HRAS-Related Costello Syndrome

Clinical characteristics.

While the majority of individuals with HRAS-related Costello syndrome (Costello syndrome) share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a mild 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 hypertrophic cardiomyopathy), congenital heart defects (usually valvular pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially abnormal 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.

Targeted therapy: Trametinib (MEK inhibitor) for treatment of hypertrophic cardiomyopathy with heart failure that is refractory to standard treatment.

Supportive care: Failure to thrive is the most common and challenging clinical problem; most infants require nasogastric or gastrostomy feeding, and many require Nissen fundoplication. Cardiac manifestations and malignancies are managed through standard protocols. 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 delay requires early intervention programs and individualized education strategies. Recurrent facial papillomata may require removal. General anesthesia may pose a risk to those with hypertrophic cardiomyopathy or those predisposed to types of atrial tachycardia.

Surveillance: Monitoring for neonatal hypoglycemia; echocardiography with electrocardiogram at the time of diagnosis with subsequent follow up by a cardiologist; 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 an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, an individual with Costello syndrome has the disorder as the result of an HRAS pathogenic variant inherited from a heterozygous parent; vertical transmission has been reported in two families with the rare, attenuated phenotype of Costello syndrome. If the HRAS pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Recurrence of Costello syndrome in sibs has been reported and is suspected to be the result of germline mosaicism in a parent. Individuals with classic Costello syndrome typically do not reproduce. If an HRAS pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Costello syndrome should be suspected in probands with the following clinical and neuroimaging findings and family history.

Clinical Findings

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 or absolute)
• 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 full cheeks, full (more...)

Figure 2.

Typical facial features seen in a boy age eight years of northern European background (A) and a Hispanic girl age ~11 years (B) with Costello syndrome Reprinted with permission from Gripp & Lin [2012]

Skin

• Loose, soft skin
• Increased pigmentation
• Deep palmar and plantar creases
• Papillomata of face and/or perianal region (typically absent in infancy but may appear in childhood)
• Hyperkeratosis and calluses
• Premature aging with 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 evolving throughout childhood)
• Positional foot deformity
• Vertical talus
• Kyphoscoliosis
• Pectus carinatum, pectus excavatum, asymmetric rib cage
• Developmental hip dysplasia

Cardiovascular system

• Cardiac hypertrophy, usually hypertrophic cardiomyopathy (i.e., idiopathic subaortic stenosis, asymmetric septal hypertrophy), although other forms (e.g., biventricular hypertrophy) have been reported
• Congenital heart defects, usually valvular 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 dilatation (typically mild, noted in fewer than 10% of individuals)
• Hypertension

Neurologic

• Chiari I malformation (may develop over time)
• Hydrocephalus
• Syringomyelia
• Tethered cord
• Seizures

Tumors. Increased occurrence of malignant solid tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults

Psychomotor development

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

Neuroimaging findings

• Posterior fossa crowding with cerebellar tonsillar ectopia or herniation
• Tethered cord
• Ventriculomegaly or hydrocephalus

Establishing the Diagnosis

The clinical diagnosis of Costello syndrome can be established in a proband based on suggestive physical exam and imaging findings, or the molecular diagnosis can be confirmed in a proband with a heterozygous pathogenic (or likely pathogenic) variant in HRAS [Aoki et al 2005, Kerr et al 2008, Grant et al 2018] (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous HRAS variant of uncertain significance does not establish or rule out the diagnosis.

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 (see Option 1), whereas genomic testing does not (see Option 2).

Option 2

When the diagnosis of Costello syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of reported HRAS pathogenic variants are within the coding region and are likely to be identified by exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Costello Syndrome

Clinical Description

HRAS-related Costello syndrome (Costello syndrome) affects multiple organ systems. The 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 (including hypertrophic cardiomyopathy [HCM], congenital heart defects, and arrhythmia). Postnatal cerebellar overgrowth can result in Chiari I malformation with associated hydrocephalus or syringomyelia. There is an approximate 15% lifetime risk for malignant tumors in individuals with Costello syndrome including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults.

