Costello Syndrome

Clinical Diagnosis

Diagnosis of Costello syndrome is made on a clinical basis. Formal diagnostic criteria for Costello syndrome have not been developed. Findings that are present in almost all affected individuals are listed in bold; findings not present in all affected individuals but distinctive for Costello syndrome are in italics. No single feature is unique for Costello syndrome, although the constellation of several creates the characteristic phenotype. Clinicians should view these guidelines in the context of the natural history.

Perinatal history

• Polyhydramnios, often severe

• Increased birth weight as a result of edema (not true macrosomia)

• Weight loss resulting from resolution of edema and failure to thrive from severe postnatal feeding difficulties

• Short stature

Figure 1. Four girls who attended the 2005 Costello (more...)

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. 1a. The two ten-year-old girls have chubby cheeks, full lips, ocular hypertelorism, downslanted eyes, and a full nasal tip. Note that the girl on the left has frizzy hair, whereas the girl on the right has straight, fine hair. 1b. Two girls ages six and nine years show the typical hand posture, wide mouth, and full lips. The darker complexion is attributed to Latino heritage in one and African-American heritage in the other.

Figure 1

• Macrocephaly (relative)

• Coarse facial features, full cheeks, full lips, large mouth

• Curly or sparse, fine hair

• Epicanthal folds

• Wide nasal bridge, short full nose

• Deep, hoarse or whispery voice

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 and confirm the diagnosis in doubtful cases

• Premature aging, hair loss

Musculoskeletal system

• Diffuse hypotonia and joint laxity

• 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

• Kyphoscoliosis

• Pectus carinatum, pectus excavatum, asymmetric rib cage

Cardiovascular system

• Cardiac hypertrophy; usually classic hypertrophic cardiomyopathy (i.e., idiopathic subaortic stenosis), although other forms (e.g., biventricular) have been reported

• Congenital heart defect; usually valvar pulmonic stenosis

• Arrhythmia; usually atrial tachycardia, typically supraventricular or paroxysmal tachycardia, most distinctive is chaotic atrial rhythm (including multifocal atrial tachycardia and ectopic atrial tachycardia)

Neurologic

• Chiari I malformation

• Hydrocephalus

• Seizures

Tumors

• Increased occurrence of Malignant solid tumors; typically, elevated urine catecholamine metabolites

Psychomotor development

• Developmental delay or mental retardation

• Sociable, outgoing personality

Note: Identification of an HRAS missense mutation by molecular genetic testing confirms the clinical diagnosis of Costello syndrome.

Molecular Genetic Testing

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Gene.   HRAS is the only gene currently known to be associated with Costello syndrome [Aoki et al 2005].

Other loci.  No other loci have been identified. The 10%-15% of individuals suspected of having Costello syndrome but lacking an HRAS mutation most likely have cardiofaciocutaneous (CFC) syndrome [Rauen 2006].

Molecular genetic testing: Clinical uses

• Confirmatory diagnostic testing

• Prenatal diagnosis

Molecular genetic testing: Clinical method

• Sequence analysis

Sequence analysis of exon 2 (the first translated exon) detects missense mutations in 80%-90% of individuals tested [Aoki et al 2005; Estep et al 2006; Gripp, Lin et al 2006; Kerr et al 2006].

If no mutation is identified in exon 2, all other coding exons need to be sequenced. A single individual was found to have a missense mutation in exon 3 (K117R); this de novo change is likely disease causing [Kerr et al 2006].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Costello Syndrome

Test Method	Mutations Detected	Mutation Detection Rate	Test Availability
Sequence analysis	HRAS mutations	80%-90%	Clinical

Interpretation of test results.  The failure to identify an HRAS mutation in an individual with a classic clinical phenotype can result from either of the following:

• Mostly commonly, the presence of a mutation in another gene, consistent with a diagnosis of CFC syndrome [Rauen 2006]

• Rarely, the presence of a low level of somatic mosaicism for the HRAS disease-causing mutation in the tested tissue [Gripp et al, in press]

For other issues to consider in the interpretation of sequence analysis results, click here.

Testing Strategy for a Proband

• Detailed clinical evaluation, including complete cardiac evaluation, as recognition of the classic phenotype can establish the diagnosis

• Molecular testing as needed for diagnostic confirmation

Genetically Related (Allelic) Disorders

Germline mutations.  No other phenotype is known to be associated with germline mutations in HRAS.

