Costello Syndrome Research Articles

Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes.

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.

Malignancy in Noonan syndrome and related disorders.

Noonan syndrome (NS) and related disorders, such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, and Costello syndrome, constitute an important group of developmental malformation syndromes with variable clinical and molecular features. Their underlying pathophysiologic mechanism involves dysregulation of the Ras/mitogen-activated protein kinase signaling pathway, an essential mediator of developmental and growth processes in the prenatal and postnatal setting. Malignant tumor development is an important complication encountered in other RASopathies, such as neurofibromatosis type 1, but the neoplastic risks and incidence of malignant tumors are less clearly defined in NS and related disorders of the Noonan spectrum. Malignant tumor development remains an important complication variably seen in the RASopathies and, thus, a clear understanding of the underlying risks is essential for appropriate clinical care in this patient population. This review discusses previously published reports of malignancies in individuals with RASopathies of the Noonan spectrum.

Costello syndrome with severe nodulocystic acne: unexpected significant improvement of acanthosis nigricans after oral isotretinoin treatment.

We report the case of 17-year-old female diagnosed with Costello syndrome. Genetic testing provided a proof with G12S mutation in the HRAS gene since 3 years of age with a presentation of severe nodulocystic acne on her face. After 2 months of oral isotretinoin treatment, improvement in her acne was observed. Interestingly, an unexpected significant improvement of acanthosis nigricans on her neck and dorsum of her hands was found as well. We present this case as a successful treatment option by using oral isotretinoin for the treatment of acanthosis nigricans in Costello syndrome patients.

0458: Outcomes of pediatric hypertrophic cardiomyopathy associated with Rasopathy

The outcomes of pediatric hypertrophic cardiomyopathy (HCM) associated to RASopathies are scarcely known. To describe outcomes of pediatric HCM associated with RASopathy. 80 cases of children with a clinical phenotype of RASopathy and HCM were included. Age at diagnosis of HCM was 11.7 months (range 0 to 168). The HCM was diagnosed prenatally in 9 cases, and before one year of age in 58 cases. 67 had Noonan syndrome, 9 had Cardiofacio-cutaneous syndrome, 3 had Costello syndrome, and 1 had Noonan syndrome with multiples lentigines. The HCM was obstructive in 37 cases. Associated cardiac defects were right ventricular outflow tract obstruction in 40 children, polyvalvular dysplasia in 18, atrial septal defect (ASD) in 13, ventricular septal defect in 3, congenital mitral regurgitation in 2, persistent arterial duct in 2, left superior caval vein in 2, aortic arch anomaly in 2, coronary anomaly in 1, and systemic arteriovenous fistula in 1. Nineteen children underwent a Konno operation for obstructive HCM. Additional surgical procedures were 9 right ventricular outflow tract surgical reliefs, 9 percutaneous dilatations of pulmonary valve stenosis, 4 percutaneous closures of ASD, 1 tricuspid valve repair, 1 Brom procedure with aortic valve repair, 1 aortic valve replacement, and 1 coronary artery bypass. Overall mortality was 21%. Fourteen (82%) deaths occurred before 1 year of life. Causes of death were cardiac in 10 cases including two sudden deaths, related to respiratory diseases causes in 5, and in utero fœtal death in 1. Factors predicting mortality were diagnosis before 2 months of life (HR=4,33, p<0,001), fœtal diagnosis of HCM (HR=3,64, p<0,001), and surgery before one year of life (HR=3,43, p=0,001). Mortality of children with HCM due to RASopathy is high and occurs early in life. Main risk factors are early diagnosis of HCM including prenatal diagnosis, and need for surgery before one year of life.

