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Costello Syndrome

, MD, FAAP, FACMG and , MD, PhD.

Author Information

Initial Posting: ; Last Update: August 29, 2019.

Estimated reading time: 36 minutes

Summary

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.

Diagnosis

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.

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.

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).

Option 1

When the clinical findings suggest the diagnosis of Costello syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of HRAS detects small intragenic deletions/insertions/indels and missense variants; typically, exon or whole-gene deletions/duplications are not detected. Because Costello syndrome is caused by activating variants in HRAS, gene-targeted deletion/duplication analysis is not likely to identify pathogenic variants.
  • A multigene panel that includes HRAS and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of Costello syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.

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

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
HRASSequence analysis 3, 4~100%
Gene-targeted deletion/duplication analysis 5Not applicable 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

More than 95% of pathogenic variants causing Costello syndrome affect amino acid p.Gly12 or p.Gly13.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Costello syndrome is caused by activating HRAS variants; therefore, gene-targeted deletion/duplication analysis is not likely to identify pathogenic variants.

Clinical Characteristics

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.

Differential Diagnosis

No other loci have been identified as causative of Costello syndrome [Grant et al 2018]. In earlier series, the 10%-15% of individuals suspected of having Costello syndrome who lacked an HRAS pathogenic variant were subsequently found to have cardiofaciocutaneous (CFC) syndrome [Rauen 2006, Gripp et al 2007] or pathogenic variants in KRAS typical for Noonan syndrome [Lo et al 2009]. Note that while Costello syndrome is difficult to distinguish from CFC syndrome and Noonan syndrome in infants and young children, the distinction between Costello syndrome and Noonan syndrome is clear in older children.

Note: The Costello syndrome phenotype would not be mistaken for any known chromosome abnormality syndrome.

Table 2.

Disorders to Consider in the Differential Diagnosis of Costello Syndrome

Differential Diagnosis DisorderGene(s)MOIClinical Features of the Differential Diagnosis Disorder
Overlapping w/Costello SyndromeDistinguishing from Costello Syndrome
Cardiofaciocutaneous (CFC) syndromeBRAF
KRAS
MAP2K1
MAP2K2
AD
  • Resembles CS in infants & young children
  • Hypotonia
  • Nystagmus
  • Mild-to-moderate ID
  • Postnatal growth deficiency
  • Feeding difficulties (may be less severe than in CS)
  • Dolichocephaly, high forehead, & slightly coarse facial features
  • Pulmonic valve stenosis & ASD
  • HCM 1
  • Lips not as thick & prominent
  • Hair more consistently sparse or curly
  • Eyebrows typically sparse or absent
  • Skin abnormalities incl severe atopic dermatitis, keratosis pilaris, & ichthyosis; absence of papillomata
  • Malignant tumors not reported
Noonan syndromeBRAF
KRAS
MAP2K1
NRAS
PTPN11
RAF1
RIT1
SOS1
AD
  • Resembles CS in infants & young children
  • Short stature
  • DD of variable degree
  • Mild ID
  • Congenital heart defects:
    • Pulmonary valve stenosis often w/dysplasia
    • HMC (may be present at birth or appear in infancy or childhood)
    • ASD & VSD
    • Branch pulmonary artery stenosis
    • Tetralogy of Fallot
  • Cryptorchidism
  • Distinctive combination of pectus carinatum & pectus excavatum
  • Broad or webbed neck
  • Characteristic facies
  • Varied coagulation defects & lymphatic dysplasia
  • Birth length usually normal
  • Final adult height near lower limit of normal
Beckwith-Wiedemann syndromeSee footnote 2.
  • In newborns:
    • Apparent "overgrowth" (more accurately: ↑ birth weight due to edema)
    • Protruding tongue
    • Coarse facial features
    • Hypoglycemia
    • HCM
  • Embryonal tumors
  • Macrosomia
  • Macroglossia
  • Visceromegaly
  • Omphalocele
  • Ear creases/pits
  • Adrenocortical cytomegaly
  • Renal abnormalities
Simpson-Golabi-Behmel syndromeGPC3XLDD
  • Macrosomia
  • Visceromegaly
  • Macroglossia
  • Renal anomalies
  • Cleft lip
  • Skeletal abnormalities (incl polydactyly)
Williams syndromeSee footnote 3.AD
  • Soft skin
  • Ligamentous laxity of small joints
  • Full lips
  • Friendly personality w/anxious demeanor in adolescence
  • ID
  • Specific cognitive profile
  • Unique personality characteristics
  • Distinctive facial features
  • Cardiovascular disease (elastin arteriopathy)
  • Range of connective tissue abnormalities
  • Hypercalcemia

AD = autosomal dominant; AR = autosomal recessive; ASD = atrial septal defect; CS = Costello syndrome; DD = developmental delay; HCM = hypertrophic cardiomyopathy; ID = intellectual disability; MOI = mode of inheritance; VSD = ventricular septal defects; XL = X-linked

1.

