family history, histopathological findings, combination with other concomitant faciocutaneous lesions) is emphasized to narrow the diagnosis. The list of genetic syndromes with faciocutaneous manifestations is still expanding. Increased awareness of faciocutaneous markers can alert physicians to underlying syndromes and malignancies, render earlier screening and detection of associated medical issues, and allow for genetic counseling of family members.

Abe Y, Aoki Y, Kuriyama S, et al.
Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey.
Am J Med Genet A. 2012; 158A(5):1083-94 [PubMed] Related Publications
Costello syndrome and cardio-facio-cutaneous (CFC) syndrome are congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, and intellectual disability. Germline mutations in HRAS cause Costello syndrome, and mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) cause CFC syndrome. Since the discovery of the causative genes, approximately 150 new patients with each syndrome have been reported. However, the clinico-epidemiological features of these disorders remain to be identified. In order to assess the prevalence, natural history, prognosis, and tumor incidence associated with these diseases, we conducted a nationwide prevalence study of patients with Costello and CFC syndromes in Japan. Based on the result of our survey, we estimated a total number of patients with either Costello syndrome or CFC syndrome in Japan of 99 (95% confidence interval, 77-120) and 157 (95% confidence interval, 86-229), respectively. The prevalences of Costello and CFC syndromes are estimated to be 1 in 1,290,000 and 1 in 810,000 individuals, respectively. An evaluation of 15 adult patients 18-32 years of age revealed that 12 had moderate to severe intellectual disability and most live at home without constant medical care. These results suggested that the number of adult patients is likely underestimated and our results represent a minimum prevalence. This is the first epidemiological study of Costello syndrome and CFC syndrome. Identifying patients older than 32 years of age and following up on the patients reported here is important to estimate the precise prevalence and the natural history of these disorders.

Siegel DH, Mann JA, Krol AL, Rauen KA
Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development.
Br J Dermatol. 2012; 166(3):601-7 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
BACKGROUND: The RASopathies are a class of human genetic syndromes caused by germline mutations in genes that encode protein components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Costello syndrome (CS) is a RASopathy caused by mutations in the HRAS gene, a key regulator of signal transduction.
OBJECTIVE: To quantify the specific cutaneous phenotype observed in 46 individuals with Costello syndrome with confirmed HRAS mutations.
METHODS: This was a cross-sectional study. Dermatological surveys were designed by the authors and were completed by parents of mutation-positive individuals with CS at the Costello Syndrome Family Network (CSFN) conferences in 2007 and 2009. Dermatological examinations were performed by the authors at the CSFN conferences.
RESULTS: Cutaneous papillomas were reported in 33 of the 46 (72%) participants, with age of onset ranging from infancy to 22years. Individuals with CS are more likely than patients with cardiofaciocutaneous syndrome (CFC) to present with cutaneous papillomas (72% vs. 5%, P<0·001) and palmoplantar keratoderma (76% vs. 36%, P<0·001). Individuals with CS are less likely than individuals with CFC to present with sparse or absent eyebrows (9% vs. 90%, P<0·001) or keratosis pilaris (33% vs. 80%, P=0·001). This study also identified that loose, redundant skin on the hands and feet, 'stippled' dermatoglyphs (pachydermatoglyphia) on the fingertips (eight of 26, 31%) and acanthosis nigricans (17 of 46, 37%) are frequent features of CS.
CONCLUSIONS: While there is significant phenotypic overlap among syndromes of the Ras/MAPK pathway, individuals with CS are more likely than individuals with CFC syndrome to present with cutaneous papillomas, palmoplantar keratoderma and full eyebrows, and are less likely to present with ulerythema ophryogenes, keratosis pilaris or multiple naevi. The dermatological features of CS, a Ras dysregulation syndrome, share many features with cutaneous paraneoplastic syndromes. This may provide further insight into the role of Ras signalling in cutaneous paraneoplastic syndromes.