RAS-pathies: Noonan syndrome and other related diseases. The literature review

The present review considers a group of diseases, known as Ras-pathies, formed in 2010. One of its representatives is Noonan syndrome is encountered in the pediatric practice in the first place as a syndrome accompanied by right-hand side cardiological disorders and short stature. The multiple molecular-genetic mechanisms underlying Noonan syndrome are associated with the activity of PTPN11, SOS1, and other genes. The group of RAS-pathies includes, besides Noonan syndrome, type 1 neurofibromatosis, Noonan syndrome with multiple lentigo (LEOPARD), craniofaciocutaneous syndrome, capillary and arteriovenous malformation syndrome, Costello syndrome, and Legius syndrome. All these conditions are associated with the molecular disturbances in the Ras/MAPK cascade that produce the characteristic clinical picture apparent as multiple dysembryogenic stigmata, short stature, cardiac disorders, and predisposition to the neoplastic growth.

Educational Implications of Costello Syndrome: The Team Approach

Since the 1990s the number of children with disabilities placed within the general education classroom has steadily increased. Many of these children are provided special education services under the generic disability title “intellectual disability.” Over the past decade, there has been a significant amount of research concerning rare genetic syndromes that result in separating developmental disabilities into categories using similar origins and characteristics. Costello syndrome is one of these rare syndromes. Although information is available to medical practitioners, it has seldom been communicated to educators. The authors have taken the available data and, using a team approach, made recommendations for involving medical and health professionals in educating students with Costello syndrome.

Behavioral phenotype in Costello syndrome with atypical mutation: A case report

Costello syndrome (CS) is a rare genetic disorder caused, in the majority of cases, by germline missense HRAS mutations affecting Gly(12) promoting enhanced signaling through the MAPK and PI3K-AKT signaling cascades. In general, the cognitive profile in CS is characterized by intellectual disability ranging from mild to severe impairment. The first published descriptions of behavior in CS children underlined the presence of irritability and shyness at younger ages with sociable personality and good empathic skills after 4-5 years of age, however some recent studies have reported autistic traits. We report on a 7-year-old boy heterozygous for a rare duplication of codon 37 (p.E37dup) in HRAS, manifesting impaired social interaction and non-verbal communication and with circumscribed interests. These additional features improve phenotype delineation in individuals with rare HRAS mutations, facilitating the development of specific behavioral treatments which could lead to improvement in cases of autism spectrum disorder.

RAS diseases in children.

RAS genes encode a family of 21 kDa proteins that are an essential hub for a number of survival, proliferation, differentiation and senescence pathways. Signaling of the RAS-GTPases through the RAF-MEK-ERK pathway, the first identified mitogen-associated protein kinase (MAPK) cascade is essential in development. A group of genetic syndromes, named "RASopathies", had been identified which are caused by heterozygosity for germline mutations in genes that encode protein components of the RAS/MAPK pathway. Several of these clinically overlapping disorders, including Noonan syndrome, Noonan-like CBL syndrome, Costello syndrome, cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type I, and Legius syndrome, predispose to cancer and abnormal myelopoiesis in infancy. This review focuses on juvenile myelomonocytic leukemia (JMML), a malignancy of early childhood characterized by initiating germline and/or somatic mutations in five genes of the RAS/MAPK pathway: PTPN11, CBL, NF-1, KRAS and NRAS. Natural courses of these five subtypes differ, although hematopoietic stem cell transplantation remains the only curative therapy option for most children with JMML. With whole-exome sequencing studies revealing few secondary lesions it will be crucial to better understand the RAS/MAPK signaling network with its crosstalks and feed-back loops to carefully design early clinical trials with novel pharmacological agents in this still puzzling leukemia.

Growth hormone replacement therapy in Costello syndrome

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 and we evaluate the long-term safety and efficacy of growth hormone replacement therapy. The index patient is a paradigm of successful and safe treatment with growth hormone for almost 7years. Since patients with CS are at increased risk for cardiac myopathy and tumor development they deserve close monitoring during treatment.

Function and disability in children with Costello syndrome and Cardiofaciocutaneous syndrome.

