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Karen W. Gripp - One of the best experts on this subject based on the ideXlab platform.
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Phenotypic spectrum of Costello Syndrome individuals harboring the rare HRAS mutation p.Gly13Asp.
American journal of medical genetics. Part A, 2017Co-Authors: Débora Romeo Bertola, Michelle Buscarilli, Deborah L. Stabley, Laura D. Baker, Daniel Doyle, Dennis Bartholomew, Katia Sol-church, Karen W. GrippAbstract:Costello Syndrome is part of the RASopathies, a group of neurocardiofaciocutaneous Syndromes caused by deregulation of the RAS mitogen-activated protein kinase pathway. Heterozygous mutations in HRAS are responsible for Costello Syndrome, with more than 80% of the patients harboring the specific p.Gly12Ser variant. These individuals show a homogeneous phenotype. The clinical characteristics of the Costello Syndrome individuals harboring rarer HRAS mutations are less understood, due to the small number of reported cases. Here, we describe the phenotypic spectrum of five additional individuals with HRAS c.38G>A; p.Gly13Asp, including one with somatic mosaicism, and review five previously described cases. The facial and hair abnormalities of the HRAS p.Gly13Asp individuals differ from the typical pattern observed in those showing the common HRAS (p.Gly12Ser) mutation, with less coarse facial features and slow growing, sparse hair with abnormal texture, the latter resembling the pattern observed in Noonan Syndrome-like disorder with loose anagen hair and individuals harboring another amino acid substitution in HRAS (p.Gly13Cys). Although some individuals with HRAS p.Gly13Asp developed papillomata and vascular proliferation lesions, no malignant tumors occurred, similar to what was reported for individuals harboring the HRAS p.Gly13Cys. The fact that no malignant tumors were described in these individuals does not allow definitive conclusions about the risk for cancer development. It remains to be determined if substitutions of amino acid 13 in HRAS (p.Gly13Asp and p.Gly13Cys) increase the risk of tumor development.
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a novel patient with an attenuated Costello Syndrome phenotype due to an hras mutation affecting codon 146 literature review and update
American Journal of Medical Genetics Part A, 2017Co-Authors: Annie Ting Gee Chiu, Karen W. Gripp, Gordon K.c. Leung, Yoyo W Y Chu, Brian H.y. ChungAbstract:De novo germline mutations in HRAS cause Costello Syndrome, with >95% of the mutations causing Costello Syndrome affecting amino acid position 12 (p.Gly12) or 13 (p.Gly13). We report on a patient with de novo missense mutation causing an amino acid change at codon 146 of HRAS, c.436G > C:p.Ala146Pro, who presented with subtle dysmorphic features, failure to thrive, global developmental delay, and hypertrophic obstructive cardiomyopathy. Mutations affecting codon 146 are observed in <1% of patients with Costello Syndrome. From literature search, there were only two other patients reported with mutations involving the same location. We summarized and updated their findings, and discussed evidence to show that these patients with less obvious signs of Costello Syndrome may not necessarily run a more benign clinical course.
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Assessing genotype–phenotype correlation in Costello Syndrome using a severity score
Genetics in Medicine, 2013Co-Authors: Elizabeth M. Mccormick, Deborah L. Stabley, Katia Sol-church, Sarah Catalano, Elizabeth Hopkins, Jobayer Hossain, Laura Conway, Karen W. GrippAbstract:Genet Med 2013:15(7):554–557 Purpose: Costello Syndrome, a rare genetic disorder with multisystemic involvement, is caused by germline HRAS mutations. Because several different missense mutations have been reported, a severity scoring system was developed to assess a possible genotype–phenotype correlation. Methods: Records of 78 individuals with Costello Syndrome were scored in early childhood, childhood, and young adulthood by a reviewer blinded to the individuals’ specific mutations. These scores were based on certain medically relevant feeding, neurologic, orthopedic, endocrine, cardiac, malignancy, and mortality manifestations. Individuals’ severity scores were then grouped by the particular HRAS mutation. The mixed-model approach for repeated-measures analysis of variance with unstructured within-subject correlation, pairwise comparisons, and contrast were used to determine whether the severity scores differed by mutation. Results: Although the sample size was small, individuals with the p.G12A or p.G12C HRAS change were more severely affected than those with other HRAS mutations. Regardless of the mutation, severity did not increase significantly over time. Conclusion: Despite its limitations, including the small number of individuals with rare mutations and possibly incomplete medical records, this work providing the first quantitative assessment of phenotypic severity in a Costello Syndrome cohort supports a medically relevant genotype–phenotype correlation.
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Orthopedic manifestations and implications for individuals with Costello Syndrome.
