How to Cite this Article: 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, Innes AM, Aoki Y, Silberbach M, Delrue M-A, White SM, Hamilton RM, O'Connor W, Grossfeld PD, Smoot LB, Padera RF, Gripp KW. 2011. Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome. Am J Med Genet Part A 155: 486–507.
Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome†
Version of Record online: 22 FEB 2011
Copyright © 2011 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Volume 155, Issue 3, pages 486–507, March 2011
How to Cite
Lin, A. E., Alexander, M. E., Colan, S. D., Kerr, B., Rauen, K. A., Noonan, J., Baffa, J., Hopkins, E., Sol-Church, K., Limongelli, G., Digilio, M. C., Marino, B., Innes, A. M., Aoki, Y., Silberbach, M., Delrue, M.-A., White, S. M., Hamilton, R. M., O'Connor, W., Grossfeld, P. D., Smoot, L. B., Padera, R. F. and Gripp, K. W. (2011), Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome. Am. J. Med. Genet., 155: 486–507. doi: 10.1002/ajmg.a.33857
- Issue online: 24 FEB 2011
- Version of Record online: 22 FEB 2011
- Manuscript Accepted: 26 NOV 2010
- Manuscript Received: 4 AUG 2010
- aortic dilation;
- cardiovascular malformation;
- chaotic atrial rhythm;
- congenital heart defect;
- ectopic atrial tachycardia;
- hypertrophic cardiomyopathy;
- multifocal atrial tachycardia;
- Noonan-spectrum syndromes;
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- Supporting Information
Cardiovascular abnormalities are important features of Costello syndrome and other Ras/MAPK pathway syndromes (“RASopathies”). We conducted clinical, pathological and molecular analyses of 146 patients with an HRAS mutation including 61 enrolled in an ongoing longitudinal study and 85 from the literature. In our study, the most common (84%) HRAS mutation was p.G12S. A congenital heart defect (CHD) was present in 27 of 61 patients (44%), usually non-progressive valvar pulmonary stenosis. Hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, was noted in 37 (61%), and 5 also had a CHD (14% of those with HCM). HCM was chronic or progressive in 14 (37%), stabilized in 10 (27%), and resolved in 5 (15%) patients with HCM; follow-up data was not available in 8 (22%). Atrial tachycardia occurred in 29 (48%). Valvar pulmonary stenosis rarely progressed and atrial septal defect was uncommon. Among those with HCM, the likelihood of progressing or remaining stable was similar (37%, 41% respectively). The observation of myocardial fiber disarray in 7 of 10 (70%) genotyped specimens with Costello syndrome is consistent with sarcomeric dysfunction. Multifocal atrial tachycardia may be distinctive for Costello syndrome. Potentially serious atrial tachycardia may present in the fetus, and may continue or worsen in about one-fourth of those with arrhythmia, but is generally self-limited in the remaining three-fourths of patients. Physicians should be aware of the potential for rapid development of severe HCM in infants with Costello syndrome, and the need for cardiovascular surveillance into adulthood as the natural history continues to be delineated. © 2011 Wiley-Liss, Inc.
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- Supporting Information
Costello syndrome (MIM #218040) is a rare multiple anomaly syndrome [Gripp and Lin, 2009], and beyond infancy, can be differentiated from phenotypically similar Ras/MAPK pathway syndromes (“RASopathies”) [Rauen et al., 2010], that is, Cardiofaciocutaneous (CFC) syndrome (#115150) and Noonan syndrome (#163950). Other RASopathies which have similar pathogenetic activation of Ras/MAPK, but have little phenotypic overlap include Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome) (#151100, #611554), capillary malformation-arteriovenous malformation syndrome (#139150), or neurofibromatosis type 1 (#162200) [Quezada and Gripp, 2007; Denayer et al., 2008; Tidyman and Rauen, 2008; Rauen et al., 2010]. Phenotypic features of Costello syndrome include polyhydramnios, increased birth weight, feeding problems, failure to thrive, short stature, developmental delay, pleasant personality, characteristic facial appearance, soft skin, papillomata, spatulate fingerpads, deep palmar creases, joint and skin laxity, kyphoscoliosis, pectus, and splayed fingers with ulnar deviation. Since the discovery that HRAS gene mutations cause Costello syndrome [Aoki et al., 2005], at least 150 genotyped patients have been studied [reviews by Estep et al., 2006; Gripp et al., 2006; Kerr et al., 2006; Zampino et al., 2007]. Consensus expert opinion recommends that Costello syndrome be defined solely by HRAS mutations [Kerr et al., 2008], which differs from the molecular heterogeneity of CFC syndrome and Noonan syndrome.
Cardiovascular abnormalities are important diagnostic and management issues for most RASopathies, especially Costello syndrome, and they have been reported in 60–75% of patients prior to molecular diagnosis [Lin et al., 2002]. Congenital heart defects (CHDs), cardiac hypertrophy, usually described as hypertrophic cardiomyopathy (HCM) and arrhythmia (especially non-reentrant atrial tachycardia) were each found in approximately one-third of Costello syndrome patients. The knock-in G12V Hras mouse model, though a rare mutation in Costello syndrome, does not appear to completely recapitulate cardiac issues seen in humans [Schuhmacher et al., 2008; Chen et al., 2009].
To extend the delineation of the type, frequency, clinical course and genotype–phenotype analysis of cardiovascular abnormalities in Costello syndrome, we report data from a cohort in a clinical molecular study combined with genotyped published cases. This comprehensive description provides data for rational decision making in a rare disease, including the mode and timing of surveillance. Differentiation of the syndromes of the Ras/MAPK pathway remains an important task for the clinician. Where possible, data from this cohort of mutation-positive patients with Costello syndrome will be compared with mutation-positive patients with Noonan and CFC syndromes.
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- Supporting Information
Clinical Molecular Study
We analyzed Costello syndrome patients with HRAS mutation confirmation who were enrolled from July 1, 2003 to June 30, 2007 in an IRB-approved study with informed consent (A. I. duPont Hospital for Children #2003-006, #2005-051, “study patients”). Patients with clinically diagnosed Costello syndrome were identified at the 2003, 2005, and 2007 International Costello Syndrome Meetings through the Costello Syndrome Family Network and through individual physician referral. Basic clinical information was obtained by self-report from the families who completed a standardized data collection form, supplemented by a review of cardiac medical records. Most families were also interviewed by the principal investigator (K.W.G.). Information about various features of these patients has been reported in a series of articles from this research group [Axelrad et al., 2004, 2007, 2009; Gripp et al., 2006, 2007, 2008, 2010; Lin et al., 2008b, 2009; Hopkins et al., 2010]. A few patients had been partially reported prior to HRAS mutation confirmation [e.g., patient 6 in Dearlove and Harper, 1997; Kerr et al., 1998; patient in Legault et al., 2001 patient 22 in Lin et al., 2004; patient 41 in Johnson et al., 1998; patient 44 in Siwik et al., 1998]. Mutation analysis was performed either as described previously [Gripp et al., 2006] at the A.I. duPont Hospital for Children by an unaffiliated CLIA approved lab.
Literature Review Cohort
We reviewed previously reported patients with adequate clinical and molecular information with Costello syndrome (HRAS) [Kerr et al., 2008], and other RASopathies, that is, Noonan syndrome (PTPN11, SOS1, RAF1), Noonan syndrome with multiple lentigines syndrome (PTPN11), CFC syndrome (BRAF mutation only, because of larger patient numbers than MEK1/2), KRAS mutations, and neurofibromatosis type 1 (NF1). We focused on large reviews that included tables with specific subjects, excluding those with aggregate cardiac data, and limited personal or cardiac history. Duplicative reports were merged. In the absence of a single review of NF1 patients with molecular confirmation including cardiac information, we studied a large survey of patients clinically diagnosed with NIH consensus criteria [Lin et al., 2000], and two series of NF-Noonan patients associated with an identified NF1 mutation [Baralle et al., 2003; De Luca et al., 2005].
