• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Costello Syndrome

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

Author Information
, MD, FAAP, FACMG
Division of Medical Genetics
AI du Pont Hospital for Children
Wilmington, Delaware
Professor of Pediatrics
T Jefferson University and Medical College
Philadelphia, Pennsylvania
, MD, FAAP, FACMG
Associate Clinical Professor of Pediatrics, Harvard Medical School
Medical Genetics
Massachusetts General Hospital for Children
Boston, Massachusetts

Initial Posting: ; Last Update: January 12, 2012.

Summary

Disease 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 missense mutations in 80%-90% of individuals with the clinical diagnosis. The clinical diagnosis should be reconsidered if an HRAS mutation 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 mutation; parents of probands are almost never affected, although somatic mosaicism occurred in one parent. Because Costello syndrome is typically caused by a de novo mutation, 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 disease-causing allele of an affected family member has been identified.

Diagnosis

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 2011]. 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

Figure

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 ten-year-old girls have chubby (more...)

Figure 2

Figure

Figure 2. Typical facial features seen in an 8-year old white boy (A) and a nearly 11-year-old Hispanic girl (B) with Costello syndrome

Gripp & Lin [2011]. 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 missense mutation by molecular genetic testing confirms the clinical diagnosis of Costello syndrome.

Molecular Genetic Testing

Gene. HRAS is the only gene in which mutations 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 mutation were later found to have cardiofaciocutaneous (CFC) syndrome [Rauen 2006, Gripp et al 2007] or mutations in KRAS typical for Noonan syndrome [Lo et al 2009].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Costello Syndrome

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
HRASSequence analysisSequence variants 280%-90% 3
Targeted mutation analysisp.Gly12Ala
p.Gly12Ser
p.Gly12Val
p.Gly13Asp
See Table 2

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

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

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

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

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

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 mutations. If a mutation 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 mutations in genes other than HRAS. Identification of a mutation in a gene other than HRAS in an individual clinically suspected of having Costello syndrome strongly suggests a different diagnosis associated with mutations in the respective gene, such as Noonan syndrome or cardiofaciocutaneous syndrome.

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

Clinical Description

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 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 mutation; 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 mutation [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 mutations 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 mutation (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 mutations, 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 mutation 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 mutations [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 mutation 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 mutation 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 mutation [Girisha et al 2010].

In a systematic review of 146 individuals with HRAS mutations, there was no apparent correlation between the specific mutation 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 mutations, 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 mutations 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.

Differential Diagnosis

In infants and young children, Costello syndrome is difficult to distinguish from cardiofaciocutaneous (CFC) syndrome or Noonan syndrome; in older children, the distinction between Costello syndrome and Noonan syndrome is clear. Feeding problems and failure to thrive are usually more severe in infants with Costello syndrome and CFC syndrome than in infants with Noonan syndrome. The distinctive combination of pectus carinatum and pectus excavatum typifies Noonan syndrome. Costello syndrome is distinguished by ulnar deviation of the hands, marked small-joint laxity, striking excess palmar skin, the presence of papillomata, and palmar calluses.

The cardiac abnormalities in Costello syndrome, CFC syndrome, and Noonan syndrome are similar [Gripp et al 2006a; Lin et al 2011] with at least one of the three main types of cardiac abnormality occurring in 75% to 95% of individuals, depending on the specific mutation (least common with CFC-BRAF; most common with Noonan syndrome-RAF1). Non-reentrant tachycardia (chaotic atrial rhythm/multifocal tachycardia) is most distinctive for (though not unique to) Costello syndrome. The co-occurrence of pulmonic stenosis and atrial septal defect is less common in Costello syndrome than in CFC and Noonan syndromes. Because of the overlap between Costello syndrome and CFC syndrome, the diagnosis of individuals with a phenotype considered borderline or atypical for Costello syndrome should be clarified by molecular genetic testing [Quezada & Gripp 2007].

