RESEARCH ARTICLE

Perinatal Features of the RASopathies: Noonan Syndrome, Cardiofaciocutaneous Syndrome and Costello Syndrome Angela Myers,1 Jonathan A. Bernstein,1 Marie-Luise Brennan,1 Cynthia Curry,3,4 Edward D. Esplin,1 Jamie Fisher,3 Margaret Homeyer,2 Melanie A. Manning,1 Eric A. Muller,1 Anna-Kaisa Niemi,1 Laurie H. Seaver,5,6 Susan R. Hintz,7 and Louanne Hudgins1* 1

Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, California

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Center for Fetal and Maternal Health, Lucile Packard Children’s Hospital, Stanford, California

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Genetic Medicine Central California, Fresno, California Department of Pediatrics, University of California, San Francisco, California

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Kapiolani Medical Specialties, Honolulu, Hawaii

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Department of Pediatrics, University of Hawaii John A. Burns School of Medicine, Honolulu, Hawaii Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University, Stanford, California

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Manuscript Received: 5 December 2013; Manuscript Accepted: 24 July 2014

The RASopathies are a family of developmental disorders caused by heritable defects of the RAS/MAPK signaling pathway. While the postnatal presentation of this group of disorders is well known, the prenatal and neonatal findings are less widely recognized. We report on the perinatal presentation of 10 patients with Noonan syndrome (NS), nine with Cardiofaciocutaneous syndrome (CFCS) and three with Costello syndrome (CS), in conjunction with the results of a comprehensive literature review. The majority of perinatal findings in NS, CS, and CFCS are shared: polyhydramnios; prematurity; lymphatic dysplasia; macrosomia; relative macrocephaly; respiratory distress; hypotonia, as well as cardiac and renal anomalies. In contrast, fetal arrhythmia and neonatal hypoglycemia are relatively specific to CS. NS, CS, and CFCS should all be considered as a possible diagnosis in pregnancies with a normal karyotype and ultrasound findings of a RASopathy. Recognition of the common perinatal findings of these disorders should facilitate both their prenatal and neonatal diagnosis. Ó 2014 Wiley Periodicals, Inc.

Key words: Noonan syndrome; Costello syndrome; Cardiofaciocutaneous syndrome; prenatal diagnosis; RASopathy

How to Cite this Article: Myers A, Bernstein JA, Brennan ML, Curry C, Esplin ED, Fisher J, Homeyer M, Manning MA, Muller EA, Niemi AK, Seaver LH, Hintz SR, Hudgins L. 2014. Perinatal features of the RASopathies: Noonan syndrome, Cardiofaciocutaneous syndrome and Costello syndrome. Am J Med Genet Part A. 9999:1–8.

drome. As a group, the RASopathies have an estimated collective prevalence of between 1 in 700 and 1 in 1250 live births [Wright and Kerr, 2010]. This report focuses on NS, CS, and CFCS; the postnatal presentations of which are well delineated. They are commonly considered in the differential diagnosis of patients with congenital heart defects, developmental delay and hair and skin abnormalities. Although less widely recognized than the manifestations in infancy, toddlerhood, and beyond, significant work has been done in delineating the perinatal features of NS, CS, and CFCS.

INTRODUCTION The RASopathies are a family of disorders resulting from dysregulation of the RAS/MAPK signaling pathway. They include Noonan syndrome (NS), Costello syndrome (CS), and Cardiofaciocutaneous syndrome (CFCS), as well as Noonan syndrome with loose anagen hair, Noonan syndrome with multiple lentigines (formerly known as LEOPARD syndrome), neurofibromatosis type 1, Legius syndrome, and neurofibromatosis-Noonan syn-

Ó 2014 Wiley Periodicals, Inc.

A. Myers and J.A. Bernstein contributed equally to this work. Conflict of interest: none  Correspondence to: Louanne Hudgins, 300 Pasteur Dr., H-315, Stanford, CA 94305 E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2014 DOI 10.1002/ajmg.a.36737

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2 The prenatal manifestations of NS were initially noted more than 20 years ago. Benacerraf et al. [1989] and Nisbet et al. [1999] reported polyhydramnios, cystic hygroma, and hydrops. The more recent literature confirms that the prenatal history in NS features fetal abnormalities that include a spectrum of lymphatic anomalies: increased nuchal translucency (NT), cystic hygroma, pleural effusions, hydrops, in combination with polyhydramnios and cardiac defects [Hiippala et al., 2001; Schluter et al., 2005; Houweling et al., 2010]. In CS, recurrent prenatal findings of polyhydramnios; cardiac structural anomalies and arrhythmia; and advanced growth parameters including relative macrocephaly have been documented [Van den Bosch et al., 2002; Hennekam, 2003; Lin et al., 2009; Smith et al., 2009]. The reported prenatal phenotype in CFCS includes polyhydramnios, prematurity, evidence of lymphatic abnormalities and congenital heart defects [Reynolds et al., 1986; Armour and Allanson, 2008]. Overlap between the prenatal findings of NS and CS has been noted [Levaillant et al., 2006]. Recognition of the shared prenatal manifestations of NS, CS, and CFCS should facilitate the pre- and postnatal diagnosis of these conditions. During the first months of life these disorders can be challenging to recognize as characteristic findings on physical exam may not fully manifest until after the newborn period. We found that consideration of the prenatal history can increase clinical suspicion of a RASopathy in cases where the postnatal findings in isolation are less suggestive. The purpose of this case series and literature review is to fully describe the perinatal features of the various RAS/MAPK syndromes (NS, CS, and CFCS) in order to facilitate early clinical diagnosis, enhanced patient management and family counseling.

