Genetic dermis elastic tissue disorder
-Rare genetic disease
-Rare skin disease
Malformation syndrome with skin/mucosae involvement
-Rare developmental defect during embryogenesis
-Rare genetic disease
Multiple congenital anomalies/dysmorphic syndrome-intellectual deficit
-Rare developmental defect during embryogenesis
-Rare genetic disease
Noonan syndrome and Noonan-related syndrome
-Rare cardiac disease
-Rare developmental defect during embryogenesis
-Rare genetic disease
Polymalformative genetic syndrome with increased risk of developing cancer
-Rare genetic disease
-Rare oncologic disease
Rare genetic intellectual deficit with developmental anomaly
-Rare genetic disease
Rare intellectual deficit with developmental anomaly
-Rare neurologic disease
Comment:
Costello syndrome belongs to the group of RASopathies and is caused by activating mutations in the proto-oncogene HRAS, a key regulator of the MAPK pathway (PMID:21495179). Individuals with HRAS-p.G12A or -p.G12C mutation are more severely affected than those with other HRAS mutations (PMID:23429430).
Costello syndrome is a rare multiple congenital anomaly syndrome associated in all cases with a characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and ... Costello syndrome is a rare multiple congenital anomaly syndrome associated in all cases with a characteristic coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, and failure to thrive. Other features include cardiac anomalies and developmental disability. Facial warts, particularly nasolabial, are often present in childhood (Kerr et al., 2006). In patients with a clinical diagnosis of Costello syndrome, Zenker et al. (2007) identified mutations in the KRAS gene, but noted that these patients may later develop features of CFC syndrome. In either case, the findings underscore the central role of Ras in the pathogenesis of these phenotypically related disorders (Zenker et al., 2007). However, Kerr et al. (2008) commented that the diagnosis of Costello syndrome should only be used to refer to patients with mutations in the HRAS gene.
Smith et al. (2009) reviewed prenatal ultrasound findings of 17 patients with Costello syndrome. Seven (41%) were preterm with delivery prior to 37 weeks' gestation, and the remaining 10 (59%) were term deliveries. There were 3 main prenatal ... Smith et al. (2009) reviewed prenatal ultrasound findings of 17 patients with Costello syndrome. Seven (41%) were preterm with delivery prior to 37 weeks' gestation, and the remaining 10 (59%) were term deliveries. There were 3 main prenatal findings on ultrasound: polyhydramnios, fetal overgrowth, and relative macrocephaly. Polyhydramnios was the most commonly reported prenatal complication, affecting 100% of pregnancies. Most (65%) patients had birth weight above the 90th centile, and 41% patients had birth weights greater than the 97th centile. A fourth less common finding was cardiac arrhythmia. Smith et al. (2009) noted that the combination of polyhydramnios and fetal overgrowth often prompts evaluation for maternal diabetes mellitus, but that recognition of Costello syndrome in utero is important because of the neonatal risk of cardiac mortality and morbidity. Kuniba et al. (2009) provided a case report of a Japanese fetus with severe Costello syndrome diagnosed using prenatal 3-dimensional ultrasonography at 23 weeks' gestation. Findings at that time included polyhydramnios, severe overgrowth (+5.3 SD using a Japanese fetal growth curve), and dysmorphic craniofacial features, such as large head, pointed chin, wide nasal bridge, and low-set ears. In addition, the wrists showed lateral deviation and flexion. Molecular analysis via amniocentesis identified an uncommon G12D mutation in the HRAS gene (190020.0013). After birth, he developed respiratory failure, severe hypoglycemia, cardiac hypertrophy, and renal failure, and died soon after birth. The phenotype was similar to that reported by Lo et al. (2008) in 2 infants with the G12D mutation, suggesting that this mutation is associated with a severe clinical outcome and death in early infancy.
