Natural History
Females and males are equally affected. Costello syndrome can theoretically be recognized in the fetus, is usually diagnosed in the young child, and changes with age, with older individuals displaying features of premature aging.
Prenatally, increased nuchal thickness, polyhydramnios (>90%), characteristic ulnar deviation of the wrists, and short humeri and femurs can be seen on prenatal ultrasonography. Because most features of the fetal phenotype are not unique and Costello syndrome is rare, the diagnosis is often not considered prenatally. Cardiac hypertrophy has not been reported, but fetal tachycardia (various forms of atrial tachycardia) has been detected in at least five fetuses subsequently diagnosed with Costello syndrome, which increases the index of suspicion of the diagnosis.
In the neonate, increased birth weight and head circumference (often >50th centile) for gestational age can lead to the categorization of macrosomia. Hypoglycemia is common. Failure to thrive and severe feeding difficulties are almost universal. Characteristic physical findings include a relatively high forehead, low nasal bridge, epicanthal folds, prominent lips and a wide mouth, ulnar deviation of wrists and fingers, loose-appearing skin with deep palmar and plantar creases, and cryptorchidism.
In infancy, severe feeding difficulties may lead to a marasmic appearance. Most infants display hypotonia, irritability, developmental delay, and nystagmus with delayed visual maturation improving with age.
Cardiac abnormalities typically present in infancy or early childhood but may be recognized at any age. Approximately 75% of HRAS mutation-positive individuals with Costello syndrome have had some type of cardiac abnormality [Gripp, Lin et al 2006], compared to 60% of individuals with Costello syndrome diagnosed by clinical findings alone [Lin et al 2002]. In the more recent HRAS mutation-positive series, congenital heart defects (usually pulmonic stenosis) were noted in 25%, arrhythmia in 42%, and hypertrophic cardiomyopathy in 47%, compared to the earlier clinical series in which each of the above abnormalities was reported in about 30% of affected individuals.
In childhood, individuals are able to take oral feeds beginning between age two and four years. The first acceptable tastes are often strong (e.g., ketchup). The onset of speech often coincides with the willingness to feed orally. Short stature is universal, delayed bone age is common [Johnson et al 1998], and testing may show partial or complete growth hormone deficiency.
Atypically, cardiac hypertrophy detected in infancy as mild non-obstructive or non-progressive thickening may progress to severe lethal hypertrophy with "storage" [Hinek et al 2005]; most hypertrophic hearts remain stable or progress mildly. The complete natural history of cardiac hypertrophy in Costello syndrome has not been defined, but adult onset of hypertrophy has not been documented.
Papillomata absent in infancy appear in young children. Acanthosis nigricans, thick calluses and toenails, strong body odor, and tight Achilles tendons may develop.
Developmental delay or mental retardation is present in all individuals [Axelrad et al 2004].
EEG abnormalities are seen in about one-third of individuals; between 20% and 50% have seizures [Delrue et al 2003, Kawame et al 2003].
Seven of ten individuals ages three to 29 years undergoing polysomnography in the sleep laboratory had obstructive events [Della Marca et al 2006].
Dental abnormalities, including enamel defects, occur frequently. Excessive secretions are often noted [Johnson et al 1998].
Individuals with Costello syndrome have very loose joints, particularly the fingers. Ulnar deviation of the wrists and fingers is common.
Adolescents often show delayed or disordered puberty, and may appear older than their chronologic age because of worsening kyphoscoliosis, sparse hair, and prematurely aged skin.
Adults. In 17 adults ranging from age 16 to 40 years, all eight individuals who had a bone density measurement had abnormal results that suggested osteoporosis or osteopenia; three had bone pain, vertebral fractures, and height loss [White et al 2005].
Adult-onset gastroeosphageal reflux was present in four individuals in the series of White et al (2005); additional cases are known [author, personal observation].
The reported adult height range is 135-150 cm [Hennekam 2003].
Solid tumors. Benign and malignant solid tumors occur with far greater frequency in individuals with Costello syndrome than in the general population. The overall tumor incidence is about 15% in persons with an identified HRAS mutation [Gripp, Lin et al 2006]. Rhabdomyosarcoma occurs most frequently, followed by neuroblastoma and transitional cell carcinoma of the bladder, and other solid tumors [for review see Gripp 2005]. Rhabdomyosarcoma and neuroblastoma are tumors of early childhood, presenting in Costello syndrome at ages comparable to the general population. In contrast, transitional cell carcinoma of the bladder occurs in older adults (70% >65 years) in the general population, whereas it occurs in adolescents with Costello syndrome. The ages at presentation in the three reported cases were ten, eleven, and sixteen years.
Neuroimaging. Typical findings include cerebral atrophy and dilated ventricles; however, shunting for hydrocephalus is rare [Delrue et al 2003]. Cerebellar abnormalities include tonsillar ectopia or Chiari malformation, occasionally associated with syringomyelia [Gripp et al 2000, Gripp et al 2002, Delrue et al 2003].