Clinical characteristics.

Costello syndrome is 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 [HCM]), 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.

Diagnosis of Costello syndrome is based on clinical findings and is confirmed by molecular genetic testing. Sequence analysis of HRAS, the only gene currently known to be associated with Costello syndrome, detects pathogenic missense variants in 80%-90% of individuals with the clinical diagnosis. The clinical diagnosis should be reconsidered if an HRAS pathogenic variant is not identified, and other syndromes of the Ras/MAPK pathway should be considered as alternative diagnoses.

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.

Prevention of secondary complications: Hemodynamically significant valvar stenoses require antibiotic prophylaxis for subacute bacterial endocarditis (SBE); 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; parents of probands are almost never affected, although somatic mosaicism occurred in one parent. Because Costello syndrome is typically caused by a de novo pathogenic variant, the risk to the sibs of a proband is 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. Although recurrence of Costello syndrome in a family is unusual, prenatal diagnosis is possible if the pathogenic allele of an affected family member has been identified.

Clinical Diagnosis

Costello syndrome is diagnosed clinically. Formal diagnostic criteria for Costello syndrome have not been developed, but have been published as informal consensus guidelines developed by experts [Kerr et al 2010 (see Table 16.1), Gripp & Lin 2012]. No single feature is unique for Costello syndrome, although the constellation of several features creates the characteristic phenotype. Clinicians should view these guidelines in the context of the natural history.

Note: Bulleted findings in bold are present in almost all affected individuals; bulleted findings in italics are not present in all affected individuals but are distinctive for Costello syndrome.

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
• Severe postnatal feeding difficulties
• Short stature

Craniofacial appearance and voice (see Figure 1, Figure 2)

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. Two girls age ten years have chubby cheeks, full lips, ocular (more...)

Figure 2.

Typical facial features seen in a white boy age eight years (A) and a nearly 11-year-old Hispanic girl (B) with Costello syndrome Gripp & Lin [2012]. Reprinted with permission from Genetics in Medicine.

• Macrocephaly (relative)
• Coarse facial features, full cheeks, full lips, large mouth, full nasal tip
• 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
• 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

Neurologic

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

Tumors. Increased occurrence of malignant solid tumors; typically, elevated urine catecholamine metabolites

Psychomotor development

• Developmental delay or intellectual disability
• Sociable, outgoing personality

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

Molecular Genetic Testing

Gene. HRAS is the only gene in which pathogenic variants are known to cause Costello syndrome [Aoki et al 2005, Kerr et al 2008].

Other loci. No other loci have been identified. In early series, the 10%-15% of individuals suspected of having Costello syndrome who lacked an HRAS pathogenic variant were later 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].

Clinical testing

• Sequence analysis
• Targeted analysis for pathogenic variants. More than 95% of allelic variants causing Costello syndrome affect amino acid p.Gly12 or p.Gly13 (see Table 2).

The failure to identify an HRAS pathogenic variant in an individual with a classic clinical phenotype of Costello syndrome can result from either of the following:

• Mostly commonly, the presence of a pathogenic variant in another gene, consistent with a diagnosis of CFC syndrome [Rauen 2006, Gripp et al 2007] or another disorder of the Ras/MAPK pathway [Quezada & Gripp 2007, Lo et al 2009]
• Rarely, the presence of a low level of somatic mosaicism for the HRAS pathogenic variant in the tested tissue [Gripp et al 2006a, Sol-Church et al 2009, Girisha et al 2010]

Testing Strategy

To confirm/establish the diagnosis in a proband

• The diagnosis is primarily established by detailed clinical evaluation, including complete cardiac evaluation.
• Molecular testing is performed as needed for diagnostic confirmation.
  Note: Some laboratories offer tiered testing first, which involves either sequencing of exon 2 or testing for a panel of pathogenic variants. If a pathogenic variant is not found, sequencing of the entire gene is performed. Other laboratories offer sequencing of multiple genes encoding proteins of the Ras/MAPK signaling pathway simultaneously on a chip array; this approach will also identify pathogenic variants in genes other than HRAS. Identification of a variant in a gene other than HRAS in an individual clinically suspected of having Costello syndrome strongly suggests a different diagnosis associated with mutation of the relevant gene, such as Noonan syndrome or cardiofaciocutaneous syndrome.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Description

Females and males are equally affected. Costello syndrome can theoretically be recognized in the fetus, is usually diagnosed in the young child, and evolves 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 ultrasonography [Lin et al 2009, Smith et al 2009]. 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 prenatally, 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 [Lin et al 2009].

