Clinical characteristics.

While the majority of individuals with Costello syndrome share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a milder or attenuated phenotype to a severe phenotype with early lethal complications. Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including: cardiac hypertrophy (usually typical hypertrophic cardiomyopathy), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults.

Diagnosis/testing.

The diagnosis of Costello syndrome is established in a proband with suggestive clinical findings and a heterozygous HRAS pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: Failure to thrive is the most common and challenging clinical problem; most infants require nasogastric or gastrostomy feeding; many require Nissen fundoplication. Treatment of cardiac manifestations and malignancy is routine. Ulnar deviation of the wrists and fingers often requires early bracing and occupational and/or physical therapy; tight Achilles tendons may require surgical tendon lengthening. Developmental disability requires early-intervention programs and individualized education strategies. Recurrent facial papillomata may require routine removal with dry ice. Hemodynamically significant valvar stenoses require antibiotic prophylaxis for subacute bacterial endocarditis; anesthesia may pose a risk to those with hypertrophic cardiomyopathy or those predisposed to some types of atrial tachycardia.

Surveillance: Monitoring for neonatal hypoglycemia; echocardiography with electrocardiogram at diagnosis with subsequent follow up by a cardiologist who is aware of the spectrum of cardiac disease and its natural history; abdominal and pelvic ultrasound examinations to screen for rhabdomyosarcoma and neuroblastoma every three to six months until age eight to ten years may be considered; annual urinalysis for evidence of hematuria to screen for bladder cancer beginning at age ten years.

Genetic counseling.

Costello syndrome is inherited in an autosomal dominant manner. To date, most probands with Costello syndrome have the disorder as the result of a de novo pathogenic variant; although parents of probands are not affected, vertical transmission has been reported in two families with the rare, attenuated phenotype. Because Costello syndrome is typically caused by a de novo pathogenic variant, the risk to the sibs of a proband is presumed to be small; however, recurrence in sibs has been reported and is suspected to be the result of germline mosaicism in a parent. Individuals with Costello syndrome typically do not reproduce. Once an HRAS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Costello syndrome should be suspected when the following findings are present.

Prenatal findings

• On ultrasound examination:
  • Increased nuchal thickness
  • Polyhydramnios (>90%)
  • Characteristic ulnar deviation of the wrists
  • Short humeri and femurs
• Fetal tachycardia (various forms of atrial tachycardia)
• Preterm delivery

Postnatal findings

• Severe postnatal feeding difficulties extending throughout early childhood
• Failure to thrive
• Short stature
• Macrocephaly (relative)
• Coarse facial features (see Figures 1 and 2)
• Curly or sparse, fine hair

Figure 1.

Four girls who attended the 2005 Costello Syndrome Conference in St Louis show several characteristic features, including the friendly, sociable personality associated with Costello syndrome. A. The two girls, both age ten years, have chubby cheeks, full (more...)

Figure 2.

Typical facial features seen in an eight-year-old boy of northern European background (A) and a nearly 11-year-old Hispanic girl (B) with Costello syndrome Gripp & Lin [2012], reprinted with permission from Genetics in Medicine

Skin

• Loose, soft skin
• Increased pigmentation
• Deep palmar and plantar creases
• Papillomata of face, perianal region (typically absent in infancy but may appear in childhood)
• Hyperkeratosis and calluses
• Premature aging, hair loss

Musculoskeletal system

• Diffuse hypotonia, joint laxity, and low muscle mass
• Ulnar deviation of wrists and fingers, splayed fingers resulting in characteristic hand posture
• Spatulate finger pads, abnormal fingernails
• Tight Achilles tendons, often developing throughout childhood
• Positional foot deformity
• Vertical talus
• Kyphoscoliosis
• Pectus carinatum, pectus excavatum, asymmetric rib cage
• Developmental hip dysplasia

Cardiovascular system

• Cardiac hypertrophy; usually typical hypertrophic cardiomyopathy (i.e., idiopathic subaortic stenosis, asymmetric septal hypertrophy), although other forms (i.e., biventricular) have been reported
• Congenital heart defect; usually valvar pulmonic stenosis
• Arrhythmia, usually supraventricular tachycardia. Most distinctive is chaotic atrial rhythm/multifocal atrial tachycardia, or ectopic atrial tachycardia (known as non-reentrant tachycardias)
• Aortic dilation, mild; noted in fewer than 10% of individuals
• Hypertension

Neurologic

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

Tumors. Increased occurrence of malignant solid tumors

Psychomotor development

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

Establishing the Diagnosis

The diagnosis of Costello syndrome is established in a proband with suggestive clinical findings and a heterozygous HRAS pathogenic variant identified by molecular genetic testing (see Table 1) [Aoki et al 2005, Kerr et al 2008, Grant et al 2018].

