Phenotype publications

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Phenotype publications

The Clinical Phenotype of Costello Syndrome

B. Kerr

Regional Genetic Service and Medical Genetics Research Group, Central Manchester and Manchester Children’s Hospitals University NHS Trust, Royal Manchester Children’s Hospital, Manchester, UK


Costello syndrome (CS) is a rare syndrome associated with developmental disability, prenatal overgrowth, and postnatal failure to thrive and short stature. Polyhydramnios, severe feeding difficulty and congenital heart disease are common features, as are hypertrophic cardiomyopathy and cardiac arrhythmia, predominantly atrial. Skin changes are striking, particularly increased skin over the palms and soles and the development of papilloma at moist body surfaces. The finding of excess palmar skin is part of a striking hand phenotype, comprising in addition, hyperextensibility of the small joints of the hand and a posture of flexion and ulnar deviation at the wrists. There is an increased risk of malignancy, particularly embryonal rhabdomyosarcoma and bladder carcinoma. The demonstration of activating missense mutations in HRAS, a component of the MAPK pathway, as causative in CS has provided a diagnostic test, and confirmation of the phenotype in classical and suspected cases. Although in most cases of CS the phenotype remains relatively homogenous and distinctive, a diagnostic test has demonstrated clinical overlap with cardio-facio-cutaneous syndrome (CFC). A severe neonatal phenotype has emerged, consisting in some cases of a multi-system disease and in others of profound hypotonia and myopathy associated on biopsy with excess muscle spindles (congenital myopathy with excess of muscle spindles, CMEMS). It is likely that further variability in the phenotype will be identified as further diagnostic testing is undertaken.

An Attenuated Phenotype of Costello Syndrome in Three Unrelated Individuals With a HRAS c.179G>A (p.Gly60Asp) Mutation Correlates With Uncommon Functional Consequences

Karen W. Gripp,1* Katia Sol-Church,2 Patroula Smpokou,3 Gail E. Graham,4 David A. Stevenson,5 Heather Hanson,6 David H. Viskochil,6 Laura C. Baker,1 Bridget Russo,2 Nick Gardner,2 Deborah L. Stabley,2 Verena Kolbe,7 and Georg Rosenberger7

1 Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware

2 Center for Applied Clinical Genomics, A. I. duPont Hospital for Children, Wilmington, Delaware

3 Division of Genetics and Metabolism, Children’s National Health System, Washington, District of Columbia

4 Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada

5 Division of Medical Genetics, Stanford University, Stanford, California

6 Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah

7 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Manuscript Received: 29 January 2015; Manuscript Accepted: 6 April 2015 Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome (CS), an intellectual disability condition with severe failure to thrive, cardiac abnormalities, predisposition to tumors, and neurologic abnormalities. More than 80% of patients share the HRAS mutation c.34G>A (p.Gly12Ser) associated with the typical, relatively homogeneous phenotype. Rarer mutations occurred in individuals with an attenuated phenotype and less characteristic facial features. Most pathogenic HRAS alterations affect hydrolyticHRAS activity resulting in constitutive activation. “Gain-of-function” and “hyperactivation” concerning downstream pathways are widely used to explain the molecular basis and dysregulation of the RAS-MAPK pathway is the biologic mechanism shared amongst rasopathies. Panel testing for rasopathies identifiedanovelHRASmutation (c.179G>A; p.Gly60Asp) in three individuals with attenuated features of Costello syndrome. De novo paternal origin occurred in two, transmission from a heterozygous mother in the third. Individuals showed subtle facial features; curly hair and relative macrocephaly were seen in three; atrial tachycardia and learning difficulties in two, and pulmonic valve dysplasia and mildly thickened left ventricle in one.

None had severe failure to thrive, intellectual disability or cancer, underscoring the need to consider HRAS mutations in individuals with an unspecific rasopathy phenotype. Functional studies revealed strongly increased HRAS Gly60Asp binding to RAF1, but not to other signaling effectors. Hyperactivation of the MAPK downstream signaling pathways was absent.Our results indicate that an increase in the proportion of activated RAS downstream signaling components does not entirely explain the molecular basis of CS. We conclude that the phenotypic variability in CS recapitulates variable qualities of molecular dysfunction.