To date, more than 100 individuals have been identified with a pathogenic variant in HRAS [Aoki et al 2005, Estep et al 2006, Gripp et al 2006a, Kerr et al 2006, van Steensel et al 2006, Lin et al 2011, Weaver et al 2014]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

Costello Syndrome: Frequency of Select Features

Growth. Increased birth weight and head circumference (often >50th centile) for gestational age can lead to the categorization of Costello syndrome as a macrosomia disorder, which is misleading. Increased birth weight is instead related to fetal hydrops. Short stature is universal, delayed bone age is common [Johnson et al 1998], and testing may show partial or complete growth hormone deficiency.

Failure to thrive and severe feeding difficulties are almost universal and typically require a gastrostomy tube. Anecdotally, affected children have very high caloric needs. Even after nutrition is improved through supplemental feeding, growth restriction persists; therefore, aggressive (hypercaloric) feeding therapy is not effective. Children are typically able to take oral feeds beginning between ages two and four years.

Normative growth charts, derived from measurements of individuals who had not used growth hormone, document very slow weight gain in early infancy as well as 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].

Neurologic. Most infants have hypotonia, irritability, developmental delay, and nystagmus.

Hypotonia may be severe with low muscle mass and a skeletal myopathy phenotype [van der Burgt et al 2007, Tidyman et al 2011].

Progressive postnatal cerebellar overgrowth may result in the development of 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 valvular pulmonic stenosis being the most common finding. Rarely, atrial septal defects are seen. Hypertrophic cardiomyopathy (HCM) comprising typical subaortic septal hypertrophy was noted in 61% and pathologic myocardial disarray was seen in 70% of those studied [Lin et al 2011].

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. Use of the MEK inhibitor trametinib may be considered in these individuals [Geddes et al 2023] (see Targeted Therapy). Multifocal atrial tachycardia and other types pf 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 that 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 (persistent in its gradient severity) or progressive (increasing 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. Non-reentrant 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 the outcomes in these individuals are not known. Hypertension is not uncommon.

Mild-to-moderate aortic dilatation not associated with bicuspid aortic valve is reported in approximately 5% of affected individuals [Lin et al 2011].

Primary vascular disease has rarely been reported.

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].

While the underlying mechanism in Costello syndrome is not known, the skills necessary for swallowing and speech development are both affected and appear closely correlated. The onset of speech frequently coincides with the willingness to feed orally.

Behavioral/social issues. Many children younger than age four years meet criteria for autism spectrum disorder (ASD). In contrast, none of the children older than age four years met criteria for ASD, suggesting that early signs consistent with ASD tend to resolve by age four years [Schwartz et al 2017].

Separation anxiety, seen in 39% of individuals with Costello syndrome, is more common in males than in females [Axelrad et al 2011]. In older individuals, anxiety was reported in 65% [Shikany et al 2020].

Limited detailed information is available on the quality of life in older individuals with Costello syndrome. Quality of life in individuals aged 16-34 years is compromised by four factors: 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 related to mobility, as well as limitations in social and cognitive domains, were documented using normative scales [Johnson et al 2015]. A query of 20 individuals aged 16 years or older found one individual living independently, three living in a residential setting, and 16 living with family [Shikany et al 2020]. A history of seizures was reported in five (25%) and Chiari I malformation in 10 (50%). Mobility issues included the use of a walker in one (5%), wheelchair or stroller for distance only in nine (45%), wheelchair reliance in three (15%), and no mobility issues in seven individuals (35%) [Shikany et al 2020].

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 and were either present or previously surgically corrected in 11 of 17 individuals (65%) [Leoni et al 2021].