Cardiofaciocutaneous (CFC) syndrome resembles Costello syndrome in young children. Hypotonia, nystagmus, mild-to-moderate intellectual disability, and postnatal growth deficiency are typical. Feeding difficulties are common but may be less severe than in Costello syndrome. The dolichocephaly, high forehead, and slightly coarse facial features may resemble Costello syndrome; but the lips are not as thick and prominent. The hair is more consistently sparse or curly; and, in contrast to Costello syndrome, the eyebrows are typically sparse or absent. Skin abnormalities include severe atopic dermatitis, keratosis pilaris, ichthyosis, and hyperkeratosis; the papillomata, characteristic of Costello syndrome, are not seen in CFC syndrome. As in Costello syndrome, pulmonic valve stenosis is common, as is atrial septal defect. Hypertrophic cardiomyopathy has been noted in approximately 40% of mutation-positive individuals, similar to Costello syndrome [Niihori et al 2006, Rodriguez-Viciana et al 2006, Gripp et al 2007]. Atrial tachycardia had not been reported until recently; in the small number of reported cases, it has not been called chaotic atrial rhythm [Niihori et al 2006]. Malignant tumors have not been reported in CFC syndrome. The discovery of germline mutations in BRAF, and less commonly in KRAS, MAP2K1, or MAP2K2, allows for molecular confirmation of a clinical diagnosis of CFC syndrome [Niihori et al 2006, Rodriguez-Viciana et al 2006, Gripp et al 2007]. Inheritance is autosomal dominant.

Noonan syndrome is characterized by short stature; congenital heart defect; broad or webbed neck; unusual chest shape with superior pectus carinatum, inferior pectus excavatum and apparently low-set nipples; developmental delay of variable degree; cryptorchidism; and characteristic facies. Varied coagulation defects and lymphatic dysplasia are frequently observed. Congenital heart defects occur in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or appear in infancy or childhood. Other frequent structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot; less common are incomplete atrioventricular canal (primum-type atrial septal defect) and coarctation. Length at birth is usually normal. Final adult height approaches the lower limit of normal. Most school-age children perform well in a normal educational setting; 10%-15% require special education. Mild intellectual disability is seen in up to one third of individuals. Mutations in PTPN11 have been identified in 50% of affected individuals, KRAS in fewer than 5%, SOS1 in approximately 13%, RAF1 in 3%-17%, and NRAS in four individuals. A single recurrent mutation in SHOC2 results in Noonan syndrome with loose anagen hair or Mazzanti syndrome. Inheritance is autosomal dominant.

Beckwith-Wiedemann syndrome may be considered in the differential diagnosis of a newborn with features suggestive of Costello syndrome; i.e., apparent "overgrowth" (more accurately, elevated birth weight as a result of edema), protruding tongue, and coarse facial features. Beckwith-Wiedemann syndrome is a disorder of growth characterized by macrosomia, macroglossia, visceromegaly, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, neonatal hypertrophic cardiomyopathy, and renal abnormalities. Macroglossia and macrosomia are generally present at birth but may have postnatal onset. Growth rate slows around age seven to eight years. Hemihyperplasia may affect segmental regions of the body or selected organs and tissues. The molecular basis of Beckwith-Wiedemann syndrome is complex.

Simpson-Golabi-Behmel syndrome is an X-linked condition that shares many features with Beckwith-Wiedemann syndrome (e.g., macrosomia, visceromegaly, macroglossia, renal anomalies). Cleft lip, skeletal abnormalities (including polydactyly), and developmental delay may be present. Although individuals with tumors have been reported, the tumor risk and range of tumors remain to be defined. Mutations in GPC3, the gene encoding glypican-3, are identified in most affected individuals.

Williams syndrome shares some findings with Costello syndrome, including soft skin and ligamentous laxity of small joints, full lips, and the friendly personality with anxious demeanor in adolescence. Williams syndrome is characterized by cognitive impairment and a specific cognitive profile, unique personality characteristics, distinctive facial features, and cardiovascular disease (elastin arteriopathy). A range of connective tissue abnormalities is observed, and hypercalcemia is common. Molecular diagnosis consists of detection by fluorescent in situ hybridization (FISH) of the contiguous gene deletion of the critical region at 7q11 that encompasses the elastin gene (ELN). Inheritance is autosomal dominant.