Zenker M
Clinical manifestations of mutations in RAS and related intracellular signal transduction factors.
Curr Opin Pediatr. 2011; 23(4):443-51 [PubMed] Related Publications
PURPOSE OF REVIEW: Recent advances in molecular genetic research have led to the definition of the new group of genetic syndromes, the RAS-mitogen-activated protein kinase (MAPK) pathway disorders or 'RASopathies'. They comprise Noonan syndrome and related disorders (cardio-facio-cutaneous and Costello syndromes), as well as neurofibromatosis type 1. This review summarizes the recent literature with a special focus on genotype-phenotype correlations.
RECENT FINDINGS: Although the picture is still incomplete, and additional genes are likely to exist, the underlying genetic alteration can now be found in a large majority of patients with a RASopathy phenotype. The most recently discovered novel genes for Noonan syndrome or Noonan syndrome-like disorders, NRAS, SHOC2, and CBL, account for small fractions of the patient population. The increasing knowledge about the spectrum of gene mutations and associated clinical manifestations has led to a refinement of genotype-phenotype correlations. Recent studies have added new insights into tumor predisposition and prenatal manifestations. Model systems are being developed to investigate innovative treatment approaches.
SUMMARY: Constitutional overactivation at various levels of the RAS-MAPK pathway causes overlapping syndromes, comprising characteristic facial features, cardiac defects, cutaneous abnormalities, growth deficit, neurocognitive delay, and predisposition to malignancies. Each syndrome also exhibits unique features that probably reflect genotype-related specific biological effects.

Kratz CP, Rapisuwon S, Reed H, et al.
Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes.
Am J Med Genet C Semin Med Genet. 2011; 157C(2):83-9 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
Noonan syndrome (NS), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and LEOPARD syndrome (now also referred to as Noonan syndrome with multiple lentigines or NSML) are clinically overlapping dominant disorders that are caused by mutations in RAS signaling pathway genes. The spectrum of cancer susceptibility in this group of disorders has not been studied in detail. We identified more than 1900 cases of NS, CS, CFCS, or NSML reported in the literature between 1937 and 2010; 88 cancers were reported. The most common cancers reported in 1051 NS subjects were neuroblastoma (n = 8), acute lymphoblastic leukemia (n = 8), low grade glioma (n = 6), and rhabdomyosarcoma (n = 6). These associations are biologically plausible, given that somatic RAS pathway mutations are known to occur in these specific cancers. In addition, 40 childhood cases of myeloproliferative disease were described in individuals with NS, several of whom experienced a benign course of this hematologic condition. We confirmed the previously described association between CS and cancer in 268 reported individuals: 19 had rhabdomyosarcoma, 4 had bladder cancer, and 5 had neuroblastoma. By age 20, the cumulative incidence of cancer was approximately 4% for NS and 15% for CS; both syndromes had a cancer incidence peak in childhood. The cancers described in CFCS and NSML overlapped with those reported in NS and CS. Future epidemiologic studies will be required to confirm the described cancer spectrum and to estimate precise cancer risks.

Rauen KA, Banerjee A, Bishop WR, et al.
Costello and cardio-facio-cutaneous syndromes: Moving toward clinical trials in RASopathies.
Am J Med Genet C Semin Med Genet. 2011; 157C(2):136-46 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
The RASopathies, one of the largest groups of multiple congenital anomaly syndromes known, are caused by germline mutations in various genes encoding components of the Ras/mitogen-activated protein kinase (MAPK) pathway. The RASopathies have many overlapping characteristics, including craniofacial manifestations, cardiac malformations, cutaneous, musculoskeletal, gastrointestinal, and ocular abnormalities, neurocognitive impairment, hypotonia, and an increased risk of developing cancer. Costello syndrome (CS) and cardio-facio-cutaneous (CFC) syndrome are two of the more rare RASopathies. CS is caused by activating mutations in HRAS, and CFC is caused by dysregulation of signaling in the Ras/MAPK pathway due to mutations in BRAF, MEK1, or MEK2. The Ras/MAPK pathway, which has been well-studied in cancer, is an attractive target for inhibition in the treatment of various malignancies utilizing small molecule therapeutics that specifically inhibit the pathway. With many inhibitors of the Ras/MAPK pathway in clinical trials, the notion of using these molecules to ameliorate developmental defects in CS and CFC is under consideration. CS and CFC, like other syndromes in their class, have a progressive phenotype and may be amenable to inhibition or normalization of signaling.