American journal of medical genetics. Part A, 2013Co-Authors: Stacey Detweiler, Elizabeth Hopkins, Mihir M Thacker, Laura Conway, Karen W. GrippAbstract:Costello Syndrome is a rare genetic condition caused by heterozygous alterations in HRAS and characterized by multi-system abnormalities. Individuals with Costello Syndrome usually present with severe feeding difficulties in infancy, short stature, coarse facial features, increased tumor risks, cardiac and neurological complications, intellectual disability and orthopedic complications. This study further defines the orthopedic manifestations affecting individuals with Costello Syndrome. We studied 43 participants and performed medical records review, clinical examinations and orthopedic inquiry forms. In 23 participants, hip and or spinal imaging assessments were completed. Serial radiographs were analyzed when available. A total of 25 orthopedic manifestations were identified. Ten manifestations were seen in the majority of the participants: hypotonia (87%), ligamentous laxity (85%), scoliosis (63%), kyphosis (58%), characteristic hand deformities (85%), ulnar deviation of the wrist (63%), elbow (55%) and shoulder contractures (65%), tight Achilles tendon (73%), and pes planus (53%). Other characteristics of special note were hip dysplasia (45%), foot deformities requiring surgical intervention (38%) and osteopenia/osteoporosis (47%). We also studied the development of the hips and spine. Uni- or bilateral hip dysplasia was congenital in some, while it developed throughout childhood in others. Spinal involvement included scoliosis, kyphosis, lordosis, and curvature reversal (thoracic lordosis and lumbar kyphosis). Based on these findings, we recommend routine referral to an orthopedic surgeon as well as instituting screening protocols for hips and spine for individuals with Costello Syndrome.
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Orthopedic manifestations and implications for individuals with Costello Syndrome.
American Journal of Medical Genetics Part A, 2013Co-Authors: Stacey Detweiler, Elizabeth Hopkins, Mihir M Thacker, Laura Conway, Karen W. GrippAbstract:Costello Syndrome is a rare genetic condition caused by heterozygous alterations in HRAS and characterized by multi-system abnormalities. Individuals with Costello Syndrome usually present with severe feeding difficulties in infancy, short stature, coarse facial features, increased tumor risks, cardiac and neurological complications, intellectual disability and orthopedic complications. This study further defines the orthopedic manifestations affecting individuals with Costello Syndrome. We studied 43 participants and performed medical records review, clinical examinations and orthopedic inquiry forms. In 23 participants, hip and or spinal imaging assessments were completed. Serial radiographs were analyzed when available. A total of 25 orthopedic manifestations were identified. Ten manifestations were seen in the majority of the participants: hypotonia (87%), ligamentous laxity (85%), scoliosis (63%), kyphosis (58%), characteristic hand deformities (85%), ulnar deviation of the wrist (63%), elbow (55%) and shoulder contractures (65%), tight Achilles tendon (73%), and pes planus (53%). Other characteristics of special note were hip dysplasia (45%), foot deformities requiring surgical intervention (38%) and osteopenia/osteoporosis (47%). We also studied the development of the hips and spine. Uni- or bilateral hip dysplasia was congenital in some, while it developed throughout childhood in others. Spinal involvement included scoliosis, kyphosis, lordosis, and curvature reversal (thoracic lordosis and lumbar kyphosis). Based on these findings, we recommend routine referral to an orthopedic surgeon as well as instituting screening protocols for hips and spine for individuals with Costello Syndrome. © 2013 Wiley Periodicals, Inc.
Deborah L. Stabley - One of the best experts on this subject based on the ideXlab platform.
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Phenotypic spectrum of Costello Syndrome individuals harboring the rare HRAS mutation p.Gly13Asp.
American journal of medical genetics. Part A, 2017Co-Authors: Débora Romeo Bertola, Michelle Buscarilli, Deborah L. Stabley, Laura D. Baker, Daniel Doyle, Dennis Bartholomew, Katia Sol-church, Karen W. GrippAbstract:Costello Syndrome is part of the RASopathies, a group of neurocardiofaciocutaneous Syndromes caused by deregulation of the RAS mitogen-activated protein kinase pathway. Heterozygous mutations in HRAS are responsible for Costello Syndrome, with more than 80% of the patients harboring the specific p.Gly12Ser variant. These individuals show a homogeneous phenotype. The clinical characteristics of the Costello Syndrome individuals harboring rarer HRAS mutations are less understood, due to the small number of reported cases. Here, we describe the phenotypic spectrum of five additional individuals with HRAS c.38G>A; p.Gly13Asp, including one with somatic mosaicism, and review five previously described cases. The facial and hair abnormalities of the HRAS p.Gly13Asp individuals differ from the typical pattern observed in those showing the common HRAS (p.Gly12Ser) mutation, with less coarse facial features and slow growing, sparse hair with abnormal texture, the latter resembling the pattern observed in Noonan Syndrome-like disorder with loose anagen hair and individuals harboring another amino acid substitution in HRAS (p.Gly13Cys). Although some individuals with HRAS p.Gly13Asp developed papillomata and vascular proliferation lesions, no malignant tumors occurred, similar to what was reported for individuals harboring the HRAS p.Gly13Cys. The fact that no malignant tumors were described in these individuals does not allow definitive conclusions about the risk for cancer development. It remains to be determined if substitutions of amino acid 13 in HRAS (p.Gly13Asp and p.Gly13Cys) increase the risk of tumor development.
