Costello syndrome: Phenotype, natural history, differential diagnosis, and possible cause

Johnson, John P.; Golabi, Mahin; Norton, Mary E.; Rosenblatt, Robert M.; Feldman, Gary M.; Yang, Samuel P.; Hall, Bryan D.; Fries, Melissa H.; Carey, John C.

doi:10.1016/s0022-3476(98)70284-7

Cited by 107 publications

(135 citation statements)

References 30 publications

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“…Excessive secretions are often noted. 29 Individuals with Costello syndrome have very natural history Females and males are equally affected. The phenotype evolves over time, and although Costello syndrome can theoretically be recognized in the fetus, it is usually diagnosed in the young child.…”

Section: Introductionmentioning

confidence: 99%

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Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

Gripp

Lin

2012

Genetics in Medicine

146

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Section: Introductionmentioning

confidence: 99%

“…The onset of speech often coincides with the willingness to feed orally. Short stature is universal, delayed bone age is common, 29 and testing may show partial or complete growth hormone (GH) deficiency. 11 Cardiovascular abnormalities are typically present in infancy or early childhood, but may be recognized at any age.…”

Section: Introductionmentioning

confidence: 99%

Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

Gripp

Lin

2012

Genetics in Medicine

146

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“…It has also been noted that patients with CS are at increased risk for the development of tumors [DeBaun, 2002;Gripp et al, 2002]. Further, a few reports describe endocrine abnormalities in some patients with CS, specifically of growth hormone (GH) [Okamoto et al, 1994;Schimke et al, 1996;Yetkin et al, 1998;Legault and Gagnon, 2002;Delrue et al, 2003] and glucose metabolism [Di Rocco et al, 1993;Johnson et al, 1998;Yetkin et al, 1998;Szalai et al, 1999;Gripp et al, 2000]. We describe a patient with CS, with partial GH deficiency and hypoglycemia.…”

mentioning

confidence: 83%

“…Affected persons tend to develop papillomata around the nose, mouth, and anus from late childhood [Johnson et al, 1998;Hennekam, 2003]. About 63% of patients with CS have cardiac abnormalities .…”

Section: Introductionmentioning

confidence: 99%

Costello syndrome with growth hormone deficiency and hypoglycemia: A new report and review of the endocrine associations

Gregersen

Viljoen

2004

American J of Med Genetics Pt A

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We describe an 18-month-old boy with Costello syndrome (CS) with proven partial growth hormone (GH) deficiency and hypoglycemic episodes. The hypoglycemia is deemed to be due to cortisol deficiency. This report represents the second published case of cortisol deficiency in the CS. A brief review of the endocrine disturbances in the syndrome is provided. We highlight the need for careful endocrinological evaluation of individuals with CS. ß 2004 Wiley-Liss, Inc.KEY WORDS: Costello syndrome; growth hormone; cortisol deficiency; glucose metabolism; endocrine disturbances INTRODUCTIONPatients with Costello syndrome (CS) typically have mental retardation, prenatal overgrowth with postnatal failure to thrive, a distinctive facial appearance suggestive of a storage disorder, soft skin with deep creases on the palms and soles, hyperextensible digits, and increased skin pigmentation [Costello, 1971]. Affected persons tend to develop papillomata around the nose, mouth, and anus from late childhood [Johnson et al., 1998;Hennekam, 2003]. About 63% of patients with CS have cardiac abnormalities . It has also been noted that patients with CS are at increased risk for the development of tumors [DeBaun, 2002;Gripp et al., 2002]. Further, a few reports describe endocrine abnormalities in some patients with CS, specifically of growth hormone (GH) [Okamoto et al., 1994;Schimke et al., 1996;Yetkin et al., 1998;Legault and Gagnon, 2002;Delrue et al., 2003] and glucose metabolism [Di Rocco et al., 1993;Johnson et al., 1998;Yetkin et al., 1998;Szalai et al., 1999;Gripp et al., 2000]. We describe a patient with CS, with partial GH deficiency and hypoglycemia. The hypoglycemia is thought to be related to abnormal cortisol metabolism. CLINICAL REPORTOur patient (Fig. 2a,b) is the second child of a nonconsanguineous couple. His 7-year-old brother is healthy. His parents were aged 26 and 30 years at the patient's conception. His mother required thyroid replacement in pregnancy, but was documented biochemically as being euthyroid throughout. The patient was born at term by caesarean section, with a birthweight of 2.7 kg (3rd centile), length of 45 cm (<3rd centile), and head circumference of 35 cm (25th centile). He was noted to have unusual facial features. A right orchidopexy and bilateral inguinal hernia repairs were performed at 6 weeks of age. Poor weight gain was noted from shortly after birth. He had sucking difficulties, but he was able to tolerate small volume feeds from a bottle, and by 6 months of age, he was feeding well.At 9 months of age the patient had a prolonged generalized seizure, and was found to be hypoglycemic (blood glucose ¼ 1.2 mmol/L) with an appropriately low insulin level (0.3 iU/L). The cortisol level was not checked during the hypoglycemic episodes, but a subsequent random level was found to be normal. Further endocrine evaluation confirmed a partial GH deficiency after a clonidine stimulation test (basal level ¼ 3.48 mg/L, peak ¼ 8.89 mg/L). Thyroid function was questionable with a low free thyroxine (FT 4 ) o...