Diagnosis and Definitions
Patients with Costello syndrome had been managed by their personal pediatric or adult cardiologist. The study diagnosis was based on the verbatim description submitted by the parent, compared to diagnostic tests, cardiology consults, catheterization procedures (especially interventional and electrophysiologic, EP), surgery, autopsy reports, and evaluated independently for accuracy. Adults (18 years and older) were assigned an informal assessment of their cardiac symptoms by the parent, often after discussion with the cardiologist, geneticist and/or senior authors.
Congenital heart defect
A CHD was defined as a structural defect of the heart and major aortic branches. Cardiac findings such those associated with prematurity or neonatal patent foramen ovale, patent ductus arteriosus, or physiologic peripheral pulmonary stenosis were excluded [Lin et al., 2002]. The severity of semilunar (usually pulmonary) valve obstruction was based on the stated diagnosis of the referring cardiologist, categorizing the peak ejection gradient as mild (<35–40 mm Hg), moderate (40–60 mm Hg), or severe (>60 mm Hg) [Prieto and Latson, 2008]. We used maximum instantaneous gradient (MIG) from echocardiography. Attempts were made to classify pulmonary stenosis by specific location (valvar, subvalvar); “not specified” was presumed to be valvar.
Hypertrophic cardiomyopathy (HCM) included unexplained (primary) cardiac hypertrophy [Colan, 2007]. The pattern (distribution), severity of left ventricular hypertrophy and/or outflow obstruction, and change over time was based on the verbatim description by the cardiologist or on the echocardiogram report. Less frequently we used the cardiologist's description as paraphrased in the geneticist consultation. Regardless of the term reported by each cardiologist (e.g., asymmetric septal hypertrophic, idiopathic subaortic stenosis, or left ventricular hypertrophy), we used the term HCM with either subaortic obstruction or mild interventricular septal thickening. Concentric hypertrophy in the absence of left ventricular outflow obstruction or hypertension was also noted, but was not the primary pattern of hypertrophy.
Arrhythmias were classified in a standard fashion using 12-lead surface electrocardiogram (ECG), and in some cases using 24-hr-Holter monitoring. When only a rhythm strip tracing from an intensive care unit was reported, a diagnosis was not recorded. Ectopic atrial tachycardia (EAT) referred to a single non-sinus atrial focus, whereas multifocal atrial tachycardia (MAT), also known as chaotic atrial rhythm (CAR), consisted of multiple (≥3) P waves [Walsh et al., 2006]. In this report, MAT was the preferred term, and “serious tachycardia” referred to any sustained atrial tachycardia. A small number of patients had EP mapping to confirm the ECG diagnoses.
Data were collected about aortic dilation and coronary artery anomalies excluding peripheral arterial anomalies. Systemic and pulmonary hypertension were noted, but inconsistently reported, thus, they were excluded from the tally of “vascular” abnormalities.
We conducted an extensive review of autopsy and biopsy findings in Costello syndrome among both the study participants and previously reported patients, and compared these to other RASopathies. Gross and microscopic data and the presence or absence of myocardial fiber disarray was recorded.
Patients were reviewed (by A.E.L.) to determine the dominant cardiac abnormality, rather than listing component defects. For example, a patient with moderate valvar pulmonary stenosis, trivial peripheral pulmonary stenosis, patent foramen ovale, and “rare” premature atrial contractions on Holter monitor was classified as having valvar pulmonary stenosis. Because previous reports have used two methods to determine occurrence, the frequency of an abnormality was reported as the number of patients (X) and its proportion to all patients (X%), as well as a comparison to the specific sub-group such as “patients with HCM” (Y, Y%). Genotype–phenotype analyses focused on mortality and specific cardiac phenotypes which were common, serious, and/or unusual. A severity analysis was also performed based on whether the HCM or valve obstruction was reported as severe; whether tachycardia was described as persistent, malignant, requiring treatment past age 1 year, or generally viewed as difficult to treat; or if a surgical or interventional catheterization procedure was performed.
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- Supporting Information
We studied 61 Costello syndrome patients confirmed by HRAS mutation, 58 patients enrolled in the A.I duPont Hospital for Children clinical molecular longitudinal study and three deceased patients (see Supplemental Appendix; subsequent citations refer to them as patients 1–61). In 54 (89%), the self-reported parental data were supplemented with medical records and/or published data. The lack of records in seven families (three outside the United States) was due to lack of address or response from family or physician-of-record. Most (80%) patients were white, and there were slightly more females (56%) (Table I). Costello syndrome was diagnosed clinically by age 1 year in almost one-third of the patients (mean age at diagnosis 4.2 years). The current age of this cohort spanned infancy to the fifth decade, and 13 (21%) study patients were older than 18 years. Eight of the 11 (73%) adults over 18 years described by their parents as having few cardiac symptoms had mild limitation of activity, one had moderate cardiac symptoms and exercise limitation and the status of two patients is unknown (one was seriously ill from rhabdomyosarcoma). The overall frequency of neoplasia (20%) and the most common tumor, rhabdomyosarcoma (12% of all patients, 58% of those with neoplasia), were similar to the 15% overall risk for solid tumors which has been estimated [Gripp and Lin, 2009]. The location of the rhabdomyosarcoma in the pelvis (3), prostate (2), perineum (1), and abdomen (1) was typical for the predominance of extra-craniofacial rhabdomyosarcoma in Costello syndrome, as was the embryonal cell type [Gripp et al., 2002]. Neoplasia was not associated with the occurrence of HCM. A detailed analysis of the impact of growth hormone (GH) on Costello syndrome was beyond the scope of this paper, but basic data were obtained (Table I). Diagnostic testing confirming GH deficiency, and GH use was reported in 25% of patients, 69% of whom received it for at least 2 years.
|Feature||Number patients (%, figures rounded)|
|Geneticist, either local, or study||61 (100)|
|Cardiologist, pediatric, or adult||60 (98)|
|Mixed (2 were African American/white)||4 (7)|
|Age at diagnosis|
|By age 1 year||19 (31)|
|Range||1 month to 40 years|
|>18 years||13 (21)|
|Rhabdomyosarcoma||7 (1 with ganglioneuroblastoma) (12)|
|Bladder cell carcinoma||3 (5)|
|Pituitary adenoma||1 (2)|
|Cancer plus HCM||7/11 (64)|
|2 bladder cell carcinoma|
|1 pituitary adenoma|
|Do not know||11 (18)|
|Do not know||4 (7)|
|Duration (n = 16)|
|≤1 year||1 (6)|
|1–2 years||2 (12)|
|>2 years||11 (69)|
|Do not know||2 (12)|
|Effective (n = 16)|
|Do not know||9 (56)|
|GH in 16 pts with HCM||11 (69)|
|Change in severity HCM|
|Do not know||1 (9)|
Six (10% of total) deaths in this study (Table II) included two with sudden death. These occurred in a -year-old boy with the common p.G12S mutation and HCM, thickened aortic and mitral valves and marked myocardial fiber disarray [Supplemental Appendix patient 5, Lin et al., 2002; patient 3 in Hinek et al., 2005], and a 27-year-old male with severe HCM, non-sustained atrial and ventricular ectopy and mild ascending aortic dilation (Table III). Postmortem examination confirmed severe HCM (360 g), and showed myxomatous mitral and tricuspid valves, a fenestrated thick aortic valve, mildly dilated ascending aorta (normal Sinus of Valsalva), and a plaque of anterior systolic motion of the mitral valve (Supplemental Appendix patient 2, Fig. 2). The atria did not appear abnormal, and the conduction system was not sectioned. Microscopically, there was myocardial fiber disarray, stenotic intramyocardial arterioles, and moderate epicardial disease, that is, premature coronary artery disease (40% narrowing of the right coronary artery). The patient had a documented normal lipid panel in the prior year.