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

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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
  • Genetics consultation

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 mutations 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 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].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face 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 mutation. 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 mutation.
  • 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 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

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 mutation, 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic 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 approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately 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.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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
    244 Taos Road
    Altadena CA 91001
    Phone: 626-676-7694; 626-794-7343 (evenings or weekends)
    Fax: 626-572-2380
    Email: taos@earthlink.net
  • International Costello Syndrome Support Group
    90 Parkfield Road North
    New Moston Manchester M40 3RQ
    United Kingdom
    Email: c.stone8@ntlworld.com
  • 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); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
    Email: info@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

Gene SymbolChromosomal LocusProtein NameHGMD
HRAS11p15​.5GTPase HRasHRAS

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Costello Syndrome (View All in OMIM)

190020V-HA-RAS HARVEY RAT SARCOMA VIRAL ONCOGENE HOMOLOG; HRAS
218040COSTELLO 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 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].

Somatic 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 in Table 2.

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

Figure 3

Figure

Figure 3. Molecular basis of the neuro-cardiofaciocutaneous syndromes. The Ras/MAPK pathway transmits signals from the cell surface to the nucleus. Mutations in genes encoding different components of this pathway result in different syndromes with overlapping (more...)

Normal allelic variants. 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.

Pathologic allelic variants. See Table 2. Germline mutations 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 mutations 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 mutations, resulting in p.Gly12Val, p.Gly12Cys, p.Gly12Glu, p.Gly13Cys, p.Gly13Asp, and p.Glu37dup occurred 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 missense mutations in exon 3, resulting in 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 mutations affecting amino acid 146, resulting in p.Ala146Thr [Zampino et al 2007] and p.Ala146Val [Gripp et al 2008].

Table 2. Selected HRAS Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Mutation Detection Frequency (# of Patients) 1Reference 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+1dupAGGp.Glu37dup<1% (1)
c.108_110dupAGAp.Glu37dup<1% (1)
c.173C>Tp.Thr58Ile<1% (1)
c.187G>Ap.Glu63Lys<1% (1)
c.350A>Gp.Lys117Arg<1% (1)
c.436G>Ap.Ala146Thr<1% (1)
c.437C>Tp.Ala146Val<1% (1)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. HRAS mutations reported in 139 individuals affected with Costello Syndrome [Sol-Church & Gripp 2009]

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 point mutations that cause Costello syndrome are identical to the somatic HRAS point mutations observed in malignant tumors unrelated to Costello syndrome. 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. These missense mutations 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 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). 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.