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Costello syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Costello syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Costello syndrome affects multiple organ systems. Its typical presentation is characterized by diffuse hypotonia and severe feeding difficulties in infancy; short stature; developmental delay or intellectual disability; characteristic facial features; curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement (hypertrophic cardiomyopathy [HCM], congenital heart defect, and arrhythmia). Postnatal cerebellar overgrowth can result in Chiari I malformation with associated hydrocephalus or syringomyelia. An approximately 15% lifetime risk for malignant tumors includes rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults. Females and males are equally affected.

In rare instances, related to the underlying HRAS pathogenic variant, the presentation is more severe with intrauterine hydrops, postnatal pulmonary effusions with respiratory compromise, and severe progressive HCM, resulting in early lethality [Lo et al 2008]. Other rare variants are associated with a milder or attenuated phenotype, encompassing milder developmental delay, less striking facial features resembling Noonan syndrome, and a lower risk for malignancies [Gripp et al 2015, Bertola et al 2017].

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

Normative growth charts, derived from measurements of individuals who had not used growth hormone, document the very slow weight gain in early infancy, as well as the short stature with the 95th centile for individuals with Costello syndrome falling into the low normal range of typical age-matched individuals [Sammon et al 2012]. The reported adult height range is 135-150 cm [Hennekam 2003].

Failure to thrive and severe feeding difficulties are almost universal and typically necessitate the placement of a gastric feeding tube. Anecdotally, affected children have very high caloric needs. Even after nutrition is improved through supplemental feeding, growth retardation persists; therefore, aggressive feeding therapy is not effective.

Children are able to take oral feeds beginning between ages two and four years.

The first acceptable tastes are often strong (e.g., ketchup).

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

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

Progressive postnatal cerebellar overgrowth may result in development of a Chiari I malformation, syringomyelia, and hydrocephalus [Gripp et al 2010]. Cerebellar abnormalities include tonsillar ectopia or Chiari malformation, occasionally associated with syringomyelia [Gripp et al 2000, Gripp et al 2002, Calandrelli et al 2015].

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

Cardiac abnormalities, which typically present in infancy or early childhood, may be recognized at any age. In 146 individuals with molecularly confirmed Costello syndrome, 87% had some type of cardiovascular abnormality. A congenital heart defect was present in 44%, with non-progressive valvar pulmonic stenosis being the most common finding. Rarely, atrial septal defects are seen. HCM comprising typical subaortic septal hypertrophy was noted in 61% and pathologic myocardial disarray was seen in 70% of those studied.

A few neonates can present with very severe HCM that is lethal. In other infants, progressively severe HCM and/or severe multifocal atrial tachycardia can lead to death in the first two years of life. Multifocal atrial tachycardia and other atrial tachycardia may be very concerning but are usually self-limited with aggressive treatment.

Pulmonic valve stenosis is usually mild to moderate, and infrequently requires surgery or interventional catheterization.

Most children with HCM have either mild or moderate involvement. Of great interest are the few with moderate-to-severe involvement who appear to have "remodeling" over many years which gives the impression of disappearance of (or marked decrease in) left ventricular obstruction. Only a small number of these individuals are being followed, and their long-term natural history is incomplete [Lin et al 2011]. In addition to the rare severe lethal form, HCM can be chronic (persistence of a gradient) or progressive (increase in gradient severity; 14/37 [37%]), stabilizing (without further increase in severity; 10/37 [27%]), or decreasing (resolving; 5/37 [14%]). Outcome was unavailable in 8/37 (22%) [Lin et al 2011], necessitating prudent surveillance.

Non-reentrant atrial tachycardias are generally self-limited, but may persist or worsen in approximately one fourth of affected individuals. Nonreentrant atrial tachycardia occurs independently of HCM [Levin et al 2018].

Older individuals (ages 16 to 40 years) with moderate HCM or new-onset arrhythmia (both atrial and ventricular) represent the greatest challenge and do not constitute a predictable outcome "phenotype" until more information is obtained. Hypertension is not uncommon.