|Cardiorespiratory||Neoplastic||Pulmonary||Multiorgan system failure||All causes|
|I. This study (# pts)|
|a5.5 yrs, HCM, sudden death||2.5 yrs, RMS, embryonal||c1.5 mos, wide QRS tachycardia (not MAT)|
|b27 yrs, HCM, aortic dilation, sudden death||c14 mos, HCM, MAT|
|c4 mos, HCM, EAT|
|II. Literature (# pts)|
], 7 yrs, HCM, RMS
Estep et al. [2006
]. 1 wk, HCM
Kuniba et al. [2009
], pt 4, 2.5 yrs, HCM, RMS
], pt 10; Lo et al. [2008
]. 6 mos, PSV, HCM, MAT
Smith et al. [2009
|Study and literature, total||11||5||2||5||23/146 (16%)|
|Patient||Gene mutation||Cardiovascular abnormalities||Severity HCM||Age, (rounded to 0.5 yr), Sex Outcome||Myocardial fiber disarray||Myocardium mm. RV; IVS; LV||Myocyte hypertrophy||Myocyte fibrosis, hyperplasia||Other|
|Supplemental Appendix pt 2||HRAS G12S||HCM Aorta dilation Moderate atherosclerosis||Moderate-severe||27 yrs, M, sudden death||Yes Severe||6, 18, 21||Yes Moderate||Yes Severe||Severe intimal proliferation, medial hypertrophy of intramyocardial arterioles. Thick, myxomatous MV, TV, AV (prominent fenestrations). Plaque of SAM of MV. Moderate (40%) atherosclerosis RCA. Remote subendocardial MI, posterior IVS|
|Supplemental Appendix pt 6||HRAS G12S||HCM||Severe||11 yrs, F, Improved after myectomy||Noa||Not done||Not done||Not done, Not done|
|Supplemental Appendix pt 35||HRAS G12S||Obstructive HCM, ASH; SVT/JT||Severe||14 yrs, M, Improved after two myectomies||Yes||NS||Yes||Yes, NS|
, pt 3]
Supplemental Appendix pt 40 [Hinek et al., 2005
|HRAS G12S||HCM Marked LVH||Severe||5 yrs, M, Sudden death||NS||NS||NS||Yes, severe||Fragmented elastic fibers. Immunostaining with chondroitin-sulfate|
|Supplemental Appendix pt 43||HRAS A146V||HCM||Severe||6 yrs, M, Improved after myectomy||Yes||NS||Yes||NS, NS|
|Supplemental Appendix pt 59||HRAS G12S||HCM, BVH; CAR||Severe||1 yr, F, Death||Yes, mild||6; 15; 9||Occasional||No, NS|
Hinek et al. [2005
], pt 1; Estep et al. [2006
], pt 44
]; Lin et al. [2008b
|HRAS G12S||HCM; Arrhythmia NOS||Severe||6.5 yrs, M, Death, RMS||Yes||7; NS; 15||Yes||NS, NS||Conduction system fibrosis at bundle of His|
|HRAS G12A||BVH HCM||Moderate||3 yrs, F, Death||Yes||NS||Yes||No, No|
|HRAS G12E||BVH HCM||Moderate-severe||0.5 Yr, F, Death||No||NS||No||No, No||Coronary artery fibromuscular dysplasia, nesidioblastosis|
|HRAS G12V||HCM||Severe||3 weeks, M, Death||Yes||NS||NS||NS, NS||Small fiber myopathy, excess muscle spindle|
Tomita et al. [1998
|NA||Obstructive HCM, ASH: SVT||Moderate-severe||1.5 yrs, F, Sudden death||Yes||ECHO: 7 mm LVFW, 10.8 mm IVS||Yes||Yes, NS||RV biopsy|
] (6 pts)
Noonan syndrome: Burch et al. [1992
|NA||HCM, symmetric BVH||10 yrs, M, Transplant||IVS; LVFW, ++||NS||NS||NS, NS|
|NA||HCM ASH||2 mos, F, Death||++||NS||NS||NS, NS|
|NA||HCM ASH||0.5 yrs, F, Death||++||NS||NS||NS, NS|
|NA||HCM ASH||2 yrs, M, Transplant||++||NS||NS||NS, NS|
|NA||HCM ASH||0.5 yrs, M, Death||++||NS||NS||NS, NS|
|NA||HCM ASH||Birth, M, Death||++||NS||NS||NS, NS|
Noonan syndrome: Noonan and O'Connor [1996
|NA||HCM, ASH, dysplastic PV||Severe||0.5 yr, F, Death||Yes||NS||NS||NS|
|NA||HCM, ASH||Severe||10 yrs, M, Death||Yes, marked||NS||NS||NS||Intramyocardial coronary artery thickening|
Noonan syndrome: Nishikawa et al. [1996
|NA||HCM, symmetrical||Severe||17 yrs, M, Death||Yes||NS||Yes||NS|
|NA||HCM||Severe||12 yrs, F, Catheterization||Yes, whorling of muscle bundle||NS||NS||NS||Intramyocardial coronary artery thickening|
Noonan syndrome: Skinker et al. [1998
|NA||HCM, symmetrical||Severe||20 yrs, F, Catheterization||Yes||NA||Yes||Yes||Abundant myocyte vacuolization|
Noonan syndrome: Ishikawa et al. [2003
|NA||HCM, ASH, ASD, dysplastic PV, SVT||Severe||1 yr, F, Death||Yes||NS||NS||Yes||Fibromuscular dysplasia of coronary arteries; intramyocardial coronary artery thickening|
] (NS if pt 1 or pt 4)
Noonan syndrome: Razzaque et al. [2007
|RAF1||Obstructive HCM||Severe||Death, NS if, pt 1 (17 yrs) or pt 4 (3 wks)||Yes||NS||NS||NS, NS|
] (2 pts)
CFC syndrome: Roberts et al. [2006
|NA||Pt 1: PS, valvar, No HCM||Not applicable||2 yrs, F, Valvotomy, 4 yrs: Death, SBE||NS||NS||NS||NS||4 valves dysplastic, 8 mm ASD|
|NA||Pt 2: Mild PS, HCM, grade 3 PVOD noted shortly before death||NS||21 yrs, M, Sudden death||Yes||NS||NS||NS||Coronary artery intimal thickening, early fibrosis “consistent with HCM”|
|NA||Pt 3: ASD, PS repaired in childhood, 20 yrs: SVT, probable EAT, secondary, chronic CHF||NS||22 yrs, M, Sudden death, VFib||Yes||NS||NS||NS|
Among 85 previously reported patients, there were 17 (20%) deaths (Table II). At least two were sudden deaths, including a 9-year-old girl with non-obstructive HCM, mild pulmonary stenosis, and severe scoliosis who did not have postmortem examination [Kerr et al., 2006], and a 3-year-old girl with HCM who had recovered from resection of a ganglioneuroblastoma and died during an episode of enterocolitis [Aoki et al., 2005, patient 62].
An additional death which is not listed on Table II since molecular confirmation had not been obtained. This 47-year-old man was the first patient reported by Costello [1971, 1977] and when re-evaluated as an adult was being treated for hypertension without CHD or HCM on echocardiogram [case 1, Costello, 1996; patient 3, White et al., 2005]. The patient was living with his parents, in good health (details not available), and died suddenly at home. His parents declined autopsy examination.