The ~40% incidence of hypertrophic cardiomyopathy noted in individuals with a molecular diagnosis of CFC is similar to that observed in Costello syndrome [Niihori et al 2006, Rodriguez-Viciana et al 2006, Gripp et al 2007]. Although atrial tachycardia has been reported in a small number individuals with CFC, it has not been called chaotic atrial rhythm [Niihori et al 2006].

2.

Beckwith-Wiedemann syndrome (BWS) is associated with abnormal regulation of gene transcription in two imprinted domains on chromosome 11p15.5. Approximately 85% of individuals with BWS have no family history of BWS; approximately 15% have a family history consistent with parent-of-origin autosomal dominant transmission.

3.

Williams syndrome is caused by a recurrent 7q11.23 contiguous gene deletion of the Williams-Beuren syndrome critical region (WBSCR) that includes ELN, the gene encoding elastin.

Management

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.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Costello Syndrome

System/ConcernEvaluationComment
ConstitutionalMeasurement of height, weight, head circumferenceFTT is common & persists in spite of adequate caloric intake.
Gastrointestinal/
Feeding
Asses nutritional status, feeding, GERDFTT is typical; a feeding tube is typically necessary.
NeurologicExamination by neurologist for clinical signs of Chiari I malformation &/or sryingomyelia
  • Brain MRI if Chiari I malformation suspected
  • Spinal cord MRI if sryingomyelia suspected
EEG if seizures are a concern
DevelopmentDevelopmental assessment
  • To incl motor, adaptive, cognitive, & speech/language evaluation
  • Evaluation for early intervention / special education
CardiacEvaluation by cardiologist for congenital heart defects, HCM, arrhythmiaStandard evaluation
RespiratoryRefer as needed to a pulmonologistUpper- & lower-airway issues may occur; hypertrophy of tonsils & adenoids may contribute to upper-airway obstruction.
MusculoskeletalEvaluation by pediatric orthopedistAssess spine & extremities w/attention to hip joint abnormalities & range of motion
GenitourinaryAssess males for cryptorchidism
EyesOphthalmology evaluation
  • Nystagmus & vision disturbance common
  • Retinal dystrophy & keratoconus rare
SkinPapillomata and hyperkeratosis require referral to a dermatologistTreat symptomatically
DentalEvaluation by a pediatric dentist recommendedEnamel defects & malocclusion are common
EndocrinePediatric endocrinology evaluation for hypoglycemia, growth hormone deficiencyMay require additional evaluation for dysregulated puberty
Psychiatric/
Behavioral
Neuropsychiatric evaluation as neededIn individuals age >4 yrs: screen for behavior problems incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD.
Miscellaneous/
Other
Consultation w/clinical geneticist &/or genetic counselorTo incl genetic counseling

ADHD = attention-deficient/hyperactivity disorder; ASD = autism spectrum disorder; FTT = failure to thrive; GERD = gastroesophageal reflux disease; HCM = hypertrophic cardiomyopathy

Treatment of Manifestations

Consensus medical management guidelines for individuals with Costello syndrome have been developed [Gripp et al 2019].

Table 4.