Mild-moderate aortic dilation not associated with bicuspid aortic valve is a recent cardiovascular finding [Lin et al 2011] that occurs in approximately 5% of affected individuals.

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

Developmental delay or intellectual disability is present in all individuals [Axelrad et al 2004, Axelrad et al 2007, Axelrad et al 2009, Axelrad et al 2011].

Recognition memory in verbal memory functioning is relatively preserved compared to other cognitive tasks [Schwartz et al 2013].

The onset of speech frequently coincides with the willingness to feed orally.

Separation anxiety, seen in 39% of individuals with Costello syndrome, is more common in males than in females [Axelrad et al 2011].

Behavioral/social issues. Many children younger than age four years meet criteria on a screening tool for autism spectrum disorder (ASD). There is a positive correlation with the need for gastrostomy tube and inability to walk independently. In contrast, none of the children older than age four years met criteria for autism, suggesting that early signs consistent with ASD tend to resolve by age four years [Schwartz et al 2017].

Limited detailed information is available on the quality of life in older individuals with Costello syndrome. Quality of life in individuals age 16-34 years is compromised by four factors [Hopkins et al 2010]: limited relationships outside of the immediate circle of friends and family, lack of independence, male gender, and the presence of major medical issues [Hopkins et al 2010]. Functional limitations from orthopedic problems regarding mobility, as well as limitations in the social and cognitive domains, were documented using normative scales [Johnson et al 2015].

Dermatologic. Papillomata, absent in infancy, appear in young children, usually in the perinasal region and less commonly in the perianal region, torso, and extremities. While papillomata are mostly of cosmetic concern, they can become noticeable and at times bothersome.

Palmoplantar keratoderma is common and can affect function in severe cases [Marukian et al 2017]. Additional findings include acanthosis nigricans and thick toenails.

Musculoskeletal. Individuals with Costello syndrome have very loose joints, particularly involving the fingers. Ulnar deviation of the wrists and fingers is also common. Developmental hip dysplasia may result in severe pain and prevent ambulation. Tight Achilles tendons may develop.

More than half of a cohort of 43 individuals examined by an orthopedic surgeon with review of radiographs as available showed ligamentous laxity, scoliosis, kyphosis, characteristic hand and wrist deformities, shoulder and elbow contractures, tight Achilles tendons, and flat feet [Detweiler et al 2013]. Hip dysplasia, seen in 45%, was not universally congenital but acquired in some.

Osteoporosis is common in young adults with Costello syndrome [White et al 2005, Detweiler et al 2013]. In adults ranging in age from 16 to 40 years, all eight individuals who had a bone density measurement had abnormal results that suggested osteoporosis or osteopenia; three had bone pain, vertebral fractures, and height loss [White et al 2005]. In a study of nine individuals with Costello syndrome who had dual-energy X-ray absorptiometry, all showed significantly decreased bone mineral density compared to age-matched controls [Leoni et al 2014].

Respiratory. Seven of ten individuals ages three to 29 years undergoing polysomnography in the sleep laboratory had obstructive events [Della Marca et al 2006]. A literature review showed respiratory complications in 78% of neonates, with the majority resolving and more severe complications only in those with rare HRAS pathogenic variants associated with the severe phenotype [Gomez-Ospina et al 2016] (see Genotype-Phenotype Correlations).

Upper-airway obstruction was seen more often in older children and young adults [Gomez-Ospina et al 2016].

Endocrine. Neonatal hyperinsulinism has been reported [Alexander et al 2005, Sheffield et al 2015] and, in one case, was correlated to focal uniparental disomy for 11p within the pancreatic nodule [Gripp et al 2016].

In older individuals, hypoglycemia may be related to growth hormone deficiency. Growth hormone deficiency is common (30%-50%) [Estep et al 2006, Gripp et al 2010].

Several patients have been diagnosed with hypothyroidism requiring treatment with hormone replacement.

Other endocrine issues may include delayed or dysregulated puberty including precocious puberty.

Solid tumors. Benign and malignant solid tumors occur with far greater frequency in individuals with Costello syndrome than in the general population. The overall tumor incidence is approximately 15% over the lifetime of individuals with an identified HRAS pathogenic variant [Gripp et al 2006a]. Kratz et al [2011] reviewed published cases and confirmed the 15% cumulative incidence of cancer in individuals with Costello syndrome by age 20 years. Rhabdomyosarcoma occurs most frequently, followed by neuroblastoma, transitional cell carcinoma of the bladder, and other solid tumors [Gripp 2005].