Costello (1977) described 2 unrelated children with a syndrome comprising short stature, redundant skin of the neck, palms, soles, and fingers, curly hair, papillomata around the mouth and nares, and mental retardation. Der Kaloustian et al. (1991) reported ... Costello (1977) described 2 unrelated children with a syndrome comprising short stature, redundant skin of the neck, palms, soles, and fingers, curly hair, papillomata around the mouth and nares, and mental retardation. Der Kaloustian et al. (1991) reported a boy with the same syndrome. The parents were not consanguineous in any of the 3 cases. The patient of Der Kaloustian et al. (1991) had an aged facial appearance with thin anterior hair of the head. Epicanthal folds, large, depressed nasal bridge, and large earlobes were noted. The verrucal lesions were present around the anus as well as around the mouth and nares. The loose skin over the hands and feet was also thickened and the palms and soles were hyperkeratotic. The skin color was generally dark. Some similarities to the cardiofaciocutaneous syndrome (CFC; 115150) and Noonan syndrome (163950) were noted. Martin and Jones (1991) reported a 15-year-old girl with mental retardation, short stature, coarse face, thick and loose skin of the hands and feet, deep plantar and palmar creases, and nasal papillomata. Berberich et al. (1991) reported 3 patients, 2 of whom were sibs, with a presumably new syndrome of failure to thrive, cardiomyopathy, and furrowing of palmar creases. Later these cases were diagnosed as Costello syndrome (Der Kaloustian, 1993; Zampino et al., 1993). Additional patients were reported by Say et al. (1993), Teebi and Shaabani (1993), Philip and Mancini (1993), and Zampino et al. (1993). Zampino et al. (1993) provided photographs of a 24-year-old patient. Di Rocco et al. (1993) reported 2 unrelated patients, a 5-year-old girl and a 3-year-old boy, with Costello syndrome and sialuria. Di Rocco et al. (1993) suggested that urine and fibroblast sialic acid should be tested in other Costello syndrome patients. In both of their patients, feeding problems and abnormal speech were related to an oral motor apraxia. The girl also had acanthosis nigricans and abnormal glucose metabolism (fasting hypoglycemia and postprandial hyperglycemia). Borochowitz et al. (1992) reported 5 unrelated patients, 1 male and 4 females, with a previously undefined multiple congenital anomalies/mental retardation (MCA/MR) syndrome which they designated the faciocutaneoskeletal (FCS) syndrome. The features included mental retardation with specific sociable, humorous behavior, characteristic facial appearance, generally excessive skin, postnatal growth failure, and skeletal abnormalities. Consanguinity was noted in 2 patients, suggesting autosomal recessive inheritance. Coarse facies, wide hirsute forehead, wide anteverted nostrils, and thick lips were pictured. Martin and Jones (1993), Der Kaloustian (1993), Teebi (1993), Philip and Mancini (1993), and Zampino et al. (1993) suggested that the FCS syndrome described by Borochowitz et al. (1992) is the same as the Costello syndrome. Borochowitz et al. (1993) concluded, on the other hand, that 'it is premature to reach a definite conclusion at this stage.' Patton and Baraitser (1993) reviewed 5 cases from their previous paper on cutis laxa (see 219200) (Patton et al., 1987) and concluded that the appropriate diagnosis was in fact Costello syndrome. Independently, Davies and Hughes (1994) reviewed case 7 from the same paper and, based on both history and clinical examination, made 'an unequivocal diagnosis of Costello syndrome.' In a longer report, Davies and Hughes (1994) described the development of one of the patients of Patton et al. (1987) for more than 10 years and again emphasized that Costello syndrome should be included in the differential diagnosis of cutis laxa in association with postnatal growth retardation and developmental delay. Izumikawa et al. (1993) reported the case of a 3-year-old boy who had typical clinical features except for the absence of nasal papillomas and who also had cardiac anomalies with extrasystoles and thick mitral valves. Kondo et al. (1993) emphasized nasal papillomata as particularly characteristic of Costello syndrome and pointed out that the age at development ranged from 2 to 15 years in reported cases. Fryns et al. (1994) described 2 unrelated patients with Costello syndrome, a 12-year-old girl and a 3.5-year-old boy. Severe postnatal growth retardation was the first clinical sign. Characteristic facial changes, loose and hyperelastic skin, and papillomata became progressively more evident with age. The patients presented a pleasant, happy nature and were mildly to moderately mentally retarded. Okamoto et al. (1994) reported the case of a Japanese patient. A fundoplication was performed at the age of 11 months to treat severe gastroesophageal reflux. The infant had congenital bilateral subluxation of the hips. At the age of 7 years, there was generalized pigmentation and acanthosis nigricans around the neck and axilla. Endocrinologic evaluation demonstrated partial deficiency of growth hormone. Stating that 16 cases had been reported, Torrelo et al. (1995) presented