Expanding the phenotype of cardiovascular malformations in Adams-Oliver syndrome

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    Expanding the Phenotype of CardiovascularMalformations in AdamsOliver SyndromeClaudia Algaze,1* Edward D. Esplin,2 Alexander Lowenthal,1 Louanne Hudgins,2 Theresa Ann Tacy,1

    and Elif Seda Selamet Tierney1

    1Division of Pediatric Cardiology, Department of Pediatrics Lucile Packard Childrens Hospital, Stanford University, Stanford, California2Division of Medical Genetics, Department of Pediatrics Lucile Packard Childrens Hospital, Stanford University, Stanford, California

    Manuscript Received: 23 September 2012; Manuscript Accepted: 27 December 2012

    We describe a newborn with a phenotype consistent with

    AdamsOliver syndrome and truncus arteriosus. Although car-diovascular malformations associated with this syndrome have

    been previously published in the literature, this is the first

    description of truncus arteriosus in a patient with AdamsOliverndrome. We review other reports of AdamsOliver syndromepreviously described with cardiovascular malformations, con-

    sider possible genetic and embryologic mechanisms, and empha-

    size the need for cardiology consultation when a diagnosis of

    AdamsOliver syndrome is suspected in the differential diag-nosis. 2013 Wiley Periodicals, Inc.

    Key words: AdamsOliver syndrome; congenital heart disease;truncus arteriosus; aplasia cutis congenital; scalp defects; limb



    AdamsOliver syndrome (AOS) was first described in 1945, andcharacterized as a syndrome with aplasia cutis congenita and

    terminal transverse limb defects as component manifestations

    [Adams and Oliver, 1945]. Since this publication, congenital heart

    disease has been reported in approximately 20% of described cases

    [Lin et al., 1998]. These reports emphasize routine evaluation for

    congenital heart disease in patients with a phenotype consistent

    with AOS. Reported cases of cardiovascular malformations have

    included ventricular septal defects, tetralogy of Fallot, and left-sided

    obstructive lesions. This is the first description of a newborn with

    AOS presenting with truncus arteriosus.


    A baby boy was born at 39 weeks gestation to a Caucasian 22-year-

    old G2P0010 female with history of a prior spontaneous abortion.

    There is a complicated social history including history of substance

    abuse (medical tetrahydrocannabinol use in the first trimester),

    depression, and migraines. Urine toxicology was negative at 6 weeks

    gestation. The pregnancy was otherwise uncomplicated. A level-2

    obstetric ultrasound was normal and no prenatal echocardiogram

    was obtained. Breech position prompted a primary cesarean at an

    outside institution. There were no labor or delivery complications.

    Birth weight was 2.9 kg (10th centile), length was 50.5 cm (50th

    centile), and head circumference was 33 cm (10th centile).

    In the first few hours of life the patient was observed to have

    several necrotic-looking streaks along the sagittal suture behind the

    anterior fontanel, somewhat shortened digits of both feet, and a

    murmur. An echocardiogram reportedly demonstrated truncus


    Upon transfer to our institution, physical examination con-

    firmed cranial aplasia cutis congenita along the sagittal suture and

    including the vertex of the scalp. Facial features were normal.

    Hypoplastic nails were noted on the 2nd and 5th digits of the right

    foot and 2nd and 3rd digits of the left foot, with mildly shortened

    2nd digits of both feet. Cutis marmorata telangiectatica congenita

    was present on the trunk. Moderate generalized edema was noted.

    Cardiac examination revealed a mildly hyperdynamic precordium,

    regular rate, and rhythm with normal first and second heart sounds,

    a grade IV/VI systolic murmur heard most prominently at the left

    lower sternal border with radiation to the apex, and full and equal

    brachial and femoral pulses with no brachio-femoral delay. Res-

    piratory examination revealed intermittent comfortable tachypnea

    up to 70 breaths per minute. Oxygen saturations were consistently

    above 95% with no oxygen supplementation.

    *Correspondence to:

    Claudia Algaze, M.D., Pediatric Heart Center, Stanford University, Welch

    Road, Suite 305, Mail Code 5731, Palo Alto, CA 94304-5731.

