Clinical characteristics.

While the majority of individuals with Costello syndrome share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a milder or attenuated phenotype to a severe phenotype with early lethal complications. Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including: cardiac hypertrophy (usually typical hypertrophic cardiomyopathy), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults.

Diagnosis/testing.

The diagnosis of Costello syndrome is established in a proband with suggestive clinical findings and a heterozygous HRAS pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: Failure to thrive is the most common and challenging clinical problem; most infants require nasogastric or gastrostomy feeding; many require Nissen fundoplication. Treatment of cardiac manifestations and malignancy is routine. Ulnar deviation of the wrists and fingers often requires early bracing and occupational and/or physical therapy; tight Achilles tendons may require surgical tendon lengthening. Developmental disability requires early-intervention programs and individualized education strategies. Recurrent facial papillomata may require routine removal with dry ice. Hemodynamically significant valvar stenoses require antibiotic prophylaxis for subacute bacterial endocarditis; anesthesia may pose a risk to those with hypertrophic cardiomyopathy or those predisposed to some types of atrial tachycardia.

Surveillance: Monitoring for neonatal hypoglycemia; echocardiography with electrocardiogram at diagnosis with subsequent follow up by a cardiologist who is aware of the spectrum of cardiac disease and its natural history; abdominal and pelvic ultrasound examinations to screen for rhabdomyosarcoma and neuroblastoma every three to six months until age eight to ten years may be considered; annual urinalysis for evidence of hematuria to screen for bladder cancer beginning at age ten years.

Genetic counseling.

Costello syndrome is inherited in an autosomal dominant manner. To date, most probands with Costello syndrome have the disorder as the result of a de novo pathogenic variant; although parents of probands are not affected, vertical transmission has been reported in two families with the rare, attenuated phenotype. Because Costello syndrome is typically caused by a de novo pathogenic variant, the risk to the sibs of a proband is presumed to be small; however, recurrence in sibs has been reported and is suspected to be the result of germline mosaicism in a parent. Individuals with Costello syndrome typically do not reproduce. Once an HRAS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Costello syndrome should be suspected when the following findings are present.

Prenatal findings

• On ultrasound examination:
  • Increased nuchal thickness
  • Polyhydramnios (>90%)
  • Characteristic ulnar deviation of the wrists
  • Short humeri and femurs
• Fetal tachycardia (various forms of atrial tachycardia)
• Preterm delivery

Postnatal findings

• Severe postnatal feeding difficulties extending throughout early childhood
• Failure to thrive
• Short stature
• Macrocephaly (relative)
• Coarse facial features (see Figures 1 and 2)
• Curly or sparse, fine hair

Figure 1.

Four girls who attended the 2005 Costello Syndrome Conference in St Louis show several characteristic features, including the friendly, sociable personality associated with Costello syndrome. A. The two girls, both age ten years, have chubby cheeks, full (more...)

Figure 2.

Typical facial features seen in an eight-year-old boy of northern European background (A) and a nearly 11-year-old Hispanic girl (B) with Costello syndrome Gripp & Lin [2012], reprinted with permission from Genetics in Medicine

Skin

• Loose, soft skin
• Increased pigmentation
• Deep palmar and plantar creases
• Papillomata of face, perianal region (typically absent in infancy but may appear in childhood)
• Hyperkeratosis and calluses
• Premature aging, hair loss

Musculoskeletal system

• Diffuse hypotonia, joint laxity, and low muscle mass
• Ulnar deviation of wrists and fingers, splayed fingers resulting in characteristic hand posture
• Spatulate finger pads, abnormal fingernails
• Tight Achilles tendons, often developing throughout childhood
• Positional foot deformity
• Vertical talus
• Kyphoscoliosis
• Pectus carinatum, pectus excavatum, asymmetric rib cage
• Developmental hip dysplasia

Cardiovascular system

• Cardiac hypertrophy; usually typical hypertrophic cardiomyopathy (i.e., idiopathic subaortic stenosis, asymmetric septal hypertrophy), although other forms (i.e., biventricular) have been reported
• Congenital heart defect; usually valvar pulmonic stenosis
• Arrhythmia, usually supraventricular tachycardia. Most distinctive is chaotic atrial rhythm/multifocal atrial tachycardia, or ectopic atrial tachycardia (known as non-reentrant tachycardias)
• Aortic dilation, mild; noted in fewer than 10% of individuals
• Hypertension

Neurologic

• Chiari I malformation, which may develop over time
• Hydrocephalus
• Syringomyelia
• Seizures
• Tethered cord

Tumors. Increased occurrence of malignant solid tumors

Psychomotor development

• Developmental delay or intellectual disability
• Sociable, outgoing personality
• Findings suggestive of autism spectrum disorder in early infancy that improve by age four years

Establishing the Diagnosis

The diagnosis of Costello syndrome is established in a proband with suggestive clinical findings and a heterozygous HRAS pathogenic variant identified by molecular genetic testing (see Table 1) [Aoki et al 2005, Kerr et al 2008, Grant et al 2018].