Gripp KW, Hopkins E, Sol-Church K, et al.
Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C.
Am J Med Genet A. 2011; 155A(4):706-16 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings.

Tartaglia M, Gelb BD, Zenker M
Noonan syndrome and clinically related disorders.
Best Pract Res Clin Endocrinol Metab. 2011; 25(1):161-79 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
Noonan syndrome is a relatively common, clinically variable developmental disorder. Cardinal features include postnatally reduced growth, distinctive facial dysmorphism, congenital heart defects and hypertrophic cardiomyopathy, variable cognitive deficit and skeletal, ectodermal and hematologic anomalies. Noonan syndrome is transmitted as an autosomal dominant trait, and is genetically heterogeneous. So far, heterozygous mutations in nine genes (PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 and CBL) have been documented to underlie this disorder or clinically related phenotypes. Based on these recent discoveries, the diagnosis can now be confirmed molecularly in approximately 75% of affected individuals. Affected genes encode for proteins participating in the RAS-mitogen-activated protein kinases (MAPK) signal transduction pathway, which is implicated in several developmental processes controlling morphology determination, organogenesis, synaptic plasticity and growth. Here, we provide an overview of clinical aspects of this disorder and closely related conditions, the molecular mechanisms underlying pathogenesis, and major genotype-phenotype correlations.

Zenker M
Genetic and pathogenetic aspects of Noonan syndrome and related disorders.
Horm Res. 2009; 72 Suppl 2:57-63 [PubMed] Related Publications
Noonan syndrome (NS) and the clinically overlapping disorders cardio-facio-cutaneous syndrome, LEOPARD syndrome, Costello syndrome and Neurofibromatosis-Noonan syndrome share the clinical features of short stature, the same spectrum of congenital heart defects, and a similar pattern of craniofacial anomalies. It is now known that all these disorders are caused by mutations in components of the RAS-MAPK signaling pathway. This pathway was previously known for its involvement in tumorigenesis. This article reviews the current knowledge on underlying genetic alterations and possible pathogenetic mechanisms responsible for NS and related disorders. It discusses the relationship between a group of developmental disorders and oncogenes. Potential future treatment prospects are based on the possibility of inhibiting RAS-MAPK signaling by pharmaceuticals.

Hasle H
Malignant diseases in Noonan syndrome and related disorders.
Horm Res. 2009; 72 Suppl 2:8-14 [PubMed] Related Publications
The overall risk of cancer in children with Noonan (NS), cardio-facial-cutaneous, Costello or LEOPARD syndrome is high, although no precise estimates are available. There are few data on cancer in adults with NS, but the reported numbers of malignancies in adults do not seem excessive. Juvenile myelomonocytic leukemia (JMML) is a rare aggressive leukemia in young children. A JMML-like myeloproliferative disorder has been described in about 30 neonates with NS and the PTPN11 mutation. The disorder often regresses spontaneously, but fatal complications may occur. A review of the literature indicates an increased risk of acute lymphoblastic leukemia and acute myeloid leukemia in NS. Young children with Costello syndrome have an extremely high risk of rhabdomyosarcoma, and also an increased risk of neuroblastoma and bladder carcinoma. Registry-based studies of patients with NS and related disorders diagnosed with molecular genetics and a high-quality long-term follow-up are necessary to further estimate the incidence of malignancy.