More than half of a cohort of 43 individuals examined by an orthopedic surgeon with review of available radiographs 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% of individuals, 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 bone density measurements 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 scans performed, all showed significantly decreased bone mineral density compared to age-matched controls [Leoni et al 2014]. A review of older individuals identified osteoporosis or osteopenia in 9/20 (45%) and kyphosis or scoliosis in 15/20 (75%) [Shikany et al 2020].

Respiratory. Seven of ten individuals ages three to 29 years who underwent polysomnography had obstructive sleep apnea [Della Marca et al 2006]. A literature review showed respiratory complications in 78% of neonates, with the majority resolving over time [Gomez-Ospina et al 2016].

More severe complications (intrauterine hydrops, postnatal pulmonary effusions with respiratory compromise, and severe progressive HCM) have been reported in a few individuals with HRAS pathogenic variants associated with the severe Costello syndrome 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 with 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 thyroid 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 the general population. The overall tumor incidence is approximately 15% over the lifetime of individuals with HRAS pathogenic variants [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].

In a meta-analysis of 234 publications reporting 621 individuals from 35 countries, more than 9% had cancer, including rhabdomyosarcoma, transitional cell carcinoma of the bladder, and neuroblastoma. Cumulative incidence by age 20 years was 13% for cancer and 11% for cancer-free death. Death rate was 3%-4% until age three years. Survival after cancer appeared reduced [Astiazaran-Symonds et al 2023].

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% occurs in adults 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. A review of cystoscopy findings in 13 individuals aged ten years or older found a macroscopic bladder lesion in 10/13 on first exam. Histology showed low-grade epithelial dysplasia in 7/10 (70%) and papillary urothelial neoplasm of low-malignant potential (PUNLMP) or low-grade bladder cancer in 3/10 (30%) [Leoni et al 2022].

Other

• Pyloric stenosis occurs more commonly in Costello syndrome than in the general population [Gripp et al 2008].
• Craniosynostosis of the sagittal and/or coronal sutures requiring surgical repair has been reported in several individuals [Weaver et al 2022].
• Cryptorchidism is frequent, structural ureteral or renal abnormalities may be found, and urachal remnants have been noted in multiple individuals [Myers et al 2014, Lorenz et al 2012].
• Adult-onset gastroesophageal reflux was present in four individuals in White et al [2005]; additional cases are known [K Gripp, 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.

Neuroimaging. A systematic review of brain and spinal cord MRI studies revealed posterior fossa crowding with cerebellar tonsillar herniation in 27/28 (96%) individuals [Gripp et al 2010]. In a majority of those with serial studies, posterior fossa 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). In individuals age 16 years or older, a Chiari I malformation was reported in 10/20 (50%) individuals [Shikany et al 2020].

Tethered cord is relatively common.

Life expectancy. Causes of death in the literature, including an analysis of cardiovascular findings [Lin et al 2011], were reported in 10% of affected individuals and include HCM, coronary artery fibromuscular dysplasia, multifocal tachycardia, neoplasia, pulmonary causes, and multiorgan failure.

Mosaic Costello syndrome. Individuals with somatic mosaicism for a pathogenic variant in HRAS 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 have 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 had the pathogenic HRAS variant p.Gly12Ser, which was not detected in DNA derived from peripheral 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 several atypical findings attributed to mosaicism (microcephaly, streaky areas of skin hypo- and hyperpigmentation, and normal menarche with subsequent regular menses) [Gripp et al 2006b].

Genotype-Phenotype Correlations

In a systematic review of 146 individuals with an HRAS pathogenic variant, there was no apparent correlation between the specific variant and the variables studied (HCM, multifocal tachycardia, aortic dilatation) [Lin et al 2011].