In the neonate, 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. 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. Pyloric stenosis occurs more commonly than in the general population [Gripp et al 2008]. Most infants display hypotonia, irritability, developmental delay, and nystagmus with delayed visual maturation improving with age. Hypotonia may be severe and suggest myopathy [van der Burgt et al 2007].

Cardiac abnormalities typically present in infancy or early childhood, but may be recognized at any age. Lin et al [2011] analyzed 146 individuals with Costello syndrome who had an HRAS pathogenic variant; 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. Costello syndrome appears to be the most identifiable cause of chaotic atrial rhythm/multifocal atrial tachycardia diagnosed neonatally. Pulmonic valve stenosis is usually mild to moderate, and infrequently requires surgery or interventional catheterization.

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 frequently 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.

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

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 intellectual disability is present in all individuals [Axelrad et al 2004, Axelrad et al 2007, Axelrad et al 2009, Axelrad et al 2011]. Separation anxiety is seen in 39% of individuals with Costello syndrome and is more common in males than in females [Axelrad et al 2011].

Progressive postnatal cerebellar overgrowth may result in development of a Chiari I malformation, syringomyelia, and hydrocephalus [Gripp et al 2010]. EEG abnormalities are seen in approximately one third of individuals; between 20% and 50% have seizures [Delrue et al 2003, Kawame et al 2003].

Seven of ten individuals age 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 involving the fingers. Ulnar deviation of the wrists and fingers is also 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 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]. Developmental hip dysplasia may result in severe pain and prevent ambulation. Quality of life in individuals age 16-34 years is compromised by four factors: 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].

Adult-onset gastroesophageal 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].

Older individuals 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. 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.

As part of the recent cardiovascular analysis [Lin et al 2011], deaths were reported in 10% of study participants, and in 20% of affected individuals described in the literature. Causes of death were: HCM in association with neoplasia, coronary artery fibromuscular dysplasia, multifocal tachycardia, neoplasia, pulmonary cause, and multiorgan failure.

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 are tumors of early childhood, presenting 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 reported cases of transitional cell carcinoma of the bladder in individuals with Costello syndrome were ten, 11, and 16 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]. A systematic review of brain and spinal cord MRI studies revealed posterior fossa crowding with cerebellar tonsillar herniation in 27/28 (96%) individuals with Costello syndrome. In a majority of those with serial studies this crowding progressed [Gripp et al 2010]. Due to the progressive nature of the cerebellar overgrowth [Gripp et al 2010] – which likely results from abnormal cell differentiation as reported by Paquin et al [2009] – repeated brain imaging may be necessary in the young child and in any symptomatic individual. Sequelae of posterior fossa crowding included hydrocephalus requiring shunt placement or ventriculostomy (7/28), Chiari I malformation (9/28) and syringomyelia (7/28) [Gripp et al 2010].

Genotype-Phenotype Correlations

Because few affected individuals with pathogenic variants other than p.Gly12Ser have been identified, limited genotype-phenotype correlations have been established. However, Kerr et al [2006] suggested that the risk for malignant tumors may be higher in individuals with the p.Gly12Ala pathogenic variant (4/7; 57%) than in those with the p.Gly12Ser variant (4/65; 7%). No individuals with p.Gly13Cys have developed a malignant tumor to date [Gripp et al 2011a].

Lo et al [2008] suggested that a more severe neonatal phenotype may be associated with certain rare pathogenic variants, including p.Gly12Asp and p.Gly12Cys. In contrast, the possibility of a milder or attenuated phenotype was noted in individuals with p.Thr58Ile and p.Ala146Val [Gripp et al 2008].