    E-mail: calgaze@stanford.edu

    Article first published online in Wiley Online Library

    (wileyonlinelibrary.com): 23 April 2013

    DOI 10.1002/ajmg.a.35864

    How to Cite this Article:Algaze C, Esplin ED, Lowenthal A, Hudgins L,

    Tacy, TA, Selamet Tierney ES. 2013.

    Expanding the phenotype of cardiovascular

    malformations in AdamsOliver syndrome.

    Am J Med Genet Part A 161A:13861389.

    2013 Wiley Periodicals, Inc. 1386

  • A transthoracic echocardiogram at our institution confirmed

    type II truncus arteriosus with the left and right pulmonary arteries

    arising directly from the arterial trunk through separate orifices

    [Van Praagh and Van Praagh, 1965]. There was also a secundum

    atrial septal defect and a right aortic arch with mirror image

    branching. A non-contrast computed tomography scan with three-

    dimensional reconstruction revealed a large midline, sagittalparasagittal skull defect in the frontal and parietal regions at the

    vertex, extending more to the right than the left and overlying

    the region over the superior sagittal sinus (Fig. 1). There was no

    evidence of intracranialmasses,mass effect,midline shift, or herniation.

    Chromosome analysis was normal showing 46,XY male karyo-

    type and chromosomal microarray was negative for microdeletions

    or microduplications. Fluorescence in situ hybridization analysis

    for 22q11 deletion syndrome and ARHGAP31 gene sequencing and

    deletion/duplication analyses for AOS type 1 were negative. The

    patient underwent uncomplicated cardiac surgical repair. Perio-

    peratively, extreme care was taken to keep the head as protected as

    possible from sources of pressure, trauma, and contamination.


    AdamsOliver syndrome including types 13, is a rare syndromephenotypically associated with aplasia cutis congenita, terminal

    transverse limb anomalies, cutis marmorata telangiectatica con-

    genita in 20% of patients, and congenital heart disease in 20% of

    patients [Snape et al., 2009]. AOS type1 is an autosomal dominant

    condition with variable expression caused by heterozygous muta-

    tions in the ARHGAP31 gene, a Cdc42/Rac1 GTPase regulator

    [Southgate et al., 2011]. AOS type 2 is an autosomal recessive form,

    which can be caused by loss-of-function homozygous or compound

    heterozygous mutations in the DOCK6 gene, an atypical guanidine

    exchange factor known to activate Cdc42 and Rac1 [Shaheen et al.,

    2011]. AOS type 3 is an autosomal dominant form, which can be

    caused by heterozygous mutations in the RBPJ gene, a primary

    transcriptional regulator for the Notch signaling pathway [Hassed

    et al., 2012]. Sporadic cases have also been reported. Our patient was

    negative for mutations in the ARHGAP31 gene; however defects in

    ARHGAP31 account for only a small proportion of patients with

    AOS [Southgate et al., 2011]. The patient was not assessed for

    DOCK6 or RBPJ mutations as clinical testing for these genes was not


    The classical clinical criteria for diagnosis of AOS include

    aplasia cutis congenita of the scalp combined with transverse

    terminal limb defects, each of which can present within a spectrum

    of severity. Additional minor features observed in AOS include

    cutis marmorata telangectasa congenita, congenital cardiac defects,

    and vascular anomalies. These major and minor features have been

    combined to develop clinical criteria for the diagnosis of AOS, as

    outlined in Table I. The presence of two major features is considered

    sufficient for a diagnosis of AOS. Accordingly our case, having

    evidence of aplasia cutis congenita and hypoplastic nails in the mild

    spectrum of terminal transverse limb defects, meets the clinical

    criteria for AOS.

