ADAMS-OLIVER SYNDROME 1; AOS1

Alternative titles; symbols

AOS
ABSENCE DEFECT OF LIMBS, SCALP, AND SKULL
CONGENITAL SCALP DEFECTS WITH DISTAL LIMB REDUCTION ANOMALIES
APLASIA CUTIS CONGENITA WITH TERMINAL TRANSVERSE LIMB DEFECTS

Other entities represented in this entry:

APLASIA CUTIS CONGENITA, CONGENITAL HEART DEFECT, AND FRONTONASAL
CYSTS, INCLUDED

Phenotype-Gene Relationships
Gene/Locu
Phenotype Phenotype
s
Location Phenotype MIM Inheritance mapping Gene/Locus
MIM
number key
number
3q13.32- Adams-Oliver
100300 ARHGAP31 610911
q13.33 syndrome 1

TEXT
A number sign (#) is used with this entry because of evidence that Adams-Oliver syndrome-1
(AOS1) is caused by heterozygous mutation in the ARHGAP31 gene (610911) on chromosome
3q13.

Description
Adams-Oliver syndrome (AOS) is a rare developmental disorder defined by the combination of
aplasia cutis congenita of the scalp vertex and terminal transverse limb defects (e.g., amputations,
syndactyly, brachydactyly, or oligodactyly). In addition, vascular anomalies such as cutis
marmorata telangiectatica congenita, pulmonary hypertension, portal hypertension, and retinal
hypervascularization are recurrently seen. Congenital heart defects have been estimated to be
present in 20% of AOS patients; reported malformations include ventricular septal defects,
anomalies of the great arteries and their valves, and tetralogy of Fallot (summary by Stittrich et al.,
2014).
Genetic Heterogeneity of Adams-Oliver Syndrome
Other autosomal dominant forms of Adams-Oliver syndrome include AOS3 (614814), caused by
mutation in the RBPJ gene (147183) on chromosome 4p15; AOS5 (616028), caused by mutation in
the NOTCH1 gene (190198) on chromosome 9q34; and AOS6 (616589), caused by mutation in the
DLL4 gene (173410) on chromosome 5q32.
Autosomal recessive forms of Adams-Oliver syndrome include AOS2 (614219), caused by mutation
in the DOCK6 gene (614194) on chromosome 19p13.2, and AOS4 (615297), caused by mutation in
the EOGT gene (614789) on chromosome 3p14.