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

• The p.Gly13 amino acid appears to be the second most commonly affected residue, with p.Gly13Cys being the most frequent pathogenic variant seen at this codon. Gripp et al [2011a] reviewed physical findings in 12 individuals with this pathogenic 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 been seen to date in individuals with p.Gly13Cys. Compared to individuals with the very common p.Gly12Ser pathogenic variant, these differences are statistically significant.
• 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 those with the p.Gly12Ser pathogenic 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 pathogenic 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 most other individuals with Costello syndrome [Gremer et al 2010].
• Five individuals with the rare p.Gly13Asp pathogenic variant showed an apparently milder presentation and none had a malignancy [Bertola et al 2017].

In rare instances related to the underlying pathogenic HRAS 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 pathogenic variants, such as p.Thr58Ile and p.Gly60Val, are associated with a milder or attenuated phenotype, encompassing milder developmental delay, less striking facial features resembling Noonan syndrome, and a lower risk of malignancy [Gripp et al 2015, Bertola et al 2017].

In one individual with early-lethal Costello syndrome due to the rare p.Gly12Glu pathogenic variant, pulmonary vascular dysplasia affecting the small arteries and veins with abnormal elastin distribution was seen in the absence of significant HCM [Weaver et al 2014].

In a recent meta-analysis of cancer risk in Costello syndrome, the rate of cancer and death associated with p.Gly12Ser were lower when compared to all other pathogenic variants affecting the same amino acid (tumor risk assessed to be 9.2% for p.Gly12Ser, 38.7% for p.Gly12Ala, and 37.5% for p.Gly12Cys) (P <0.05). Higher mortality for p.Gly12Cys, p.Gly12Asp, p.Gly12Val, and p.Gly60Val and higher malignancy rate for p.Gly12Ala were confirmed (P <0.05) [Astiazaran-Symonds et al 2023].

Penetrance

Penetrance for Costello syndrome is 100% to date [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 to be 1:380,000 in the United Kingdom [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 bias.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Costello syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Costello Syndrome: Recommended Evaluations Following Initial Diagnosis

Treatment of Manifestations

Targeted Therapy

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Table 5.

Costello Syndrome: Targeted Therapy

Supportive Care

There is no cure for Costello syndrome. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Table 6.

Costello Syndrome: Treatment of Manifestations

Growth hormone (GH) treatment. If treatment with GH is contemplated, its unproven benefit and potential risks should be thoroughly discussed in view of the established risks of cardiomyopathy and malignancy in individuals with Costello syndrome. GH replacement has not been shown to increase these risks.

• Unproven benefit. Individuals with Costello syndrome frequently have low GH levels.
  • True GH deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [Stein et al 2004].
  • It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial GH deficiency. An abnormal GH response on testing and a good initial growth response have been reported [Legault et al 2001].
• Cardiac hypertrophy. Whether the anabolic actions of GH accelerate preexisting cardiac hypertrophy is not known, but early descriptive studies do not suggest a clear association [Lin et al 2002, Lin et al 2011]. In rare cases, cardiomyopathy has progressed after initiation of GH treatment; whether the relationship was causal or coincidental is unknown (see, e.g., Kerr et al [2003]).
• Malignancy. The effect of GH on tumor predisposition has not been determined. Two reports have raised the possibility of an association.
  • Bladder carcinoma occurred in an individual age 16 years treated with GH [Gripp et al 2000].
  • A rhabdomyosarcoma was diagnosed in an individual age 26 months receiving GH from age 12 months [Kerr et al 2003].
  • On review of 35 affected individuals, 16 had documented GH deficiency (46%). Thirteen of these 16 received GH treatment (37%). In this cohort, 7/35 had tumors, including four rhabdomyosarcomas, one pituitary adenoma, one benign bladder tumor, and one bladder carcinoma. Of the seven with tumors, four (57%) were naïve to GH at the time of tumor diagnosis and three (43%) received GH prior to tumor diagnosis. Of the individuals who developed rhabdomyosarcoma, two never received GH, one received GH after tumor diagnosis, and one received GH prior to the diagnosis of rhabdomyosarcoma [Rauen et al 2008].

