Clinical Description
Costello syndrome affects multiple organ systems. Its typical presentation is characterized by diffuse hypotonia and severe feeding difficulties in infancy; short stature; developmental delay or intellectual disability; characteristic facial features; curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement (hypertrophic cardiomyopathy [HCM], congenital heart defect, and arrhythmia). Postnatal cerebellar overgrowth can result in Chiari I malformation with associated hydrocephalus or syringomyelia. An approximately 15% lifetime risk for malignant tumors includes rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults. Females and males are equally affected.
In rare instances, related to the underlying HRAS pathogenic variant, the presentation is more severe with intrauterine hydrops, postnatal pulmonary effusions with respiratory compromise, and severe progressive HCM, resulting in early lethality [Lo et al 2008]. Other rare variants are associated with a milder or attenuated phenotype, encompassing milder developmental delay, less striking facial features resembling Noonan syndrome, and a lower risk for malignancies [Gripp et al 2015, Bertola et al 2017].
Growth. Increased birth weight and head circumference (often >50th centile) for gestational age can lead to the categorization of Costello syndrome as macrosomia, which is misleading. Short stature is universal, delayed bone age is common [Johnson et al 1998], and testing may show partial or complete growth hormone deficiency.
Normative growth charts, derived from measurements of individuals who had not used growth hormone, document the very slow weight gain in early infancy, as well as the short stature with the 95th centile for individuals with Costello syndrome falling into the low normal range of typical age-matched individuals [Sammon et al 2012]. The reported adult height range is 135-150 cm [Hennekam 2003].
Failure to thrive and severe feeding difficulties are almost universal and typically necessitate the placement of a gastric feeding tube. Anecdotally, affected children have very high caloric needs. Even after nutrition is improved through supplemental feeding, growth restriction persists; therefore, aggressive feeding therapy is not effective.
Children are able to take oral feeds beginning between ages two and four years.
The first acceptable tastes are often strong (e.g., ketchup).
Neurologic. Most infants show hypotonia, irritability, developmental delay, and nystagmus.
Hypotonia may be severe with low muscle mass and a skeletal myopathy [van der Burgt et al 2007, Tidyman et al 2011].
Progressive postnatal cerebellar overgrowth may result in development of a Chiari I malformation, syringomyelia, and hydrocephalus [Gripp et al 2010]. Cerebellar abnormalities include tonsillar ectopia or Chiari malformation, occasionally associated with syringomyelia [Gripp et al 2000, Gripp et al 2002, Calandrelli et al 2015].
EEG abnormalities are seen in approximately one third of individuals; between 20% and 50% have seizures [Delrue et al 2003, Kawame et al 2003].
Cardiac abnormalities, which typically present in infancy or early childhood, may be recognized at any age. In 146 individuals with molecularly confirmed Costello syndrome, 87% had some type of cardiovascular abnormality. A congenital heart defect was present in 44%, with non-progressive valvar pulmonic stenosis being the most common finding. Rarely, atrial septal defects are seen. HCM comprising typical subaortic septal hypertrophy was noted in 61% and pathologic myocardial disarray was seen in 70% of those studied.
A few neonates can present with very severe HCM that is lethal. In other infants, progressively severe HCM and/or severe multifocal atrial tachycardia can lead to death in the first two years of life. Multifocal atrial tachycardia and other atrial tachycardia may be very concerning but are usually self-limited with aggressive treatment.
Pulmonic valve stenosis is usually mild to moderate, and infrequently requires surgery or interventional catheterization.
Most children with HCM have either mild or moderate involvement. Of great interest are the few with moderate-to-severe involvement who appear to have "remodeling" over many years which gives the impression of disappearance of (or marked decrease in) left ventricular obstruction. Only a small number of these individuals are being followed, and their long-term natural history is incomplete [Lin et al 2011]. In addition to the rare severe lethal form, HCM can be chronic (persistence of a gradient) or progressive (increase in gradient severity; 14/37 [37%]), stabilizing (without further increase in severity; 10/37 [27%]), or decreasing (resolving; 5/37 [14%]). Outcome was unavailable in 8/37 (22%) [Lin et al 2011], necessitating prudent surveillance.
Non-reentrant atrial tachycardias are generally self-limited, but may persist or worsen in approximately one fourth of affected individuals. Nonreentrant atrial tachycardia occurs independently of HCM [Levin et al 2018].
Older individuals (ages 16 to 40 years) with moderate HCM or new-onset arrhythmia (both atrial and ventricular) represent the greatest challenge and do not constitute a predictable outcome "phenotype" until more information is obtained. Hypertension is not uncommon.
Mild-moderate aortic dilatation not associated with bicuspid aortic valve is a recent cardiovascular finding [Lin et al 2011] that occurs in approximately 5% of affected individuals.
Primary vascular disease has rarely been reported. In one individual with early lethal Costello syndrome due to the rare p.Gly12Glu variant, pulmonary vascular dysplasia affecting small arteries and veins with abnormal elastin distribution was seen in the absence of significant HCM [Weaver et al 2014].
Developmental delay or intellectual disability is present in all individuals [Axelrad et al 2004, Axelrad et al 2007, Axelrad et al 2009, Axelrad et al 2011].
Recognition memory in verbal memory functioning is relatively preserved compared to other cognitive tasks [Schwartz et al 2013].
The onset of speech frequently coincides with the willingness to feed orally.
Separation anxiety, seen in 39% of individuals with Costello syndrome, is more common in males than in females [Axelrad et al 2011].
