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.
Claudia Algaze, M.D., Pediatric Heart Center, Stanford University, Welch
Road, Suite 305, Mail Code 5731, Palo Alto, CA 94304-5731.
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 23 April 2013
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  CHD, unspecifiedSybert  VSDToriello et al.  Right ventricular hypertrophy, pulmonary vein stenosis, PAHKuster et al.  TOFSantos et al.  CoA, VSDSwartz et al.  Double outlet right ventricle, PAHDavid et al.  VSDDer Kaloustian et al.  TOF, ASDChitayat et al.  BAVIshikiriyama et al.  TOF, pulmonary atresiaFrank and Frosch  Secundum ASDLin et al.  TOFAl-Sannaa et al.  Aorto-pulmonary collaterals without cardiac abnormalityVerdyck et al.  BAVBamforth et al.  TOFZapata et al.  PMVZapata et al.  Subaortic membrane, aortic valve stenosisLin et al.  Parachute mitral valve, BAV, Hypoplastic aortic arch, ASD, PDA (Twin A)Lin et al.  BAV, ASD (Twin B)Lin et al.  BAV, mild aortic valve stenosisSankhyan et al.  Tricuspid atresia with intact ventricular septum, secundum ASDHeras Mulero et al.  CoAAnandan et al.  VSD, pulmonary stenosisMitsiakos et al.  Secundum ASDSnape et al.  BAV, mild branch pulmonary artery stenosisSnape et al.  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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