Rhabdomyosarcoma and neuroblastoma, tumors of early childhood, present in Costello syndrome at ages comparable to the general population. In contrast, transitional cell carcinoma of the bladder, which occurs in older adults (70% age >65 years) in the general population, may be found in adolescents with Costello syndrome. The ages at presentation in the three individuals with Costello syndrome with transitional cell carcinoma of the bladder were ten, 11, and 16 years.

Other

• Pyloric stenosis occurs more commonly than in the general population [Gripp et al 2008].
• Adult-onset gastroesophageal reflux was present in four individuals in the series of White et al [2005]; additional cases are known [Author, personal observation].
• Dental abnormalities, including enamel defects, occur frequently. Malocclusion with maxillary first molars positioned posteriorly to the mandibular first molars is common and may contribute to obstructive sleep apnea [Goodwin et al 2014]. Excessive secretions are often noted [Johnson et al 1998].
• In addition to the common vision disturbance and nystagmus, less common eye abnormalities include retinal dystrophy [Pierpont et al 2017] and keratoconus [Gripp & Demmer 2013].
• Adolescents may appear older than their chronologic age because of worsening kyphoscoliosis, sparse hair, and prematurely aged skin.

Life expectancy. Causes of death reported in 10% of individuals included in an analysis of cardiovascular findings [Lin et al 2011] and in 20% of affected individuals described in the literature were: HCM in association with neoplasia, coronary artery fibromuscular dysplasia, multifocal tachycardia, neoplasia, pulmonary cause, and multiorgan failure.

Somatic mosaicism. Individuals with somatic mosaicism for an HRAS pathogenic variant may show patchy skin findings only (as reported in the father of an individual with typical Costello syndrome [Sol-Church et al 2009]) [Bertola et al 2017], or findings indistinguishable from Costello syndrome caused by a germline pathogenic variant [Girisha et al 2010].

One individual with somatic mosaicism (20%-30% of DNA derived from buccal cells exhibited the HRAS variant p.Gly12Ser, which was not detected in DNA derived from blood cells) had typical findings attributed to Costello syndrome (intellectual disability, short stature, sparse hair, coarse facial features, nasal papillomata, and tight Achilles tendons) as well as atypical findings attributed to mosaicism (microcephaly, streaky areas of skin hypo- and hyperpigmentation, and normal menarche with subsequent regular menses) [Gripp et al 2006b].

Neuroimaging. A systematic review of brain and spinal cord MRI studies revealed posterior fossa crowding with cerebellar tonsillar herniation in 27/28 (96%) [Gripp et al 2010]. In a majority of those with serial studies this crowding progressed. Due to the progressive nature of the cerebellar overgrowth – which likely results from abnormal cell differentiation as reported by Paquin et al [2009] – the sequelae of posterior fossa crowding included hydrocephalus requiring shunt placement or ventriculostomy (7/28), Chiari I malformation (9/28), and syringomyelia (7/28).

Tethered cord is relatively common.

Genotype-Phenotype Correlations

In a systematic review of 146 individuals with an HRAS pathogenic variant, no apparent correlation was observed between the specific variant and the variables studied (HCM, multifocal tachycardia, aortic dilation [Lin et al 2011] (see Table V). In some cases, small numbers prevented formal statistical analysis.

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

• Kerr et al [2006] suggested that the risk for malignant tumors may be higher in individuals with the p.Gly12Ala pathogenic variant (4/7) than in those with the p.Gly12Ser variant (4/65). No individuals with p.Gly13Cys have developed a malignant tumor to date [Gripp et al 2011a].
• The suggestion of Lo et al [2008] that a more severe neonatal phenotype may be associated with certain rare pathogenic variants, including p.Gly12Ala and p.Gly12Cys, was confirmed by McCormick et al [2013].
• The possibility of a milder or attenuated phenotype was noted in individuals with the variants p.Thr58Ile and p.Ala146Val [Gripp et al 2008], as well as p.Gly60Val [Gripp et al 2017].
• Two unrelated individuals with p.Glu37dup shared phenotypic findings including very sparse hair and facial features that appear less coarse than in most other individuals with Costello syndrome [Gremer et al 2010].
• The p.Gly13 amino acid appears to be the second most commonly substituted, with p.Gly13Cys being the most frequent change seen at this codon. Gripp et al [2011a] reviewed physical findings in 12 individuals with this variant and noted a distinctive phenotype including dolichocilia (extremely long eye lashes, often requiring trimming) and loose anagen hair syndrome; neither of these findings had previously been noted in individuals with Costello syndrome. Papillomata or multifocal atrial tachycardia have not yet been seen in individuals with p.Gly13Cys, and fewer had short stature. Compared to individuals with the very common p.Gly12Ser variant, these differences are statistically significant.
• Five individuals with the rare p.Gly13Asp missense variant showed an apparently milder presentation and none had a malignancy [Bertola et al 2017].