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

• IEP services:
  • An IEP provides specially designed instruction and related services to children who qualify.
  • IEP services will be reviewed annually to determine whether any changes are needed.
  • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
  • Vision consultants should be a part of the child's IEP team to support access to academic material.
  • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
  • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation, osteopenia).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations may be considered. When feeding dysfunction is severe, which is typical in infants and children, an NG-tube or G-tube may be necessary. G-tube placement should be considered sooner than in typical individuals as the prolonged oral feeding difficulties are to be expected.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Neurobehavioral/Psychiatric Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Table 7.

Costello Syndrome: Recommended Surveillance

Agents/Circumstances to Avoid

Aggressive feeding therapy in infancy and early childhood is not likely to improve oral intake and may result in oral aversion.

Neuroblastoma screening by measuring catecholamine metabolites is not helpful because elevated values were observed in individuals without an identifiable tumor.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

HRAS-related Costello syndrome (Costello syndrome) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• To date, most individuals with Costello syndrome have the disorder as the result of a de novo HRAS pathogenic variant.
  An association with advanced parental age has been documented [Giannoulatou et al 2013]. Most but not all de novo pathogenic variants arise in the paternal germline; Sol-Church et al [2006] reported 14 de novo pathogenic variants of paternal origin and two of maternal origin.
• Rarely, an individual with Costello syndrome has the disorder as the result of an HRAS pathogenic variant inherited from a heterozygous parent. Vertical transmission has been reported in two families with the rare, attenuated phenotype of Costello syndrome (see Genotype-Phenotype Correlations) [Gripp et al 2012, Gripp et al 2015].
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and germline mosaicism for an HRAS pathogenic variant may show patchy skin findings only (as reported in the mosaic father of an individual with typical Costello syndrome [Sol-Church et al 2009]).

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If the HRAS pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Recurrence of Costello syndrome in sibs has been reported and is suspected to be the result of germline mosaicism in a parent [Zampino et al 1993, Johnson et al 1998, Gripp et al 2011b].
• If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the parents have not been tested for the HRAS pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for Costello syndrome because of the possibility of parental mosaicism.

Offspring of a proband

• Each child of an individual with an attenuated phenotype has a 50% chance of inheriting the HRAS pathogenic variant.
• Individuals with characteristic Costello syndrome typically do not reproduce.

Other family members. If the proband has Costello syndrome as the result of a de novo pathogenic variant, other family members are not at increased risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of children with Costello syndrome.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. If an HRAS pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Ultrasound examination in a pregnancy not known to be at increased risk for Costello syndrome. The fetal phenotype of Costello syndrome (including increased nuchal thickness, macrocephaly, mild shortness of the long bones, polyhydramnios, and fetal tachycardia) is not unique, and as a rare disorder, Costello syndrome is often not considered. However, the presence of severe polyhydramnios in the pregnancy of a fetus with normal chromosome analysis or chromosome microarray and fetal atrial tachycardia may warrant consideration of the diagnosis of Costello syndrome.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The RAS oncogenes, HRAS, KRAS, and NRAS, encode 21-kd proteins collectively called p21RAS. The p21RAS proteins are localized to the inner plasma membrane, where they bind GDP and GTP and have low intrinsic GTPase activity [Corbett & Alber 2001]. The GDP-bound conformation is the inactive state of the RAS molecule. An extracellular stimulus – for example, through growth factor receptors – initiates release of GDP and subsequent binding of GTP. The GTP-bound form is active and permits signal transduction. This transmission of mitogenic and growth signals allows the widely expressed RAS proteins to regulate cell proliferation, differentiation, transformation, and apoptosis. Hydrolysis of the bound GTP to GDP reverses the active state. The low intrinsic GTPase activity of RAS proteins is increased through GTPase-activating proteins (GAPs) and other regulators including neurofibromin protein (see Neurofibromatosis Type 1). Normally, most p21RAS within a cell is present in an inactive GDP-bound state.