Overview of Costello Syndrome
Table IV lists the cardiovascular abnormalities in 61 study and 85 previously reported patients with Costello syndrome, and in selected related RASopathies [references in footnote, details in Supplemental Appendix]. Nearly all patients with Costello syndrome in this study and the literature had at least one cardiovascular abnormality.
|Clinical syndrome||Costello syndrome, this study||Costello syndrome, literature1–13||CFC syndrome14–17||Noonan syndrome19–24||Noonan syndrome with multiple lentigines25–27||Noonan syndrome31,32||Noonan syndrome33–35||Multiple phenotypes36–40,44||Neuro-fibromatosis, type 1% [also, NF-NS]41–43|
|45Total pts||61||85||58||28641||23||5631||50||25||[22 NFNS]|
|Any CV||52/61,||76/85,||31/4218||239/286||20/23,||10/13,||47/50,||19/25,||54/2322, 2%|
|% total;||27/61, 44%||19/85, 22%||26/58, 45%||215/286, 75%||13/23, 56%||9/1332, 69%||33/50, 33%||9/25, 36%||54/2322, 2%|
|% any CV problem||27/52, 52%||19/76, 25%||26/31, 84%.||215/239, 90%||13/20, 65%||9/10, 90%||33/47, 70%||9/19, 47%||54/54, 100%|
|PS valvar or||25/58,|
|% total;||12/61, 20%||8/85, 9%||5/46, 31%14 only||192/286, 67%||6/23, 26%||41/5631, 73%||13/50, 26%||7/25, 28%||25/2322, 1%|
|% any CV problem||12/52, 23%||8/19, 42%||192/239, 80%||6/20 30%||NA||13/47, 28||7/9, 78%||25/54, 46%|
|ASD2, ASD nos;||19%,15 22%,14 50%16|
|% total;||4/61, 7%||4/85, 5%||10/5631, 18%|
|% any CV problem||4/28, 14%||4/76, 5%||41/170, 24%29||Rare||NA||10/50, 20%||3/25, 12%||Rare|
|Other CHDs||MV prolapse||MV||MV||AVSD||MVP||MV||VSD||Rare|
|46Outcome||24/30, 80%||N.A.||N.A.||N.A.||3/23 (12%)||N.A.||N.A.||N.A.||N.A.|
|% total CHD||Stable or||Stable|
|% total;||37/61, 61%||58/85, 68%||21/58, 36%||26/286, 9%||15/23, 65%||6/5631, 11%||41/50, 82%||10/25, 40%||Rare|
|% any CV problem||37/52, 71%||57/76, 76%||16/42, 38%||26/239, 11%||15/20, 75%||NA||41/47, 87%||10/19, 52%|
|Outcome||15/37, 41%||N.A.||N.A.||N.A.47||17/23 (74%)||N.A.||N.A.||Resolved||N.A.|
|% total HCM||Stable or||Stable||(1 pt)39|
|regressed (4 pts)|
|Arrhythmia||4/20, 45%.||17 1 pt with|
|% total;||34/61, 56%||34/85, 40%||5/53, 9%||NSVT 5/23,||HCM and|
|% CV problem||34/52, 65%||34/76, 45%||N.A.||22%||6/50, 12%||unspecified|
|No||5/20, 25%||No||6/47, 13%||arrhythmia||No|
|% total;||15/61, 25%||6/85, 7%||SVT||No||No||No||1 pt||No||No|
|% CV problem||15/52, 29%||6/76, 8%|
|15/34, 44%||6/34, 9%|
|% total||Stable, self-|
|% total;||4/61,7%||1 (Pt. 4)2||No||Rare||No30||No||No||No||No|
|% any CV problem||4/52, 7%|
|Coronary||1 (Pt 32)3|
|artery abn.||No||Fibro-||No||No||Dilation 28,29||No||No||No||Yes|
|% total pts;||muscular||Peripheral|
|% cardiac pts||dysplasia||aneurysms|
Congenital heart defects
Less than half (44% of total; 52% with any cardiovascular abnormality) of all Costello syndrome patients had a CHD. In addition to pulmonary valve stenosis or dysplasia in 12 (20% of total), anomalies of the other valves were seen in 10 (19% of total). There were four patients with isolated valve anomalies including thick aortic valve (1) and mitral valve prolapse without HCM (3), and 3 with two or more valve anomalies such as polyvalvar dysplasia (one each with mitral/tricuspid valve prolapse; thick mitral/aortic valve and dysplasia of all 4 valves; mitral valve prolapse/bicuspid aortic valve). Two patients had valve anomalies associated with various minor CHDs including muscular ventricular septal defect and thick aortic valve (1), and atrial septal defect with bicuspid aortic valve (1). Septal defects were usually hemodynamically insignificant, including ventricular septal defect, type unspecified (3), isolated atrial septal defect (1), atrial septal defect with pulmonary stenosis (2), and combinations (one each with coarctation, ventricular septal defect, atrial septal defect; membranous ventricular septal defect, transient polyvalvar disease). There were no complex CHDs such as heterotaxy, single ventricle, conotruncal or atrioventricular canal defects. The outcome of CHDs, in general, was reassuring, since 86% were stable or resolved. Pulmonary stenosis resolved (5/12, 42%) or was stable and mild (7/12, 58%). Additional levels of pulmonary obstruction included 3 with supravalvar pulmonary stenosis, and one patient with severe sub-pulmonary obstruction as a double-chambered right ventricle in the setting of HCM and requiring two surgical resections [patient 44; first reported as Siwik et al., 1998]. No patient required surgical or balloon valvotomy for severe pulmonary stenosis. Overall, atrial septal defects were uncommon and mild, only one requiring surgical closure. Patient 48 required a mitral valve replacement with a porcine valve at age 19 years, which was replaced with a St. Jude prosthetic valve at age 25 years; patient 6 is a 16-year-old girl with severe HCM and mitral regurgitation who has avoided valve replacement with aggressive medical management.
Among previously reported patients, there were about half as many reported CHDs (22% of total; 25% any cardiovascular abnormality). The frequency of uncomplicated pulmonary stenosis was decreased among all patients (8/85, 9%), but identical among those with a cardiovascular abnormality (8/19, 42%), which may represent ascertainment bias. There was one additional patient with pulmonary stenosis and a ventricular septal defect. Outcomes could not be assessed among the literature patients.
HCM was reported with similar frequency in this study cohort and previously reported patients (61–68% of total, 71–76% any cardiovascular abnormality). We did not consistently solicit a family history of HCM, but none was reported. Most (23, 38% of total, 62% with HCM) patients had subaortic septal hypertrophy (reported also as asymmetric septal hypertrophy, idiopathic subaortic stenosis), with variable obstruction. Other patterns included global or concentric left ventricular hypertrophy (n = 14), mild interventricular septal “thickening” (n = 2), or unspecified or variable HCM (n = 4). One patient had “biventricular” involvement of HCM with a double-chambered right ventricle. There were no patients with isolated apical HCM, dilated or noncompaction cardiomyopathy, or progression from HCM to “end-stage” dilated cardiomyopathy. Of 37 HCM patients, the clinical course was chronically severe or progressive in 14 (38%), stabilized in 11 (30%), regressed in 4 (11%), and unknown in 8 (22%). Myectomy was used in 9 (24%) of 37 HCM patients (64% of the 14 with severe or progressive disease).
The age of HCM diagnosis ranged from the rare neonatal phenotype when it was severe [Hinek et al., 2005; Lo et al., 2008] to the more common presentation in childhood. Prenatal onset of HCM has not yet been observed in Costello syndrome [Lin et al., 2009; Smith et al., 2009], even in a 31-week fetus scanned using 3-D ultrasonography who had “cardiac hypertrophy” postnatally [Kuniba et al., 2009].