Somatic mutations.  Malignant solid tumors of adulthood, such as bladder carcinoma or lung carcinoma, are often associated with somatic HRAS mutations [Giehl 2005]. Mutation hotspots are the glycines in positions 12 and 13 and the glutamine in position 61. Missense mutations at these positions lead to increased activity of the gene product.

Natural History

Females and males are equally affected. Costello syndrome can theoretically be recognized in the fetus, is usually diagnosed in the young child, and changes with age, with older individuals displaying features of premature aging.

Prenatally, increased nuchal thickness, polyhydramnios (>90%), characteristic ulnar deviation of the wrists, and short humeri and femurs can be seen on prenatal ultrasonography. Because most features of the fetal phenotype are not unique and Costello syndrome is rare, the diagnosis is often not considered prenatally. Cardiac hypertrophy has not been reported, but fetal tachycardia (various forms of atrial tachycardia) has been detected in at least five fetuses subsequently diagnosed with Costello syndrome, which increases the index of suspicion of the diagnosis.

In the neonate, increased birth weight and head circumference (often >50th centile) for gestational age can lead to the categorization of macrosomia. Hypoglycemia is common. Failure to thrive and severe feeding difficulties are almost universal. Characteristic physical findings include a relatively high forehead, low nasal bridge, epicanthal folds, prominent lips and a wide mouth, ulnar deviation of wrists and fingers, loose-appearing skin with deep palmar and plantar creases, and cryptorchidism.

In infancy, severe feeding difficulties may lead to a marasmic appearance. Most infants display hypotonia, irritability, developmental delay, and nystagmus with delayed visual maturation improving with age.

Cardiac abnormalities typically present in infancy or early childhood but may be recognized at any age. Approximately 75% of HRAS mutation-positive individuals with Costello syndrome have had some type of cardiac abnormality [Gripp, Lin et al 2006], compared to 60% of individuals with Costello syndrome diagnosed by clinical findings alone [Lin et al 2002]. In the more recent HRAS mutation-positive series, congenital heart defects (usually pulmonic stenosis) were noted in 25%, arrhythmia in 42%, and hypertrophic cardiomyopathy in 47%, compared to the earlier clinical series in which each of the above abnormalities was reported in about 30% of affected individuals.

In childhood, individuals are able to take oral feeds beginning between age two and four years. The first acceptable tastes are often strong (e.g., ketchup). The onset of speech often coincides with the willingness to feed orally. Short stature is universal, delayed bone age is common [Johnson et al 1998], and testing may show partial or complete growth hormone deficiency.

Atypically, cardiac hypertrophy detected in infancy as mild non-obstructive or non-progressive thickening may progress to severe lethal hypertrophy with "storage" [Hinek et al 2005]; most hypertrophic hearts remain stable or progress mildly. The complete natural history of cardiac hypertrophy in Costello syndrome has not been defined, but adult onset of hypertrophy has not been documented.

Papillomata absent in infancy appear in young children. Acanthosis nigricans, thick calluses and toenails, strong body odor, and tight Achilles tendons may develop.

Developmental delay or mental retardation is present in all individuals [Axelrad et al 2004].

EEG abnormalities are seen in about one-third of individuals; between 20% and 50% have seizures [Delrue et al 2003, Kawame et al 2003].

Seven of ten individuals ages three to 29 years undergoing polysomnography in the sleep laboratory had obstructive events [Della Marca et al 2006].

Dental abnormalities, including enamel defects, occur frequently. Excessive secretions are often noted [Johnson et al 1998].

Individuals with Costello syndrome have very loose joints, particularly the fingers. Ulnar deviation of the wrists and fingers is common.

Adolescents often show delayed or disordered puberty, and may appear older than their chronologic age because of worsening kyphoscoliosis, sparse hair, and prematurely aged skin.

Adults.  In 17 adults ranging from age 16 to 40 years, all eight individuals who had a bone density measurement had abnormal results that suggested osteoporosis or osteopenia; three had bone pain, vertebral fractures, and height loss [White et al 2005].

Adult-onset gastroeosphageal reflux was present in four individuals in the series of White et al (2005); additional cases are known [author, personal observation].

The reported adult height range is 135-150 cm [Hennekam 2003].