Campus R, Di Rocco M, Sementa AR, et al.
[Gastric fibroid polyp in a 4-month-old girl with Costello syndrome].
Pediatr Med Chir. 2007 Sep-Oct; 29(5):267-9 [PubMed] Related Publications
We describe the case of a 4-month-old girl with a gastric fibroid polyp. This was an occasional radiographic finding, confirmed by sonography and computerized tomography. This very rare benign tumor was surgically removed. The diagnosis of Costello syndrome was based on clinical appearance. This is the first report of a gastric fibroid polyp in Costello syndrome, a genetic disease with a high tumor frequency.

Quezada E, Gripp KW
Costello syndrome and related disorders.
Curr Opin Pediatr. 2007; 19(6):636-44 [PubMed] Related Publications
PURPOSE OF REVIEW: Costello syndrome is a rare congenital disorder affecting multiple organ systems, encompassing severe failure to thrive, cardiac anomalies including hypertrophic cardiomyopathy and atrial tachycardia, tumor predisposition, and cognitive impairment. Costello syndrome shares findings with cardio-facio-cutaneous syndrome and the diagnosis can be challenging. The discovery of gene mutations underlying these and other closely related disorders allows for molecular confirmation of a clinical diagnosis.
RECENT FINDINGS: The identification of germline HRAS mutations in Costello syndrome, and mutations in BRAF, MEK1 and MEK2 in cardio-facio-cutaneous syndrome, uncovered the biologic mechanism for the shared phenotypic findings based on the close interaction of the gene products within the Ras-mitogen-activated protein kinase pathway. Changes in other genes encoding mitogen-activated protein kinase pathway proteins are responsible for Noonan syndrome and the KRAS mutation phenotype.
SUMMARY: Costello syndrome is caused by heterozygous de-novo point mutations in HRAS, resulting in increased activation of the mitogen-activated protein kinase pathway. Despite their overlapping presentation, Costello syndrome and its related disorders are distinct, and the phenotypes become more distinctive with age. Molecular testing is available and a clinical diagnosis should be reconsidered if it is inconsistent with the molecular result.

Arpa E, Domínguez-Cunchillos F, Martínez-Montero I, et al.
[Intraductal breast papillomas in patients with Costello syndrome].
Cir Esp. 2007; 81(6):345-7 [PubMed] Related Publications
Costello syndrome is a multisystemic congenital disorder with a very low prevalence. The pathogenesis remains unclear and predisposes to the development of tumors of ectodermal origin. Diagnosis is clinical, based on findings of mental and growth retardation and a characteristic phenotype. We report the case of a patient with Costello syndrome who was referred to our unit with a suspected diagnosis of intraductal papilloma based on the presence of various episodes of nipple discharge. Postoperative histopathological study confirmed the diagnosis of multiple intraductal papilloma. We review the literature on the topic and discuss the advisability of aggressive surgical therapy, given the predisposition of these patients to develop both benign and malignant tumors.

Rauen KA
HRAS and the Costello syndrome.
Clin Genet. 2007; 71(2):101-8 [PubMed] Related Publications
Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies and a predisposition to develop neoplasia, both benign and malignant. CS is caused by activating germline mutations in HRAS and belongs to an exciting class of genetic syndromes that are caused by perturbation of function through the Ras pathway. Some of these other syndromes include Noonan syndrome, LEOPARD syndrome, neurofibromatosis 1 and cardio-facio-cutaneous syndrome. Ras is a critical signaling hub in the cell and is activated by receptor tyrosine kinases, G-protein-coupled receptors, cytokine receptors and extracellular matrix receptors. The downstream effectors of Ras are many and control vital cellular functions including cell cycle progression, cell survival, motility, transcription, translation and membrane trafficking. Understanding the genetic etiology of CS is the first step in gaining insight to the role Ras plays in human development, cellular signaling and cancer pathogenesis.

