Costello syndrome, which belongs to the group of RASopathies, is a very rare disease with an estimated incidence of 1:300,000 (United Kingdom) or 1:1,230,000 (Japan). The inheritance is autosomal dominant. Symptoms typical of RASopathies such as prenatal neck edema, postnatal facial dysmorphia, dwarfism, mild to moderate mental retardation and heart defects are also described here. The main characteristic is perinasal and/or perinanal benign cutaneous papillomas. Increased skin pigmentation is also characteristic.
In 90% of those affected, severe polyhydramnion or neck edema is detected during prenatal ultrasound. Perinatal edema is largely responsible for an initially high birth weight, which is followed by severe failure to thrive due to significant nutritional problems. Heart defects are mainly hypertrophic cardiomyopathy (HCM) and atrial septum defects associated with arrhythmias. The risk of developing solid tumors (mainly rhabdomyosarcoma) in childhood or early adulthood is increased to about 15%.
The only gene in which pathogenic variants related to Costello syndrome are found in the HRAS gene. 80-90% of the pathogenic variants affect the amino acid glycine at position 12 in exon 2 of the protein GTPase HRas, occasionally pathogenic variants at other amino acid positions of the HRAS gene are also described.
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