Solid tumors.  Benign and malignant solid tumors occur with far greater frequency in individuals with Costello syndrome than in the general population. The overall tumor incidence is about 15% in persons with an identified HRAS mutation [Gripp, Lin et al 2006]. Rhabdomyosarcoma occurs most frequently, followed by neuroblastoma and transitional cell carcinoma of the bladder, and other solid tumors [for review see Gripp 2005]. Rhabdomyosarcoma and neuroblastoma are tumors of early childhood, presenting in Costello syndrome at ages comparable to the general population. In contrast, transitional cell carcinoma of the bladder occurs in older adults (70% >65 years) in the general population, whereas it occurs in adolescents with Costello syndrome. The ages at presentation in the three reported cases were ten, eleven, and sixteen years.

Neuroimaging.  Typical findings include cerebral atrophy and dilated ventricles; however, shunting for hydrocephalus is rare [Delrue et al 2003]. Cerebellar abnormalities include tonsillar ectopia or Chiari malformation, occasionally associated with syringomyelia [Gripp et al 2000, Gripp et al 2002, Delrue et al 2003].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been noted. However, Kerr et al (2006) suggested that the risk for malignant tumors may be higher in individuals with the G12A mutation (4/7, or 57%) than in those with the G12S (4/65, or 7%).

One individual with somatic mosaicism (20%-30% of DNA derived from buccal cells exhibited the HRAS mutation G12S, which was not detected in DNA derived from blood cells) had an atypical phenotype attributed to her mosaicism. Findings typical for Costello syndrome included mental retardation, short stature, sparse hair, coarse facial features, nasal papillomata, and tight Achilles tendons. Atypical findings included microcephaly, streaky areas of skin hypo- and hyperpigmentation, and normal menarche with subsequent regular menses [Gripp et al, in press].

Penetrance

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

Nomenclature

Costello reported the first individuals with this condition in 1971, providing follow-up in 1977 and 1996 [Costello 1971, 1977, 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].

Phenotypic overlap with cardiofaciocutaneous (CFC) syndrome has been debated on clinical grounds. The discovery of pathogenic mutations in different genes in Costello syndrome and CFC now allows clarification of the diagnosis in many cases.

Prevalence

Costello syndrome is rare, with only about 250 individuals reported worldwide, and others identified through the advocacy group network [authors, personal observation].

Evaluations at Initial Diagnosis to Establish the Extent of Disease

At the time of initial diagnosis of Costello syndrome, a series of evaluations is recommended to help guide medical management:

• Complete physical and neurologic examination

• Plotting of growth parameters

• Nutritional assessment

• Cardiologic evaluation with two-dimensional and Doppler echocardiography, baseline electrocardiography

• Ophthalmology evaluation

• Clinical assessment of spine and extremities, range of motion

• Multidisciplinary developmental evaluation

• Genetics consultation

Treatment of Manifestations

Growth.   Most infants require nasogastric or gastrostomy feeding. Because of gastroesophageal reflux and irritability, Nissen fundoplication is often performed. Anecdotally, affected children have very high caloric needs. Even after nutrition is improved through supplemental feeding, growth retardation persists.

Cardiac.   Treatment of cardiac manifestations is generally the same as in the general population. All individuals with Costello syndrome, especially those with an identified cardiac abnormality, should be followed by a cardiologist who is aware of the spectrum of cardiac disease and its natural history [Lin et al 2002]. Ongoing studies of the natural history will be needed to define the management for older individuals. Arrhythmias have been well documented but incompletely defined from a management point of view. Malignant rhythms may require aggressive anti-arrhythmic drugs and ablation.

Pharmacologic and surgical treatment (myectomy) has been used to address cardiac hypertrophy.

Individuals with Costello syndrome and severe cardiac problems may choose to wear a Medic Alert^® bracelet.

Skeletal.   Ulnar deviation of the wrists and fingers responds well to early bracing and occupational and/or physical therapy.

Limited extension of large joints should be addressed early through physical therapy. Surgical tendon lengthening, usually of the Achilles tendon, is often required.

Kyphoscoliosis may require surgical correction.

Central nervous system.   When seizures occur, underlying causes including hydrocephalus, hypoglycemia, and low serum cortisone concentration need to be considered [Gregersen & Viljoen 2004].

Cognitive.   Developmental disability should be addressed by early-intervention programs and individualized learning strategies.

Speech delay and expressive language limitations should be addressed early with appropriate therapy and later with an appropriate educational plan.

Alternate means of communication should be considered if expressive language is significantly limited.

Respiratory.   A high index of suspicion should be maintained for obstructive sleep apnea as the cause for sleep disturbance.