Behavioral/social issues. Many children younger than age four years meet criteria on a screening tool for autism spectrum disorder (ASD). There is a positive correlation with the need for gastrostomy tube and inability to walk independently. In contrast, none of the children older than age four years met criteria for autism, suggesting that early signs consistent with ASD tend to resolve by age four years [Schwartz et al 2017].
Limited detailed information is available on the quality of life in older individuals with Costello syndrome. Quality of life in individuals age 16-34 years is compromised by four factors [Hopkins et al 2010]: limited relationships outside of the immediate circle of friends and family, lack of independence, male sex, and the presence of major medical issues [Hopkins et al 2010]. Functional limitations from orthopedic issues regarding mobility, as well as limitations in the social and cognitive domains, were documented using normative scales [Johnson et al 2015].
Dermatologic. Papillomata, absent in infancy, appear in young children, usually in the perinasal region and less commonly in the perianal region, torso, and extremities. While papillomata are mostly of cosmetic concern, they can become noticeable and at times bothersome.
Palmoplantar keratoderma is common and can affect function in severe cases [Marukian et al 2017]. Additional findings include acanthosis nigricans and thick toenails.
Musculoskeletal. Individuals with Costello syndrome have very loose joints, particularly involving the fingers. Ulnar deviation of the wrists and fingers is also common. Developmental hip dysplasia may result in severe pain and prevent ambulation. Tight Achilles tendons may develop.
More than half of a cohort of 43 individuals examined by an orthopedic surgeon with review of radiographs as available showed ligamentous laxity, scoliosis, kyphosis, characteristic hand and wrist deformities, shoulder and elbow contractures, tight Achilles tendons, and flat feet [Detweiler et al 2013]. Hip dysplasia, seen in 45%, was not universally congenital but acquired in some.
Osteoporosis is common in young adults with Costello syndrome [White et al 2005, Detweiler et al 2013]. In adults ranging in age from 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]. In a study of nine individuals with Costello syndrome who had dual-energy X-ray absorptiometry, all showed significantly decreased bone mineral density compared to age-matched controls [Leoni et al 2014].
Respiratory. Seven of ten individuals ages three to 29 years undergoing polysomnography in the sleep laboratory had obstructive events [Della Marca et al 2006]. A literature review showed respiratory complications in 78% of neonates, with the majority resolving and more severe complications only in those with rare HRAS pathogenic variants associated with the severe phenotype [Gomez-Ospina et al 2016] (see Genotype-Phenotype Correlations).
Upper-airway obstruction was seen more often in older children and young adults [Gomez-Ospina et al 2016].
Endocrine. Neonatal hyperinsulinism has been reported [Alexander et al 2005, Sheffield et al 2015] and, in one case, was correlated to focal uniparental disomy for 11p within the pancreatic nodule [Gripp et al 2016].
In older individuals, hypoglycemia may be related to growth hormone deficiency. Growth hormone deficiency is common (30%-50%) [Estep et al 2006, Gripp et al 2010].
Several affected individuals have been diagnosed with hypothyroidism requiring treatment with hormone replacement.
Other endocrine issues may include delayed or dysregulated puberty including precocious puberty.
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 approximately 15% over the lifetime of individuals with an identified HRAS pathogenic variant [Gripp et al 2006a]. Kratz et al [2011] reviewed published cases and confirmed the 15% cumulative incidence of cancer in individuals with Costello syndrome by age 20 years. Rhabdomyosarcoma occurs most frequently, followed by neuroblastoma, transitional cell carcinoma of the bladder, and other solid tumors [Gripp 2005].
Rhabdomyosarcoma and neuroblastoma, tumors of early childhood, present in Costello syndrome at ages comparable to the general population. In contrast, transitional cell carcinoma of the bladder, which occurs in older adults (70% age >65 years) in the general population, may be found in adolescents with Costello syndrome. The ages at presentation in the three individuals with Costello syndrome with transitional cell carcinoma of the bladder were ten, 11, and 16 years.
Other
Life expectancy. Causes of death reported in 10% of individuals included in an analysis of cardiovascular findings [Lin et al 2011] and in 20% of affected individuals described in the literature were: HCM in association with neoplasia, coronary artery fibromuscular dysplasia, multifocal tachycardia, neoplasia, pulmonary cause, and multiorgan failure.
Somatic mosaicism. Individuals with somatic mosaicism for an HRAS pathogenic variant may show patchy skin findings only (as reported in the father of an individual with typical Costello syndrome [Sol-Church et al 2009]) [Bertola et al 2017], or findings indistinguishable from Costello syndrome caused by a germline pathogenic variant [Girisha et al 2010].
One individual with somatic mosaicism (20%-30% of DNA derived from buccal cells exhibited the HRAS variant p.Gly12Ser, which was not detected in DNA derived from blood cells) had typical findings attributed to Costello syndrome (intellectual disability, short stature, sparse hair, coarse facial features, nasal papillomata, and tight Achilles tendons) as well as atypical findings attributed to mosaicism (microcephaly, streaky areas of skin hypo- and hyperpigmentation, and normal menarche with subsequent regular menses) [Gripp et al 2006b].
Neuroimaging. A systematic review of brain and spinal cord MRI studies revealed posterior fossa crowding with cerebellar tonsillar herniation in 27/28 (96%) [Gripp et al 2010]. In a majority of those with serial studies this crowding progressed. Due to the progressive nature of the cerebellar overgrowth – which likely results from abnormal cell differentiation as reported by Paquin et al [2009] – the sequelae of posterior fossa crowding included hydrocephalus requiring shunt placement or ventriculostomy (7/28), Chiari I malformation (9/28), and syringomyelia (7/28).
Tethered cord is relatively common.