A comparison of the association of neoplasia and HCM was not helpful due to the small number of patients with malignancies (data not shown).
An arrhythmia was reported in slightly more than half of the study patients. Some form of atrial tachycardia was reported in 34 (56% of total; 65% any cardiovascular abnormality) patients, which includes MAT, and EAT (15, 25% total; 44% of those with arrhythmia), supraventricular/paroxysmal tachycardia or junctional tachycardia (7, 11% of total; 24% with arrhythmia), unspecified atrial tachycardia (4, 7% of total, 14% with arrhythmia) and inappropriate sinus tachycardia (4, 7%, 14% with arrhythmia). Late-onset atrial fibrillation with/without flutter occurring in 16- (patient 17) and 19- (patient 48)-year-old males is a new finding in Costello syndrome, though frequent in many forms of HCM. Ventricular arrhythmia was limited to the 1.5 months old (patient 61) without HCM who died in the setting of wide QRS tachycardia. Arrhythmia in Costello syndrome appeared to resolve, was stable or self-limited in 24 (39% of total; 71% with arrhythmia). However, in eight patients (13% total, 24% with arrhythmia) the course was chronically severe or worsened. Three patients had ablation procedures including two young children (patients 26 and 29) for hemodynamically important and drug refractory tachycardia; one required an AV sequential pacemaker because of the therapeutically induced heart block (Supplemental Appendix patient 36, Fig. 1). No additional patients underwent an invasive EP study or had an implantable cardioverter-defibrillator (ICD). Standard medical therapies were effective in many.
Mild–moderate aortic root dilation was documented in four study patients (7% of total; patients 2, 17, 33, 38) in which the maximal age and BSA-adjusted Z score was 3–7.8. In patient 2, the dilation involved the ascending aorta, whereas dilation in the other patients involved the Sinus of Valsalva. Bicuspid aortic valve was not reported. Aortic root dilation was also noted in one literature patient beginning at age 17 years [patient 4, Estep et al., 2006] without bicuspid aortic valve, who had been treated for 6 years for mild labile systemic hypertension; Z score was not available. There were no patients with aortic aneurysm or dissection.
The following patients are included as examples of possible “vasculopathy,” but not included in the tally of total patients with cardiovascular abnormalities. Hypertension required treatment in one male (patient 55) with moderate-severe HCM, and one young woman from the literature [patient 4, Estep et al., 2006]. Systemic blood pressure was not consistently reported, and was normal in 24 (89% of those measured). Idiopathic neonatal pulmonary hypertension occurred in one study infant (patient 59) with lethal HCM. One infant who had a p.G12A mutation with severe HCM had fibromuscular dysplasia of the coronary arteries at autopsy [patient 11, Kerr et al., 2006].
Table III lists 11 patients with postmortem (n = 8) or biopsy (n = 3) tissue available for pathologic review. In addition to the initial description of myocardial fiber disarray in a clinically described Costello syndrome patient [Tomita et al., 1998], we report 7 (four study patients, three from the literature review) genotyped patients with disarray (7/10, 70% of all genotyped pathologic specimens). Additional findings included mild conduction system fibrosis at the bundle of His [patient 1 in Hinek et al., 2005; Estep et al., 2006; patient 44 in Lin et al., 2008b], coronary artery fibromuscular dysplasia with nesidioblastosis [patient 11 in Kerr et al., 2006], and small fiber myopathy with excess muscle spindle [patient 1 in van der Burgt et al., 2007]. Atrial fibrosis was not reported. As in Noonan syndrome and non-syndromic HCM patients, myxomatous valve degeneration and thickened intramural coronary arteries were observed (Fig. 2, patient 2).
The other RASopathies have been also associated with myocardial fiber disarray in 12 clinically diagnosed patients with Noonan syndrome prior to the availability of mutation analysis and one patient with a RAF1 mutation (Table III). Three patients had intramyocardial coronary artery thickening resembling nonsyndromic HCM, and one patient had fibromuscular dysplasia. Myocardial fiber disarray was reported in two clinically diagnosed patients with CFC syndrome [Roberts et al., 2006], one of whom had coronary artery intimal thickening.
Genotype–Phenotype Correlation of HRAS Mutations
The vast majority of patients had the p.G12S mutation in both our study cohort (84%) and the previously reported patients (71%), with 14 additional non-G12S mutations in 1–6 patients, each (Table V). Of the two most common mutations, HCM was present in 64% and 44% of patients with the p.G12S and p.G12A mutation, respectively. The p.G12S mutation was present in 13/15 (87%) patients with serious tachycardia, and one each with the p.G12A and p.G12C mutation. The small number of patients with less common mutations prevents a meaningful comparison of the cardiac phenotype severity. Of the 111 total patients with the p.G12S mutation, 57% had two or more cardiac abnormalities, whereas 50% of p.G12C and p.G13C patients had a single defect. Data from a “severity comparison” analysis are not shown on Table IV. In descending order, the frequency of patients with any severe cardiovascular abnormality was 100% for p.A146V (1/1 patient), 50% for p.G13C (2/4 patients), 40% for p.G12C (2/5 patients), 22% for p.G12S (24/111 patients), and 10% for p.G12A (1/11 patients).
|HRAS mutation||Number of patients, N (%)a||Selected cardiovascular abnormality, N (% pts with mutation), N (% pts with feature)||Severity||Deaths|
|Current study||Literature||Total||HCM (current pts + literature)||MAT, EAT (current pts)||Aortic root dilation (current pts)||Number of cardiac abnormalities 0–4 (current pts)||Number patients|
|Total||61||85||146||97/146 (66)||15/61 (25)||5/61 (8)||20/146 (14)|
|p.G12S||51/61 (84)||60/85 (71)||111/146 (76)||72/111 (64); 72/97 (74)||13/15 (87); 13/61 (21)||4/5 (80); 4/61 (7)||0: 8 (16); 1: 14 (27); >2: 29 (57)||8/111 (7); 8/20 (40)|
|p.G12A||3/61 (5)||6/85 (7)||9/146 (6)||4/9 (44); 4/97 (4)||1/15 (1); 1/61 (2)||0||1: 2 (67); 3: 1 (33)||2/9 (22); 2/20 (10)|
|p.G12C||2/61 (4)||3/85 (4)||5/146 (3)||4/5 (80); 4/97 (4)||1/15/(1); 1/61 (2)||0||1: 1 (50); 3: 1 (50)|
|p.G12D||0||4/85 (5)||4/146 (3)||4/4 (100); 4/97 (4)||0||NA|
|p.G13C||3/61 (5)||1/85 (1)||4/146 (3)||3/4 (75); 3/97 (3)||0||1/5 (20); 1/61 (2)||1: 1 (50); 2: 1 (50)|
|p.G12V||0||2/85 (2)||2/146 (1)||2/2 (100); 2/97 (2)||0||0||NA||2/2 (100) 2/20 (10)|
|p.G13D||0||3/85 (4)||3/146 (2)||2/3 (67); 2/97 (2)||0||NA|
|p.G12E||0||1/85 (1)||1/146 (1)||1/1 (100); 1/97 (1)||0||0||NA||1/1 (100); 1/20 (5)|
|p.G13A||0||1/85 (1)||1/146 (1)||1/1/ (100); 1/97 (1)||0||NA|
|p.Q22K||0||1/85 (1)||1/146 (1)||1/1 (100); 1/97 (1)||0||0||NA|
|p.T58I||1/61 (2)||0 (1)||1/146 (1)||0||0||0||1: 1 (100)|
|p.E63K||0||1/85 (1)||1/146 (1)||1/1/(100); 1/97 (1)||0||0||NA||1/1 (100); 1/20 (5)|
|p.K117R||0||1/85 (1)||1/146 (1)||1/1 (100); 1/97 (1)||0||0||NA|
|p.A146T||0||1/85 (1)||1/146 (1)||1/1 (100); 1/97 (1)||0||0||NA|
|p.A146V||1/61 (2)||0||1/146 (1)||1/1 (100); 1/97 (1)||0||0||3: 1 (100)|
Comparison With RASopathies
Table IV presents detailed data on the Costello syndrome study patients and previously reported patients and other patients with one of the RASopathies. The analysis of SOS1 illustrates the individualized approach for each syndrome and mutation. Since Roberts et al.  listed each patient allowing complete analysis, and Zenker et al. [2007b] provided a summary table useful for many data points, both references were used in a complementary fashion; a smaller series [Narumi et al., 2008] was omitted as per general methods. A condensed comparison is shown in Table VI based on study patient data only. In general, the frequency of having any cardiovascular abnormality is similar, ranging from 74% to 77% in CFC syndrome (BRAF) and Noonan syndrome (SOS1), to a high of 94% in Noonan syndrome (RAF1). The frequency (2%) of cardiovascular problems in NF1 is much less and based on a clinical survey, not directly comparable. The predominance of pulmonary stenosis is similar in NF1, whereas HCM has been reported anecdotally. NF1 was not analyzed further.
