Costello Syndrome – Definition
Costello syndrome (OMIM #218040) is an autosomal-dominant, hereditary developmental disorder with a distinct phenotype (see the clinical features) and a greatly increased risk of cancer.
Synonyms:
–
Genes:
HRAS
Gene product:
HRAS
Function:
Ras signaling pathway
Heredity:
Autosomal dominant
Prevalence:
Rare
Genotype-phenotype correlation:
The pathogenic variant G12A-HRAS appears to be associated with the highest risk of cancer.
Penetrance:
100% (for to the syndrome as opposed to developing the neoplasia)
Costello Syndrome – Diagnosis
Diagnosis
The diagnosis is made clinically based on the characteristic features (see below). In many cases, evidence of a pathogenic variant HRAS can be detected by sequence analysis or targeted pathogenic variant analysis.
Differential Diagnoses
- Noonan syndrome
- CFC syndrome
- Neurofibromatosis type 1
- Legius syndrome
Clinical Presentation
Clinical Presentation
In addition to the typical features of Noonan syndrome, children with Costello syndrome exhibit pronounced mental disability, feeding problems, frequent hypertrophic cardiomyopathy, tachycardia, typical skin and hair changes, and more course facial features. In addition, there is also a high risk of cancer, particularly embryonal rhabdomyosarcomas, neuroblastomas, and early-onset bladder cancer. Approximately 15% of patients develop a tumor by the age of 20.
Special Features of Treatment
The cancer treatment should be discussed with the principal investigator of the respective study. In theory, it may be worth considering treatment with an MEK inhibitor.
Diagnosis of Costello Syndrome- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of Costello Syndrome - What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Surveillance Recommendations
According to the latest AACR guidelines, the following screening tests are recommended for patients with pathogenic HRAS variants:
Rhabdomyosarcoma
- Children aged 0-14 years: Physical examination and abdominal and pelvic ultrasound every 3 months
If the quality of the ultrasound is poor, it can be replaced by an MRI scan. MRI is not the method of choice for early detection because of the sedation and side effects associated with it.
Neuroblastoma
- Children aged 0-6 years: Abdominal and pelvic ultrasound every 3 months
- Children aged 6-10 years: Abdominal and pelvic ultrasound every 6 months
- Children >10 years: No screening recommended
No testing for catecholamine metabolites as these are regularly elevated in Costello syndrome and therefore cannot be used as screening parameters.
Urothelial carcinoma of the bladder
- Urinalysis with cytology from 10 years of age annually (if possible as part of a clinical trial): perform cystoscopy in the presence of micro- or macrohaematuria
- Consider cystoscopy every 2 years from the age of 10