the case of a 15-year-old girl and emphasized the cutaneous manifestations of the disorder. Umans et al. (1995) described the natural history of the Costello syndrome in a child followed from birth to the age of 12 years. Severe feeding difficulties and poor sucking with swallowing difficulties are features. The history of polyhydramnios in almost all pregnancies indicates that diminished swallowing starts very early in fetal life. Generalized lymphoedema was noted at birth and hypotonia is a feature. Mori et al. (1996) described a case of Costello syndrome. The main clinical findings were loose skin of the neck, hands, and feet, deep palmar and plantar creases, typical 'coarse' face with thick lips and macroglossia, relative macrocephaly, mental retardation, short stature, arrhythmia, large size for gestational age, and poor feeding. The infant died of rhabdomyolysis at the age of 6 months. The major pathologic findings were fine, disrupted, and loosely-constructed elastic fibers in the skin, tongue, pharynx, larynx, and upper esophagus, but not in the bronchi, alveoli, aorta, or coronary arteries. The degeneration of elastic fibers was confirmed in the skin of a second Costello syndrome patient, that described previously by Yoshida et al. (1993). Autopsy also showed degeneration of the atrial conduction system, calcification and ballooning of skeletal muscle fibers with infiltration of macrophages, and myoglobin deposits in the collecting ducts of the kidney, consistent with rhabdomyolysis. They analyzed the clinical findings in 14 cases. Costello (1996) provided an update on the original cases and commented on other reported examples of this syndrome. Case 1 was reviewed at the age of 32 years. In summary, he had been known to have hypertension since the age of 17 years. Surgical operation had been required for recurrent inguinal hernia, ruptured cornea associated with keratoconus in the left eye, and hemorrhoidectomy. Duodenal ulcer and gastroesophageal reflux were diagnosed at age 20 following an episode of hematemesis and melena. Case 2 was reviewed at the age of 27 years. In summary, she had been asthmatic since age 18 years. Mammography at age 21 suggested severe fibroadenosis; warty hyperkeratosis of the nipples and lichenified eczema of the neck were noted. A cardiologic assessment was made at age 22 for a systolic murmur. Costello (1996) presented a table of manifestations frequently seen in Costello syndrome and also in Noonan syndrome and/or CFC syndrome, as well as a table of manifestations frequently seen in Costello syndrome but infrequent or absent in the other 2 syndromes. Out of 16 cases reviewed, 13 had low-set ears with large/thick lobes, 13 had thick lips, 12 had nasal papillomas and/or papillomas elsewhere, 16 had loose skin of the hands and feet, 14 had deep palmar creases, 12 had hyperkeratotic palms and soles, and 12 had hyperextensible fingers. Costello (1996) concluded that it is possible to make the clinical diagnosis of Costello syndrome with confidence. In particular, it is possible to differentiate Costello syndrome clearly from Noonan and CFC syndromes. Siwik et al. (1998) reviewed the cardiac manifestations of Costello syndrome in 30 patients, 18 of whom had at least 1 cardiac abnormality. Of these 18, 9 had structural heart disease, 6 had hypertrophic cardiomyopathy (mean age of onset 6.5 years, range 5 months to 20 years), and 5 had tachyarrhythmias. The authors recommended cardiac evaluation for any patient in whom the diagnosis of Costello syndrome has been established, and subsequent follow-up of affected individuals for the development of hypertrophic cardiomyopathy. Lin et al. (2002) reviewed the cardiac abnormalities in 94 patients with Costello syndrome and found the following in 59 (63%) patients: cardiovascular malformation in 30% (most commonly pulmonic stenosis), cardiac hypertrophy in 34%, and rhythm disturbances in 33% (most commonly atrial tachycardia). Most (68%) of the patients with a rhythm abnormality had a cardiovascular malformation, cardiac hypertrophy, or both. The authors recommended baseline and additional cardiac evaluations in all patients with Costello syndrome. Van Eeghen et al. (1999) reported the case of a 34-year-old woman with the diagnosis of Costello syndrome. Features included mental retardation, short stature, macrocephaly, 'coarse' face, hoarse voice, and redundant skin with deep palmar and plantar creases. She had wart-like lesions of the skin. Feingold (1999) reported a child with Costello syndrome who developed an alveolar rhabdomyosarcoma of the right foot at the age of 6 months. Kerr et al. (1998) reported 2 children diagnosed with Costello syndrome in the first months of life who developed retroperitoneal embryonal rhabdomyosarcoma. They suggested that increased risk of malignancy may be part of Costello syndrome. Moroni et al. (2000) reported a patient with Costello syndrome who developed an intrathoracic ganglioneuroblastoma. They cited several other patients with tumors and suggested that neural crest neoplasia may be a significant risk factor for children with Costello syndrome. Franceschini et al. (1999) reported a 12-year-old boy with Costello syndrome who was born