Costello syndrome (ORPHA:3071)
A rare syndrome with intellectual disability, characterized by failure to thrive, short stature, joint laxity, soft skin, and distinctive facial features. Cardiac and neurological involvement is common and there is an increased lifetime risk of certain tumors. Costello syndrome belongs to the RASopathies, a group of conditions resulting from germline derived point mutations affecting the RAS-mitogen activated protein kinase pathway.
Epidemiology
Costello syndrome (CS) estimated number of patients worldwide is 300. Estimated birth prevalence has been reported to be 1/300,000 to 1/1 250 000.
Clinical description
Patients have above-average birth weight from mild hydrops and usually present with severe postnatal feeding difficulties and failure to thrive. The severe feeding difficulties typically necessitate the placement of a feeding tube. Developmental delay with short stature and mild to moderate intellectual disability are present in most cases. Features include relative macrocephaly, coarse facial features (epicanthal folds, full cheeks, low set and prominent ears, upturned nasal nasal tip, large mouth with prominent lips), curly or sparse, fine hair, loose soft skin with deep palmar and plantar creases, and papillomata (torso, extremities, perinasal and/or perianal region generally during childhood). Musculoskeletal features include joint laxity and ulnar deviation of wrists and fingers, hip dysplasia, and kyphoscoliosis in older individuals. Cardiovascular manifestations include valvular pulmonary stenosis, arrhythmia (ectopic or multifocal atrial tachycardia), hypertrophic cardiomyopathy and rarely aortic dilation. The reported neurological signs are hydrocephalus, seizures, Arnold-Chiari malformation type I, syringomyelia, and tethered spinal cord. In later childhood, patients often develop tight Achilles tendons that may require surgical correction. Puberty is often delayed or disordered. The disorder progresses with age and patients often show signs of premature ageing, osteoporosis and osteopenia. An increased risk of about 10-15% for solid malignant tumors (embryonal rhabdomyosarcoma, neuroblastoma in early childhood and transitional cell carcinoma of the bladder in adolescence) is reported.
Etiology
CS is caused by heterozygous germline mutations in the proto-oncogene HRAS (11p15.5) involved in controlling cell growth and division in multiple organ systems. The most common variant results in the p.Gly12Ser amino acid substitution, present in about 80% of patients.
Diagnostic methods
Diagnosis is based on the constellation of clinical findings, although no single feature is characteristic of the disorder. Diagnosis can be confirmed by molecular genetic testing.
Differential diagnosis
Costello syndrome shows significant clinical overlap with Noonan syndrome and cardiofaciocutaneous syndrome, which are also RASopathies. Other disorders to consider include Beckwith-Wiedemann, Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome) and Simpson-Golabi-Behmel syndromes.
Antenatal diagnosis
Prenatal diagnosis is possible if the disease-causing mutation has been identified in an affected family member, or if the diagnosis of CS is suspected prenatally and HRAS sequence analysis is performed.
Genetic counseling
An autosomal dominant pattern of inheritance may be found, typically due to de novo dominant mutations. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Failure to thrive and cardiac manifestations should be treated with standard measures. Specific educational and intervention strategies may be required for intellectual development and developmental delay. Facial papillomata may require removal with cryotherapy or electrocoagulation. Abdominal and pelvic ultrasound examinations can be considered to screen for embryonal rhabdomyosarcoma and neuroblastoma until 8-10 years of age. Neoplastic complications are treated with standard approaches. Tethered cord may be screened by imaging. Hip dysplasia should be evaluated by an orthopedist.
Prognosis
The risk of neoplasia and severe hypertrophic cardiomyopathy negatively affects the prognosis. The prognosis varies by the specific missense mutations, with neonatal lethal phenotypes and attenuated phenotypes reported.

                            Last update: 
                            September 2019


                            - Expert reviewer(s): 
                            Dr Karen GRIPP