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Assessing genotype–phenotype correlation in Costello Syndrome using a severity score
Genetics in Medicine, 2013Co-Authors: Elizabeth M. Mccormick, Deborah L. Stabley, Katia Sol-church, Sarah Catalano, Elizabeth Hopkins, Jobayer Hossain, Laura Conway, Karen W. GrippAbstract:Genet Med 2013:15(7):554–557 Purpose: Costello Syndrome, a rare genetic disorder with multisystemic involvement, is caused by germline HRAS mutations. Because several different missense mutations have been reported, a severity scoring system was developed to assess a possible genotype–phenotype correlation. Methods: Records of 78 individuals with Costello Syndrome were scored in early childhood, childhood, and young adulthood by a reviewer blinded to the individuals’ specific mutations. These scores were based on certain medically relevant feeding, neurologic, orthopedic, endocrine, cardiac, malignancy, and mortality manifestations. Individuals’ severity scores were then grouped by the particular HRAS mutation. The mixed-model approach for repeated-measures analysis of variance with unstructured within-subject correlation, pairwise comparisons, and contrast were used to determine whether the severity scores differed by mutation. Results: Although the sample size was small, individuals with the p.G12A or p.G12C HRAS change were more severely affected than those with other HRAS mutations. Regardless of the mutation, severity did not increase significantly over time. Conclusion: Despite its limitations, including the small number of individuals with rare mutations and possibly incomplete medical records, this work providing the first quantitative assessment of phenotypic severity in a Costello Syndrome cohort supports a medically relevant genotype–phenotype correlation.
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Assessing genotype-phenotype correlation in Costello Syndrome using a severity score
Genetics in medicine : official journal of the American College of Medical Genetics, 2013Co-Authors: Elizabeth M. Mccormick, Deborah L. Stabley, Katia Sol-church, Sarah Catalano, Elizabeth Hopkins, Jobayer Hossain, Laura Conway, Karen W. GrippAbstract:Costello Syndrome, a rare genetic disorder with multisystemic involvement, is caused by germline HRAS mutations. Because several different missense mutations have been reported, a severity scoring system was developed to assess a possible genotype–phenotype correlation. Records of 78 individuals with Costello Syndrome were scored in early childhood, childhood, and young adulthood by a reviewer blinded to the individuals’ specific mutations. These scores were based on certain medically relevant feeding, neurologic, orthopedic, endocrine, cardiac, malignancy, and mortality manifestations. Individuals’ severity scores were then grouped by the particular HRAS mutation. The mixed-model approach for repeated-measures analysis of variance with unstructured within-subject correlation, pairwise comparisons, and contrast were used to determine whether the severity scores differed by mutation. Although the sample size was small, individuals with the p.G12A or p.G12C HRAS change were more severely affected than those with other HRAS mutations. Regardless of the mutation, severity did not increase significantly over time. Despite its limitations, including the small number of individuals with rare mutations and possibly incomplete medical records, this work providing the first quantitative assessment of phenotypic severity in a Costello Syndrome cohort supports a medically relevant genotype–phenotype correlation. Genet Med 2013:15(7):554–557
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Molecular confirmation of HRAS p.G12S in siblings with Costello Syndrome.
American journal of medical genetics. Part A, 2011Co-Authors: Karen W. Gripp, Deborah L. Stabley, Elizabeth Hopkins, Peter L Geller, David A Stevenson, John C Carey, Katia Sol-churchAbstract:Costello Syndrome was first reported based on its characteristic phenotype. Its presentation affects multiple organ systems, including severe failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto-oncogene HRAS have been recognized to cause Costello Syndrome, and its inheritance pattern would thus be autosomal dominant. Here, we report on the identification of an HRAS mutation c.34G>A, predicting a p.G12S amino acid substitution, in the surviving brother of a previously reported sibling pair, and documentation of the same change in autopsy material from his deceased sister. This represents, to our knowledge, the first molecularly confirmed Costello Syndrome in siblings. We did not detect the mutation in a heterozygous state or mosaicism in peripheral white blood cell or cheek swab-derived DNA samples from either parent. Using single nucleotide polymorphic markers and allele-specific amplification, we clearly identified the mutation in the surviving sibling to be of maternal origin. While we cannot exclude two independently occurring de novo mutations, the complete sharing of polymorphic markers around the mutation site in both siblings supports maternal germ cell mosaicism. Recurrence risk counseling for families with apparently de novo occurring autosomal dominant conditions includes discussion of germ cell mosaicism, and this report underscores the applicability of this concern to Costello Syndrome.