Treatment of Manifestations in Individuals with Costello Syndrome

Manifestation/ConcernTreatmentConsiderations/Other
FeedingMost infants require nasogastric or gastrostomy feeding.May need Nissen fundoplication for GERD & irritability
Pyloric stenosisStandard surgical treatment
Seizures
  • As per standard practice
  • Education of parents/caregivers 1
Consider hydrocephalus, hypoglycemia, and cortisol deficiency
Developmental delay /
Intellectual disability
See Developmental Delay / Intellectual Disability Management Issues.
Non-reentrant tachycardia
(chaotic atrial rhythm /
multifocal tachycardia)
May require aggressive antiarrhythmic drugs or ablation
  • Pharmacologic & surgical treatment (myectomy) have been used for severe cardiac hypertrophy.
  • Consider Medic Alert® bracelet.
Congenital heart defectsAs per standard practiceCertain congenital heart defects (notably valvar pulmonic stenosis) require antibiotic prophylaxis for SBE.
Aortic dilationBecause aortic dilation has not been studied long term, is rare & typically mild-moderate in severity & not associated w/dissection to date, there are no data to recommend treatment; care should be individualized.
Upper- & lower-airway
obstruction
  • Obstructive apnea may be cause of sleep disturbance.
  • Tonsil/adenoid surgery
MusculoskeletalUlnar deviation of wrist and fingersEarly bracing; OT &/or PT
PT for those w/limited extension of large joints
  • Surgical tendon lengthening (usually Achilles tendon) is often required.
  • Hip joint abnormalities may require surgical intervention.
Kyphoscoliosis may require surgical correction.
CryptorchidismSurgical correction
Eyes/visionNystagmusNo treatment
Visual impairmentEducational intervention
Refractive errorSpectacle correction
KeratoconusSpecialist evaluation & treatment
SkinRemove inflamed/irritating papillomata in hard-to-clean body regions as appropriate; treat hyperkeratosis.For recurrent facial papillomata: consider regular removal using dry ice; shave removal.
DentalBy a pediatric dentist/orthodontistEnamel defects; malocclusion that contributes to obstructive sleep apnea
HypoglycemiaDiazoxideFor neonatal hyperinsulinism
GH replacement 2 (see also text following table)For GH deficiency
CortisolFor cortisol deficiency
Dysregulated pubertyAs per patient needs
Malignant tumorsFollows standard protocolsMost commonly rhabdomyosarcoma, neuroblastoma, transitional cell carcinoma of the bladder
Anesthesia risks /
Sedation
  • Anesthesia may pose a risk in those w/unrecognized hypertrophic cardiomyopathy &/or predisposition to some types of atrial tachycardia.
  • Relatively high doses of medication may be required for sedation. No standardized information is available; review of medical records documenting previous dosages may provide guidance.
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Care coordination to manage multiple sub-specialty appointments, equipment, medications, & supplies
Consider involvement in adaptive sports or Special Olympics.

GERD=gastroesophageal reflux disease; GH = growth hormone; OT = occupational therapy; PT = physical therapy; SBE = subacute bacterial endocarditis

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

2.

It is suggested that treatment of confirmed growth hormone deficiency proceed only after a cardiac evaluation for hypertrophic cardiomyopathy.

Growth hormone (GH) treatment. If treatment with growth hormone 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 growth hormone 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 growth hormone deficiency. An abnormal growth hormone response on testing and a good initial growth response have been reported [Legault et al 2001].
  • Cardiac hypertrophy. Whether the anabolic actions of growth hormone accelerate pre-existing 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 growth hormone treatment; whether the relationship was causal or coincidental is unknown (see, e.g., Kerr et al [2003]).
  • Malignancy. The effect of growth hormone on tumor predisposition has not been determined. Two reports have raised the possibility of an association:
    • Bladder carcinoma occurred in a 16-year-old treated with growth hormone [Gripp et al 2000].
    • A rhabdomyosarcoma was diagnosed in a 26-month-old receiving growth hormone from age 12 months [Kerr et al 2003].

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. In the US, early intervention is a federally funded program available in all states.

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.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies 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 if any changes are needed.
    • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
    • Vision and hearing 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 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.
  • Consider use of durable medical equipment 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. Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended for affected individuals who have difficulty feeding due to poor oral motor control.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. Severe feeding dysfunction typically requires an NG-tube or G-tube.

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 and in many cases, can improve it.

Social/Behavioral 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

Table 5.