Penetrance

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

Nomenclature

Costello reported the first individuals with this condition in 1971, providing follow up in 1977 and 1996 [Costello 1971, Costello 1977, Costello 1996]. The eponym was applied for the first time by Der Kaloustian et al [1991].

Early examples of Costello syndrome were reported as:

• AMICABLE syndrome (amicable personality, mental retardation, impaired swallowing, cardiomyopathy, aortic defects, bulk, large lips and lobules, ectodermal defects) [Hall et al 1990];
• Faciocutaneous-skeletal syndrome [Borochowitz et al 1992].

Prevalence

The birth prevalence of Costello syndrome is estimated at 1:380,000 in the UK [Giannoulatou et al 2013]. In contrast, an epidemiologic study using national surveys suggested a prevalence of 1:1,230,000 in Japan [Abe et al 2011]; this may be an underestimate due to ascertainment procedures.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Costello syndrome, the evaluations summarized Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

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

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

• Unproven benefit. Individuals with Costello syndrome frequently have low GH levels:
  • True growth hormone deficiency requires GH replacement. Three individuals with GH deficiency showed increased growth velocity without adverse effects after three to seven years of replacement therapy, but two continued to have short stature [Stein et al 2004].
  • It is unclear from the literature if the use of GH is beneficial in individuals with Costello syndrome with partial growth hormone deficiency. An abnormal growth hormone response on testing and a good initial growth response have been reported [Legault et al 2001].
• Cardiac hypertrophy. Whether the anabolic actions of growth hormone accelerate pre-existing cardiac hypertrophy is not known, but early descriptive studies do not suggest a clear association [Lin et al 2002, Lin et al 2011]. In rare cases, cardiomyopathy has progressed after initiation of growth hormone treatment; whether the relationship was causal or coincidental is unknown (see, e.g., Kerr et al [2003]).
• Malignancy. The effect of growth hormone on tumor predisposition has not been determined. Two reports have raised the possibility of an association:
  • Bladder carcinoma occurred in a 16-year-old treated with growth hormone [Gripp et al 2000].
  • A rhabdomyosarcoma was diagnosed in a 26-month-old receiving growth hormone from age 12 months [Kerr et al 2003].

Surveillance

Evaluation of Relatives at Risk

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

Therapies Under Investigation

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

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• To date, most probands with Costello syndrome have the disorder as the result of a de novo pathogenic variant. An association with advanced parental age had been documented [Giannoulatou et al 2013]. Most but not all de novo pathogenic variants arise in the paternal germline; Sol-Church et al [2006] reported 14 de novo pathogenic variants of paternal origin and two of maternal origin.
• Vertical transmission has been reported in two families with the rare, attenuated phenotype of Costello syndrome (see Clinical Description) [Gripp et al 2012, Gripp et al 2015].
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the HRAS pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the proband most likely has a de novo pathogenic variant; another possible explanation is parental somatic/germline mosaicism.
  One clinical report suggested possible somatic/germline 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].

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

• If the proband has a known HRAS pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
• Recurrence of Costello syndrome in sibs has been reported and is suspected to be the result of germline mosaicism in a parent [Zampino et al 1993, Johnson et al 1998]. See Parents of a proband.