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phenotypic analysis of individuals with Costello Syndrome due to hras p g13c
American Journal of Medical Genetics Part A, 2011Co-Authors: Karen W. Gripp, Deborah L. Stabley, Daniel Doyle, Katia Solchurch, Marni E Axelrad, Elizabeth Hopkins, John P. Johnson, William B. Dobyns, Cindy Hudson, Romano TenconiAbstract: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. © 2011 Wiley-Liss, Inc.
Katia Sol-church - One of the best experts on this subject based on the ideXlab platform.
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Phenotypic spectrum of Costello Syndrome individuals harboring the rare HRAS mutation p.Gly13Asp.
American journal of medical genetics. Part A, 2017Co-Authors: Débora Romeo Bertola, Michelle Buscarilli, Deborah L. Stabley, Laura D. Baker, Daniel Doyle, Dennis Bartholomew, Katia Sol-church, Karen W. GrippAbstract:Costello Syndrome is part of the RASopathies, a group of neurocardiofaciocutaneous Syndromes caused by deregulation of the RAS mitogen-activated protein kinase pathway. Heterozygous mutations in HRAS are responsible for Costello Syndrome, with more than 80% of the patients harboring the specific p.Gly12Ser variant. These individuals show a homogeneous phenotype. The clinical characteristics of the Costello Syndrome individuals harboring rarer HRAS mutations are less understood, due to the small number of reported cases. Here, we describe the phenotypic spectrum of five additional individuals with HRAS c.38G>A; p.Gly13Asp, including one with somatic mosaicism, and review five previously described cases. The facial and hair abnormalities of the HRAS p.Gly13Asp individuals differ from the typical pattern observed in those showing the common HRAS (p.Gly12Ser) mutation, with less coarse facial features and slow growing, sparse hair with abnormal texture, the latter resembling the pattern observed in Noonan Syndrome-like disorder with loose anagen hair and individuals harboring another amino acid substitution in HRAS (p.Gly13Cys). Although some individuals with HRAS p.Gly13Asp developed papillomata and vascular proliferation lesions, no malignant tumors occurred, similar to what was reported for individuals harboring the HRAS p.Gly13Cys. The fact that no malignant tumors were described in these individuals does not allow definitive conclusions about the risk for cancer development. It remains to be determined if substitutions of amino acid 13 in HRAS (p.Gly13Asp and p.Gly13Cys) increase the risk of tumor development.
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Assessing genotype–phenotype correlation in Costello Syndrome using a severity score
Genetics in Medicine, 2013Co-Authors: Elizabeth M. Mccormick, Deborah L. Stabley, Katia Sol-church, Sarah Catalano, Elizabeth Hopkins, Jobayer Hossain, Laura Conway, Karen W. GrippAbstract:Genet Med 2013:15(7):554–557 Purpose: Costello Syndrome, a rare genetic disorder with multisystemic involvement, is caused by germline HRAS mutations. Because several different missense mutations have been reported, a severity scoring system was developed to assess a possible genotype–phenotype correlation. Methods: Records of 78 individuals with Costello Syndrome were scored in early childhood, childhood, and young adulthood by a reviewer blinded to the individuals’ specific mutations. These scores were based on certain medically relevant feeding, neurologic, orthopedic, endocrine, cardiac, malignancy, and mortality manifestations. Individuals’ severity scores were then grouped by the particular HRAS mutation. The mixed-model approach for repeated-measures analysis of variance with unstructured within-subject correlation, pairwise comparisons, and contrast were used to determine whether the severity scores differed by mutation. Results: Although the sample size was small, individuals with the p.G12A or p.G12C HRAS change were more severely affected than those with other HRAS mutations. Regardless of the mutation, severity did not increase significantly over time. Conclusion: Despite its limitations, including the small number of individuals with rare mutations and possibly incomplete medical records, this work providing the first quantitative assessment of phenotypic severity in a Costello Syndrome cohort supports a medically relevant genotype–phenotype correlation.