MATERIAL AND METHODS We reviewed the records of 39 patients with NS, CS, or CFCS who were evaluated at the authors’ institutions between 2006 and 2011. We identified a cohort of 22 patients including 13 (59%) males and 9 (41%) females. Ten were diagnosed with NS, three with CS, and nine with CFCS; 17 patients were excluded from the study as perinatal data were not available. All subjects, with one exception, had a clinical and molecular genetic diagnosis. This individual’s gestation was notable for the presence of a cystic hygroma; it was otherwise uncomplicated. At birth, he had pedal edema, and as of our last clinical encounter in 2011, a cardiac anomaly had not been observed. His family history is notable for paternal short stature, webbed neck, history of pulmonic stenosis, and lymphedema. His parents also had a pregnancy loss due to fetal hydrops. DNA sequencing has been negative for mutations in PTPN11, SOS1 and KRAS. The family declined further genetic testing. In the remaining nine NS cases for which a mutation was identified there were six in PTPN11, two in SHOC2, and one in RAF1. The three CS cases had mutations in HRAS. Two were predicted to result in p.Gly12Ser and one p.Gly12Asp. Of the nine cases with CFCS six had mutations in BRAF, two in MAP2K1, and one in KRAS. We reviewed the medical literature on the perinatal presentations of individuals with a clinical diagnosis of NS, CS, and CFCS.

AMERICAN JOURNAL OF MEDICAL GENETICS PART A The primary search was performed in the PubMed database and limited to articles in the English language literature published between 1985 and 2012. Keywords used were “Noonan syndrome,” “Costello syndrome,” and “Cardiofaciocutaneous syndrome” as well as “polyhydramnios”, “lymphatic anomalies,” “heart defects,” “prenatal diagnosis,” “ultrasound,” “hydrops,” “amniocentesis,” “chorionic villus sampling,” “perinatal,” and “neonatal.” A secondary search was performed by identifying pertinent articles cited in articles identified in the primary search. We attempted to identify all cases for which prenatal data were available. For many cases neonatal data were also available. Information on prenatal manifestations was assembled for 257 cases including: 94 cases with NS [Witt et al., 1987; Benacerraf et al., 1989; Izquierdo et al., 1990; Donnenfeld et al., 1991; Sonesson et al., 1992; Nisbet et al., 1999; Achiron et al., 2000; Bradley et al., 2001; Menashe et al., 2002; Witters et al., 2002; Eccles et al., 2003; Gandhi et al., 2004; Ragavan and Vause, 2005; Schluter et al., 2005; Becker et al., 2007; Kiyota et al., 2008; Gonza´lez-Huerta et al., 2010; Houweling et al., 2010; Bakker et al., 2011; Baldassarre et al., 2011], 94 cases with CS [Der Kaloustian et al., 1991; Martin and Jones, 1991; Zampino et al., 1993; Johnson et al., 1998; Kerr et al., 1998; van Eeghen et al., 1999; Sigaudy et al., 2000; Gripp et al., 2002; Kaji et al., 2002; Van den Bosch et al., 2002; Estep et al., 2006; Gripp et al., 2006; Levaillant et al., 2006; Lo et al., 2008; Kuniba et al., 2009; Lin et al., 2009; Smith et al., 2009], and 69 cases with CFCS [Reynolds et al., 1986; Chrzanowska et al., 1989; Borochowitz et al., 1992; Somer et al., 1992; Lopez-Rangel et al., 1993; McDaniel and Fujimoto, 1997; Gripp et al., 2007; Armour and Allanson, 2008; Witters et al., 2008].Of these cases neonatal findings were available for 205 cases including: 94 cases of NS, 45 of CS, and 66 of CFCS. Not all subjects had information available about each clinical finding. In reporting the frequency of clinical features in this report, the denominator used refers to the number of subjects for which information on a specific feature was available in either the prenatal or neonatal period. In this report the phrase perinatal data is used to refer to information that would potentially be available to clinicians at or around the time of delivery, including both prenatal and neonatal findings. Approval for this study was obtained from the Stanford Institutional Review Board.

