Costello syndrome (CS) is a rare disorder (so-called RAS-opathy, see below), affecting up to 300 people worldwide. First described by Dr Jack Costello in 1977, the syndrome is characterised by failure to thrive (FTT), poor feeding, short stature, developmental delay, distinctive facial features, excessive loose skin, cardiac abnormalities, and an increased risk of tumour development.
RAS is a family of genes coding for small GTPases and includes amongst others HRAS. The HRAS gene is a proto-oncogene, which forms part of the MAPK (mitogen activated protein kinase) signalling pathway. Up-regulation of this signalling pathway causes unopposed cell growth, causing tumour predisposition. The MAPK pathway is also the site of mutations causing both CFC and Noonan syndrome. CS can be caused by a number of mutations in the HRAS gene. Most mutations do occur de novo, but there is some evidence that a minority are inherited in an autosomal dominant manner. Patients with CS are born large for gestational age, and there is a strong association with polyhydramnios and preterm labour. Growth later slows due to feeding difficulties. Head circumference is affected to a lesser degree than height and weight, which gives rise to relative macrocephaly. Growth Hormone (GH) deficiency can cause neonatal hypoglycaemia, and con¬tributes to growth retardation. The disease is characterised by distinctive facial features including downslanting palpebral fissures, epicanthic folds, ptosis, flattened nasal bridge (hypertelorism), low set ears, thick lips, macroglossia and short neck. Facial features become increasingly coarse with age, hair thins and patients begin to look older than their biological age. They are often hypotonic, adopting a hyperextended arched posture. They have increased ligamentous laxity, and deep palmar and plantar creases. They also have excessive loose soft tissue particularly around the hands but this feature, despite being one of the most classical features of CS, doesn’t manifest until after infancy, making the diagnosis difficult in the first year of life. Scoliosis, hip dysplasia and club foot are present frequently. Cardiac involvement is a common feature of CS and may comprise congenital pulmonary stenosis, hypertrophic obstructive cardiomyopathy (HOCM) and superventricular arrhythmias. Latter are typically multifocal, may occur independently of cardiomyopathy and may cause sudden cardiac death in patients with CS. Neurologic deficits may include nystagmus, hypotonia, epilepsy and cognitive delays. Ex-pressive language is particularly affected. Structural brain abnormalities may include relative ventriculomegaly, macrocephaly, syrinx, cerebellar tonsillar herniation and posterior fossa crowding which may require ventriculostomy or a ventriculoperitoneal shunt. Dysphagia and gastro-oesophageal reflux may be present. Excessive tissue may result in abnormalities of the glottis aperture. Laryngeal papillomas have been reported. Obstructive sleep apnoea is a common feature. The papillomata that are typical of CS occur at bodily openings, but develop only in later childhood making the distinction between CS, CFC and Noonan syndrome difficult in infancy. As a result of the unopposed activation of the MAPK pathway, patients with CS have an increased risk of tumour formation. Typical are rhabdomyosarcomas, while neuroblastomas and bladder transitional cell carcinomas also may occur.