There is limited research on function in individuals with RASopathies. Our hypothesis was that there was function and disability differences between Costello syndrome (CS) and Cardiofaciocutaneous syndrome (CFCS). The purpose of this study was to describe and compare the functional performance and level of disability of children with CS and CFCS using the Pediatric Outcomes Data Collection Instrument (PODCI) and Pediatric Evaluation of Disability Index (PEDI). Parents of individuals with a medical diagnosis of CS and CFCS completed the computer or paper version of the questionnaires. Comparisons of response data were made between the two syndromes and published normative data. Fifty-two parents participated in the study, 38 in the CS group and 14 in the CFCS group. There were no significant differences in PODCI or PEDI scores between the CS and CFCS groups. There were statistically significant differences from normative values for all PODCI domains (P ≤ 0.012). The PEDI T-scores of both groups were greater than two standard deviations below normative scores in mobility (CS = 12.37, CFCS = 2.37), social (CS = 24.01, CFCS = 20.08), and activity (CS = 15.88, CFCS = 14.32). Responsibility T scores were in the normal range (30-70) for the CS group (31.38), but not for the CFCS group (28.40). The CS and CFCS groups had activity limitations in the PODCI domains of upper extremity function, transfers, and mobility, sport and physical function. These functional limitations cause significant disability in the PEDI domains of daily activity, mobility, and socialization and cognition. CS and CFCS are similar conditions in respect to functional limitations and severity of disability.

Abstract PR01: H-RasG12V overexpression in the central nervous system leads to expansion of oligodendrocyte precursor cells and neural crest cells

Abstract Somatic mutations in Ras proto-oncogenes have been found in a large number of different cancers. In addition, germline mutations in the H-Ras gene have been shown to be the causative genetic alteration underlying Costello Syndrome (CS). Costello Syndrome belongs to the large group of Ras/MAPK pathway diseases commonly termed Rasopathies. CS patients exhibit craniofacial and cardiac abnormalities, mental retardation and are prone to develop cancers including neural crest derived neoplasias. Since Costello Syndrome is a rare disease, the effects of H-RasG12V expression on the development of the central nervous system remain largely uncharacterized. Towards this goal, we have established a zebrafish model suitable for live imaging and cost-effective drug screening. Using the Gal4/UAS system we have enforced expression of H-RasG12V in the central nervous system starting at early neurulation stages. H-RasG12V expressing embryos develop hyperplasia of the forebrain and the spinal cord and show an outgrowth in the dorsal tail region around 3 days post fertilization (dpf). In situ hybridisation revealed an increase in oligodendrocyte precursor cells, similar to what has been reported for zebrafish neurofibromin 1 mutants. In addition, cells expressing the neural crest markers Sox10 and FoxD3 accumulate lateral to the neural tube and notochord. Time-lapse imaging revealed that H-RasG12V expressing cells indeed migrate out of the spinal cord. This migration was ectopic, occuring several hours after normal neural crest migration. Furthermore, coinciding with the accumulation of neural crest like cells around the neural tube, the intersomitic vasculature hyperbranches to form new blood vessels towards domains of H-RasG12V expressing cells. Taking advantage of the early onset and obvious phenotypes in our H-RasG12V overexpression model we performed a pilot drug screen to identify potential therapeutic compounds for Costello Syndrome. We found the Mek1/Mek2 inhibitor PD98059 successfully inhibited hyperplasia of the forebrain and the spinal cord, with normal numbers of oligodendrocyte precursor cells and neural crest cells. Thus, this zebrafish model will be a valuable tool to further investigate the mechanisms underlying CNS- abnormalities of Costello Syndrome patients, including the formation of neural crest derived neoplasias and will be useful to identify therapies against this disease. This abstract is also presented as Poster A3. Citation Format: Martin Distel, David Traver. H-RasG12V overexpression in the central nervous system leads to expansion of oligodendrocyte precursor cells and neural crest cells. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr PR01.

Cardio-facio-cutaneous syndrome: clinical features, diagnosis, and management guidelines.

Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies that bears many clinical features in common with the other syndromes in this group, most notably Noonan syndrome and Costello syndrome. CFC is genetically heterogeneous and caused by gene mutations in the Ras/mitogen-activated protein kinase pathway. The major features of CFC include characteristic craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. It is essential that this condition be differentiated from other RASopathies, as a correct diagnosis is important for appropriate medical management and determining recurrence risk. Children and adults with CFC require multidisciplinary care from specialists, and the need for comprehensive management has been apparent to families and health care professionals caring for affected individuals. To address this need, CFC International, a nonprofit family support organization that provides a forum for information, support, and facilitation of research in basic medical and social issues affecting individuals with CFC, organized a consensus conference. Experts in multiple medical specialties provided clinical management guidelines for pediatricians and other care providers. These guidelines will assist in an accurate diagnosis of individuals with CFC, provide best practice recommendations, and facilitate long-term medical care.

Early postnatal diagnosis of Costello syndrome.

Costello syndrome is a rare congenital disease with typical craniofacial and musculoskeletal features, cutaneous lesions, cardiac defects and cancer susceptibility. Affected patients show severe feeding difficulties for the first years of life and developmental delay. We present the case of a patient, in whom fetal tachycardia, polyhdramnios and physical characteristics led to an early diagnosis of Costello syndrome. Based on this patient we describe challenges and problems of therapeutic management of infants with Costello syndrome.

Cardiac Imaging in RASopathies/Mitogen Activated Protein Kinase Syndromes

RASopathies include a spectrum of disorders due to dysregulation of RAS/mitogen activated protein kinase pathway that plays an essential role in the control of the cell cycle and differentiation. As a consequence, its dysregulation has profound developmental consequences, in particular cardiac malformations. RASopathies with cardiac features are: Noonan syndrome, multiple lentigines syndrome, cardio-faciocutaneous syndrome, Costello syndrome, neurofibromatosis- 1, Legius syndrome, neurofibromatosis- Noonan syndrome. The former syndromes are associated with a high rate of cardiac involvement (60-85%) and 12 genes: PTPN11, SOS1, RAF1, KRAS, HRAS, BRAF, MEK1/MAP2K1, MEK2/MAP2K2, NRAS, SHOC2, CBL and SPRED1. Although the majority of these diseases are readily distinguishable in clinical terms, an integrated imaging study of the cardiac condition associated to RASopathies helps to better define risk assessment, surveillance, and management of these patients.

The perinatal presentation of cardiofaciocutaneous syndrome

There is limited information available related to the perinatal course of cardiofaciocutaneous syndrome (CFC) compared to other syndromes within the Ras-MAP kinase pathway (rasopathies) such as Noonan and Costello syndrome. Retrospective chart review revealed four cases of CFC with molecular confirmation between 2005 and 2012 at Hawaii's largest obstetric and pediatric referral center. We report on details of the prenatal, neonatal, and infancy course and long-term follow-up beyond infancy in two patients. This report includes novel features including systemic hypertension, hyponatremia, and chronic respiratory insufficiency, not previously reported in CFC. We provide pathologic diagnosis of loose anagen hair in one patient. Some of these findings have been reported in the other rasopathies, documenting further clinical overlap among these conditions. Molecular testing can be useful to differentiate CFC from other rasopathies and in counseling families about potential complications and prognosis. We recommend a full phenotypic evaluation including echocardiogram, renal ultrasound, brain imaging, and ophthalmology examination. We additionally recommend close follow-up of blood pressure, pulmonary function, and monitoring for electrolyte disturbance and extra-vascular fluid shifts.

Craniofacial and dental development in Costello syndrome

Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen-activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n = 41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo-mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio-facio-cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development.