References

Literature Cited

  1. Abe Y, Aoki Y, Kuriyama S, Kawame H, Okamoto N, Kurasawa K, Ohashi H, Mizuno S, Ogata T, Kure S, Niihori T, Matsubara Y. Epidemiological features of Costello syndrome and Cardio-facio-cutaneous syndrome: findings from the first nationwide survey. Chicago, IL: International Meeting on Genetic Syndromes of the Ras/MAPK Pathway; 2011.
  2. Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara Y. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005;37:1038–40. [PubMed: 16170316]
  3. Axelrad ME, Glidden R, Nicholson L, Gripp KW. Adaptive skills, cognitive, and behavioral characteristics of Costello syndrome. Am J Med Genet A. 2004;128A:396–400. [PubMed: 15264285]
  4. Axelrad ME, Nicholson L, Stabley DL, Sol-Church K, Gripp KW. Longitudinal assessment of cognitive characteristics in Costello syndrome. Am J Med Genet A. 2007;143A:3185–93. [PubMed: 17963256]
  5. Axelrad ME, Schwartz DD, Katzenstein JM, Hopkins E, Gripp KW. Neurocognitive, adaptive, and behavioral functioning of individuals with Costello syndrome: a review. Am J Med Genet C Semin Med Genet. 2011;157:115–22. [PubMed: 21495179]
  6. Bentires-Alj M, Kontaridis MI, Neel BG. Stops along the RAS pathway in human genetic disease. Nat Med. 2006;12:283–5. [PubMed: 16520774]
  7. Bodkin NM, Mortimer ES, Demmer LA. Male to male transmission of Costello syndrome consistent with autosomal dominant inheritance. Am J Hum Genet. 1999;65:143.
  8. Borochowitz Z, Pavone L, Mazor G, Rizzo R, Dar H. New multiple congenital anomalies: mental retardation syndrome (MCA/MR) with facio-cutaneous-skeletal involvement. Am J Med Genet. 1992;43:678–85. [PubMed: 1621757]
  9. Corbett KD, Alber T. The many faces of Ras: recognition of small GTP-binding proteins. Trends Biochem Sci. 2001;26:710–6. [PubMed: 11738594]
  10. Costello JM. A new syndrome. NZ Med J. 1971;74:397.
  11. Costello JM. A new syndrome: mental subnormality and nasal papillomata. Aust Paediatr J. 1977;13:114–8. [PubMed: 907573]
  12. Costello JM. Costello syndrome: update on the original cases and commentary. Am J Med Genet. 1996;62:199–201. [PubMed: 8882404]
  13. Della Marca G, Vasta I, Scarano E, Rigante M, De Feo E, Mariotti P, Rubino M, Vollono C, Mennuni GF, Tonali P, Zampino G. Obstructive sleep apnea in Costello syndrome. Am J Med Genet A. 2006;140:257–62. [PubMed: 16419102]
  14. Delrue MA, Chateil JF, Arveiler B, Lacombe D. Costello syndrome and neurological abnormalities. Am J Med Genet A. 2003;123A:301–5. [PubMed: 14608654]
  15. Der Kaloustian VM, Moroz B, McIntosh N, Watters AK, Blaichman S. Costello syndrome. Am J Med Genet. 1991;41:69–73. [PubMed: 1951465]
  16. Estep AL, Tidyman WE, Teitell MA, Cotter PD, Rauen KA. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A. 2006;140:8–16. [PubMed: 16372351]
  17. Giehl K. Oncogenic Ras in tumour progression and metastasis. Biol Chem. 2005;386:193–205. [PubMed: 15843165]
  18. Girisha KM, Lewis LE, Phadke SR, Kutsche K. Costello syndrome with severe cutis laxa and mosaic HRAS G12S mutation. Am J Med Genet A. 2010;152A:2861–2864. [PubMed: 20979192]
  19. Gregersen N, Viljoen D. Costello syndrome with growth hormone deficiency and hypoglycemia: a new report and review of the endocrine associations. Am J Med Genet A. 2004;129A:171–5. [PubMed: 15316966]
  20. Gremer L, De Luca A, Merbitz-Zahradnik T, Dallapiccola B, Morlot S, Tartaglia M, Kutsche K, Ahmadian MR, Rosenberger G. Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor-dependent MAPK and AKT activation. Hum Mol Genet. 2010;19:790–802. [PubMed: 19995790]
  21. Gripp KW. Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet. 2005;137C:72–7. [PubMed: 16010679]