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Costello syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Costello syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

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 retardation 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 dilation 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 gender, and the presence of major medical issues [Hopkins et al 2010]. Functional limitations from orthopedic problems 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 patients 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

• Pyloric stenosis occurs more commonly than in the general population [Gripp et al 2008].
• Adult-onset gastroesophageal reflux was present in four individuals in the series of White et al [2005]; additional cases are known [Author, personal observation].
• Dental abnormalities, including enamel defects, occur frequently. Malocclusion with maxillary first molars positioned posteriorly to the mandibular first molars is common and may contribute to obstructive sleep apnea [Goodwin et al 2014]. Excessive secretions are often noted [Johnson et al 1998].
• In addition to the common vision disturbance and nystagmus, less common eye abnormalities include retinal dystrophy [Pierpont et al 2017] and keratoconus [Gripp & Demmer 2013].
• Adolescents may appear older than their chronologic age because of worsening kyphoscoliosis, sparse hair, and prematurely aged skin.

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.

Genotype-Phenotype Correlations

In a systematic review of 146 individuals with an HRAS pathogenic variant, no apparent correlation was observed between the specific variant and the variables studied (HCM, multifocal tachycardia, aortic dilation [Lin et al 2011] (see Table V). In some cases, small numbers prevented formal statistical analysis.

Because few affected individuals with HRAS pathogenic variants other than p.Gly12Ser have been identified, limited genotype-phenotype correlations have been established:

• Kerr et al [2006] suggested that the risk for malignant tumors may be higher in individuals with the p.Gly12Ala pathogenic variant (4/7) than in those with the p.Gly12Ser variant (4/65). No individuals with p.Gly13Cys have developed a malignant tumor to date [Gripp et al 2011a].
• The suggestion of Lo et al [2008] that a more severe neonatal phenotype may be associated with certain rare pathogenic variants, including p.Gly12Ala and p.Gly12Cys, was confirmed by McCormick et al [2013].
• The possibility of a milder or attenuated phenotype was noted in individuals with the variants p.Thr58Ile and p.Ala146Val [Gripp et al 2008], as well as p.Gly60Val [Gripp et al 2017].
• Two unrelated individuals with p.Glu37dup shared phenotypic findings including very sparse hair and facial features that appear less coarse than in most other individuals with Costello syndrome [Gremer et al 2010].
• The p.Gly13 amino acid appears to be the second most commonly substituted, with p.Gly13Cys being the most frequent change seen at this codon. Gripp et al [2011a] reviewed physical findings in 12 individuals with this variant and noted a distinctive phenotype including dolichocilia (extremely long eye lashes, often requiring trimming) and loose anagen hair syndrome; neither of these findings had previously been noted in individuals with Costello syndrome. Papillomata or multifocal atrial tachycardia have not yet been seen in individuals with p.Gly13Cys, and fewer had short stature. Compared to individuals with the very common p.Gly12Ser variant, these differences are statistically significant.
• Five individuals with the rare p.Gly13Asp missense variant showed an apparently milder presentation and none had a malignancy [Bertola et al 2017].

Penetrance

Penetrance is complete [Aoki et al 2005, Estep et al 2006, Gripp et al 2006a, Kerr et al 2006].

Nomenclature

Costello reported the first individuals with this condition in 1971, providing follow up in 1977 and 1996 [Costello 1971, Costello 1977, Costello 1996]. The eponym was applied for the first time by Der Kaloustian et al [1991].

Early examples of Costello syndrome were reported as:

• AMICABLE syndrome (amicable personality, mental retardation, impaired swallowing, cardiomyopathy, aortic defects, bulk, large lips and lobules, ectodermal defects) [Hall et al 1990];
• Faciocutaneous-skeletal syndrome [Borochowitz et al 1992].

Prevalence

The birth prevalence of Costello syndrome is estimated at 1:380,000 in the UK [Giannoulatou et al 2013]. In contrast, an epidemiologic study using national surveys suggested a prevalence of 1:1,230,000 in Japan [Abe et al 2011]; this may be an underestimate due to ascertainment procedures.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Costello syndrome, the evaluations summarized Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.