|Type of cardiac problem||RASopathy syndrome|
|Costello syndrome HRAS||CFC syndrome BRAF||Noonan syndrome PTPN11||Noonan syndrome with multiple lentigines PTPN11||Noonan syndrome SOS1||Noonan syndrome RAF1||KRAS||NF1|
|Serious atrial tachycardia||++||−||−||−; (VT)||−||+||−||−|
Congenital heart defects
Among the RASopathies, CHDs appear most common (∼90% of patients with a cardiac problem) in Noonan syndrome caused by a mutation in PTPN11 or SOS1. They occur in the majority of CFC syndrome (BRAF) and Noonan syndrome (RAF1) patients, in all syndromes due to the predominance of pulmonary valve stenosis. The analysis of CFC syndrome (BRAF) was less extensive because individual patient data was not available in each of the CFC reports, thus, the frequency of pulmonary stenosis (31%) was based on one series [Rodriguez-Viciana et al., 2006]. Outcome data about pulmonary stenosis from our Costello syndrome study patients indicates that it is stable or resolving in most (86%), although comparable data are not available for the other syndromes. Subaortic stenosis due to anomalous insertion of the mitral valve, alone or in association with partial atrioventricular canal, has been reported in patients with a clinical diagnosis of Noonan syndrome [Marino et al., 1995] illustrating the aspect of “non-muscular” aortic obstruction in these syndromes. A greater diversity in the scope of CHDs beyond the septal defects, frequent valve anomalies, and rare coarctation in Costello syndrome was observed in association with each of the Noonan syndrome genes. We did not pursue an extended analysis of atrial septal defect because of challenges in case classification.
HCM occurs with similar frequency in Costello syndrome (this study and literature review), Noonan syndrome with multiple lentigines (PTPN11), and Noonan syndrome (RAF1), and is less common in CFC syndrome (BRAF), Noonan syndrome (PTPN11, SOS1), and KRAS. In approximately one-third of Costello syndrome patients each, HCM was chronically severe or worsened or was stable. The resolution or regression of HCM in 14% (five patients) by well-documented echocardiographic follow-up was also reported in one patient with a KRAS mutation [patient 2 in Sovik et al., 2007].
Among Costello syndrome patients with a cardiovascular problem, the frequent occurrence of arrhythmia (65% this study, 45% in literature review) is striking. Only patients with a RAF1 mutation approach this in overall frequency (13% among all patients), or with any atrial tachycardia (31%), one of whom had EAT [Kobayashi et al., 2010]. The finding of an abnormal electrocardiogram with conduction abnormalities in Noonan syndrome with multiple lentigines syndrome is well-described (45% reporting patients) and is not compared to patients with non-reentrant atrial tachycardia.
Aortic dilation has been rarely reported in patients with Noonan syndrome. Coronary artery dilation and peripheral aneurysms have been reported in Noonan syndrome with multiple lentigines [Yagubyan et al., 2004; Limongelli et al., 2007; Iwasaki et al., 2009], with aortic dilation in one clinically diagnosed patient [Goyal and Aragam, 2006].
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This study of Costello syndrome patients with documented HRAS mutations affirms the high frequency of cardiovascular abnormalities and the frequent occurrence of serious tachycardia, provides new information about outcome and pathologic findings, and demonstrates similarities to the other RASopathies.
Congenital Heart Defects
The greater frequency of CHDs in the current study may be due to the bias of underreporting simple CHDs in the literature, or an increase due to prospective echocardiographic surveillance. Costello syndrome is not associated with major complex CHDs in postnatal life, but it is unknown whether they would be present in earlier fetal development. Pulmonary stenosis, usually valvar, is common, and may include muscular subpulmonary obstruction (related to HCM), as well as supravalvar narrowing. Rare patients with severe subpulmonary stenosis described as “double-chambered right ventricle” may have accounted for early reports of “biventricular” cardiomyopathy. Structural mitral valve anomalies, such as mitral valve prolapse, were rare (3, 5%) after excluding cases in which mitral valve thickening in HCM was associated with systolic anterior motion of the mitral valve (SAM) and left ventricular outflow tract obstruction
The frequency of HCM in this study is about twice as common as in the first review (two-thirds vs. one-third of all patients) [Lin et al., 2002] which may reflect more careful documentation, reporting more serious literature cases, or increased cardiac imaging among all patients. There is less detailed information about patient age in Lin et al.  with a general mean age calculated as 4.6 years, not directly comparable to the mean age at diagnosis (4.2) or current age (12) in this study. There has been no report of fetal HCM, which may reflect ascertainment, given the multiple reports of neonatal HCM [Hinek et al., 2005; Digilio et al., 2007; Limongelli et al., 2008; Lo et al., 2008]. We now include mild interventricular septal “thickening” as HCM since previously unclassified cases have now been observed to progress to typical HCM. HCM is chronically severe or deteriorates in over one-third of patients, but in 41% the progression slows. We are intrigued by the apparent decrease in HCM in 5 well-imaged patients followed for a mean of 8 years by pediatric cardiologists familiar with Costello syndrome in whom the severity was moderate in one (#4) and mild in four (patients 9, 22, 23, 51) patients (ages 7–20, mean 11.8 years). Patients 9 and 23 used GH for four and 1 year, respectively, and discontinuation was related to non-cardiac factors. “Resolution” or subtle regression in wall thickness with aging has been interpreted as widespread remodeling in adults with HCM, leading to an understanding that HCM is not a static disease [reviewed in Maron, 2002].
In sarcomeric HCM, myocardial fiber disarray is significantly associated with left ventricular hypertrophy and does not vary from sections of the left ventricle. Disarray is reported on Table III in one clinically diagnosed [Tomita et al., 1998] and 7 mutation-positive patients with Costello syndrome, a single patient with a KRAS mutation, 13 (one genotyped, 12 clinically diagnosed) Noonan syndrome and two clinically diagnosed CFC syndrome patients. Although the histologic and gross phenotype of HCM in Costello syndrome (Fig. 2) is strikingly similar to HCM caused by sarcomeric protein coding mutations [Maron, 2002, Fig. 2], the mechanism of a dysregulated signaling cascade in the former differs from the structural protein in the latter. HCM in the RASopathies demonstrates subaortic obstruction, systolic anterior motion of the mitral valve, decreased left ventricular compliance, and myocardial disarray. The existing mouse model based on an oncogenic p.G12V mutation does not exhibit myocyte disarray [Fig. 10, Schuhmacher et al., 2008], which may mean that the mutant is not a completely comparable animal model [Chen et al., 2009]. The mice have cardiomyocyte hypertrophy and concentric left ventricular hypertrophy in the setting of hypertension. Right ventricular hypertrophy with subpulmonary obstruction is rare in Costello syndrome, and may reflect right-sided HCM. Despite the high frequency (60%) of HCM in Costello syndrome, it is relatively unfamiliar to non-geneticists and non-pediatric cardiologists compared to Noonan syndrome. The presence of severe, often lethal HCM in infants and very young children mandates increased awareness.