Offspring of a proband

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

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

Related Genetic Counseling Issues

Family planning

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

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

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. If an HRAS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

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

Cancer and Benign Tumors

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

Literature Cited

• 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.
• Alexander S, Ramadan D, Alkhayyat H, Al-Sharkawi I, Backer KC, El-Sabban F, Hussain K. Costello syndrome and hyperinsulinemic hypoglycemia. Am J Med Genet. 2005;139:227–30. [PubMed: 16278907] [CrossRef]
• 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]
• 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]
• 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]
• Axelrad ME, Schwartz DD, Fehlis JE, Hopkins E, Stabley DL, Sol-Church K, Gripp KW. Longitudinal course of cognitive, adaptive, and behavioral characteristics in Costello syndrome. Am J Med Genet A. 2009;149A:2666–72. [PMC free article: PMC2787985] [PubMed: 19919001]
• 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;157C:115–22. [PubMed: 21495179]
• Bertola D, Buscarilli M, Stabley DL, Baker L, Doyle D, Bartholomew DW, Sol-Church K, Gripp KW. Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp. Am J Med Genet. 2017;173:1309–18. [PMC free article: PMC5397353] [PubMed: 28371260]
• 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.
• 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]
• Calandrelli R, D'Apolito G, Marco P, Zampino G, Tartaglione T, Colosimo C. Costello syndrome: Analysis of the posterior cranial fossa in children with posterior fossa crowding. Neuroradiol J. 2015;28:254–8. [PMC free article: PMC4757298] [PubMed: 26246091]
• Chiu AT, Zhu L, Mok GT, Leung GK, Chow CB, Chung BH. Before and after - Nutritional transformation of dysmorphism in a case of Costello syndrome. Eur J Med Genet. 2016;59:573–6. [PubMed: 27705751]
• Corbett KD, Alber T. The many faces of Ras: recognition of small GTP-binding proteins. Trends Biochem Sci. 2001;26:710–6. [PubMed: 11738594]
• Costello JM. A new syndrome. NZ Med J. 1971;74:397.
• Costello JM. A new syndrome: mental subnormality and nasal papillomata. Aust Paediatr J. 1977;13:114–8. [PubMed: 907573]
• Costello JM. Costello syndrome: update on the original cases and commentary. Am J Med Genet. 1996;62:199–201. [PubMed: 8882404]
• 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]
• Delrue MA, Chateil JF, Arveiler B, Lacombe D. Costello syndrome and neurological abnormalities. Am J Med Genet A. 2003;123A:301–5. [PubMed: 14608654]
• Der Kaloustian VM, Moroz B, McIntosh N, Watters AK, Blaichman S. Costello syndrome. Am J Med Genet. 1991;41:69–73. [PubMed: 1951465]
• Detweiler S, Thacker MM, Hopkins E, Conway L, Gripp KW. Orthopedic manifestations and implications for individuals with Costello syndrome. Am J Med Genet. 2013;161A:1940–9. [PubMed: 23813656]
• 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]
• Giannoulatou E, McVean G, Taylor IB, McGowan SJ, Maher GJ, Iqbal Z, Pfeifer SP, Turner I, Burkitt Wright EM, Shorto J, Itani A, Turner K, Gregory L, Buck D, Rajpert-De Meyts E, Looijenga LH, Kerr B, Wilkie AO, Goriely A. Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline. Proc Natl Acad Sci USA. 2013;110:20152–7. [PMC free article: PMC3864328] [PubMed: 24259709]
• Giehl K. Oncogenic Ras in tumour progression and metastasis. Biol Chem. 2005;386:193–205. [PubMed: 15843165]
• 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:2861–4. [PubMed: 20979192]
• Gomez-Ospina N, Kuo C, Ananth AL, Myers A, Brennan ML, Stevenson DA, Bernstein JA, Hudgins L. Respiratory system involvement in Costello syndrome. Am J Med Genet. 2016;170:1849–57. [PMC free article: PMC5509842] [PubMed: 27102959]
• Goodwin AF, Oberoi S, Landan M, Charles C, Massie JC, Fairley C, Rauen KA, Klein OD. Craniofacial and dental development in Costello syndrome. Am J Med Genet. 2014;164A:1425–30. [PMC free article: PMC4115793] [PubMed: 24668879]
• Grant AR, Cushman BJ, Cave H, Dillon MW, Gelb BD, Gripp KW, Lee JA, Mason-Suares H, Rauen KA, Tartaglia M, Vincent LM, Zenker M. Assessing the gene-disease association of 19 genes with the RASopathies using the ClinGen gene curation framework. Hum Mutat. 2018;39:1485–93. [PMC free article: PMC6326381] [PubMed: 30311384]
