Costello syndrome associated with novel germline HRAS mutations: An attenuated phenotype?

Abstract

Costello syndrome is a rare congenital disorder typically characterized by severe failure-to-thrive, cardiac abnormalities including tachyarrhythmia and hypertrophic cardiomyopathy, distinctive facial features, a predisposition to papillomata and malignant tumors, neurologic abnormalities, developmental delay, and mental retardation. Its underlying cause is de novo germline mutations in the oncogene HRAS. Almost all Costello syndrome mutations affect one of the glycine residues in position 12 or 13 of the protein product. More than 80% of patients with Costello syndrome share the same underlying mutation, resulting in a G12S amino acid change. We report on two patients with novel HRAS mutations affecting amino acids 58 (T58I) and 146 (A146V), respectively. Despite facial features that appear less coarse than those typically seen in Costello patients, both patients show many of the physical and developmental problems characteristic for Costello syndrome. These novel HRAS mutations may be less common than the frequently reported G12S change, or patients with these changes may be undiagnosed due to their less coarse facial features. In addition to the findings previously known to occur in Costello syndrome, one of our patients had hypertrophic pyloric stenosis. This led us to review the medical histories on a cohort of proven HRAS mutation positive Costello syndrome patients, and we found a statistically significantly (P < 0.001) increased frequency of pyloric stenosis in Costello syndrome (5/58) compared to the general population frequency of 2-3/1,000. Thus we add hypertrophic pyloric stenosis to the abnormalities seen with increased frequency in Costello syndrome.

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

“…Similarly, an individual with the p.T58I HRAS mutation was reported to have milder facial findings but a comparable severity of Costello syndrome in other respects. 12 This study reports similar findings, given that this scoring system did not take facial features into consideration.…”

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

“…Pyloric stenosis occurs more commonly than in the general population. 24 Most infants display hypotonia, irritability, developmental delay, and nystagmus with delayed visual maturation improving with age. Hypotonia may be severe and suggest myopathy.…”

“…In contrast, the possibility of a milder or attenuated phenotype was noted in individuals with p.Thr58Ile and p.Ala146Val. 24 Distinctive phenotypic findings are associated with the p.Gly13Cys change and include dolichocilia (extremely long eye lashes, often requiring trimming) and loose anagen hair. 8 Papillomata or multifocal atrial tachycardia have not yet been seen in individuals with p.Gly13Cys, and fewer have short stature.…”

HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome

“…The number of fatal cases was 5/138 patients with p.G12S, 4/6 with p.G12C, 3/17 with p.G12A, 3/4 with p.G12D, 2/2 with p.G12V, 1/1 with p.G12E and 1/1 with p.E63K. 3,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] The mortality of patients with p.G12C or p.G12D was significantly higher than that of the patients with the more common p.G12S (P¼0.026 by Fisher's exact test). Previous studies have shown that the p.G12V substitution has the highest transformative potential (p.G12V4p.G12A, p.G12S, p.G12C, p.G12D4p.G13D) and is the most frequently found mutation in human tumors.…”

“…3 It has been suggested that the CS diagnosis should be applied only to patients with a mutation in HRAS because of the high risk of malignancies associated with HRAS mutations and the relative homogeneity of the CS phenotype. 4 A total of 14 HRAS missense mutations and one duplication mutation have been reported in 185 patients with CS 3,[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] or congenital myopathy with excess of muscle spindles. 24 Most of these mutations have previously been reported as somatic and oncogenic mutations in various tumors.…”