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Assessing genotype-phenotype correlation in Costello Syndrome using a severity score
Genetics in medicine : official journal of the American College of Medical Genetics, 2013Co-Authors: Elizabeth M. Mccormick, Deborah L. Stabley, Katia Sol-church, Sarah Catalano, Elizabeth Hopkins, Jobayer Hossain, Laura Conway, Karen W. GrippAbstract:Costello Syndrome, a rare genetic disorder with multisystemic involvement, is caused by germline HRAS mutations. Because several different missense mutations have been reported, a severity scoring system was developed to assess a possible genotype–phenotype correlation. Records of 78 individuals with Costello Syndrome were scored in early childhood, childhood, and young adulthood by a reviewer blinded to the individuals’ specific mutations. These scores were based on certain medically relevant feeding, neurologic, orthopedic, endocrine, cardiac, malignancy, and mortality manifestations. Individuals’ severity scores were then grouped by the particular HRAS mutation. The mixed-model approach for repeated-measures analysis of variance with unstructured within-subject correlation, pairwise comparisons, and contrast were used to determine whether the severity scores differed by mutation. Although the sample size was small, individuals with the p.G12A or p.G12C HRAS change were more severely affected than those with other HRAS mutations. Regardless of the mutation, severity did not increase significantly over time. Despite its limitations, including the small number of individuals with rare mutations and possibly incomplete medical records, this work providing the first quantitative assessment of phenotypic severity in a Costello Syndrome cohort supports a medically relevant genotype–phenotype correlation. Genet Med 2013:15(7):554–557
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Molecular confirmation of HRAS p.G12S in siblings with Costello Syndrome.
American journal of medical genetics. Part A, 2011Co-Authors: Karen W. Gripp, Deborah L. Stabley, Elizabeth Hopkins, Peter L Geller, David A Stevenson, John C Carey, Katia Sol-churchAbstract:Costello Syndrome was first reported based on its characteristic phenotype. Its presentation affects multiple organ systems, including severe failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto-oncogene HRAS have been recognized to cause Costello Syndrome, and its inheritance pattern would thus be autosomal dominant. Here, we report on the identification of an HRAS mutation c.34G>A, predicting a p.G12S amino acid substitution, in the surviving brother of a previously reported sibling pair, and documentation of the same change in autopsy material from his deceased sister. This represents, to our knowledge, the first molecularly confirmed Costello Syndrome in siblings. We did not detect the mutation in a heterozygous state or mosaicism in peripheral white blood cell or cheek swab-derived DNA samples from either parent. Using single nucleotide polymorphic markers and allele-specific amplification, we clearly identified the mutation in the surviving sibling to be of maternal origin. While we cannot exclude two independently occurring de novo mutations, the complete sharing of polymorphic markers around the mutation site in both siblings supports maternal germ cell mosaicism. Recurrence risk counseling for families with apparently de novo occurring autosomal dominant conditions includes discussion of germ cell mosaicism, and this report underscores the applicability of this concern to Costello Syndrome.
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Phenotypic analysis of individuals with Costello Syndrome due to HRAS p.G13C.
American Journal of Medical Genetics Part A, 2011Co-Authors: Karen W. Gripp, Deborah L. Stabley, Daniel Doyle, Katia Sol-church, Marni E Axelrad, Elizabeth Hopkins, John P. Johnson, William B. Dobyns, Cindy Hudson, Romano TenconiAbstract: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
Angela E Lin - One of the best experts on this subject based on the ideXlab platform.
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living with Costello Syndrome quality of life issues in older individuals
American Journal of Medical Genetics Part A, 2010Co-Authors: Elizabeth Hopkins, Deborah L. Stabley, Katia Solchurch, Angela E Lin, Marni E Axelrad, Katherine E. Krepkovich, Jobayer Hossain, Karen W. GrippAbstract:Clinical and molecular analyses of Costello Syndrome are proceeding at a rapid pace, including the delineation of the adult phenotype. We designed a two-part survey in order to describe the quality of life (QoL) of older individuals with Costello Syndrome. The survey consisted of the Costello Syndrome quality of life (CSQoL): Caregiver Questionnaire, to obtain objective information such as skills, activities, and medical issues from caregivers; and the CSQoL:Self-Questionnaire assessing subjective information including self-esteem, life satisfaction, and interpersonal relations from affected individuals. Thirteen of 18 (72%) individuals with Costello Syndrome (age 16–34 years, mean 22 years) and caregiver pairs responded. The data were analyzed to study day-to-day life, and to determine potential impediments on QoL for older individuals with Costello Syndrome. The CSQoL:Caregiver total scores were significantly lower than the CSQoL:Self total scores as demonstrated by the Wilcoxon Signed Ranks Test (P < 0.008). The CSQoL:Caregiver total scores appear negatively correlated with total number of medical issues (r = −0.549; P = 0.065). No association was found between the CSQoL:Self scores and total number of medical issues (r = −0.107; P = 0.769). Four impediments to QoL for individuals with Costello Syndrome were identified: relationships outside of their immediate circle of family and friends, lack of independence, male gender, and the presence of major medical issues. This information may be useful to the families and health care professionals of adults with Costello Syndrome. As a measurable characteristic, QoL may have utility as a metric in future therapeutic trials. © 2009 Wiley-Liss, Inc.
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Living with Costello Syndrome: quality of life issues in older individuals.