Dental.   Dental abnormalities should be addressed by a pediatric dentist.

Papillomata.   Papillomata usually appear in the peri-nasal region and less commonly in the perianal region, torso, and extremities. While they are mostly of cosmetic concern, papillomata may give rise to irritation or inflammation in hard-to-clean body regions and may be removed as appropriate.

Recurrent facial papillomata have been successfully managed with regular dry ice removal.

Endocrinopathies.   Neonatal hypoglycemia has frequently been reported and a high level of suspicion should be maintained. Rarely, hypoglycemia occurs in older individuals and may present with seizures. Under these circumstances, growth hormone (GH) deficiency needs to be excluded as the underlying cause [Gripp et al 2000]. Hypoglycemic episodes unresponsive to GH therapy responded well to cortisone replacement in another individual [Gregersen & Viljoen 2004]; thus, cortisol deficiency may also be considered.

Malignant tumors.   Treatment of malignant tumors follows standard protocols.

Prevention of Secondary Complications

Cardiac.  Certain congenital heart defects (notably valvar pulmonic stenosis) require antibiotic prophylaxis for subacute bacterial endocarditis (SBE), available by prescription from the cardiologist or other physician caregiver.

Sedation.  Individuals with Costello syndrome may require relatively high doses of medication for sedation. No standardized information is available, but review of an individual's medical records documenting previously given dosages may provide guidance.

Anesthesia may pose a risk to individuals with some forms of unrecognized hypertrophic cardiomyopathy or those who have a predisposition to some types of atrial tachycardia.

Surveillance

Hypoglycemia.  Neonatal hypoglycemia has frequently been reported and a high level of suspicion should be maintained. Monitoring of blood glucose concentration should follow typical protocols for neonates at risk for hypoglycemia.

Cardiac.  While data regarding the natural history are insufficient to determine a schedule for repeating cardiac assessments if the initial evaluation is normal, it appears that the onset of new cardiovascular abnormalities declines after adolescence. The follow-up schedule must be customized based on the overall clinical situation and the treating cardiologist. The cardiologist should be aware of Costello syndrome-associated heart abnormalities and schedule tests as indicated.

As more information about the natural history of cardiac abnormalities (especially hypertrophic cardiomyopathy, hypertension, and aortic dilatation) becomes available, the following recommendations may change:

• If the newborn evaluation is normal, follow-up with echocardiogram at about age six to 12 months

• For those without an apparent cardiac abnormality, follow-up approximately every one to three years until about age five to ten years and less frequently if the individual remains healthy

• In an affected adolescent with a normal baseline cardiology evaluation who maintains normal blood pressure, echocardiogram at three- to five-year intervals

• For any child with a cardiac abnormality, scheduled assessment as recommended by the treating cardiologist

Because tachycardia is an important cause of death with or without underlying structural defect or cardiac hypertrophy, health professionals and caregivers should be aware of the possibility of sudden cardiovascular collapse.

Tumor screening consisting of abdominal and pelvic ultrasound and urine testing for catecholamine metabolites and hematuria was proposed by Gripp et al (2002). However, a subsequent report [Gripp et al 2004] on elevated catecholamine metabolites in individuals with Costello syndrome without an identifiable tumor concluded that screening for abnormal catecholamine metabolites is not helpful.

Serial abdominal and pelvic ultrasound screening for rhabdomyosarcoma and neuroblastoma was proposed every three to six months until age eight to ten years. Urinalysis for hematuria was suggested annually beginning at age ten years to screen for bladder cancer Gripp et al 2002.

Neither of the above screening approaches has yet been shown to be beneficial; however, studies are ongoing. The most important factor for early tumor detection remains parental and physician awareness of the increased cancer risk.

Bone density.  Osteoporosis is common in young adults with Costello syndrome [White et al 2005], and bone density assessment is recommended as a baseline, with follow-up depending upon the initial result.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

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 and the unknown effect of growth hormone on 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 was reported [Legault et al 2001].

Cardiac hypertrophy.  Whether the anabolic actions of growth hormone accelerate pre-existing cardiac hypertrophy is not known [Lin et al 2002]. In rare cases, cardiomyopathy has progressed after initiation of growth hormone treatment; whether the relationship was causal or coincidental is unknown [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].

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• To date, most probands with Costello syndrome have the disorder as the result of a de novo mutation.

• Parents of probands have not been proven to be affected. One report suggested possible somatic mosaicism and others implied possibly affected parents [Johnson et al 1998, Bodkin et al 1999].

