CLINICAL REPORT

Expanding the Phenotype of CardiovascularMalformations in Adams–Oliver 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 Children’s Hospital, Stanford University, Stanford, California2Division of Medical Genetics, Department of Pediatrics Lucile Packard Children’s Hospital, Stanford University, Stanford, California

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

We describe a newborn with a phenotype consistent with

Adams–Oliver 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 Adams–Oliver

ndrome. We review other reports of Adams–Oliver syndrome

previously described with cardiovascular malformations, con-

sider possible genetic and embryologic mechanisms, and empha-

size the need for cardiology consultation when a diagnosis of

Adams–Oliver syndrome is suspected in the differential diag-

nosis. � 2013 Wiley Periodicals, Inc.

Key words: Adams–Oliver syndrome; congenital heart disease;

truncus arteriosus; aplasia cutis congenital; scalp defects; limb

defects

INTRODUCTION

Adams–Oliver syndrome (AOS) was first described in 1945, and

characterized 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.

CLINICAL REPORT

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

arteriosus.

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 Adams–Oliver syndrome.

Am J Med Genet Part A 161A:1386–1389.

� 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, sagittal–parasagittal 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.

DISCUSSION

Adams–Oliver syndrome including types 1–3, is a rare syndrome

phenotypically 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

available.

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, sagittal–parasagittal skull

defect 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

diagnosis.

TABLE I. Clinical Features of Adams–Oliver 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, Adams–Oliver syndrome; ASD, atrial septal defect; TOF, tetralogy of Fallot.

TABLE II. Cardiovascular Malformations Associated With Adams–Oliver 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-Sanna’a 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.

1388 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

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