    Congenital heart disease is observed in approximately 20% of

    patients diagnosed with AOS [Lin et al., 1998]. Reported cases

    include ventricular septal defects, tetralogy of Fallot, and left-sided

    obstructive lesions (Table II). This is the first case described in the

    literature of a patient with clinical features consistent with AOS who

    is diagnosed with truncus arteriosus. Embryological mechanisms

    suggested to cause developmental abnormalities and subsequent

    clinical features of AOS include vascular disruption and altered

    fetal blood hemodynamics [Toriello et al., 1988; Jaeggi et al., 1990;

    Der Kaloustian et al., 1991; Hoyme et al., 1991], as well as alteration

    FIG. 1. Computed tomography of the head without contrast and three-dimensional reconstruction shows a large midline, sagittalparasagittal skulldefect in the frontal and parietal regions at the vertex. There is overlying irregularity of the cutaneous tissues. SD, skull defect.

    ALGAZE ET AL. 1387

  • in neural crest cell migration [Clark, 1990; Minoux and Rifli, 2010].

    Both of these mechanisms are considered to affect the conotruncal

    musculature, which may lead to the development of cardiovascular

    malformations observed in AOS. In particular, aberration in

    cardiac neural crest migration has been associated with the develop-

    ment of truncus arteriosus [Restivo et al., 2006]. This new

    report of truncus arteriosus in association with a phenotype

    consistent with AOS supports previous considerations of AOS as

    a syndrome arising from heterogeneous genetic and embryologic

    mechanisms [Zapata et al., 1995; Lin et al., 1998]. This report

    highlights the need for cardiology consultation when the diagnosis

    of AOS is suspected and expands the spectrum of the congenital

    heart lesions present in AOS to be considered in the differential


    TABLE I. Clinical Features of AdamsOliver Syndrome

    Clinical presentationMajor features

    Aplasia cutis congenita Limited to scalp vertex ! involving scalp, skull, and/or duraTerminal transverse limb defects Hypoplastic nail anomalies! limb hemimeliaFamily history of AOS Wide phenotypic variability

    Minor featuresCutis marmorata telangiectasia congenita Combined livedo reticularis and superficial telangiectasiaCongenital cardiac defect Secundum ASD, TOF, left-sided obstructive lesionsVascular anomaly Arterial hypoplasia, hepatoportal sclerosis, broncho-pulmonary

    hemangioma, arterial aplasiaPresence of two major features is sufficient for a diagnosis of AOS. Combination of one major and one minor feature is consistent with a high likelihood of AOS [Snape et al., 2009].AOS, AdamsOliver syndrome; ASD, atrial septal defect; TOF, tetralogy of Fallot.

    TABLE II. Cardiovascular Malformations Associated With AdamsOliver Syndrome

    Refs. Cardiac malformationFarmer and Maxmen [1960] CHD, unspecifiedSybert [1985] VSDToriello et al. [1988] Right ventricular hypertrophy, pulmonary vein stenosis, PAHKuster et al. [1988] TOFSantos et al. [1989] CoA, VSDSwartz et al. [1999] Double outlet right ventricle, PAHDavid et al. [1991] VSDDer Kaloustian et al. [1991] TOF, ASDChitayat et al. [1992] BAVIshikiriyama et al. [1992] TOF, pulmonary atresiaFrank and Frosch [1993] Secundum ASDLin et al. [1993] TOFAl-Sannaa et al. [2000] Aorto-pulmonary collaterals without cardiac abnormalityVerdyck et al. [2003] BAVBamforth et al. [1994] TOFZapata et al. [1995] PMVZapata et al. [1995] Subaortic membrane, aortic valve stenosisLin et al. [1998] Parachute mitral valve, BAV, Hypoplastic aortic arch, ASD, PDA (Twin A)Lin et al. [1998] BAV, ASD (Twin B)Lin et al. [1998] BAV, mild aortic valve stenosisSankhyan et al. [2006] Tricuspid atresia with intact ventricular septum, secundum ASDHeras Mulero et al. [2007] CoAAnandan et al. [2008] VSD, pulmonary stenosisMitsiakos et al. [2009] Secundum ASDSnape et al. [2009] BAV, mild branch pulmonary artery stenosisSnape et al. [2009] TOF

    ASD, atrial septal defect; BAV, bicuspid aortic valve; CHD, congenital heart disease; PAH, pulmonary arterial hypertension; TOF, tetralogy of Fallot; CoA, coarctation of the aorta;VSD, ventricular septal defect.



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