• An association with advanced parental age had been documented [Lurie 1994]. Most but not all mutations arise in the paternal germline; Sol-Church et al (2006) reported 14 de novo mutations of paternal origin and two of maternal origin.

Sibs of a proband

• The risk to the sibs of the proband depends upon the genetic status of the proband's parents.

• Because Costello syndrome typically occurs as a result of de novo mutation, the risk to the sibs of a proband is small.

• Recurrence 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].

Offspring of a proband.  Individuals with Costello syndrome typically do not reproduce. The theoretical risk to offspring is 50%.

Other family members of a proband.  Because Costello syndrome typically occurs as the result of a de novo mutation, other family members are not at increased risk.

Related Genetic Counseling Issues

Family planning.  The optimal time for determination of genetic risk is before pregnancy.

DNA banking.  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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Although recurrence of Costello syndrome in a family is unusual, prenatal diagnosis is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination.  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 and fetal atrial tachycardia may warrant consideration of the diagnosis of Costello syndrome.

Molecular Genetic Pathogenesis

Malignant solid tumors of adulthood, such as bladder carcinoma or lung carcinoma, are often associated with somatic HRAS mutations [Giehl 2005].

HRAS is a well-known oncogene, and aberrant activation is often found in sporadic somatic tumors; it is thus not surprising to see the increased cancer incidence in individuals with a germline HRAS mutation. 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).

Mutation hotspots are bases encoding the glycines in positions 12 and 13, and the glutamine in position 61. Missense mutations at these positions lead to increased activity of the gene product. As the germline mutations in Costello syndrome affect similar codons, it can be inferred that they have a similar effect on the gene product. The increased propensity for malignancies in Costello syndrome is likely associated with the mutations listed here.

Figure 2. Molecular basis of the neuro-cardiofaciocutaneous (more...)

Figure 2. Molecular basis of the neuro-cardiofaciocutaneous syndromes
Adapted from Bentires-Alj et al (2006)

Figure 2

Normal allelic variants: The HRAS gene consists of six exons. Five exons (2-6) code for a protein of 189 amino acids with a molecular weight of 21 kd (p21). Alternative splicing, excluding residues 152-165, gives rise to a protein of 170 amino acids.

Pathologic allelic variants: Nucleotide substitutions leading to amino acid substitutions of the glycine residue at positions 12 or 13 are typical in Costello syndrome. A review of 81 unrelated individuals [Aoki et al 2005; Gripp, Lin et al 2006; Kerr et al 2006] shows the nucleotide substitution 34G>A, resulting in G12S amino acid change, to be the most common (65/81, or 80%). The 35G>A nucleotide resulting in G12A was seen in seven individuals (9%).

Estep et al (2006) reported the same two mutations and aggregate clinical data on 33 individuals. (Some of those reported by Estep et al were included in the study by Gripp, Lin et al (2006). Because the individuals included in both studies cannot be identified, the data of Estep et al (2006) are not included in this tally.)

Other mutations, resulting in G12V, G12C, G12E, G13C, and G13D, occurred in one or two individuals each [Aoki et al 2005; Estep et al 2006; Gripp, Lin et al 2006; Kerr et al 2006].

Only one individual with a mutation affecting an amino acid other than G12/13 (K117R) has been identified [Kerr et al 2006].

Normal gene product: The RAS oncogenes, HRAS, KRAS, and NRAS, encode 21-kd proteins called p21s. RAS 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, as the point mutations in Costello syndrome are identical to those seen in malignant tumors. Activating point mutations 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.

The amino acid changes lead either to decreased GTPase activity (if amino acids 12, 13, 59, 61, 63 are involved) so that oncogenic RAS mutants 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). All point mutations cause an accumulation of activated RAS-GTP complexes, leading to continuous signal transduction by facilitating accumulation of constitutively active, GTP-bound RAS protein.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Readings

Author Notes

Drs. Gripp and Lin are Co-Directors, Professional Advisory Board and Costello Syndrome Family Support Group

Acknowledgments

Special thanks to Lisa Schoyer, President of the Costello Syndrome Family Network, and Colin Stone, President of the International Costello Syndrome Support Group, to the individuals with Costello Syndrome and their families, and our colleagues on the Professional Advisory Board.

Revision History

• 29 August 2006 (me) Review posted to live Web site

• 2 March 2006 (kg) Original submission