to consanguineous parents. At age 11 years, this patient developed bladder carcinoma, a rare event in childhood, supporting an increased risk of malignancy in this syndrome. Gripp et al. (2000) likewise reported a case of transitional cell carcinoma of the bladder in a patient with Costello syndrome. Birth weight and birth length had been greater than the 95th centile but at the 50th centile within weeks or months. Gastrostomy tube placement was required at 6 months because of feeding problems and failure to thrive. Redundancy of skin folds of palms, labia majora, and other body areas was noted at that time. Biventricular concentric hypertrophic cardiomyopathy with asymmetric septal hypertrophy and a large pressure gradient from the left ventricle to the aorta were seen. Treatment with the beta blocker propranolol over a period of several years led to relief of the left ventricular outflow tract obstruction. Papillomata (squamous acanthomas) of the cheeks were noted at age 4; perineal papillomata developed at age 14. Hair growth was extremely slow requiring trims once a year. Nails were thin and dysplastic. Body odor was a persistent problem. The bladder cancer was discovered at the age of 14 years. Gripp et al. (2002) reported 5 new cases of rhabdomyosarcoma in Costello syndrome, bringing the number of reported cases of solid tumors to 17. They pointed out that the frequency is in the same order of magnitude as that of solid tumors in Beckwith-Wiedemann syndrome (BWS; 130650) and may justify tumor screening. Based on the recommendations for screening BWS patients, they proposed a screening protocol consisting of ultrasound examination of the abdomen and pelvis every 3 to 6 months until age 8 to 10 years looking for rhabdomyosarcoma and abdominal neuroblastoma; urine catecholamine metabolite analysis every 6 to 12 months until age 5 years for neuroblastoma; and urinalysis for hematuria annually for bladder carcinoma after age 10 years. In 8 of the 10 cases of Costello syndrome with rhabdomyosarcoma, the tumor originated from the abdomen, pelvis, or urogenital areas. Prior diagnosis of Costello syndrome was a prerequisite for the implementation of any screening protocol. Conversely, the diagnosis of Costello syndrome should be considered in individuals with rhabdomyosarcoma and physical findings suggestive of Costello syndrome. DeBaun (2002) reviewed the usefulness of screening in Costello syndrome. Ioan and Fryns (2002) described Costello syndrome in a brother and sister, with minor manifestations in their mother. The sibs had severe mental and motor retardation, feeding difficulties, failure to thrive in the first months of life, coarse facial appearance, skin hyperlaxity, and skeletal deformities. The mother presented with mild to moderate mental retardation, short stature, facial fullness, and wart-like lesions on her face. Hennekam (2003) stated that 115 cases of Costello syndrome had been described. He summarized clinical data on 73 of the cases and illustrated the characteristic facial appearance and palm of the hand. Kawame et al. (2003) retrospectively reviewed the clinical records and findings in 5 girls and 5 boys with Costello syndrome. All showed significant postnatal growth retardation and severe feeding difficulties leading to failure to thrive from early infancy. All required tube feeding and some needed high-calorie formulas for variable periods. Developmental quotients/IQs in 7 children were 50 or less, and 3 were in the mildly retarded range. Five had seizures. Although happy and sociable personality had previously been established as characteristic of the disorder, Kawame et al. (2003) noted that during infancy, all 10 children showed significant irritability, including hypersensitivity to sound and tactile stimuli, sleep disturbance, and excessive shyness with strangers. These symptoms usually disappeared around 2 to 4 years of age. Other clinical features were cardiac abnormalities in 8, musculoskeletal abnormalities in all 10, and ophthalmologic manifestations in 5. Only 3 girls had papillomata. Axelrad et. al. (2004) performed standardized testing on 18 individuals with Costello syndrome. The Leiter International Performance Scale-Revised, a standardized nonverbal measure of intellectual ability, revealed a mean brief-IQ score of 57 (SD 12.5), within the range of mild mental retardation. In total, 17% of the participants had IQ scores within the severe range of mental retardation, 28% had IQ scores within the moderate range, 39% within the mild range, and 17% within the borderline range of intellectual functioning. Receptive language skills as assessed by the Peabody picture vocabulary test, 3rd edition, ranged from average functioning to 4 SD below the mean. Delays found on the Vineland adaptive behavior scales in the daily living skills, communication, and motor skills domains were comparable to the results seen in the Leiter brief-IQ. However, in the adaptive area of socialization, less than 50% participants fell in the low range of delay, and 25% of participants showed no delay in this domain. Axelrad et. al. (2004) concluded that their study provides evidence supporting anecdotal data that Costello patients are quite social