Search for a rare disease
Costello syndrome (CS) is a rare multisystemic disorder characterized by failure to thrive, short stature, developmental delay or intellectual disability, joint laxity, soft skin, and distinctive facial features. Cardiac and neurological involvement is common and there is an increased lifetime risk of certain tumors.
The estimated number of patients worldwide is 300. Estimated birth prevalence has been reported to be 1/300,000 to 1/1.25 million.
Patients have above-average birth weight and usually present with severe postnatal feeding difficulties and failure to thrive, leading to weight loss. 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, largemouth 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 ventriculomegaly, valvular pulmonary stenosis (see this term), arrhythmia (ectopic or multifocal atrial tachycardia; see these terms), hypertrophic cardiomyopathy (see this term) and rarely aortic dilation. The reported neurological signs are hydrocephalus, seizures, Arnold-Chiari malformation type I (see this term), syringomyelia, and tethered spinal cord (see these terms). 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. A 10-15% increased risk for solid malignant tumors (embryonal rhabdomyosarcoma, neuroblastoma in early childhood and transitional cell carcinoma of the bladder in adolescence) is reported (see these terms).
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.
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.
Costello syndrome shows significant clinical overlap with Noonan syndrome and cardiofaciocutaneous syndrome (see these terms). Other disorders to consider include Beckwith-Wiedemann, Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome) and Simpson-Golabi-Behmel syndromes (see these terms).
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.
An autosomal dominant pattern of inheritance is found, typically due to de novo dominant mutations.
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.
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.