Recommended Surveillance for Individuals with Costello Syndrome

System/ConcernEvaluationFrequency
EndocrineFor neonatal hypoglycemiaTypical protocols for neonates at risk for hypoglycemia
Growth hormone deficiencyCommon, requires replacement
CardiovascularBy cardiologist familiar w/the spectrum of cardiac disease & its natural history, transitioning from pediatric cardiologist to adult specialist when age appropriateSee footnote 1.
NeurologicRepeat brain imaging for evidence of Chiari 1 malformation may be needed in the young child & in any symptomatic individual.At age 1 yr; subsequently when symptomatic
Imaging for tethered cordBy age 1 yr; thereafter if symptomatic
Monitor those w/seizures as clinically indicated.Following standard recommendations of treating neurologist
Tumor screening 2Serial abdominal & pelvic ultrasound screening for rhabdomyosarcoma & neuroblastoma 3Every 3-6 mos until age 8-10 yrs
Urinalysis for hematuria to screen for bladder cancerAnnually beginning at age 10 yrs
MusculoskeletalBaseline bone density assessment in individuals w/fracturesDepends on outcome of baseline study
Developmental delay / Intellectual disabilityMonitor developmental progress & educational needsAt diagnosis; thereafter at least annually in school-age individuals
Psychiatric/
Behavioral
Behavioral assessment for anxiety, attention, & aggressive or self-injurious behaviorAs needed; at least annually in school-age individuals
1.

General guidelines [Lin et al 2011] (see Figure 4) can be pragmatically dichotomized based on the presence or absence of HCM, with close evaluation in the first two years of life depending on the severity of hypertrophy, subsequent annual examinations, and appropriate risk stratification.

2.

To date, neither screening approaches has been shown to be beneficial; studies are ongoing. The most important factor for early tumor detection is parental and physician awareness of the increased cancer risk [Gripp et al 2002].

3.

Because elevated catecholamine metabolites were observed in individuals with Costello syndrome without an identifiable tumor, it was concluded that screening for abnormal catecholamine metabolites is not helpful [Gripp et al 2004].

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Costello syndrome is inherited in an autosomal dominant manner, typically as the result of a de novo dominant pathogenic variant.

Risk to Family Members

Parents of a proband

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

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. Because Costello syndrome typically occurs as the result of de novo pathogenic variant, other family members are presumed not be 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. If 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.

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 (CMA) and fetal atrial tachycardia may warrant consideration of the diagnosis of Costello syndrome.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Costello Syndrome Family Network
    1702 Tyndall Drive
    Panama City FL 32401
    Phone: 848-228-CSFN (2736); 850-832-4055
    Email: info@CostelloSyndromeUSA.org; sandra@CostelloSyndromeUSA.org; Cherie@CostelloSyndromeUSA.org
  • CostelloKids UK
    Manchester
    United Kingdom
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • RASopathiesNet
    244 Taos Road
    Atlandena CA 91001
    Phone: 626-676-7694
    Email: lisa@rasopathies.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free)
    Email: contactCCA@ccakids.com
  • MAGIC Foundation
    4200 Cantera Drive #106
    Warrenville IL 60555
    Phone: 800-362-4423 (Toll-free Parent Help Line); 630-836-8200
    Fax: 630-836-8181
    Email: contactus@magicfoundation.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Costello Syndrome: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
HRAS11p15​.5GTPase HRasHRASHRAS

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Costello Syndrome (View All in OMIM)

190020HRAS PROTOONCOGENE, GTPase; HRAS
218040COSTELLO SYNDROME; CSTLO

Gene structure. HRAS is a small gene of about 3300 bp. The longest transcript variant NM_005343.3 has six exons, four of which code for isoform 1, a 189-amino acid protein with a molecular weight of 21 kd (p21) (NP_005334.1). Alternative splicing results in transcript variant NM_176795.4, which encodes isoform 2, a protein of 170 amino acids (NP_789765.1). Compared to isoform 1, isoform 2 lacks residues 152-165.

For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table 6 for selected pathogenic variants. Germline pathogenic variants leading to nucleotide substitutions and the consequent amino acid substitutions of the glycine residue at positions 12 or 13 are typical in Costello syndrome [Sol-Church & Gripp 2009].

A review of 81 unrelated individuals [Aoki et al 2005, Gripp et al 2006a, Kerr et al 2006] shows the nucleotide substitution c.34G>A (resulting in p.Gly12Ser amino acid change) to be the most common (65/81, or 80%). The c.35G>C nucleotide resulting in p.Gly12Ala was seen in seven individuals (9%).

Estep et al [2006] reported the same two variants and aggregate clinical data on 33 individuals. Note: Some individuals reported by Estep et al were included in the study by Gripp et al [2006a]. Because the individuals included in both studies cannot be identified, the data of Estep et al [2006] are not included in this tally.