Phenotypic Analysis of Individuals With Costello Syndrome due to HRAS p.G13C

Karen W. Gripp,1* Elizabeth Hopkins,1 Katia Sol-Church,2 Deborah L. Stabley,2 Marni E. Axelrad,3 Daniel Doyle,4 William B. Dobyns,5 Cindy Hudson,6 John Johnson,6 Romano Tenconi,7 Gail E. Graham,8 Ana Berta Sousa,9 Raoul Heller,10 Maria Piccione,11 Giovanni Corsello,11 Gail E. Herman,12 Marco Tartaglia,13 and Angela E. Lin14

1 Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware

2 Department of Biomedical Research, Nemours’ Children’s Clinic, Wilmington, Delaware

3 Psychology Service, Texas Children’s Hospital, Section of Psychology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas

4 Division of Endocrinology, A. I. duPont Hospital for Children, Wilmington, Delaware

5 Seattle Children’s Research Institute, Seattle, Washington

6 Medical Genetics, Shodair Children’s Hospital, Helena, Montana

7 Clinical Genetics Unit, Department of Pediatrics, University of Padova, Padova, Italy

8 Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada

9 Servic¸o de Genetica Medica, Hospital de Santa Maria, Lisboa, Portugal

10 Institut f€ur Humangenetik, Klinikum der Universit€at zu K€oln, K€oln, Germany

11 Mother and Child Department, University of Palermo, Palermo, Italy

12 The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio

13 Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy

14 Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts

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, andmore than 80% of patients share p.G12S. To test the hypothesis that subtle genotype–phenotype differences exist, we report the first cohortcomparison between 12 Costellosyndrome 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-value¼0.033), ulnar deviation of the wrist (P<0.001) and papillomata (P¼0.003), and fewer neurosurgical procedures (P¼0.024). 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. 

Transmission of the Rare HRAS Mutation (c. 173C>T; p.T58I) Further Illustrates Its Attenuated Phenotype

Karen W. Gripp,1* Elizabeth Hopkins,1 Alvaro Serrano,2 Norma J. Leonard,3 Deborah L. Stabley,4 and Katia Sol-Church4

1 Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware

2 University of Iowa Children’s Hospital, Iowa City, Iowa

3 Department of Medical Genetics, University of Alberta, Edmonton, Canada

4 Department of Biomedical Research, Nemours’ Children’s Clinic, Wilmington, Delaware

Costello syndrome was delineated based on its distinctive phenotype  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 cause Costello syndrome, and its inheritance pattern would thus be autosomal dominant. With exception of two instances of parental mosaicism, one presumed gonadal and the other proven somatic mosaicism for the p.G12S change, all published cases resulted from de novo mutations, typically arising in the paternal germline. More than 90% of these mutations affect the glycine residues in position 12 or 13, and result in a gain-of-function of the altered protein. A rare heterozygous HRAS alteration (c.173C>T; p.T58I) associated with an attenuated phenotype was previously reported in one patient.

We identified two additional individuals with this mutation, father and son. Further studies supported origin of the alteration in the grand-paternal germline. Transmission of the mutation underscores its attenuated phenotype compatible with reproduction. We reviewed the phenotype in the newly identified individuals (Patient 1, 2) and include updated information on the first previously reported individual with HRAS p.T58I (Patient 3). Macrocephaly was present in all three. Cardiac findings included hypertrophic cardiomyopathy with double-chambered right ventricle; or mitral valve prolapse in one patient each. While subtle neurologic abnormalities or developmental delay were present in all, only one showed significant cognitive and functional impairment. None developed papillomata or a malignant tumor. Genetic counseling for Costello syndrome needs to take into consideration the particular HRAS mutation.

Assessing genotype–phenotype correlation in Costello syndrome using a severity score


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.

Elizabeth M. McCormick, MS1, Elizabeth Hopkins, MS1, Laura Conway, PhD2, Sarah Catalano, BS3, Jobayer Hossain, PhD4, Katia Sol-Church, PhD4, Deborah L. Stabley, BS4 and Karen W. Gripp, MD1


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.


Costello syndrome (OMIM no. 218040) is a rare genetic disorder characterized by failure-to-thrive in infancy, short stature, characteristic facial features, curly or sparse hair, papillomata, osteoporosis, cardiovascular malformations such as pulmonic stenosis and hypertrophic cardiomyopathy, and rhythm disturbances such as multifocal atrial tachycardia;1 neurological abnormalities including intellectual disability,2 syringomyelia, Chiari I malformation, and hydrocephalus;3 and a predisposition to malignancies.4 Costello syndrome is caused by heterozygous germline HRAS mutations that typically occur de novo.5–9  Although more than 80% of patients share the p.G12S HRAS mutation, other missense mutations have been reported.10 Genotype–phenotype correlations have been characterized for several HRAS mutations, with associations found between the p.G12A HRAS change and increased predisposition to malignancy,8 p.G12C and p.G12D and severe hypertrophic cardiomyopathy and neonatal mortality,11 p.T58I and p.A146V and milder facial findings,12 and p.G13C and lower rates of neurological abnormalities requiring surgery, lack of multifocal atrial tachycardia and papillomata, and long eyelashes requiring trimming.13 Here, we describe the implementation of a severity scoring system in order to standardize and quantify genotype– phenotype correlation of medically relevant manifestations in Costello syndrome.