American Journal of Medical Genetics Part A, 2009Co-Authors: Elizabeth Hopkins, Deborah L. Stabley, Katia Sol-church, Angela E Lin, Marni E Axelrad, Katherine E. Krepkovich, Jobayer Hossain, Karen W. GrippAbstract:Clinical and molecular analyses of Costello Syndrome are proceeding at a rapid pace, including the delineation of the adult phenotype. We designed a two-part survey in order to describe the quality of life (QoL) of older individuals with Costello Syndrome. The survey consisted of the Costello Syndrome quality of life (CSQoL): Caregiver Questionnaire, to obtain objective information such as skills, activities, and medical issues from caregivers; and the CSQoL:Self-Questionnaire assessing subjective information including self-esteem, life satisfaction, and interpersonal relations from affected individuals. Thirteen of 18 (72%) individuals with Costello Syndrome (age 16–34 years, mean 22 years) and caregiver pairs responded. The data were analyzed to study day-to-day life, and to determine potential impediments on QoL for older individuals with Costello Syndrome. The CSQoL:Caregiver total scores were significantly lower than the CSQoL:Self total scores as demonstrated by the Wilcoxon Signed Ranks Test (P
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Living with Costello Syndrome: quality of life issues in older individuals.
American journal of medical genetics. Part A, 2009Co-Authors: Elizabeth Hopkins, Deborah L. Stabley, Katia Sol-church, Angela E Lin, Marni E Axelrad, Katherine E. Krepkovich, Jobayer Hossain, Karen W. GrippAbstract:Clinical and molecular analyses of Costello Syndrome are proceeding at a rapid pace, including the delineation of the adult phenotype. We designed a two-part survey in order to describe the quality of life (QoL) of older individuals with Costello Syndrome. The survey consisted of the Costello Syndrome quality of life (CSQoL): Caregiver Questionnaire, to obtain objective information such as skills, activities, and medical issues from caregivers; and the CSQoL:Self-Questionnaire assessing subjective information including self-esteem, life satisfaction, and interpersonal relations from affected individuals. Thirteen of 18 (72%) individuals with Costello Syndrome (age 16-34 years, mean 22 years) and caregiver pairs responded. The data were analyzed to study day-to-day life, and to determine potential impediments on QoL for older individuals with Costello Syndrome. The CSQoL:Caregiver total scores were significantly lower than the CSQoL:Self total scores as demonstrated by the Wilcoxon Signed Ranks Test (P < 0.008). The CSQoL:Caregiver total scores appear negatively correlated with total number of medical issues (r = -0.549; P = 0.065). No association was found between the CSQoL:Self scores and total number of medical issues (r = -0.107; P = 0.769). Four impediments to QoL for individuals with Costello Syndrome were identified: relationships outside of their immediate circle of family and friends, lack of independence, male gender, and the presence of major medical issues. This information may be useful to the families and health care professionals of adults with Costello Syndrome. As a measurable characteristic, QoL may have utility as a metric in future therapeutic trials.
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male to male transmission of Costello Syndrome g12s hras germline mutation inherited from a father with somatic mosaicism
American Journal of Medical Genetics Part A, 2009Co-Authors: Katia Solchurch, Deborah L. Stabley, Laurie A Demmer, Abigail Agbulos, Angela E Lin, Leslie B Smoot, Linda Nicholson, Karen W. GrippAbstract:Costello Syndrome is a rare congenital anomaly Syndrome associated with mental retardation and predisposition to benign and malignant tumors, caused by heterozygous missense mutations in the HRAS oncogene. Previously, all molecularly analyzed mutations appeared de novo, and most arose in the paternal germline. A single patient with somatic mosaicism for a Costello Syndrome causing HRAS mutation has been reported. Here we describe the first documented transmission of an HRAS mutation from a parent with somatic mosaicism to a child with typical Costello Syndrome. Prior to the identification of the underlying gene mutation in Costello Syndrome, this family had been identified clinically. The proband was subsequently found to carry a G12S HRAS germline mutation. Testing of the parents for parental origin identified his father as mosaic for the same HRAS mutation. The mother was found not to carry an HRAS mutation. The causative familial mutation is identified as a c.34G > A, which is the most common mutation in the HRAS gene in patients with Costello Syndrome. The father carries the mutation in 7–8% of his alleles. This is the second case of mosaicism observed in Costello Syndrome and the first direct molecular evidence of father-to-son transmission of the disease-causing mutation. Our observation underlines the importance of parental evaluation, and may have implications for genetic counseling and clinical practice. © 2009 Wiley-Liss, Inc.