  22. Gripp KW, Hopkins E, Doyle D, Dobyns WB. High incidence of progressive postnatal cerebellar enlargement in Costello syndrome: brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities. Am J Med Genet A. 2010;152A:1161–8. [PubMed: 20425820]
  23. Gripp KW, Hopkins E, Sol-Church K, Stabley DL, Axelrad ME, Doyle D, Dobyns WB, Hudson C, Johnson J, Tenconi R, Graham GE, Sousa AB, Heller R, Piccione M, Corsello G, Herman GE, Tartaglia M, Lin AE. Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C. Am J Med Genet Part A. 2011a;155A:706–716. [PubMed: 21438134]
  24. Gripp KW, Innes AM, Axelrad ME, Gillan TL, Parboosingh JS, Davies C, Leonard NJ, Lapointe M, Doyle D, Catalano S, Nicholson L, Stabley DL, Sol-Church K. Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype? Am J Med Genet A. 2008;146A:683–90. [PubMed: 18247425]
  25. Gripp KW, Kawame H, Viskochil DH, Nicholson L. Elevated catecholamine metabolites in patients with Costello syndrome. Am J Med Genet A. 2004;128A:48–51. [PubMed: 15211656]
  26. Gripp KW, Lin AE. Costello syndrome: A Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations. Genet Med. 2011 [PubMed: 22261753]
  27. Gripp KW, Lin AE, Nicholson L, Allen W, Cramer A, Jones KL, Kutz W, Peck D, Rebolledo MA, Wheeler PG, Wilson W, Al-Rahawan MM, Stabley DL, Sol-Church K. Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. Am J Med Genet A. 2007;143A:1472–80. [PubMed: 17551924]
  28. Gripp KW, Lin AE, Stabley DL, Nicholson L, Scott CI, Doyle D, Aoki Y, Matsubara Y, Zackai EH, Lapunzina P, Gonzalez-Meneses A, Holbrook J, Agresta CA, Gonzalez IL, Sol-Church K. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006a;140:1–7. [PubMed: 16329078]
  29. Gripp KW, Scott CI, Nicholson L, Figueroa TE. Second case of bladder carcinoma in a patient with Costello syndrome. Am J Med Genet. 2000;90:256–9. [PubMed: 10678668]
  30. Gripp KW, Scott CI, Nicholson L, McDonald-McGinn DM, Ozeran JD, Jones MC, Lin AE, Zackai EH. Five additional Costello syndrome patients with rhabdomyosarcoma: proposal for a tumor screening protocol. Am J Med Genet. 2002;108:80–7. [PubMed: 11857556]
  31. Gripp KW, Stabley DL, Geller PL, Hopkins E, Stevenson DA, Carey JC, Sol-Church K. Molecular confirmation of HRAS p.G12S in siblings with Costello syndrome. Am J Med Genet Part A. 2011b;155A:2263–2268. [PMC free article: PMC3158836] [PubMed: 21834037]
  32. Gripp KW, Stabley DL, Nicholson L, Hoffman JD, Sol-Church K. Somatic mosaicism for an HRAS mutation causes Costello syndrome. Am J Med Genet A. 2006b;140:2163–9. [PubMed: 16969868]
  33. Hall BD, Berbereich FR, Berbereich MS. AMICABLE syndrome: A new unique disorder involving facial, cardiac, ectodermal, growth and intellectual abnormalities. Proc Greenwood Genet Center. 1990;9:103A.
  34. Hennekam RC. Costello syndrome: an overview. Am J Med Genet Part C Semin Med Genet. 2003;117C:42–8. [PubMed: 12561057]
  35. Hopkins E, Lin AE, Krepkovich KE, Axelrad ME, Sol-Church K, Stabley DL, Hossain J, Gripp KW. Living with Costello syndrome: Quality of life issues in older individuals. Am J Med Genet Part A. 2010;152A:84–90. [PubMed: 20034064]
  36. Johnson JP, Golabi M, Norton ME, Rosenblatt RM, Feldman GM, Yang SP, Hall BD, Fries MH, Carey JC. Costello syndrome: phenotype, natural history, differential diagnosis, and possible cause. J Pediatr. 1998;133:441–8. [PubMed: 9738731]
  37. Kawame H, Matsui M, Kurosawa K, Matsuo M, Masuno M, Ohashi H, Fueki N, Aoyama K, Miyatsuka Y, Suzuki K, Akatsuka A, Ochiai Y, Fukushima Y. Further delineation of the behavioral and neurologic features in Costello syndrome. Am J Med Genet A. 2003;118A:8–14. [PubMed: 12605434]
  38. Kerr B, Allanson J, Delrue MA, Gripp KW, Lacombe D, Lin AE, Rauen KA. The diagnosis of Costello syndrome: nomenclature in Ras/MAPK pathway disorders. Am J Med Genet A. 2008;146A:1218–20. [PubMed: 18386799]