despite their cognitive difficulties. White et al. (2005) reviewed the clinical findings of 17 adults with Costello syndrome and found the major health problems to be bladder carcinoma, benign tumors including benign breast disease, Chiari malformations, gastroesophageal reflux, pubertal delay, and osteoporosis. Intellectual disability was mild to moderate in 14 of the patients and severe in 3. Piccione et al. (2009) reported a premature male infant born at 29 weeks' gestation due to fetal distress who was found to have Costello syndrome confirmed by genetic analysis (G13C; 190020.0007). At birth, he was asystolic, neurologically depressed, had no spontaneous respiration, and had bilateral pneumothoraces. Further studies showed periventricular hyperechogenicity, septum pellucidum cysts, small choroid plexus hemorrhage, abdominal ascites, and atrial septal defect. At 4 months of age, he was noted to have relative macrocephaly, coarse face with hypertelorism, downslanting palpebral fissures, epicanthal folds, prominent eyes, short nose, low-set ears, large mouth, short neck, loose skin of hands and feet, sparse hair, hyperpigmented skin, deep palmar creases, joint laxity, reduced subcutaneous adipose tissue, and bilateral cryptorchidism. These features led to the clinical diagnosis of Costello syndrome. At 11 months of age, he had delayed motor development with central hypotonia, but adequate mental and speech development. Papillomata were not present. Piccione et al. (2009) noted that the distinctive features of Costello syndrome may be absent during the first months of life, especially in preterm infants who often have failure to thrive and decreased subcutaneous adipose tissue. The striking facial features of the disorder become more evident after the critical neonatal period. Smith et al. (2009) reported a female infant with Costello syndrome born at 27 weeks' gestation in a pregnancy complicated by mild polyhydramnios and preterm labor. She had fetal overgrowth, large anterior fontanel, low-set thickened and posteriorly rotated ears, and coarse facies. She developed an arrhythmia with multiple ectopic foci (chaotic atrial rhythm) at 4 weeks of age. Cardiac examination showed a hyperdynamic precordium with a systolic heart murmur, and echocardiogram showed concentric hypertrophic cardiomyopathy with pulmonary valve stenosis. Other features included hepatomegaly, hand posturing with ulnar deviation of the wrist, and hypoplastic labia. She died at 6 months of age from complications of cardiac arrhythmia and bronchopulmonary dysplasia. Genetic analysis identified a G12S mutation in the HRAS gene (190020.0003). Smith et al. (2009) emphasized the neonatal cardiac morbidity and mortality associated with Costello syndrome. - Congenital Myopathy With Excess of Muscle Spindles De Boode et al. (1996) reported 2 unrelated patients with progressive hypertrophic obstructive cardiomyopathy, Noonan syndrome-like facial anomalies, and increased density of muscle spindles in skeletal muscle biopsies. Both showed polyhydramnios on prenatal ultrasound and 1 had fetal hydrops. Death occurred at ages 3 weeks and 10 months, respectively. Selcen et al. (2001) reported an infant with congenital weakness, hypotonia, arthrogryposis, atrial tachycardia, hypertrophic cardiomyopathy, and marked excess of muscle spindles on biopsy. He died at age 14 months from cardiorespiratory failure. Postmortem examination showed organomegaly. He also had bifrontal hallowing with fat pads below, triangular mouth, high-arched palate, and congenital neuroblastoma. Stassou et al. (2005) reported a preterm neonate with arthrogryposis, hydrops fetalis, hypertrophic cardiomyopathy, and flaccid quadriplegia. Skeletal muscle biopsy showed increased muscle spindles encapsulated by fibrous tissue within most of the muscle fascicles sampled. She died at age 7 months. Lin et al. (2011) reviewed the cardiac features of 61 patients with Costello syndrome ranging in age from 1 month to 40 years, with 13 patients over age 18 years. Cardiovascular abnormalities were present in 85% of patients. The most common finding was hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, which was present in 37 (61%) of the 61 patients. Among these patients, HCM was chronic or progressive in 14 (38%), stabilized in 11 (37%), regressed in 4 (11%), and was unknown in 8 (22%). A congenital heart defect was present in 27 (44%) of the 61 patients, most commonly nonprogressive valvar pulmonary stenosis. Arrhythmia occurred in 34 (56%) patients, atrial tachycardia in 15 (25%), and aortic dilation in 4 (7%). The cardiac features of 85 patients with HRAS mutations from the literature were also assessed. Congenital heart disease was present in 22% of patients, HCM in 68%, arrhythmia in 40%, atrial tachycardia in 7%, and aortic dilation in 1 patient. Cardiac tissue showed myocardial fiber disarray in 7 (70%) of 10 specimens, consistent with sarcomeric dysfunction. Ten (43%) of 23 deaths among both cohorts occurred in infants less than 1 year of age, and most of these deaths were cardiac-related. The most common HRAS mutation was G12S (190020.0003), occurring in 84% of patients from the study and 71% of patients from the literature.