Other pathogenic variants (i.e., p.Gly12Val, p.Gly12Cys, p.Gly12Glu, p.Gly13Cys, p.Gly13Asp, p.Glu37dup. p.Gly60Asp, p.Gly60Val) were found in a few individuals each [Aoki et al 2005, Estep et al 2006, Gripp et al 2006a, Kerr et al 2006, Gremer et al 2010, Gripp et al 2015, Bertola et al 2017].

Two individuals were identified with pathogenic missense variants in exon 3: p.Thr58Ile [Gripp et al 2008] and p.Glu63Lys [van der Burgt et al 2007]. Several individuals with changes in exon 4 have been reported, one resulting in p.Lys117Arg [Kerr et al 2006], and three with a variant affecting amino acid 146, resulting in p.Ala146Thr [Zampino et al 2007], p.Ala146Val [Gripp et al 2008], and p.Ala146Pro [Chiu et al 2016].

HRAS is a well-known oncogene, and aberrant activation is often found in sporadic somatic tumors; it is thus not surprising to see increased cancer incidence in individuals with a germline HRAS pathogenic variant. The work performed by Kerr et al [2003] showing loss of heterozygosity for 11p15.5 in rhabdomyosarcoma from individuals with Costello syndrome suggests 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 rhabomyosarcoma demonstrated by Estep et al [2006] and the monoallelic expression in a tumor, but not in fibroblasts, reported by Aoki et al [2005].

Table 6.

Selected HRAS Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeVariant Detection Frequency (# of Individuals 1)Reference Sequences
c.34G>Ap.Gly12Ser81.3% (113)NM_005343​.2
NP_005334​.1
c.34G>Tp.Gly12Cys2% (3)
c.35G>Cp.Gly12Ala7.2% (10)
c.35_36delGCinsTTp.Gly12Val1.4% (2)
c.35_36delGCinsAAp.Gly12Glu<1% (1)
c.37G>Tp.Gly13Cys1.4% (2)
c.38G>Ap.Gly13Asp1.4% (2)
c.64C>Ap.Gln22Lys<1% (1)
c.110_111+1dupAGG 2p.Glu37dup<1% (1) 2
c.108_110dupAGA 2p.Glu37dup<1% (1) 2
c.173C>Tp.Thr58Ile<1% (1)
c.179G>Ap.Gly60Asp4 individuals; see footnote 3.
c.179G>Tp.Gly60Val2 individuals; see footnote 3.
c.187G>Ap.Glu63Lys<1% (1)
c.350A>Gp.Lys117Arg<1% (1)
c.436G>Ap.Ala146Thr<1% (1)
c.436G>Cp.Ala146Pro1 individual; see footnote 3.
c.437C>Tp.Ala146Val<1% (1)

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Except where noted, # of affected individuals with HRAS pathogenic variants reported by Sol-Church & Gripp [2009] (total = 139).

2.
3.

Variants discussed in this GeneReview reported after 2010

Normal gene product. The RAS oncogenes, HRAS, KRAS, and NRAS, encode 21-kd proteins collectively called p21RAS. p21RAS proteins are localized in the inner plasma membrane; 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 the 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.

Abnormal gene product. Much of what is known about the abnormal gene product has been learned through cancer research because the germline HRAS single-nucleotide variants that cause Costello syndrome are identical to the somatic HRAS single-nucleotide variants observed in sporadic malignant tumors unrelated to Costello syndrome. Activating single-nucleotide 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 pathways [Rosenberger et al 2009]. A more complex dysregulation of the signaling pathways was reported for the rare HRAS p.Gly60Asp variant [Gripp et al 2015].

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

Cancer and Benign Tumors

Malignant solid tumors of adulthood (including bladder carcinoma or lung carcinoma) are often associated with somatic HRAS pathogenic variants that are not present in the germline [Giehl 2005]. In these circumstances predisposition to these tumors is not heritable. Somatic mutation hot spots are the glycines at amino acid residues 12 and 13 and the glutamine at residue 61. Pathogenic missense variants in these codons lead to increased activity of the gene product.

References

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Chapter Notes

Author Notes

Drs Karen Gripp and Katherine Rauen are co-directors of the Professional Advisory Committee of the Costello Syndrome Family Support Group.

Acknowledgments

Special thanks to Sandra Taylor, 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 WGripp, MD, FAAP, FACMG (2006-present)
Angela E Lin, MD, FAAP, FACMG; Harvard Medical School (2006-2019)
Katherine A Rauen, MD, PhD (2019-present)

Revision History

  • 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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