  39. Kerr B, Delrue MA, Sigaudy S, Perveen R, Marche M, Burgelin I, Stef M, Tang B, Eden OB, O'Sullivan J, De Sandre-Giovannoli A, Reardon W, Brewer C, Bennett C, Quarell O, M'Cann E, Donnai D, Stewart F, Hennekam R, Cavé H, Verloes A, Philip N, Lacombe D, Levy N, Arveiler B, Black G. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006;43:401–5. [PMC free article: PMC2564514] [PubMed: 16443854]
  40. Kerr B, Einaudi MA, Clayton P, Gladman G, Eden T, Saunier P, Genevieve D, Philip N. Is growth hormone treatment beneficial or harmful in Costello syndrome? J Med Genet. 2003;40:e74. [PMC free article: PMC1735496] [PubMed: 12807973]
  41. Kerr BK, Gripp KW, Lin AE. Costello syndrome. In: Cassidy SB, Allanson JE, eds. Management of Genetic Syndromes. 3 ed. Hoboken, NJ: John Wiley & Sons; 2010:211-24.
  42. Kratz CP, Rapisuwon S, Reed H, Hasle H, Rosenberg PS. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet C Semin Med Genet. 2011;157:83–9. [PMC free article: PMC3086183] [PubMed: 21500339]
  43. Legault L, Gagnon C, Lapointe N. Growth hormone deficiency in Costello syndrome: a possible explanation for the short stature. J Pediatr. 2001;138:151–2. [PubMed: 11148542]
  44. Lin AE, Alexander ME, Colan SD, Kerr B, Rauen KA, Noonan J, Baffa J, Hopkins E, Sol-Church K, Limongelli G, Digilio MC, Marino B, Ines AM, Aoki Y, Silberbach M, Del-Rue MA, While SM, Hamilton RM, O’Connor W, Grossfeld PD, Smoot LB, Padera RF, Gripp KW. Clinical, pathological and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK Pathway syndrome. Am J Med Genet Part A. 2011;155A:486–507. [PubMed: 21344638]
  45. Lin AE, Grossfeld PD, Hamilton RM, Smoot L, Gripp KW, Proud V, Weksberg R, Wheeler P, Picker J, Irons M, Zackai E, Marino B, Scott CI, Nicholson L. Further delineation of cardiac abnormalities in Costello syndrome. Am J Med Genet. 2002;111:115–29. [PubMed: 12210337]
  46. Lin AE, O'Brien B, Demmer LA, Almeda KK, Blanco CL, Glasow PF, Berul CI, Hamilton R, Micheil Innes A, Lauzon JL, Sol-Church K, Gripp KW. Prenatal features of Costello syndrome: ultrasonographic findings and atrial tachycardia. Prenat Diagn. 2009;29:682–90. [PubMed: 19382114]
  47. Lo FS, Lin JL, Kuo MT, Chiu PC, Shu SG, Chao MC, Lee YJ, Lin SP. Noonan syndrome caused by germline KRAS mutation in Taiwan: report of two patients and a review of the literature. Eur J Pediatr. 2009;168:919–23. [PubMed: 18958496]
  48. Lo IF, Brewer C, Shannon N, Shorto J, Tang B, Black G, Soo MT, Ng DK, Lam ST, Kerr B. Severe neonatal manifestations of Costello syndrome. J Med Genet. 2008;45:167–71. [PubMed: 18039947]
  49. Niihori T, Aoki Y, Narumi Y, Neri G, Cavé H, Verloes A, Okamoto N, Hennekam RC, Gillessen-Kaesbach G, Wieczorek D, Kavamura MI, Kurosawa K, Ohashi H, Wilson L, Heron D, Bonneau D, Corona G, Kaname T, Naritomi K, Baumann C, Matsumoto N, Kato K, Kure S, Matsubara Y. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006;38:294–6. [PubMed: 16474404]
  50. Paquin A, Hordo C, Kaplan DR, Miller FD. Costello syndrome H-Ras alleles regulate cortical development. Dev Biol. 2009;330:440–51. [PubMed: 19371735]
  51. Quezada E, Gripp KW. Costello syndrome and related disorders. Curr Opin Pediatr. 2007;19:636–44. [PubMed: 18025929]
  52. Rauen KA. Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype. Am J Med Genet A. 2006;140:1681–3. [PubMed: 16804887]
  53. Rauen KA. HRAS and the Costello syndrome. Clin Genet. 2007;71:101–8. [PubMed: 17250658]
  54. Rauen KA, Hefner E, Carrillo K, Taylor J, Messier L, Aoki Y, Gripp KW, Matsubara Y, Proud VK, Hammond P, Allanson JE, Delrue MA, Axelrad ME, Lin AE, Doyle DA, Kerr B, Carey JC, McCormick F, Silva AJ, Kieran MW, Hinek A, Nguyen TT, Schoyer L. Molecular aspects, clinical aspects and possible treatment modalities for Costello syndrome: Proceedings from the 1st International Costello Syndrome Research Symposium 2007. Am J Med Genet A. 2008;146A:1205–17. [PubMed: 18412122]