Nguyen V, Buka RL, Roberts BJ, Eichenfield LF
Cutaneous manifestations of Costello syndrome.
Int J Dermatol. 2007; 46(1):72-6 [PubMed] Related Publications
Cutaneous findings are common in Costello syndrome, but have not been extensively reviewed in the dermatology literature. We present the cutaneous and histopathologic findings from two cases of Costello syndrome and review previously described cutaneous features of this syndrome. Both patients had manifestations of Costello syndrome with thick, lax skin on the dorsal aspects of hands and feet, deep palmar and plantar creases, curly hair, hyperkeratoses, acanthosis nigricans, papillomas, and multiple pigmented lesions. One patient had multiple syringomas on the forearms, a finding not previously reported. Pigmented lesions have previously been reported as nevi in the literature though no biopsies have been reported. We conclude that thick, loose skin on the dorsal aspects of hands and feet and deep palmar and plantar creases are cardinal manifestations of Costello syndrome and benign tumors of ectodermal origin such as papillomas, calcified epitheliomas, dermoid cysts, mammary fibroadenosis, and syringomas are important features of this syndrome.

Kratz CP, Steinemann D, Niemeyer CM, et al.
Uniparental disomy at chromosome 11p15.5 followed by HRAS mutations in embryonal rhabdomyosarcoma: lessons from Costello syndrome.
Hum Mol Genet. 2007; 16(4):374-9 [PubMed] Related Publications
Costello syndrome (CS; MIM 218040) is characterized by short stature, facial dysmorphism, cardiac defects and predisposition to embryonal rhabdomyosarcoma (CS/ERMS) and other neoplasias. CS is caused by germline mutations in the HRAS gene on chromosome 11p15.5, a region showing allelic imbalances in sporadic ERMS and CS/ERMS. The critical gene for ERMS development in this region is unknown. The association of CS and ERMS as well as previous reports illustrating that somatic HRAS mutations are found in a proportion of these tumors prompted us to clarify the significance and a possible correlation of HRAS mutations and genomic rearrangements at 11p15.5 in sporadic ERMS. We screened for somatic HRAS mutations and 11p15.5 imbalances in six sporadic ERMS samples. This analysis uncovered five ERMS samples with uniparental disomy (UPD) at the HRAS locus, two of which harbored HRAS mutations. By analyzing informative genetic variations in or at the HRAS gene locus, we show that one HRAS allele is entirely lost in specimens with UPD at 11p15.5. Notably, in both cases with UPD and HRAS mutations these mutations were heterozygous. Therefore, they must have succeeded the emergence of UPD. In contrast, HRAS germline mutations are the first step in CS/ERMS. Subsequent development of UPD at 11p15.5 may explain previous observations that CS/ERMS express mutant HRAS only. These data implicate that in sporadic ERMS, UPD at 11p15.5 is not driven by HRAS mutations and that imbalances at 11p15.5 and HRAS mutations represent independent but cooperating events during ERMS development.

Della Marca G, Vasta I, Scarano E, et al.
Obstructive sleep apnea in Costello syndrome.
Am J Med Genet A. 2006; 140(3):257-62 [PubMed] Related Publications
Costello syndrome (CS) was initially described by Costello in 1971; it is caused by a germline mutation in HRAS proto-oncogene. The aim of the present study was to evaluate the respiratory activity during sleep in a group of subjects with CS. We studied 10 consecutive patients, 4 males and 6 females, aged 3-29 years, affected by CS. All patients underwent clinical, neurological, otholaryngologic and radiologic evaluation, and a full-night polysomnography in the sleep laboratory. Polysomnography showed that seven patients presented a relevant number of respiratory events of obstructive type during sleep. The apnea-hypopnea index (AHI) ranged from 0 to 19.2 events per hour (mean index = 7.5 +/- 6.9 events/hr). In one patient AHI was not evaluable because of tracheostomy. Apnea induced mild or moderate hemoglobin desaturations (mean of lowest SpO2 values = 85.4 +/- 5.5%). Only sporadic respiratory pauses of central type were observed (mean number of central apnea per study: 7.2 +/- 6.8 events/hr). Sleep structure was fragmented, with a high number of awakenings (mean number of awakenings was 13.2 +/- 8.1; of these, 4.8 +/- 2.5 lasted longer than 2 min). In all patients, otolaryngologic and radiologic observations revealed one or more sites of narrowing in the upper airways. Our results suggest that Costello patients have a high prevalence of obstructive sleep-related respiratory disorders, which need to be assessed by means of polysomnography.