Gripp et al. (2007) reported 13 unrelated patients ages 0 to 8 years with a clinical diagnosis of Costello syndrome, Costello-like syndrome, or thought to have either CFC syndrome or Costello syndrome who were negative for mutations in ... Gripp et al. (2007) reported 13 unrelated patients ages 0 to 8 years with a clinical diagnosis of Costello syndrome, Costello-like syndrome, or thought to have either CFC syndrome or Costello syndrome who were negative for mutations in the HRAS gene. De novo heterozygous BRAF or MEK1 mutations were identified in 8 and 5 patients, respectively. In a comparison to a group of previously published patients with HRAS mutations, Gripp et al. (2007) found several significant clinical differences between the 2 groups. Patients with an HRAS mutation and Costello syndrome tended to have polyhydramnios, ulnar deviation, growth hormone deficiency, and tachycardia more frequently than patients with BRAF or MEK1 mutations. Those with BRAF or MEK1 mutations had more cardiovascular malformations. Although the presence of more than 1 papilloma strongly suggested Costello syndrome over CFC, the authors noted that these lesions typically develop over time and thus may not be very helpful in the differential diagnosis of younger children. Gripp et al. (2007) concluded that the 13 patients in their study had CFC syndrome and not Costello syndrome, based on the clinical and molecular findings. The authors noted the phenotypic overlap between the 2 disorders, but suggested that Costello syndrome be reserved for patients with HRAS mutations. Gripp et al. (2011) examined 12 individuals with Costello syndrome due to the HRAS G13C (190020.0007) mutation and compared the phenotype to those with the HRAS G12S (190020.0003) mutation. Individuals with G13C had many typical findings including polyhydramnios, failure to thrive, hypertrophic cardiomyopathy, macrocephaly, posterior fossa crowding, and developmental delay. Their facial features were less coarse and short stature was less severe. Statistically significant differences included the absence of several common features, including multifocal atrial tachycardia, ulnar deviation of the wrist, and papillomata; a noteworthy absence of malignant tumors did not reach statistical significance. There were some novel ectodermal findings associated with the G13C mutation, including loose anagen hair and long eyelashes requiring trimming (termed 'dolichocilia'). McCormick et al. (2013) developed a severity score for Costello syndrome based on various criteria, including feeding difficulties, cardiac abnormalities, orthopedic abnormalities, neurologic abnormalities, malignancies, bone density, and stature as well as mortality, and assessed 78 individuals blind to genotype. They then compared this to genotypes of the individuals and found that individuals with the G12A (190020.0004) and the G12C (190020.0014) HRAS mutations were more severely affected than those with other HRAS mutations.
Because of phenotypic overlap between Costello syndrome and Noonan syndrome (163950), and because mutations in the SHP2/PTPN11 gene (176876) had been demonstrated in the latter, Tartaglia et al. (2003) screened a cohort of 27 patients with clinically diagnosed ... Because of phenotypic overlap between Costello syndrome and Noonan syndrome (163950), and because mutations in the SHP2/PTPN11 gene (176876) had been demonstrated in the latter, Tartaglia et al. (2003) screened a cohort of 27 patients with clinically diagnosed Costello syndrome for PTPN11 mutations; they found none. The previous exclusion of PTPN11 mutations in cardiofaciocutaneous syndrome by Ion et al. (2002) indicates that these 3 syndromes are distinct. Troger et al. (2003) likewise found no mutation in the PTPN11 gene in 18 patients with Costello syndrome. Gain-of-function mutant SHP2 proteins identified in Noonan syndrome have enhanced phosphatase activity, which results in activation of a RAS-MAPK cascade in a cell-specific manner. Aoki et al. (2005) hypothesized that genes mutated in Costello syndrome and in PTPN11-negative Noonan syndrome encode molecules that function upstream or downstream of SHP2 in signal pathways. Among these molecules, they sequenced the entire coding region of 4 RAS genes in genomic DNA from 13 individuals with Costello syndrome and 28 individuals with PTPN11-negative Noonan syndrome. In 12 of the 13 individuals with Costello syndrome, they found a heterozygous mutation in the HRAS gene (190020.0001, 190020.0003-190020.0005). All 4 of the mutations had previously been identified somatically in various tumors. Examination of genomic DNA from unaffected parents in 4 families identified no mutations, suggesting that mutations in the affected individuals arose de novo, although the possibility of germline mosaicism in a parent could not be excluded. No mutations in KRAS (190070), NRAS (164790), HRAS, or ERAS (300437) were observed in the 28 individuals with Noonan syndrome or in 1 individual with Costello syndrome. The observations suggested that germline mutations in HRAS perturb human development and increase susceptibility to tumors. Gripp et al. (2006) and Estep et al. (2006) simultaneously analyzed the HRAS gene in samples collected at International Costello Syndrome meetings over several years and identified heterozygous mutations in 33 of 40 and 33 of 36 patients diagnosed with Costello syndrome, respectively (20 patients participated in both studies, for a total of 56 different patients). All mutations were in