HRAS is an oncogene that is aberrantly activated in sporadic tumors. Therefore, much of what is known about the abnormal gene product has been learned through cancer research because the germline HRAS single-nucleotide pathogenic variants that cause Costello syndrome are identical to the somatic HRAS single-nucleotide pathogenic variants observed in sporadic malignant tumors unrelated to Costello syndrome. Activating single-nucleotide pathogenic variants leading to an amino acid substitution at positions 12, 13, and 61 are the most common in malignant tumors; less commonly, amino acids 59, 63, 116, 117, 119, or 146 are affected. These pathogenic missense variants result in constitutive activation of the abnormal protein product, and thus lead to increased signaling through the Ras-MAPK [Sol-Church & Gripp 2009] and the PI3K-AKT-MTOR pathways [Rosenberger et al 2009]. A more complex dysregulation of the signaling pathways was reported for the rare HRAS p.Gly60Asp pathogenic variant [Gripp et al 2015].

Amino acid changes lead either to decreased GTPase activity (if amino acids 12, 13, 59, 61, or 63 are involved), so that oncogenic RAS mutated proteins are locked in the active GTP-bound state, or decreased nucleotide affinity and, hence, increased exchange of bound GDP for cytosolic GTP (if amino acids 116, 117, 119, or 146 are affected). Single-nucleotide pathogenic variants cause an accumulation of activated RAS-GTP complexes, leading to continuous signal transduction by facilitating accumulation of constitutively active, GTP-bound RAS protein.

Kerr et al [2003] identified loss of heterozygosity for 11p15.5 in rhabdomyosarcoma from individuals with Costello syndrome, suggesting that loss of the wild type allele is the second hit in tumor development. This theory is supported by the loss of the wild type allele in a rhabdomyosarcoma demonstrated by Estep et al [2006] and the monoallelic expression in a tumor, but not in fibroblasts, reported by Aoki et al [2005]. Robbins et al [2016] studied 11 rhabdomyosarcoma samples from eight unrelated individuals with Costello syndrome. Eight tumors showed complete paternal uniparental disomy (UPD) of chromosome 11 (pUPD11), whereas two had UPD only at 11p. A second primary rhabdomyosarcoma showed UPD limited to 11p15.5 [Robbins et al 2016].

Mechanism of disease causation. Gain of function

Table 8.

HRAS Pathogenic Variants Referenced in This GeneReview

Author Notes

Dr Karen Gripp is a codirector of the Professional Advisory Committee of the Costello Syndrome Family Network. She is a member of the ClinGen expert panels on RASopathies and inherited cancer syndromes.

Dr Nicole Weaver is a member of the Professional Advisory Committee of the Costello Syndrome Family Network. She is a member of the ClinGen expert panel on congenital heart disease.

Drs Gripp and Weaver are actively involved in clinical research regarding individuals with Costello syndrome. They would be happy to communicate with persons who have any questions regarding diagnosis of Costello syndrome or other considerations.

Acknowledgments

Special thanks to Sandra Taylor, Executive Director, and Mary Ernst, President of the Costello Syndrome Family Network; Lisa Schoyer, Chair of the Research Advisory Committee, and Colin Stone, President of the International Costello Syndrome Support Group; the individuals with Costello syndrome and their families; and our colleagues on the Professional Advisory Committee.

Author History

Karen W Gripp, MD, FAAP, FACMG (2006-present)
Angela E Lin, MD, FAAP, FACMG; Harvard Medical School (2006-2019)
Katherine A Rauen, MD, PhD; University of California, Davis (2019-2023)
K Nicole Weaver, MD, FAAP, FACMG (2023-present)

Revision History

• 21 December 2023 (gm) Comprehensive update posted live
• 29 August 2019 (bp) Comprehensive update posted live
• 12 January 2012 (me) Comprehensive update posted live
• 19 May 2009 (me) Comprehensive update posted live
• 29 August 2006 (me) Review posted live
• 2 March 2006 (kg) Original submission

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