RESULTS In the authors’ experience, consideration of the prenatal findings has been helpful in establishing a diagnosis in cases of NS, CS, and CFCS in the neonatal period. This led to the assembly of the cohort presented in this study. Initial analyses suggested the presence of a shared perinatal phenotype among the disorders. We present results from the systematic evaluation of findings in our cohort along with those from a comprehensive literature review. Data are presented within the text as well as in the tables. Tables I–III show the frequency of clinical features for NS, CS, and CFCS respectively in the present cohort, the historical literature based cohort and the aggregate of these two cohorts. Table IV presents a summary of the data for all three disorders. Data for the historical literature-based cohort are sourced from the references indicated above under Materials and Methods.

MYERS ET AL.

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TABLE I. Findings in Noonan Syndrome: Current and Literature Cohorts Number of patients Congenital heart defect Arrhythmia Fetal abdominal circumference >90th centile Small or absent stomach Long bones 90th centile Polyhydramnios Renal anomaly

Birth weight >90th centile Birth OFC >90th centile Congenital heart defect Arrhythmia Feeding difficulty Hypoglycemia Hypotonia Laryngomalacia Respiratory distress Lymphatic dysplasia Preterm delivery ( 25 cm or gestational-age-specific AFI > 97.5th centile was common in NS, CS, and CFCS. Polyhydramnios was reported 158/277 (57%) of cases overall; 39/102 (38%) in NS, 71/97 (73%) in CS, and 48/78 (62%) in CFCS. In our cohort polyhydramnios was initially noted on ultrasound between 19 and 27 weeks gestation. The appearance of a small or absent fetal stomach, potentially associated with decreased swallowing, was observed in 6/11 (54%) of cases; 1/5 (20%) in NS and 5/6 (83%) in CS. Small fetal stomach

was not identified in patients with CFCS in our cohort, nor in the literature. Postnatal feeding problems were seen in 71/87 (82%) of cases overall; 7/10 (70%) in NS, 36/48 (75%) in CS, and 28/29 (97%) in CFCS. Preterm delivery prior to 37 weeks gestation was observed in 65/ 144 (45%) in the aggregate data: 17/32 (53%) in NS, 19/48 (40%) in CS, and 29/64 (45%) in CFCS.

Increased Head Circumference, Macrosomia, and Fetal Long Bone Measurements Evidence of macrosomia during the second trimester as defined by abdominal circumference above the 90th centile was seen in 8/56 (14%) of gestations in the aggregate data; NS 1/4 (25%), CS 3/3 (100%), CFCS 4/49 (8%). Head circumference greater than the 90th centile, was seen in 4/20 (20%) of gestations; NS 1/4 (25%), CS 2/7 (29%), CFCS 1/9 (11%). In our cohort increased fetal growth parameters were initially noted between 20 and 29 weeks gestation. In contrast to findings of increased body size and head circumference, short femora were seen prenatally in 8/55 (14%) of cases overall; 4/9 (44%) in NS, 2/6 (33%) in CS, and 2/40 (5%) in CFCS.

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AMERICAN JOURNAL OF MEDICAL GENETICS PART A

TABLE II. Findings in Costello Syndrome: Current and Literature Cohorts

Congenital Heart Defect Arrhythmia Fetal abdominal circumference >90th centile Small or absent stomach Long bones 90th centile Polyhydramnios Renal anomaly

Current 3 PRENATAL FINDINGS 1/3 (33%)a 0/3 (0%) 2/3 (67%) 2/3 (67%) 1/3 (33%) 2/3 (67%)b 2/3 (67%) 2/3 (67%) 2/3 (67%)c

1/1 6/14 3/3 3/3 1/3 9/13 2/7 69/94 3/3

(100%) (43%) (100%) (100%) (33%) (69%) (29%) (75%) (100%)

2/4 6/17 5/6 5/6 2/6 11/16 4/10 71/97 5/6

(50%) (35%) (83%) (83%) (33%) (69%) (40%) (73%) (83%)

Birth weight >90th centile Birth OFC >90th centile Congenital Heart Defect Arrhythmia Feeding difficulty Hypoglycemia Hypotonia Laryngomalacia Respiratory distress Lymphatic dysplasia Preterm Delivery (90th centile Small or absent stomach Long bones 90th centile Polyhydramnios Renal anomaly

Current 9 PRENATAL FINDINGS 1/9 (11%)a 0/9 (0%) 2/9 (22%) n.d. n.d. 2/9 (22%)b 1/9 (11%) 8/9 (89%) 5/9 (55%)c

n.d. n.d. 2/40 (5%) n.d. 2/40 (5%) 5/42 (12%) n.d 40/69 (58%) 2/40 (5%)

1/9 (11%) 0/9 (0%) 4/49 (8%) n.d. 2/40 (5%) 7/51 (14%) 1/9 (11%) 48/78 (62%) 7/49 (14%)

Birth weight>90th centile Birth OFC >90th centile Congenital Heart Defect Arrhythmia Feeding difficulty Hypoglycemia Hypotonia Laryngomalacia Respiratory distress Lymphatic dysplasia Preterm Delivery (

Perinatal features of the RASopathies: Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome.

The RASopathies are a family of developmental disorders caused by heritable defects of the RAS/MAPK signaling pathway. While the postnatal presentatio...
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