Estep AL, Tidyman WE, Teitell MA, et al.
HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.
Am J Med Genet A. 2006; 140(1):8-16 [PubMed] Related Publications
Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Based on similarities with other cancer syndromes, we previously hypothesized that CS is likely due to activation of signal transduction through the Ras/MAPK pathway [Tartaglia et al., 2003]. In this study, the HRAS coding region was sequenced for mutations in a large, well-characterized cohort of 36 CS patients. Heterogeneous missense point mutations predicting an amino acid substitution were identified in 33/36 (92%) patients. The majority (91%) had a 34G --> A transition in codon 12. Less frequent mutations included 35G --> C (codon 12) and 37G --> T (codon 13). Parental samples did not have an HRAS mutation supporting the hypothesis of de novo heterogeneous mutations. There is phenotypic variability among patients with a 34G --> A transition. The most consistent features included characteristic facies and skin, failure to thrive, developmental delay, musculoskeletal abnormalities, visual impairment, cardiac abnormalities, and generalized hyperpigmentation. The two patients with 35G --> C had cardiac arrhythmias whereas one patient with a 37G --> T transversion had an enlarged aortic root. Of the patients with a clinical diagnosis of CS, neoplasia was the most consistent phenotypic feature for predicating an HRAS mutation. To gain an understanding of the relationship between constitutional HRAS mutations and malignancy, HRAS was sequenced in an advanced biphasic rhabdomyosarcoma/fibrosarcoma from an individual with a 34G --> A mutation. Loss of the wild-type HRAS allele was observed, suggesting tumorigenesis in CS patients is accompanied by additional somatic changes affecting HRAS. Finally, due to phenotypic overlap between CS and cardio-facio-cutaneous (CFC) syndromes, the HRAS coding region was sequenced in a well-characterized CFC cohort. No mutations were found which support a distinct genetic etiology between CS and CFC syndromes.

Gripp KW, Lin AE, Stabley DL, et al.
HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.
Am J Med Genet A. 2006; 140(1):1-7 [PubMed] Related Publications
Costello syndrome is a rare condition comprising mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy, and/or atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities. Recently mutations in HRAS were identified in 12 Japanese and Italian patients with clinical information available on 7 of the Japanese patients. To expand the molecular delineation of Costello syndrome, we performed mutation analysis in 34 North American and 6 European (total 40) patients with Costello syndrome, and detected missense mutations in HRAS in 33 (82.5%) patients. All mutations affected either codon 12 or 13 of the protein product, with G12S occurring in 30 (90.9%) patients of the mutation-positive cases. In two patients, we found a mutation resulting in an alanine substitution in position 12 (G12A), and in one patient, we detected a novel mutation (G13C). Five different HRAS mutations have now been reported in Costello syndrome, however genotype-phenotype correlation remains incomplete.

Aoki Y, Niihori T, Kawame H, et al.
Germline mutations in HRAS proto-oncogene cause Costello syndrome.
Nat Genet. 2005; 37(10):1038-40 [PubMed] Related Publications
Costello syndrome is a multiple congenital anomaly and mental retardation syndrome characterized by coarse face, loose skin, cardiomyopathy and predisposition to tumors. We identified four heterozygous de novo mutations of HRAS in 12 of 13 affected individuals, all of which were previously reported as somatic and oncogenic mutations in various tumors. Our observations suggest that germline mutations in HRAS perturb human development and increase susceptibility to tumors.