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Male‐to‐male transmission of Costello Syndrome: G12S HRAS germline mutation inherited from a father with somatic mosaicism
American Journal of Medical Genetics Part A, 2009Co-Authors: Katia Sol-church, Deborah L. Stabley, Laurie A Demmer, Abigail Agbulos, Angela E Lin, Leslie B Smoot, Linda Nicholson, Karen W. GrippAbstract:Costello Syndrome is a rare congenital anomaly Syndrome associated with mental retardation and predisposition to benign and malignant tumors, caused by heterozygous missense mutations in the HRAS oncogene. Previously, all molecularly analyzed mutations appeared de novo, and most arose in the paternal germline. A single patient with somatic mosaicism for a Costello Syndrome causing HRAS mutation has been reported. Here we describe the first documented transmission of an HRAS mutation from a parent with somatic mosaicism to a child with typical Costello Syndrome. Prior to the identification of the underlying gene mutation in Costello Syndrome, this family had been identified clinically. The proband was subsequently found to carry a G12S HRAS germline mutation. Testing of the parents for parental origin identified his father as mosaic for the same HRAS mutation. The mother was found not to carry an HRAS mutation. The causative familial mutation is identified as a c.34G > A, which is the most common mutation in the HRAS gene in patients with Costello Syndrome. The father carries the mutation in 7–8% of his alleles. This is the second case of mosaicism observed in Costello Syndrome and the first direct molecular evidence of father-to-son transmission of the disease-causing mutation. Our observation underlines the importance of parental evaluation, and may have implications for genetic counseling and clinical practice. © 2009 Wiley-Liss, Inc.
Elizabeth Hopkins - One of the best experts on this subject based on the ideXlab platform.
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Assessing genotype–phenotype correlation in Costello Syndrome using a severity score
Genetics in Medicine, 2013Co-Authors: Elizabeth M. Mccormick, Deborah L. Stabley, Katia Sol-church, Sarah Catalano, Elizabeth Hopkins, Jobayer Hossain, Laura Conway, Karen W. GrippAbstract:Genet Med 2013:15(7):554–557 Purpose: Costello Syndrome, a rare genetic disorder with multisystemic involvement, is caused by germline HRAS mutations. Because several different missense mutations have been reported, a severity scoring system was developed to assess a possible genotype–phenotype correlation. Methods: Records of 78 individuals with Costello Syndrome were scored in early childhood, childhood, and young adulthood by a reviewer blinded to the individuals’ specific mutations. These scores were based on certain medically relevant feeding, neurologic, orthopedic, endocrine, cardiac, malignancy, and mortality manifestations. Individuals’ severity scores were then grouped by the particular HRAS mutation. The mixed-model approach for repeated-measures analysis of variance with unstructured within-subject correlation, pairwise comparisons, and contrast were used to determine whether the severity scores differed by mutation. Results: Although the sample size was small, individuals with the p.G12A or p.G12C HRAS change were more severely affected than those with other HRAS mutations. Regardless of the mutation, severity did not increase significantly over time. Conclusion: Despite its limitations, including the small number of individuals with rare mutations and possibly incomplete medical records, this work providing the first quantitative assessment of phenotypic severity in a Costello Syndrome cohort supports a medically relevant genotype–phenotype correlation.
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Orthopedic manifestations and implications for individuals with Costello Syndrome.
American journal of medical genetics. Part A, 2013Co-Authors: Stacey Detweiler, Elizabeth Hopkins, Mihir M Thacker, Laura Conway, Karen W. GrippAbstract:Costello Syndrome is a rare genetic condition caused by heterozygous alterations in HRAS and characterized by multi-system abnormalities. Individuals with Costello Syndrome usually present with severe feeding difficulties in infancy, short stature, coarse facial features, increased tumor risks, cardiac and neurological complications, intellectual disability and orthopedic complications. This study further defines the orthopedic manifestations affecting individuals with Costello Syndrome. We studied 43 participants and performed medical records review, clinical examinations and orthopedic inquiry forms. In 23 participants, hip and or spinal imaging assessments were completed. Serial radiographs were analyzed when available. A total of 25 orthopedic manifestations were identified. Ten manifestations were seen in the majority of the participants: hypotonia (87%), ligamentous laxity (85%), scoliosis (63%), kyphosis (58%), characteristic hand deformities (85%), ulnar deviation of the wrist (63%), elbow (55%) and shoulder contractures (65%), tight Achilles tendon (73%), and pes planus (53%). Other characteristics of special note were hip dysplasia (45%), foot deformities requiring surgical intervention (38%) and osteopenia/osteoporosis (47%). We also studied the development of the hips and spine. Uni- or bilateral hip dysplasia was congenital in some, while it developed throughout childhood in others. Spinal involvement included scoliosis, kyphosis, lordosis, and curvature reversal (thoracic lordosis and lumbar kyphosis). Based on these findings, we recommend routine referral to an orthopedic surgeon as well as instituting screening protocols for hips and spine for individuals with Costello Syndrome.