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“…[1][2][3][4][5][6][7][8][9] Recently, Costello syndrome has been identified as the first example of a disorder associated with activating germ-line mutations in the HRAS proto-oncogene. [10][11][12][13][14][15][16][17] In addition to Costello syndrome, a group of multiple congenital anomaly syndromes collectively named RASopathies have been shown to be associated with germline mutations in various genes of the RAS/MAPK pathway.…”

Section: Introductionmentioning

confidence: 99%

C4ST-1/CHST11-controlled chondroitin sulfation interferes with oncogenic HRAS signaling in Costello syndrome

et al. 2012

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Costello syndrome is a pediatric genetic disorder linked to oncogenic germline mutations in the HRAS gene. The disease is characterized by multiple developmental abnormalities, as well as predisposition to malignancies. Our recent observation that heart tissue from patients with Costello syndrome showed a loss of the glycosaminoglycan chondroitin-4-sulfate (C4S) inspired our present study aimed to explore a functional involvement of the chondroitin sulfate (CS) biosynthesis gene Carbohydrate sulfotransferase 11/Chondroitin-4-sulfotransferase-1 (CHST11/C4ST-1), as well as an impaired chondroitin sulfation balance, as a downstream mediator of oncogenic HRAS in Costello syndrome. Here we demonstrate a loss of C4S, as well as a reduction in C4ST-1 mRNA and protein expression, in primary fibroblasts from Costello syndrome patients. We go on to show that expression of oncogenic HRAS in normal fibroblasts can repress C4ST-1 expression, whereas interference with oncogenic HRAS signaling in Costello syndrome fibroblasts elevated C4ST-1 expression, thus identifying C4ST-1 as a negatively regulated target gene of HRAS signaling. Importantly, we show that forced expression of C4ST-1 in Costello fibroblasts could rescue the proliferation and elastogenesis defects associated with oncogenic HRAS signaling in these cells. Our results indicate reduced C4ST-1 expression and chondroitin sulfation imbalance mediating the effects of oncogenic HRAS signaling in the pathogenesis of Costello syndrome. Thus, our work identifies C4ST-1-dependent chondroitin sulfation as a downstream vulnerability in oncogenic RAS signaling, which might be pharmacologically exploited in future treatments of not only Costello syndrome and other RASopathies, but also human cancers associated with activating RAS mutations.

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Costello syndrome: Phenotype, natural history, differential diagnosis, and possible cause

Cited by 107 publications

References 30 publications

Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations

Costello syndrome with growth hormone deficiency and hypoglycemia: A new report and review of the endocrine associations

C4ST-1/CHST11-controlled chondroitin sulfation interferes with oncogenic HRAS signaling in Costello syndrome

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