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 most common p.Gly12Ser, these differences are statistically significant.

A severe newborn presentation mimicking congenital myopathy was described in four individuals, three of whom had less common HRAS pathogenic variants [van der Burgt et al 2007]. Muscle biopsy revealed excess muscle spindles, leading to the description "congenital myopathy with excess of muscle spindles." However, this represents an unusual presentation of Costello syndrome rather than a separate disorder.

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 an atypical phenotype attributed to her mosaicism. Findings typical for Costello syndrome included intellectual disability, 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 2006b]. 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], or findings indistinguishable from Costello syndrome caused by a germline-derived variant [Girisha et al 2010].

In a systematic review of 146 individuals with HRAS pathogenic variants, there was no apparent correlation 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. With increased identification of individuals with rare variants, this area of research may yield new insights.

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].

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

Prevalence

Costello syndrome is rare, with approximately 300 individuals reported worldwide, and others identified through the international advocacy group network [Authors, personal observation]. The birth prevalence of Costello syndrome is estimated at 1:300,000 in the UK [Bronwyn Kerr, personal communication]. In contrast, an epidemiologic study using national surveys suggested a prevalence of 1:1,230,000 in Japan [Abe et al 2011]; this may be an underestimate due to ascertainment procedures.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Costello syndrome, the following evaluations are recommended:

• Complete physical and neurologic examination
• Plotting of growth parameters, including head circumference
• Nutritional assessment
• Cardiologic evaluation with two-dimensional and Doppler echocardiography, baseline electrocardiography, and Holter examination as needed. Children with HCM and arrhythmia require specialty pediatric cardiology care, which may include exercise testing in certain older cooperative individuals.
• Brain MRI, including MRI of the spinal cord as needed, in order to evaluate for Chiari I malformation and sryingomyelia
• Ophthalmology evaluation
• Clinical assessment of spine and extremities, with particular concern for hip joint abnormalities and range of motion
• Multidisciplinary developmental evaluation
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Growth. Most infants require nasogastric or gastrostomy feeding. Because of gastroesophageal reflux and irritability, Nissen fundoplication is often performed. Pyloric stenosis is treated surgically.

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 2011]. Ongoing studies of the natural history will continue to define management for older individuals. Arrhythmias have been well documented, but incompletely defined from a management point of view. Non-reentrant tachycardia (chaotic atrial rhythm/multifocal tachycardia) may require aggressive anti-arrhythmic drugs or ablation.

Pharmacologic and surgical treatment (myectomy) has been used to address severe 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. Hip joint abnormalities are common and may require surgical correction.

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 of sleep disturbance.

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

Papillomata. Papillomata usually appear in the perinasal 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. Because aortic dilation has not been studied long term, is infrequent, is typically mild-moderate in severity, and has not been associated with dissection to date, there are no data to recommend treatment; care should be individualized.

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. All individuals with Costello syndrome, especially those with a cardiovascular abnormality, should be followed by a cardiologist who is aware of the spectrum of cardiac disease and its natural history. Rather than propose a unique set of guidelines, we advise providers and families to receive individualized care by a pediatric cardiologist, transitioning to an adult specialist following the “best practices” for the particular defect. 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. It is beyond the scope of this review to delineate the complex decision making involved in treating HCM or atrial tachycardia.

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 continues to be parental and physician awareness of the increased cancer risk.

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

Evaluation of Relatives at Risk

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

Therapies Under Investigation

The Ras/MAPK pathway has long been a drug development target because of its involvement in malignant tumors [Rauen 2007]. It is likely that drugs targeting this pathway will be considered for use in Costello syndrome and other disorders caused by germline pathogenic variants affecting pathway-related genes [Rauen et al 2008].

In a mouse model, the ACE inhibitor captopril appeared beneficial in reducing systemic hypertension and cardiomyopathy [Schuhmacher et al 2008].

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe 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 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].