Gripp KW
Tumor predisposition in Costello syndrome.
Am J Med Genet C Semin Med Genet. 2005; 137C(1):72-7 [PubMed] Related Publications
Costello syndrome (CS) is a rare congenital anomaly syndrome. Although it may be classified as an "overgrowth" syndrome due to slightly increased birth weight and relative macrocephaly, it is characterized by severe postnatal failure to thrive and short stature. Patients with CS have an increased risk for malignant tumors, a hallmark of several model overgrowth syndromes. The most common tumor in CS is rhabdomyosarcoma (RMS), followed by neuroblastoma and bladder carcinoma. The occurrence of bladder carcinoma in adolescents is distinctly unusual as this is typically a neoplasm of older adults and is not seen with increased frequency in other tumor predisposition syndromes. The increased tumor frequency in CS led to the proposal of a screening protocol, consisting of abdominal and pelvic ultrasounds, and urine studies for catecholamine metabolites and hematuria. It has since become apparent that patients with CS have an increased excretion of catecholamine metabolites in urine without the presence of an identifiable catecholamine secreting tumor. Thus, the urine assay for catecholamines is unhelpful as a screening test for neuroblastoma and should not be used in this population. The benefit of abdominal and pelvic ultrasound and urinalysis for hematuria as screening tests remains to be shown. A timely diagnosis of CS is a necessary prerequisite for awareness of the increased tumor risk. Once a malignancy has been identified, treatment should follow standard protocols. Additional medical problems characteristic for CS, such as hypertrophic cardiomyopathy and arrhythmia, need to be considered and addressed appropriately.

White SM, Graham JM, Kerr B, et al.
The adult phenotype in Costello syndrome.
Am J Med Genet A. 2005; 136(2):128-35 [PubMed] Related Publications
We report clinical findings in 17 adults with Costello syndrome ranging in age from 16 to 40 years. Two patients in this series have had bladder carcinoma, the only malignancy reported to affect adults with Costello syndrome. Benign tumors included multiple ductal papillomata in two women, and a fourth ventricle mass in one man, thought to be a choroid plexus papilloma. Endocrine problems in this series were osteoporosis, central hypogonadism, and delayed puberty. Other health problems were symptomatic Chiari malformations in three patients. Four patients had adult-onset gastro-esophageal reflux, three of whom had Chiari malformations. Fourteen adults had mild to moderate intellectual disability with three individuals having severe intellectual disability; 15 individuals attained some reading and writing skills and 14 showed ongoing acquisition of new skills into adulthood. On the basis of this data, we recommend that neuro-imaging be considered in adults with Costello syndrome if they develop symptoms suggestive of a Chiari malformation. In the event of pubertal delay, endocrine investigations are indicated and hormone treatment may be required. Bone density assessments should be performed in adults with Costello syndrome, particularly in those with pubertal abnormalities. Screening for microscopic hematuria as a marker for bladder carcinoma may be indicated, although this requires further evaluation.

Kerr B, Eden OB, Dandamudi R, et al.
Costello syndrome: two cases with embryonal rhabdomyosarcoma.
J Med Genet. 1998; 35(12):1036-9 [PubMed] Article available free on PMC after 14/04/2016 Related Publications
Costello syndrome is a well delineated mental retardation syndrome of unknown aetiology in which the occurrence of benign tumours, especially papillomata, is recognised. We report two children in whom the diagnosis of Costello syndrome was made in the first months of life, who both developed a retroperitoneal embryonal rhabdomyosarcoma. Although not previously reported, the occurrence of this relatively uncommon childhood tumour in two girls with Costello syndrome suggests that an increased risk of malignancy may be part of this condition. The genetic basis of this susceptibility requires further clarification.

Franceschini P, Licata D, Di Cara G, et al.
Bladder carcinoma in Costello syndrome: report on a patient born to consanguineous parents and review.
Am J Med Genet. 1999; 86(2):174-9 [PubMed] Related Publications
We report on a 12-year-old boy with Costello syndrome born to consanguineous (first cousins once removed) parents, supporting the hypothesis of recessive transmission of this syndrome. At age 11 years, the patient developed a bladder carcinoma, a rare pediatric tumor not previously described in Costello syndrome. This suggests that an increased risk of malignancy may be part of this condition.