codons 12 and 13; the majority in both studies (91% and 91%, respectively) were a G12S substitution (190020.0003). Gripp et al. (2006) analyzed 19 sets of parents, none of whom carried the mutation, confirming the de novo nature of mutations in Costello syndrome patients. Estep et al. (2006) also analyzed 8 well-characterized patients diagnosed with cardiofaciocutaneous syndrome (CFC; 115150) and found no mutations in the HRAS coding region, supporting a distinct etiology between the Costello and CFC syndromes. In a detailed review of these reports, Lin et al. (2008) noted that Gripp et al. (2006) and Estep et al. (2006) had described a total of 49 patients, not 56 as originally stated. Lin et al. (2008) also provided a detailed list of the clinical features of these patients and emphasized the need for a central registry in order to keep track of biologic material. In 2 patients originally diagnosed with Costello syndrome but with features overlapping those of CFC, in whom no HRAS mutations were found (Estep et al., 2006), Rauen (2006) identified missense mutations in the BRAF gene (164757.0020 and 164757.0021, respectively). Rauen (2006) stated that Costello syndrome and CFC can be distinguished by mutation analysis of genes in the RAS/MAPK pathway. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%). The mutations were de novo in all cases in which DNA samples were available from the parents. The most common mutation was G12S, which was found in 30 of 37 mutation-positive patients. All of the mutation-positive cases had failure to thrive as well as the facial appearance and hands characteristic of Costello syndrome; macrocephaly was found in 32 mutation-positive cases. In a patient with autistic features and microretrognathism, Kerr et al. (2006) identified a substitution in a novel region of HRAS (K117R; 190020.0006). Kerr et al. (2006) stated that, together with previously published series (Aoki et al., 2005 and Gripp et al., 2006), mutations in HRAS had been found in 82 (85%) of 96 patients with a clinical diagnosis of Costello syndrome and that overall, the frequency of malignancy in the published mutation-positive cases was 11%. Zampino et al. (2007) identified the common G12S mutation in 8 of 9 unrelated patients with Costello syndrome; the ninth child had a different mutation (190020.0008). All mutations were de novo, paternally inherited and associated with advanced paternal age. None of 36 patients with Noonan syndrome or 4 with CFC syndrome had a mutation in the HRAS gene. Zenker et al. (2007) identified 2 different heterozygous mutations in the KRAS gene (190070.0017-190070.0018) in 2 unrelated infants with Costello syndrome. Both patients had coarse facies, loose and redundant skin with deep palmar creases, heart defects, failure to thrive, and moderate mental retardation. Zenker et al. (2007) noted that the patients may later develop features of CFC, which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders. In a 20-year-old woman with clinical features typical of Costello syndrome and additional findings seen in Noonan syndrome, who was negative for mutations in the PTPN11 and HRAS genes, Bertola et al. (2007) identified a mutation in the KRAS gene (K5E; 190070.0019) that was not found in her unaffected mother or brother or in 100 controls. The patient was diagnosed with hypertrophic cardiomyopathy soon after birth, and evolved with severe developmental delay; lymphedema began in her lower extremities at age 15 years, and at age 18 years she developed nasal papillomata. The initial diagnosis was Noonan syndrome, but the presence of relative macrocephaly, coarse facial features, loose skin in the hands and feet with deep creases, dark skin, and particularly the development of nasal papillomata led to the diagnosis of Costello syndrome. Bertola et al. (2007) noted that this mutation was in the same codon as that of 1 of the patients reported by Zenker et al. (2007) (K5N; 190070.0017). Van der Burgt et al. (2007) identified mutations in the HRAS gene (see, e.g., 190020.0001; 190020.0003; 190020.0009; 190020.0010) in patients with congenital myopathy with excess muscle spindles, a variant of Costello syndrome. Three of the patients had been reported by de Boode et al. (1996), Selcen et al. (2001), and Stassou et al. (2005). Schulz et al. (2008) identified mutations in the HRAS gene in 28 (90.3%) of 31 patients with Costello syndrome. All mutations occurred in codons 12 or 13, and the HRAS mutations in 14 informative families could all be traced to the paternal allele. G12S was the most common mutation, occurring in 82.1% of patients. The phenotype was relatively homogeneous. In 2 unrelated patients with Costello syndrome, Gripp et al. (2008) identified 2 different novel mutations in the HRAS gene (190020.0011; 190020.0012). The facial features of both patients were less coarse than typically seen in Costello syndrome. Lo et al. (2008) described 4 infants with an unusually severe Costello syndrome, in whom they identified 3 mutations in the HRAS gene (190020.0003, 190020.0013, and 190020.0014, respectively). The authors stated that hypoglycemia, renal abnormalities, severe early cardiomyopathy, congenital lung and airway abnormalities, pleural and pericardial effusion, chylous ascites, and pulmonary lymphangectasia are part of the clinical spectrum seen in Costello syndrome, and noted that lung pathology resembling alveolar capillary dysplasia was reported in 1 case.
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....