MAT in children is usually idiopathic; however, it may occur with lung disease, or postoperatively with a CHD [Dodo et al., 1995; Wang et al., 2000]. Based on our data, Costello syndrome is the most common syndrome association. The cause of MAT in Costello syndrome remains unknown, but appears to represent an independent arrhythmia, unassociated with severe pulmonary stenosis or HCM. The current autopsies did not report atrial fibrosis. There were no reports of microdissection of the conduction system to validate Mori et al.'s  observation of “degeneration of the conduction system” in which abnormalities of the conduction pathways led to the atrioventricular node. The existing mouse model does not exhibit tachycardia [Schuhmacher et al., 2008; Chen et al., 2009]. Atrial tachycardia may be a functional consequence of diastolic dysfunction in adults with HCM where increased filling pressure is associated with increased atrial stretch leading to dysrhythmia [Brembilla-Perrot et al., 1997]. However, the proportion of patients having an arrhythmia (almost all atrial tachycardia) was similar whether or not there was HCM (12/16, 75% without HCM vs. 22/28, 78% with HCM). No patient had well-documented recurrent ventricular tachycardia, but individual patients were followed for ventricular ectopy and “wide QRS tachycardia” (atrial or “ventricular”).
The literature tends to be biased towards the severe forms of Costello syndrome, such as the fetal phenotype [Kuniba et al., 2009; Lin et al., 2009; Smith et al., 2009] and lethal infantile presentation [Hinek et al., 2005; Digilio et al., 2007; Limongelli et al., 2008; Lo et al., 2008], thus, our study patients expand the phenotypic spectrum to the mild end. It is reasonable to assume that diagnosis of Costello syndrome is more likely to be missed in early lethal cases when infants with hypertrophic cardiomyopathy and hypotonia may be diagnosed as having a metabolic or mitochondrial disease. Limited data about the functional status of adolescents and adults was obtained from parents reporting “mild” symptoms in most cases. Several parents suggested their child had a noncardiac reason for being less that fully active, such as anxiety, sedentary lifestyle, or having a musculoskeletal problem. The recent death of a 27-year-old male with moderately severe HCM contrasts with the clinical assessment of him as “mildly symptomatic” and having an active lifestyle. Risk assessment and management for sudden death in pediatric patients with HCM, in general, remains an enormous challenge [Colan et al., 2007; Colan, 2008]. Current data are derived from adult series and derivation of pediatric-specific recommendations is hampered by diverse etiologies, age-specific mortality risks, and greater therapeutic risks.
The frequency of deaths (this study 10%; literature 20%) cannot be used as an epidemiologic measure, merely the first general description of mortality in Costello syndrome. Our study does not allow patients to be enrolled after death, which may be offset by the inclusion of the three prenatally diagnosed patients who later died [Lin et al., 2009]. Despite these weaknesses in ascertainment, we noted that most (10 of 23, 43%) deaths occurred in infants less than 1 year. Four (17%) deaths occurred in children, and two (9%) in young men with HCM (one who also had pulmonary fibrosis).
Growth hormone has been used to treat short stature and prevent osteoporosis in Costello syndrome, but its possible impact on HCM in Costello syndrome has not been fully elucidated. A small study with preliminary data on the safety of growth hormone in Costello syndrome has been presented [Rauen et al., 2008].
Comparison to Other RASopathies
The very young child with Costello syndrome can be misdiagnosed as having Noonan syndrome. Both can present with HCM of variable severity, including severe infantile HCM [Hinek et al., 2005; Limongelli et al., 2007; Lo et al., 2008]. Infants with Costello syndrome are less likely to have severe pulmonary stenosis, or pulmonary stenosis with an atrial septal defect. The lack of complex CHDs currently distinguishes Costello syndrome from Noonan syndrome (PTPN11, RAF1) (and rarely, NF1) in which tetralogy of Fallot or atrioventricular septal defect have been reported occasionally [Lin et al., 2000; Sarkozy et al., 2003; Pandit et al., 2007; Razzaque et al., 2007]. The predominance of valve dysplasia and paucity of cardiac malformation is consistent with the view that these are disorders of dysplasia, rather than malformation. Because NF1 was delineated first and is more common, it can be viewed as the prototype “multiple dysplasia syndrome” [Riccardi, 2010], although Noonan syndrome is probably the model of the heart anomalies.
There are inadequate data in this review to compare HCM in CFC and Costello syndrome. Anecdotal experience (J.N.) suggests that severe subaortic obstruction requiring surgical treatment is more frequent in Costello syndrome than in Noonan or CFC. HCM due to RAF1 mutations [Kobayashi et al., 2010] and in Noonan syndrome with multiple lentigines [Limongelli et al., 2007] is often severe, and longitudinal studies are needed to delineate a comparison to Costello syndrome. The resolution by echocardiographic criteria of HCM in five patients with Costello syndrome is not unique among RASopathies, and requires monitoring across the spectrum of RASopathies in longitudinal studies.
The association of Costello syndrome with non-reentrant atrial tachycardia, including MAT and EAT may help differentiate it from CFC or Noonan syndrome when other phenotypic features are supportive, but should not be viewed as a pathognomonic feature [Lin et al., 2002, 2009; Gripp et al., 2006]. CFC syndrome has been reported with supraventricular tachycardia [Rodriguez-Viciana et al., 2006], unspecified arrhythmia, or atrial tachycardia [Niihori et al., 2006; Narumi et al., 2007]. Because of the similarities, we hypothesize that the non-reentrant tachycardias will be identified in the other RASopathies. Careful evaluations are needed to determine if ventricular arrhythmias occur in Costello syndrome. In Noonan syndrome with multiple lentigines, ventricular arrhythmias, potentially related to HCM (hypertrophy, fibrosis, and probably disarray) are well-documented, and supraventricular arrhythmias are attributed to HCM and dilated left atrium. A comparison between the outcome of Costello syndrome with MAT in young children and Noonan syndrome with multiple lentigines with older patients with conduction defects or ventricular arrhythmia associated with HCM is not meaningful (Table IV), but they represent the RASopathies currently with the most frequent and distinctive “arrhythmia phenotypes.”
Mild aortic dilation in Costello syndrome was not related to bicuspid aortic valve [Keane et al., 2000] and may be a manifestation of an intrinsic vasculopathy. Prospective surveillance in the other RASopathies is needed to determine if aortic dilation, coronary artery dysplasia and hypertension (systemic and pulmonary) constitute a vasculopathy. The mild atherosclerosis noted in the young man with severe HCM (patient 26) is a reminder that all adults need screening for this widespread problem.
Nearly 80% of patients with Costello syndrome have the HRAS p.G12S mutation, with 14 additional mutations in 1–6 patients, each, rendering genotype–phenotype correlation an ongoing challenge. Mutations in HRAS p.G12C and p.G12D may represent a severe phenotype of HCM and infant death [Lo et al., 2008] based on five and four patients, respectively. Discordance between the facial/developmental phenotype and the heart is suggested by the two patients with an attenuated phenotype [Gripp et al., 2008]. A mildly affected boy with a p.T58I (patient 50) mutation had only mitral valve prolapse, whereas a girl with a p.A146V (patient 43) mutation had an unspecified self-limited tachycardia and rapidly progressive HCM which required myectomy at years (myocardial fiber disarray noted on biopsy).