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Orthopedic manifestations and implications for individuals with Costello Syndrome.
American Journal of Medical Genetics Part A, 2013Co-Authors: Stacey Detweiler, Elizabeth Hopkins, Mihir M Thacker, Laura Conway, Karen W. GrippAbstract:Costello Syndrome is a rare genetic condition caused by heterozygous alterations in HRAS and characterized by multi-system abnormalities. Individuals with Costello Syndrome usually present with severe feeding difficulties in infancy, short stature, coarse facial features, increased tumor risks, cardiac and neurological complications, intellectual disability and orthopedic complications. This study further defines the orthopedic manifestations affecting individuals with Costello Syndrome. We studied 43 participants and performed medical records review, clinical examinations and orthopedic inquiry forms. In 23 participants, hip and or spinal imaging assessments were completed. Serial radiographs were analyzed when available. A total of 25 orthopedic manifestations were identified. Ten manifestations were seen in the majority of the participants: hypotonia (87%), ligamentous laxity (85%), scoliosis (63%), kyphosis (58%), characteristic hand deformities (85%), ulnar deviation of the wrist (63%), elbow (55%) and shoulder contractures (65%), tight Achilles tendon (73%), and pes planus (53%). Other characteristics of special note were hip dysplasia (45%), foot deformities requiring surgical intervention (38%) and osteopenia/osteoporosis (47%). We also studied the development of the hips and spine. Uni- or bilateral hip dysplasia was congenital in some, while it developed throughout childhood in others. Spinal involvement included scoliosis, kyphosis, lordosis, and curvature reversal (thoracic lordosis and lumbar kyphosis). Based on these findings, we recommend routine referral to an orthopedic surgeon as well as instituting screening protocols for hips and spine for individuals with Costello Syndrome. © 2013 Wiley Periodicals, Inc.
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Assessing genotype-phenotype correlation in Costello Syndrome using a severity score
Genetics in medicine : official journal of the American College of Medical Genetics, 2013Co-Authors: Elizabeth M. Mccormick, Deborah L. Stabley, Katia Sol-church, Sarah Catalano, Elizabeth Hopkins, Jobayer Hossain, Laura Conway, Karen W. GrippAbstract:Costello Syndrome, a rare genetic disorder with multisystemic involvement, is caused by germline HRAS mutations. Because several different missense mutations have been reported, a severity scoring system was developed to assess a possible genotype–phenotype correlation. Records of 78 individuals with Costello Syndrome were scored in early childhood, childhood, and young adulthood by a reviewer blinded to the individuals’ specific mutations. These scores were based on certain medically relevant feeding, neurologic, orthopedic, endocrine, cardiac, malignancy, and mortality manifestations. Individuals’ severity scores were then grouped by the particular HRAS mutation. The mixed-model approach for repeated-measures analysis of variance with unstructured within-subject correlation, pairwise comparisons, and contrast were used to determine whether the severity scores differed by mutation. Although the sample size was small, individuals with the p.G12A or p.G12C HRAS change were more severely affected than those with other HRAS mutations. Regardless of the mutation, severity did not increase significantly over time. Despite its limitations, including the small number of individuals with rare mutations and possibly incomplete medical records, this work providing the first quantitative assessment of phenotypic severity in a Costello Syndrome cohort supports a medically relevant genotype–phenotype correlation. Genet Med 2013:15(7):554–557
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Molecular confirmation of HRAS p.G12S in siblings with Costello Syndrome.
American journal of medical genetics. Part A, 2011Co-Authors: Karen W. Gripp, Deborah L. Stabley, Elizabeth Hopkins, Peter L Geller, David A Stevenson, John C Carey, Katia Sol-churchAbstract:Costello Syndrome was first reported based on its characteristic phenotype. Its presentation affects multiple organ systems, including severe failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto-oncogene HRAS have been recognized to cause Costello Syndrome, and its inheritance pattern would thus be autosomal dominant. Here, we report on the identification of an HRAS mutation c.34G>A, predicting a p.G12S amino acid substitution, in the surviving brother of a previously reported sibling pair, and documentation of the same change in autopsy material from his deceased sister. This represents, to our knowledge, the first molecularly confirmed Costello Syndrome in siblings. We did not detect the mutation in a heterozygous state or mosaicism in peripheral white blood cell or cheek swab-derived DNA samples from either parent. Using single nucleotide polymorphic markers and allele-specific amplification, we clearly identified the mutation in the surviving sibling to be of maternal origin. While we cannot exclude two independently occurring de novo mutations, the complete sharing of polymorphic markers around the mutation site in both siblings supports maternal germ cell mosaicism. Recurrence risk counseling for families with apparently de novo occurring autosomal dominant conditions includes discussion of germ cell mosaicism, and this report underscores the applicability of this concern to Costello Syndrome.