  55. Rodriguez-Viciana P, Tetsu O, Tidyman WE, Estep AL, Conger BA, Cruz MS, McCormick F, Rauen KA. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science. 2006;311:1287–90. [PubMed: 16439621]
  56. Rosenberger G, Meien S, Kutsche K. Oncogenic HRAS mutations cause prolonged PI3K signaling in response to epidermal growth factor in fibroblasts of patients with Costello syndrome. Hum Mutat. 2009;30:352–62. [PubMed: 19035362]
  57. Schuhmacher AJ, Guerra C, Sauzeau V, Cañamero M, Bustelo XR, Barbacid M. A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition. J Clin Invest. 2008;118:2169–79. [PMC free article: PMC2381749] [PubMed: 18483625]
  58. Smith LP, Podraza J, Proud VK. Polyhydramnios, fetal overgrowth and macrocephaly: Prenatal ultrasound findings of Costello syndrome. Am J Med Genet A. 2009;149A:779–84. [PubMed: 19288554]
  59. Sol-Church K, Gripp KW: The molecular basis of Costello syndrome. In: Zenker M, ed. Noonan Syndrome and Related Disorders. Monographs in Human Genetics. 2009; 17: 94-103.
  60. Sol-Church K, Stabley DL, Demmer LA, Agbulos A, Lin AE, Smoot L, Nicholson L, Gripp KW. Male-to-male transmission of Costello syndrome: G12S HRAS germline mutation inherited from a father with somatic mosaicism. Am J Med Genet A. 2009;149A:315–21. [PMC free article: PMC2653086] [PubMed: 19206176]
  61. Sol-Church K, Stabley DL, Nicholson L, Gonzalez IL, Gripp KW. Paternal bias in parental origin of HRAS mutations in Costello syndrome. Hum Mutat. 2006;27:736–41. [PubMed: 16835863]
  62. Stein RI, Legault L, Daneman D, Weksberg R, Hamilton J. Growth hormone deficiency in Costello syndrome. Am J Med Genet A. 2004;129A:166–70. [PubMed: 15316968]
  63. van der Burgt I, Kupsky W, Stassou S, Nadroo A, Barroso C, Diem A, Kratz CP, Dvorsky R, Ahmadian MR, Zenker M. Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation. J Med Genet. 2007;44:459–62. [PMC free article: PMC2598013] [PubMed: 17412879]
  64. White SM, Graham JM, Kerr B, Gripp K, Weksberg R, Cytrynbaum C, Reeder JL, Stewart FJ, Edwards M, Wilson M, Bankier A. The adult phenotype in Costello syndrome. Am J Med Genet A. 2005;136:128–35. [PubMed: 15940703]
  65. Zampino G, Mastroiacovo P, Ricci R, Zollino M, Segni G, Martini-Neri ME, Neri G. Costello syndrome: further clinical delineation, natural history, genetic definition, and nosology. Am J Med Genet. 1993;47:176–83. [PubMed: 8213903]
  66. Zampino G, Pantaleoni F, Carta C, Cobellis G, Vasta I, Neri C, Pogna EA, De Feo E, Delogu A, Sarkozy A, Atzeri F, Selicorni A, Rauen KA, Cytrynbaum CS, Weksberg R, Dallapiccola B, Ballabio A, Gelb BD, Neri G, Tartaglia M. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat. 2007;28:265–72. [PubMed: 17054105]

Suggested Reading

  1. Lin AE, Rauen KA, Gripp KW, Carey JC. Clarification of previously reported Costello syndrome patients. Am J Med Genet A. 2008;146:940–3. [PubMed: 18302240]
  2. 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 Part A. 2010;152A:4–24. [PMC free article: PMC4051786] [PubMed: 20014119]
  3. Stevenson DA, Yang FC. The musculoskeletal phenotype of the RASopathies. Am J Med Genet C Semin Med Genet. 2011;157:90–103. [PubMed: 21495174]
  4. 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;157:104–14. [PubMed: 21495178]

Chapter Notes

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 to live Web site
  • 2 March 2006 (kg) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1507PMID: 20301680
PubReader format: click here to try

Views

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...