Diagnosis
Clinical DiagnosisCostello 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 historyPolyhydramnios, often severeIncreased birth weight as a result of edema (not true macrosomia)Weight loss resulting from resolution of edema and failure to thrive Severe postnatal feeding difficultiesShort statureCraniofacial appearance and voice (see Figure 1, Figure 2)FigureFigure 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...)FigureFigure 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 tipCurly or sparse, fine hairEpicanthal foldsWide nasal bridge, short full noseDeep, hoarse or whispery voiceSkinLoose, soft skinIncreased pigmentationDeep palmar and plantar creasesPapillomata of face, perianal region; typically absent in infancy but may appear in childhood and confirm the diagnosis in doubtful casesPremature aging, hair lossMusculoskeletal systemDiffuse hypotonia and joint laxityUlnar deviation of wrists and fingers, splayed fingers resulting in characteristic hand postureSpatulate finger pads, abnormal fingernailsTight Achilles tendons, often developing throughout childhoodPositional foot deformityVertical talusKyphoscoliosisPectus carinatum, pectus excavatum, asymmetric rib cageDevelopmental hip dysplasiaCardiovascular systemCardiac hypertrophy; usually typical hypertrophic cardiomyopathy (i.e., idiopathic subaortic stenosis, asymmetric septal hypertrophy), although other forms (i.e., biventricular) have been reportedCongenital heart defect; usually valvar pulmonic stenosisArrhythmia, 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 individualsNeurologicChiari I malformation, which may develop over timeHydrocephalusSyringomyeliaSeizuresTethered cordTumorsIncreased occurrence of malignant solid tumors; typically, elevated urine catecholamine metabolitesPsychomotor developmentDevelopmental delay or intellectual disabilitySociable, outgoing personalityNote: Identification of an HRAS missense mutation by molecular genetic testing confirms the clinical diagnosis of Costello syndrome.Molecular Genetic TestingGene. 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 testingSequence analysis Targeted mutation analysis. More than 95% of mutations causing Costello syndrome affect amino acid p.Gly12 or p.Gly13 (see Table 2).Table 1. Summary of Molecular Genetic Testing Used in Costello SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityHRASSequence analysis
Sequence variants 280%-90% 3Clinical Targeted mutation analysisp.Gly12Ala p.Gly12Ser p.Gly12Val p.Gly13AspSee Table 21. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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:Mostly commonly, the presence of a mutation in another gene, consistent with a diagnosis of CFC syndrome [Rauen 2006, Gripp et al 2007] or another disorder of the Ras/MAPK pathway [Quezada & Gripp 2007, Lo et al 2009]Rarely, the presence of a low level of somatic mosaicism for the HRAS disease-causing mutation in the tested tissue [Gripp et al 2006a, Sol-Church et al 2009, Girisha et al 2010 ] Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandThe 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.Genetically Related (Allelic) DisordersGermline mutations. No other phenotype is known to be associated with germline mutations in HRAS.Somatic mutations. Malignant solid tumors of adulthood, such as bladder carcinoma or lung carcinoma, are often associated with somatic HRAS mutations [Giehl 2005]. Mutation hotspots are the glycines at amino acid residues 12 and 13 and the glutamine at residue 61 (see Table 2). Missense mutations in these codons lead to increased activity of the gene product.
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....
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].
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]....
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.
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....
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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Costello syndrome, the following evaluations are recommended:...
Management
Evaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Costello syndrome, the following evaluations are recommended:Complete physical and neurologic examinationPlotting of growth parameters, including head circumferenceNutritional assessmentCardiologic 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 sryingomyeliaOphthalmology evaluationClinical assessment of spine and extremities, with particular concern for hip joint abnormalities and range of motionMultidisciplinary developmental evaluationGenetics consultationTreatment of ManifestationsGrowth. 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 ComplicationsCardiac. 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.SurveillanceHypoglycemia. 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationThe 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.OtherGrowth 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].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDHRAS11p15.5
GTPase HRasCatalogue of Somatic Mutations in Cancer (COSMIC)HRASData 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) View in own window 190020V-HA-RAS HARVEY RAT SARCOMA VIRAL ONCOGENE HOMOLOG; HRAS 218040COSTELLO SYNDROMEMolecular Genetic PathogenesisMalignant 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.FigureFigure 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 VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Mutation Detection Frequency (# of Patients) 1Reference Sequencesc.34G>Ap.Gly12Ser81.3% (113)NM_005343.2 NP_005334.1c.34G>Tp.Gly12Cys2% (3)c.35G>Cp.Gly12Ala7.2% (10)c.35_36delGCinsTTp.Gly12Val1.4% (2)c. 35_36delGCinsAAp.Gly12Gluc.37G>Tp.Gly13Cys1.4% (2)c.38G>Ap.Gly13Asp1.4% (2)c.64C>Ap.Gln22Lysc.110_111+1dupAGGp.Glu37dupc.108_110dupAGAp.Glu37dupc.173C>Tp.Thr58Ilec.187G>Ap.Glu63Lysc.350A>Gp.Lys117Argc.436G>Ap.Ala146Thrc.437C>Tp.Ala146ValSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 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.