Cardiac hypertrophy, cutaneous overgrowth, and neoplasia in Costello syndrome suggest a gain-of-function mutation, interestingly the same mechanism for PTPN11 mutations in NS [Tartaglia et al., 2001]. The notion that HCM in Costello syndrome is driven by Ras/MAPK activation is supported by the recent description of a transgenic mouse model where targeted expression of an H-Ras-G12V mutant has Costello syndrome features and develops significant cardiac hypertrophy [Zheng et al., 2004]. A zebrafish model of Costello syndrome expressing oncogenic H-RASV12 also had thicker heart walls [Santoriello et al., 2009], but the observed defects in early heart morphogenesis cannot be directly compared to humans with Costello syndrome (most of whom have the p.G12S mutation). The mitogen-activated protein kinase (MAPK) cascades, p38, JNK, and ERK, have profound effects in the development of HCM and remodeling [Harris et al., 2004; Dwyer et al., 2008; Rohini et al., 2010; Streicher et al., 2010]. However, it is important to note that the myocardial phenotypic heterogeneity is striking. Why 40% of individuals with RAS mutations do not develop HCM is unclear. Future studies comparing the patients in whom HCM is absent and present (Fig. 3) may shed light on factors that modulate Ras/MAPK signaling in Costello syndrome.
Study Strengths and Weaknesses
This is the largest prospectively enrolled cohort of patients with Costello syndrome with molecular confirmation of HRAS mutation. The cardiology evaluations were performed at various institutions, including 8 (13%) at 3 pediatric hospitals (4 at Children's Hospital of Boston, two at A.I. duPont Hospital for Children, two at the Hospital for Sick Children, Toronto). Measurements and terminology were not standardized for the study, and the absence of consistent indices for ventricular function, gradient and thickness precludes more than general description of HCM. Parents of the older patients reported their opinion about exercise tolerance and cardiac quality of life, in most cases, discussed with their cardiologist and/or geneticist; none had formal exercise testing. By omitting patients whose cardiac findings were published in aggregate form, we had smaller comparison groups than the actual number of reported patients. The CFC syndrome analysis focused only on BRAF mutations, which had the largest number of patients, and subsequent studies must include MEK1/2. The information about the small number of deaths is novel data, but cannot be viewed as an estimate of mortality prevalence rate, incidence, or lifetime risk. We did not systematically obtain a family history of HCM or arrhythmia in the study survey. In most cases, an astute geneticist or cardiologist would probably have obtained this information in the course of patient care.
Impact of Study on Guidelines for Evaluation and Management
Throughout the lifespan of a Costello syndrome person, decision-making by parents and providers integrates medical, psychosocial, cultural, and financial factors to personalize care. We continue [Lin et al., 2002] to recommend a complete consultation by a skilled cardiologist for all patients with Costello syndrome at the time of diagnosis. Whereas previous recommendations were generalized, the data from this study can guide the timing and frequency, although all care is still individualized by a personal cardiologist following “best practices” for the particular defect. The presence or absence of HCM is a useful feature to understand the clinical and management “flow” (Figs. 3 and 4).
Newborns who had fetal tachycardia will need a postnatal high quality 12-lead surface ECG and consideration of Holter monitoring [Lin et al., 2009]; rhythm strips from intensive care units are usually insufficient for diagnosis. When diagnosis is made in infancy, serial echocardiograms in the first year of life will monitor for the possibility of rapidly progressing HCM. Late onset HCM is often asymptomatic, and when outflow obstruction is absent, no murmur will be heard making clinical status unreliable. Periodic echocardiograms are warranted throughout life. The onset of serious atrial tachycardia is generally before 1 year of age. For older children and adolescents, screening echocardiography should be based on existing findings. Unlike non-syndromic HCM, the guidelines for echocardiographic screening in Costello syndrome are not currently based on well-studied risk stratification [Maron et al., 2003; Colan et al., 2007; Maron, 2008]. In-depth review of pharmacotherapy was beyond the scope of this article, and patients should be treated by cardiologists using “best practices.” Children who are receiving growth hormone, especially in the setting of pre-existing HCM, may require more frequent echocardiography.
The risk of sudden death in Costello syndrome relative to other forms of HCM is unknown. It is appropriate for families to discuss with their cardiologist the possibility of periodic monitoring for predictors of sudden death using exercise testing and Holter monitoring, and when justified by risk stratification, consideration of an ICD in high risk patients (Fig. 4). Exercise stress testing may play a role in assessing HCM risk (e.g., arrhythmia, hypotension).
The caregivers of adults with syndromes associated with cardiac abnormalities need assistance in transitioning care from pediatric to adult cardiologists [Lin et al., 2008a]. Likewise, the families of older individuals often struggle to find appropriate physicians, which underscore a responsibility of clinical geneticist to assist in the transition of their patients through various stages of life [Rauen et al., 2008]. Because of the risk of sudden death associated with HCM, and the potential for new onset disease, we advise that cardiology surveillance be maintained after the second decade, even in the minority of patients who are thought to be free of cardiac disease. Apparently new HCM may reflect recognition, or remodeling of pre-existing HCM [case 2, Costello, 1977, 1996], and caregivers can be reassured that massive severe HCM is unlikely. Attention should be given to valve dysplasia and late onset tachyarrhythmia.
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HRAS mutation confirmation permits more accurate analysis of the cardiac abnormalities, though genotype–phenotype correlations are limited. The Costello syndrome cardiac phenotype overlaps from fetal life to postnatal presentation, and through childhood with other RASopathies. The cardiac features more characteristic of Costello syndrome are serious atrial tachycardia, and mild pulmonary stenosis. With rare exception, resolution of HCM has not been documented in other RASopathies, and may be more common with longitudinal studies. Future studies, especially cardiac specific mouse models, are needed to evaluate the genetic basis, and to provide optimal medical and surgical treatment. In anticipation of possible therapeutic trials, we propose that HCM may play a role as a metric if echocardiography can be performed according to rigorous standards.
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We thank the families and parent leaders of the Costello Syndrome Family Network for their participation and support. In particular, we dedicate this paper to the individuals who are no longer with us, but inspire our work. We acknowledge many colleagues who have cared for individuals, provided suggestions, or assisted us in other ways including Dr. Lisa Bergesen, Dr. Paul Benke, Dr. Theonia Boyd, Dr. John Brownlee, Dr. Laurie Demmer, Dr. Patricia Dickson, Dr. Ira Dubrow, Dr. Lars Erickson, Dr. Anne Fournier, Dr. John Graham, Dr. Raoul Hennekam, Dr. Alek Hinek, Dr. Jodi Hoffman, Dr. John Johnson, Dr. Prapti Kanani, Dr. Hiroshi Kawame, Dr. Mary Kukolich, Dr. Pablo Lapunzina, Dr. Nilima Malaiya, Dr. Yoichi Matsubara, Dr. John Moeschler, Dr. Maria Piccione, Dr. Michael Rebodello, Dr. Edwin Rodriquez-Cruz, Dr. Amarjit Singh, Dr. Alain Verloes, Dr. Joseph Weiss, Dr. Rosanna Weksberg, Dr. Patricia Wheeler and Dr. Elaine Zackai. Dr. Lin is indebted to the librarian support of Meaghan Muir and Nhu Nguyen. As this article was nearing publication, we learned of the death of Dr. Jack Costello. We recall his important contribution to pediatrics and genetics.
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|ajmg_33857_sm_SuppApp.doc||140K||Appendix: Summary of Clinical and Molecular Features of 61 Patients in this Study with Costello Syndrome|
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