• 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]
• Gripp KW. Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet. 2005;137C:72–7. [PubMed: 16010679]
• Gripp KW, Demmer LA. Keratoconus in Costello syndrome. Am J Med Genet. 2013;161A:1132–6. [PubMed: 23494969]
• 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. [PMC free article: PMC4910816] [PubMed: 20425820]
• Gripp KW, Hopkins E, Serrano A, Leonard N J, Stabley DL, Sol-Church K. Transmission of the rare HRAS mutation (c. 173C>T; p.T58I) further illustrates its attenuated phenotype. Am J Med Genet Part A. 2012;158A:1095–101. [PMC free article: PMC4164267] [PubMed: 22488832]
• 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 A. 2011a;155A:706–16. [PMC free article: PMC4166651] [PubMed: 21438134]
• 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]
• 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]
• Gripp KW, Kolbe V, Brandenstein LI, Rosenberger G. Attenuated phenotype of Costello syndrome and early death in a patient with an HRAS Mutation (c.179G>T; p.Gly60Val) affecting signalling dynamics. Clin Genet. 2017;92:332–7. [PubMed: 28139825]
• Gripp KW, Lin AE. Costello syndrome: A Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations. Genet Med. 2012;14:285–92. [PubMed: 22261753]
• 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]
• Gripp KW, Lin AE, Stabley DL, Nicholson L, Scott CI Jr, 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]
• Gripp KW, Morse LA, Axelrad M, Chatfield KC, Chidekel A, Dobyns W, Doyle D, Kerr B, Lin AE, Schwartz DD, Sibbles BJ, Siegel D, Shankar SP, Stevenson DA, Thacker MM, Weaver KN, White SM, Rauen KA. Costello syndrome: clinical phenotype, genotype, and management guidelines. Am J Med Genet. 2019;179:1725–44. [PubMed: 31222966]
• Gripp KW, Robbins KM, Sheffield BS, Lee AF, Patel MS, Yip S, Doyle D, Stabley D, Sol-Church K. Paternal uniparental disomy 11p15.5 in the pancreatic nodule of an infant with Costello syndrome: Shared mechanism for hyperinsulinemic hypoglycemia in neonates with Costello and Beckwith-Wiedemann syndrome and somatic loss of heterozygosity in Costello syndrome driving clonal expansion. Am J Med Genet. 2016;170:559–64. [PMC free article: PMC4784973] [PubMed: 26572961]
• Gripp KW, Scott CI Jr, 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]
• Gripp KW, Scott CI Jr, 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]
• Gripp KW, Sol-Church K, Smpokou P, Graham GE, Stevenson DA, Hanson H, Viskochil DH, Baker LC, Russo B, Gardner N, Stabley DL, Kolbe V, Rosenberger G. An attenuated phenotype of Costello syndrome in three unrelated individuals with a HRAS c.179G>A (p.Gly60Asp) mutation with uncommon functional consequences. Am J Med Genet A. 2015;167A:2085–97. [PMC free article: PMC4830354] [PubMed: 25914166]
• 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 A. 2011b;155A:2263–8. [PMC free article: PMC3158836] [PubMed: 21834037]
• 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]
• 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.
• Hennekam RC. Costello syndrome: an overview. Am J Med Genet Part C Semin Med Genet. 2003;117C:42–8. [PubMed: 12561057]
• 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 A. 2010;152A:84–90. [PubMed: 20034064]
• 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]
• Johnson B, Goldberg-Strassler D, Gripp K, Thacker M, Leoni C, Stevenson D. Function and disability in children with Costello syndrome and Cardiofaciocutaneous syndrome. Am J Med Genet. 2015;167A:40–4. [PubMed: 25346259]
• 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]
• 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]
• 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]
• 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]
• 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;157C:83–9. [PMC free article: PMC3086183] [PubMed: 21500339]
• 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]
• Leoni C, Stevenson DA, Martini L, De Sanctis R, Mascolo G, Pantaleoni F, De Santis S, La Torraca I, Persichilli S, Caradonna P, Tartaglia M, Zampino G. Decreased bone mineral density in Costello syndrome. Mol Genet Metab. 2014;111:41–5. [PubMed: 24246682]