Sigaudy S, Vittu G, David A, et al.
Costello syndrome: report of six patients including one with an embryonal rhabdomyosarcoma.
Eur J Pediatr. 2000; 159(3):139-42 [PubMed] Related Publications
UNLABELLED: Costello syndrome was first described in 1971. Besides papillomata, which were part of the initial description, patients tends to develop benign tumours of ectodermal origin. Aetiology is yet unknown but it is supposed to be the result of a sporadic dominant mutation. We report six patients with typical clinical findings and emphasise the importance of cardiac manifestations and the tendency to develop tumours. One patient developed an embryonal rhabdomyosarcoma, the occurrence of which has been reported twice before in patients with Costello syndrome.
CONCLUSION: There might be a causal link between the development of rare tumours and this genetic disorder which may provide a new clue concerning the identification of the gene involved in Costello syndrome.

Gripp KW, Scott CI, Nicholson L, et al.
Five additional Costello syndrome patients with rhabdomyosarcoma: proposal for a tumor screening protocol.
Am J Med Genet. 2002; 108(1):80-7 [PubMed] Related Publications
We report five new cases of rhabdomyosarcoma (RMS) in Costello syndrome. These cases, combined with those previously reported, increase the number of solid tumors to 17 (10 RMSs, 3 neuroblastomas, 2 bladder carcinomas, 1 vestibular schwannoma, 1 epithelioma), in at least 100 known Costello syndrome patients. Despite possible ascertainment bias, and the incomplete identification of all Costello syndrome patients, the tumor frequency could be as high as 17%. This is comparable to the 7-21% frequency of solid tumors in Beckwith-Wiedemann syndrome (BWS), and may justify tumor screening. Based on the recommendations for screening BWS patients, we propose a screening protocol consisting of ultrasound examination of the abdomen and pelvis every 3-6 months until age 8-10 years for RMS and abdominal neuroblastoma; urine catecholamine metabolite analysis every 6-12 months until age 5 years for neuroblastoma; and urinalysis for hematuria annually for bladder carcinoma after age 10 years. These recommendations may need to be modified, as new information becomes available. Potential criticism of the tumor screening protocol concerns the lack of evidence for improved outcome, and possible overestimation of the tumor risk. The ability of RMSs to occur at various sites complicates tumor screening, but 8 of the 10 RMSs in Costello syndrome patients originated from the abdomen, pelvis and urogenital area. Prior diagnosis of Costello syndrome is a prerequisite for the implementation of any screening protocol. The diagnosis of Costello syndrome should also be considered in individuals with RMS and physical findings suggestive of Costello syndrome.

Flores-Nava G, Canún-Serrano S, Moysen-Ramírez SG, et al.
[Costello syndrome associated to a neuroblastoma. Presentation of a case].
Gac Med Mex. 2000 Nov-Dec; 136(6):605-9 [PubMed] Related Publications
We present the case of a newborn with Costello syndrome who died due to heart arrhythmia. In the autopsy, a neuroblastoma was found. The male patient was born at term. During the first hours of life, he developed severe respiratory failure requiring mechanical ventilation. Phenotypic features included cranial and facial dysmorphia, short thorax, tachycardia, heart murmur, abdominal distention, hepatomegaly, short extremities, widespread petechias, diminished muscular tone, ungueal hypoplasia in toes, bilateral cryptorchidia, and generalized redundant skin. In the evolution he presented several sepsis episodes, difficulty for feeding, supraventricular arrhythmia, two heart arrests, and opisthotonos, and died at 65 days of life due to heart arrhythmia. The autopsy revealed hydrocephaly, a neuroblastoma, and a heart without anatomic alterations. Costello syndrome was diagnosed. Costello syndrome is not frequent; in this patient, the diagnosis was suspected in life and was confirmed postmortem, the topic is reviewed, the important aspect in this case is the association with a neuroblastoma.

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