Uniparental Trisomy of a Mutated HRAS Proto-Oncogene in Embryonal Rhabdomyosarcoma of a Patient With Costello Syndrome

Uniparental Trisomy of a Mutated <i>HRAS</i> Proto-Oncogene in Embryonal Rhabdomyosarcoma of a Patient With Costello Syndrome

Behavioral Profile in RASopathies

Here, we describe neurobehavioral features in patients with RASopathies (i.e., Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome), developmental disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. Parents of 70 individuals with a RASopathy were asked to fill out the following questionnaires: Child Behavior Checklist (CBCL), Social Communication Questionnaire version lifetime (SCQ-L), and Modified Checklist for Autism in toddlers (M-CHAT). Data analysis indicated high rates of internalizing (37%) and externalizing problems (31%) on CBCL. Scores over the cut-off were documented in 64% of patients with cardiofaciocutaneous syndrome, 44% with Costello syndrome, and 12% with Noonan syndrome on SCQ-L/M-CHAT. Our findings indicate that mutations promoting dysregulation of the RAS-MAPK cascade mark an increased psychopathological risk and highlight that autistic-like behavior could be underdiagnosed in patients with RASopathies.

Diagnosis of Noonan syndrome and related disorders using target next generation sequencing

BackgroundNoonan syndrome is an autosomal dominant developmental disorder with a high phenotypic variability, which shares clinical features with other rare conditions, including LEOPARD syndrome, cardiofaciocutaneous syndrome, Noonan-like syndrome with loose anagen hair, and Costello syndrome. This group of related disorders, so-called RASopathies, is caused by germline mutations in distinct genes encoding for components of the RAS-MAPK signalling pathway. Due to high number of genes associated with these disorders, standard diagnostic testing requires expensive and time consuming approaches using Sanger sequencing. In this study we show how targeted Next Generation Sequencing (NGS) technique can enable accurate, faster and cost-effective diagnosis of RASopathies.MethodsIn this study we used a validation set of 10 patients (6 positive controls previously characterized by Sanger-sequencing and 4 negative controls) to assess the analytical sensitivity and specificity of the targeted NGS. As second step, a training set of 80 enrolled patients with a clinical suspect of RASopathies has been tested. Targeted NGS has been successfully applied over 92% of the regions of interest, including exons for the following genes: PTPN11, SOS1, RAF1, BRAF, HRAS, KRAS, NRAS, SHOC, MAP2K1, MAP2K2, CBL.ResultsAll expected variants in patients belonging to the validation set have been identified by targeted NGS providing a detection rate of 100%. Furthermore, all the newly detected mutations in patients from the training set have been confirmed by Sanger sequencing. Absence of any false negative event has been excluded by testing some of the negative patients, randomly selected, with Sanger sequencing.ConclusionHere we show how molecular testing of RASopathies by targeted NGS could allow an early and accurate diagnosis for all enrolled patients, enabling a prompt diagnosis especially for those patients with mild, non-specific or atypical features, in whom the detection of the causative mutation usually requires prolonged diagnostic timings when using standard routine. This approach strongly improved genetic counselling and clinical management.

Bilateral branch pulmonary artery stenosis and Mitral valve prolapse in a patient with Noonan syndrome: A case report

Rasopathy syndromes are a class of phenotypically similar, but genetically distinct multiple anomaly syndromes caused by germ line mutations in genes that encode protein components of the Ras/mitogen activated protein kinase (MAPK) pathway. Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome are part of this group of developmental syndromes and have similar cardiac abnormalities. A 19-year-old male presented with complaints of exertional breathlessness class I for 6 months. Clinical examination revealed characteristic facial features, skeletal abnormalities, growth and neurocognitive problems reported in patients with Noonan syndrome. There was evidence of severe pulmonary hypertension. Trans-thoracic echocardiography revealed right atrial and right ventricular enlargement, severe pulmonary hypertension, no intra cardiac shunt, prolapse of anterior mitral leaflet with mild mitral regurgitation. CT pulmonary angiogram revealed bilateral branch pulmonary artery stenosis. A final diagnosis of Noonan syndrome was made.