A novel patient with an attenuated Costello syndrome phenotype due to an <i>HRAS</i> mutation affecting codon 146—Literature review and update

Chiu, Annie Ting Gee; Leung, Gordon K. C.; Chu, Yoyo Wing-Yiu; Gripp, Karen W.; Chung, Brian Hon‐Yin

doi:10.1002/ajmg.a.38118

Cited by 8 publications

(7 citation statements)

References 25 publications

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“…Hennekam (2003) confirmed the high prevalence of polyhydramnios, found in 58% (39/67) of mothers of individuals with CS, a high prevalence of poor feeding (97%, 56/58) and hypotonia among infants. This finding is commonly followed in the neonatal period by poor sucking, swallowing dysfunction, slow feeding, and failure to thrive (Chiu, Leung, Chu, Gripp, & Chung, 2017; Digilio et al, 2008; Gripp et al, 2012; Hiippala et al, 2016; Ioan & Fryns, 2002; Kawame et al, 2003; Nwakalor, Said‐Delgado, Krinshpun, & Velinov, 2021; Piccione et al, 2009; Pratesi et al, 1998; Syu et al, 2022; Vuralli et al, 2020; Weaver et al, 2022) (Table 1) (Box 1).…”

Section: Feeding Difficultiesmentioning

confidence: 99%

Management of nutritional and gastrointestinal issues in RASopathies: A narrative review

Onesimo

Giorgio

Viscogliosi

et al. 2022

American J of Med Genetics Pt C

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Noonan, Costello, and cardio-facio-cutaneous syndrome are neurodevelopmental disorders belonging to the RASopathies, a group of syndromes caused by alterations in the RAS/MAPK pathway. They are characterized by similar clinical features, among which feeding difficulties, growth delay, and gastro-intestinal disorders are frequent, causing pain and discomfort in patients. Hereby, we describe the main nutritional and gastrointestinal issues reported in individuals with RASopathies, specifically in Noonan syndrome, Noonan syndrome-related disorders, Costello, and cardio-faciocutaneous syndromes. Fifty percent of children with Noonan syndrome may experience feeding difficulties that usually have a spontaneous resolution by the second year of life, especially associated to genes different than PTPN11 and SOS1. More severe manifestations often require artificial enteral nutrition in infancy are observed in Costello syndrome, mostly associated to c.34G>A substitution in the HRAS gene.In cardio-facio-cutaneous syndrome feeding issues are usually present (90-100% of cases), especially in individuals carrying variants in BRAF, MAP2K1, and MAP2K2 genes, and artificial enteral intervention, even after scholar age, may be required.Moreover, disorders associated with gastrointestinal dysmotility as gastroesophageal reflux and constipation are commonly reported in all the abovementioned syndromes. Given the impact on growth and on the quality of life of these patients, early evaluation and prompt personalized management plans are fundamental.

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Section: Feeding Difficultiesmentioning

confidence: 99%

Management of nutritional and gastrointestinal issues in RASopathies: A narrative review

Onesimo

Giorgio

Viscogliosi

et al. 2022

American J of Med Genetics Pt C

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“…A de novo variant in HRAS at Lys117, the homologous equivalent of Lys128 in RALA, was found in two unrelated probands with Costello Syndrome [22]. Lastly, a de novo HRAS variant at Ala146, the homologous equivalent of Ala158 in RALA, was reported in at least three patients with Costello Syndrome [23]. Variation at this residue has also been reported as a recurrent somatic variant in colorectal cancers [24].…”

Section: Resultsmentioning

confidence: 99%

De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

et al. 2018

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Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10−11) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.

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“…A variant of maternal inheritance was identified in HRAS , which has been associated with Costello syndrome (OMIM #218040), a rare dominant syndrome which increases the risk of tumors development 50 . It is not known how HRAS mutations cause the other features of Costello syndrome besides cancer predisposition such as intellectual disability, distinctive facial features, and heart problems, but many of the signs and symptoms probably result from cell overgrowth and abnormal cell division [51][52][53] . Interestingly, a LoF was observed in the ZNF215 , disruptions in this gene were proposed to play a role in the etiology of Beckwith-Wiedemann syndrome.…”

Section: Discussionmentioning

confidence: 99%

Birth Defects and Childhood Cancer: A Shared Biological Pathway for Hirschsprung Disease and Hepatoblastoma Development?

Aguiar

Teixeira

Barros

et al. 2020

Preprint

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Background: The association of birth defects and developmental alterations with pediatric cancer is a recognized long-standing global observation, although very few syndromes confer a high risk of hepatoblastoma development. Procedures: Here we describe the results of germline exome analysis of two syndromic patients with Hirschsprung disease who developed hepatoblastoma. Results: Germline variants of uncertain clinical significance (VUS) were disclosed in 28 genes that might be related to patients' phenotypes. More importantly, germline VUS were detected in eight known cancer predisposition genes (APC, BRCA1, ERBB2, ERCC2, HRAS, ODC1, SERPINA6, and MCC). Additionally, our data disclosed two candidate genes with germline variants potentially contributing to the phenotype of these patients, namely, CEP164 and CYP1A1. The last one was the only gene presenting variants of uncertain significance in both patients. This gene encodes the most important xenobiotic-metabolizing enzyme of the placenta for which relevant inducible activity has been demonstrated throughout pregnancy. Conclusion: our data pointed out a set of genes that are enriched for pathways already related to cancer and developmental biology, suggesting they could have a broader role in cancer and congenital abnormalities. These results can help future studies to understand the biology of Hirschsprung disease and its association with hepatoblastoma.

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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

Cited by 8 publications

References 25 publications

Management of nutritional and gastrointestinal issues in RASopathies: A narrative review

Management of nutritional and gastrointestinal issues in RASopathies: A narrative review

De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

Birth Defects and Childhood Cancer: A Shared Biological Pathway for Hirschsprung Disease and Hepatoblastoma Development?

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