Mode of Inheritance

Costello syndrome is inherited in an autosomal dominant manner, typically as the result of a de novo dominant pathogenic variant. However, inheritance from a parent with somatic mosaicism involving the germline has been described.

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 pathogenic variant.
• One clinical report suggested possible somatic mosaicism in a parent [Bodkin et al 1999], which has since been molecularly confirmed [Sol-Church et al 2009]. Haplotype analysis in the only sib pair with molecularly confirmed Costello syndrome suggested maternal germline mosaicism as the underlying mechanism [Gripp et al 2011b]. It is therefore important to consider the possibility of somatic and germline mosaicism in parents.
• An association with advanced parental age had been documented. Most but not all pathogenic variants arise in the paternal germline; Sol-Church et al [2006] reported 14 de novo pathogenic variants of paternal origin and two of maternal origin.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• Because Costello syndrome typically occurs as a result of a de novo pathogenic variant, 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]. See Parents of a proband.

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

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

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

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 Diagnosis

Molecular genetic testing. If the HRAS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible. Recurrence of Costello syndrome in a family is unusual.

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 pathogenic variants [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 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].

Somatic mutation hotspots are bases encoding the glycines in positions 12 and 13 and the glutamine in position 61. Pathogenic missense variants at these positions leads to increased activity of the gene product. As the germline pathogenic variants 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 pathogenic variants listed in Table 2.

Figure 3 shows the molecular genetic relationship of several syndromes with phenotypic overlap.

Figure 3.

Molecular basis of the neuro-cardiofaciocutaneous syndromes. The Ras/MAPK pathway transmits signals from the cell surface to the nucleus. Pathogenic variants in genes encoding different components of this pathway result in different syndromes with overlapping (more...)

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

Pathogenic variants. See Table 2. 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, and p.Glu37dup) were found in one or two individuals each [Aoki et al 2005, Estep et al 2006, Gripp et al 2006a, Kerr et al 2006, Gremer et al 2010].

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]. Three individuals with changes in exon 4 have been reported, one resulting in p.Lys117Arg [Kerr et al 2006], and two with mutation affecting amino acid 146, resulting in p.Ala146Thr [Zampino et al 2007] and p.Ala146Val [Gripp et al 2008].

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 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].

The amino acid changes lead either to decreased GTPase activity (if amino acids 12, 13, 59, 61, 63 are involved) so that oncogenic RAS mutated 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.

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Suggested Reading

• Lin AE, Rauen KA, Gripp KW, Carey JC. Clarification of previously reported Costello syndrome patients. Am J Med Genet A. 2008;146A:940–3. [PubMed: 18302240]
• Rauen KA, Schoyer L, McCormick F, Lin AE, Allanson JE, Stevenson DA, Gripp KW, Neri G, Carey JC, Legius E, Tartaglia M, Schubbert S, Roberts AE, Gelb BD, Shannon K, Gutmann DH, McMahon M, Guerra C, Fagin JA, Yu B, Aoki Y, Neel BG, Balmain A, Drake RR, Nolan GP, Zenker M, Bollag G, Sebolt-Leopold J, Gibbs JB, Silva AJ, Patton EE, Viskochil DH, Kieran MW, Korf BR, Hagerman RJ, Packer R, Melesi T. Proceedings from the 2009 Genetic Syndromes of the Ras/MAPK Pathway: From Bedside to Bench and Back. Am J Med Genet A. 2010;152A:4–24. [PMC free article: PMC4051786] [PubMed: 20014119]
• Stevenson DA, Yang FC. The musculoskeletal phenotype of the RASopathies. Am J Med Genet C Semin Med Genet. 2011;157C:90–103. [PubMed: 21495174]
• Tidyman WE, Lee HS, Rauen KA. Skeletal muscle pathology in Costello and cardio-facio-cutaneous syndromes: developmental consequences of germline Ras/MAPK activtation on myogenesis. Am J Med Genet C Semin Med Genet. 2011;157C:104–14. [PubMed: 21495178]

Author Notes

Drs Gripp and Lin are Co-Directors with Dr Katherine Rauen 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.

Revision History

• 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