• Levin MD, Saitta SC, Gripp KW, Wenger TL, Ganesh J, Kalish JM, Epstein MR, Smith R, Czosek RJ, Ware SM, Goldenberg P, Myers A, Chatfield KC, Gillespie MJ, Zackai EH, Lin AE. Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients. Am J Med Genet. 2018;176:1711–22. [PMC free article: PMC6107379] [PubMed: 30055033]
• 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 A. 2011;155A:486–507. [PubMed: 21344638]
• 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 Jr, Nicholson L. Further delineation of cardiac abnormalities in Costello syndrome. Am J Med Genet. 2002;111:115–29. [PubMed: 12210337]
• 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]
• 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]
• Marukian NV, Levinsohn JL, Craiglow BG, Milstone LM, Choate KA. Palmoplantar Keratoderma in Costello Syndrome Responsive to Acitretin. Pediatr Dermatol. 2017;34:160–162. [PubMed: 28008647]
• McCormick EM, Hopkins E, Conway L, Catalano S, Hossain J, Sol-Church K, Stabley DL, Gripp KW. Assessing genotype-phenotype correlation in Costello syndrome using a severity score. Genet Med. 2013;15:554–7. [PubMed: 23429430]
• 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]
• Paquin A, Hordo C, Kaplan DR, Miller FD. Costello syndrome H-Ras alleles regulate cortical development. Dev Biol. 2009;330:440–51. [PubMed: 19371735]
• Pierpont ME, Richards M, Engel WK, Mendelsohn NJ, Summers CG. Retinal dystrophy in two boys with Costello syndrome due to the HRAS p.Gly13Cys mutation. Am J Med Genet. 2017;173:1342–7. [PubMed: 28337834]
• 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]
• 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]
• 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]
• Sammon MR, Doyle D, Hopkins E, Sol-Church K, Stabley DL, McGready J, Schulze K, Alade Y, Hoover-Fong J, Gripp KW. Normative growth charts for individuals with Costello syndrome. Am J Med Genet. 2012;158A:2692–9. [PubMed: 22887473]
• Schwartz DD, Katzenstein JM, Highley EJ, Stabley DL, Sol-Church K, Gripp KW, Axelrad ME. Age-related differences in prevalence of autism spectrum disorder symptoms in children and adolescents with Costello syndrome. Am J Med Genet. 2017;173:1294–1300. [PMC free article: PMC5397350] [PubMed: 28374929]
• Schwartz DD, Katzenstein JM, Hopkins E, Stabley DL, Sol-Church K, Gripp KW, Axelrad ME. Verbal memory functioning in adolescents and young adults with Costello syndrome: evidence for relative preservation in recognition memory. Am J Med Genet. 2013;161A:2258–65. [PMC free article: PMC3745536] [PubMed: 23918324]
• Sheffield BS, Yip S, Ruchelli ED, Dunham CP, Sherwin E, Brooks PA, Sur A, Singh A, Human DG, Patel MS, Lee A. Fatal congenital hypertrophic cardiomyopathy and a pancreatic nodule morphologically identical to focal lesion of congenital hyperinsulinism in an infant with Costello syndrome. case report and review of the literature. Pediatr Dev Pathol. 2015;18:237–44. [PubMed: 25668678]
• Sol-Church K, Gripp KW. The molecular basis of Costello syndrome. In: Zenker M, ed. Noonan Syndrome and Related Disorders. Monographs in Human Genetics. Basel, Switzerland: Karger. 2009;17:94-103.
• 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]
• 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]
• 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]
• Tidyman WE, Lee HS, Rauen KA. Skeletal muscle pathology in Costello and cardio-facio-cutaneous syndrome: developmental consequences of germline Ras/MAPK activation on myogenesis. Am J Med Genet C Semin Med Genet. 2011;157C:104–14. [PubMed: 21495178]
• 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]
• Weaver KN, Wang D, Cnota J, Gardner N, Stabley D, Sol-Church K, Gripp KW, Witte DP, Bove KE, Hopkin RJ. Early-lethal Costello syndrome due to rare HRAS tandem base substitution (c.35_36GC>AA; p.G12E) associated pulmonary vascular disease. Pediatr Dev Pathol. 2014;17:421–430. [PMC free article: PMC4294968] [PubMed: 25133308]
• White SM, Graham JM Jr, 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]
• 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]
• 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]

Author Notes

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

Acknowledgments

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

Author History

Karen WGripp, MD, FAAP, FACMG (2006-present)
Angela E Lin, MD, FAAP, FACMG; Harvard Medical School (2006-2019)
Katherine A Rauen, MD, PhD (2019-present)

Revision History

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