HRAS is the gene recorded for Costello syndrome, with definitive ClinGen gene-disease validity. The packet lists sporadic and autosomal dominant inheritance patterns. GeneReviews describes the condition as an autosomal dominant disorder typically caused by a de novo pathogenic variant, so that most affected individuals are the only affected person in their family. It documents an association with advanced parental age and states that most, but not all, de novo variants arise in the paternal germline. Rarely, a variant is inherited from a heterozygous parent, with vertical transmission reported in two families with an attenuated phenotype, and GeneReviews notes parental germline mosaicism as a possibility when a variant is not found in either parent. GeneReviews reports that penetrance has been 100% to date.

GeneReviews describes limited genotype-phenotype correlations. A systematic review of 146 individuals found no apparent correlation between the specific variant and cardiac variables studied, whereas some rarer variants are associated with a more severe neonatal presentation and others with a milder or attenuated presentation, and tumor risk differs among variants affecting the same amino acid. This indicates variable expressivity among affected individuals.

The packet does not record an FDA-approved treatment for this condition. According to GeneReviews, there is no cure for Costello syndrome, and supportive care aimed at improving quality of life, maximizing function and reducing complications ideally involves multidisciplinary care by specialists in relevant fields. GeneReviews describes MEK inhibitors, a class of kinase inhibitor, as having been used for severe cardiac hypertrophy; this is described as a targeted therapy in GeneReviews and is not an FDA approval claim.

Supportive care described in GeneReviews includes feeding therapy, with gastrostomy tube placement commonly required for persistent feeding issues; standard surgical treatment for pyloric stenosis; treatment of epilepsy by an experienced neurologist, with no antiseizure medication demonstrated effective specifically for this disorder; surgical approaches for Chiari I malformation, tethered cord and craniosynostosis; pharmacologic or surgical treatment for severe cardiac hypertrophy; management of airway obstruction; and bracing, physical therapy and occasionally surgery for musculoskeletal problems.

GeneReviews describes surveillance across feeding and growth, gastrointestinal, neurologic, developmental, respiratory, endocrine, cardiovascular and musculoskeletal systems. Its tumor screening entries list serial abdominal and pelvic ultrasound for rhabdomyosarcoma and neuroblastoma until about age 8 to 10 years and urinalysis for hematuria to screen for bladder cancer beginning at about age 10 years. GeneReviews also notes that aggressive feeding therapy in infancy and early childhood is not likely to improve oral intake and may result in oral aversion, and that neuroblastoma screening by catecholamine metabolites is not helpful because elevated values were observed in individuals without an identifiable tumor.

According to GeneReviews, no consensus clinical diagnostic criteria for Costello syndrome have been published to date. GeneReviews lists suggestive findings. Prenatal ultrasound findings include increased nuchal thickness, polyhydramnios, ulnar deviation of the wrists, short humeri and femurs, and fetal tachycardia; preterm delivery is also listed. Postnatal findings include severe feeding difficulties, failure to thrive, short stature, relative or absolute macrocephaly, coarse facial features, curly or sparse fine hair, and loose soft skin with increased pigmentation. Other listed features include papillomata, diffuse hypotonia, joint laxity, ulnar deviation of the wrists and fingers, cardiac hypertrophy, congenital heart defects, arrhythmia, Chiari I malformation, hydrocephalus, syringomyelia, tethered cord and seizures. Neuroimaging findings include posterior fossa crowding with cerebellar tonsillar ectopia, tethered cord, and ventriculomegaly or hydrocephalus.

GeneReviews states that the clinical diagnosis can be established based on suggestive physical examination and imaging findings, or the molecular diagnosis can be confirmed by a heterozygous pathogenic or likely pathogenic variant in HRAS.

Prognosis is described here only from the GeneReviews clinical description. GeneReviews describes an approximate 15% lifetime risk for malignant tumors. It states that stature typically remains short even with growth hormone treatment, and that growth restriction persists even after nutrition is improved through supplemental feeding. Several features are described as changing over time: Chiari I malformation may develop over time, and scoliosis or kyphosis may increase with age. Postnatal cerebellar overgrowth can result in Chiari I malformation with associated hydrocephalus or syringomyelia. A separate natural history summary is not certified in this packet.

Certified active trial records are present for this condition, several of them listed under the broader RASopathy category. They include NCT05361811, a study of acceptance and commitment therapy for caregivers of children with a RASopathy (recruiting; National Cancer Institute); NCT04888936, the Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies (recruiting; National Cancer Institute); NCT04395495, the RASopathy Biorepository (recruiting; Children's Hospital Medical Center, Cincinnati); and NCT07005297, a Clinical Genetics Branch eligibility screening survey (not yet recruiting; National Cancer Institute). Titles alone do not establish the interventions studied or their efficacy. A patient organization is noted as maintaining a registry. Active clinical trials for this condition are listed on ClinicalTrials.gov.