Clinical Features
Adams and Oliver (1945) reported a boy with absence of the lower extremities below the midcalf
region, absence of all digits and some of the metacarpals of the right hand, a denuded ulcerated area
on the vertex of the scalp present at birth, and a bony defect of the skull underlying the scalp defect.
The skin and skull lesions were similar to those of aplasia cutis congenita (ACC; 107600). The
proband had 4 unaffected brothers and a sister and brother with identical defects of limbs, scalp, and
skull. The father was born with absence of toes 2-5 on the left foot, short terminal phalanges of all
fingers, and a scalp defect. The father was 1 of 10 children, 3 of whom had defects of the
extremities. The father's father was said to have had short fingers. Whitley and Gorlin (1991)
provided a follow-up on the family studied by Adams and Oliver (1945); the disorder had been
transmitted to a member of a fourth generation. In the intervening 45 years, the original proband
had survived to adulthood and was employed, using orthotic devices for lower limb defects. He
reported good quality of life and no other medical problems.
Scribanu and Temtamy (1975) described a family with aplasia cutis congenita with terminal
transverse defects of the limbs. The proband was a 3-year-old boy with striking cutis marmorata
telangiectatica congenita (CMTC; 219250). There was variable expressivity and reduced
penetrance.
Toriello et al. (1988) described cutis marmorata telangiectatica congenita in a child with the Adams-
Oliver syndrome. He also had pulmonary hypertension in association with pulmonary vein stenosis
and died at age 4 months of cardiopulmonary arrest. The mother had CMTC without other features.
Kuster et al. (1988) described 10 individuals with AOS, 7 of them in 2 families and 3 sporadic. The
most common features included absence of middle and distal phalanges, brachydactyly, malformed
toes, syndactyly of the toes, nail dysplasia, hairless scalp patches, and osseous skull defects. One
child had tetralogy of Fallot. The authors identified 11 affected families and 19 sporadic cases that
had been reported and found great variability of limb anomalies, ranging from brachydactyly to
absent lower limbs. The family data suggested autosomal dominant inheritance.
Santos et al. (1989) reported a girl with scalp ACC and no distal limb anomalies, who also had
aortic coarctation and ventricular septal defect; her mother had ACC and upper and lower limb
reductions, and her maternal grandmother had typical ACC. The authors suggested that congenital
heart disease could be a component manifestation of AOS.
Jaeggi et al. (1990) reported an affected mother and child as well as a third sporadic case. Among
the 31 reported patients with the full syndrome, major hemorrhage from the scalp defect occurred in
10, with 2 fatalities. Local infection was noted in 7 babies, with 1 case of fatal meningitis. Only
30% of the patients had surgical treatment of their scalp defects by skin grafting.
Whitley and Gorlin (1991) found reports of 81 cases in 32 families with approximately equal
distribution between males and females. The limb defects were usually asymmetric and ranged from
hypoplastic nails to absence of a hand or foot. Vertical transmission in at least 8 families was
consistent with autosomal dominant inheritance. Despite large defects of the cranium, the authors
stated that central nervous system abnormalities had not been found in this disorder and intellectual
development appeared to be normal.
David et al. (1991) reported congenital heart disease in association with the features of Adams-
Oliver syndrome. This brought to 6 the number of cases of such an association. Ishikiriyama et al.
(1992) added to the description of the association and suggested that ventricular septal defect,
including tetralogy of Fallot, may be the predominant type of congenital heart defect in the Adams-
Oliver syndrome.
Fryns et al. (1992) reported a 6-month-old, developmentally retarded male with a congenital scalp
defect associated with a ventricular septal defect and valvular pulmonary stenosis. Hands and feet
were relatively small with short distal phalanges and small nails of the fifth fingers. Brain CT scan
showed marked cerebellar hypoplasia and vermis agenesis. They noted that Paltzik and Aiello
(1985) had reported scalp defect in association with ventricular septal defect and pulmonary
stenosis.
On the basis of a sporadic case in a 10-year-old male, Chitayat et al. (1992) suggested that acrania is
a severe form of aplasia cutis congenita and is within the spectrum of Adams-Oliver syndrome. In
acrania, the flat bones of the cranial vault are absent, whereas the bones at the base of the skull are
normal.
Farrell et al. (1993) described a sporadic case of AOS in a male infant. In addition to typical
manifestations, he had atrial septal defect, chylothorax, and chronic juvenile myelogenous leukemia
which was diagnosed at 9 months. Review of the literature (102 cases) showed that 78% of patients
had defects of lower limbs and 59% had defects of upper limbs. To avoid ascertainment bias, Farrell
et al. (1993) excluded propositi for calculations of scalp and skull defects. After this exclusion, 56%
of patients had scalp defects and 21% had skull defects.
Bamforth et al. (1994) reported AOS in a mother and her 3 children with variable scalp defects and
limb defects. Other anomalies included congenital heart disease, microcephaly, epilepsy, mental
retardation, arhinencephaly, hydrocephaly, anatomic bronchial anomalies, and renal anomalies. The
3 children were by 2 different fathers.
Zapata et al. (1995) reported 2 patients with Adams-Oliver syndrome and congenital cardiac
malformations. A literature review demonstrated that 13.4% of individuals with this syndrome have
congenital heart anomalies.
Pousti and Bartlett (1997) described cutis aplasia congenita in twin boys born to a mother with a
history of cutis aplasia. One of the infants had associated distal limb anomalies and the other had
cardiac anomalies.
Lin et al. (1998) reported a mother with scalp ACC but normal digits, who had heart sounds
consistent with a bicuspid aortic valve. She had twin boys with AOS and heart anomalies: the
cardiac findings were consistent with Shone complex in 1 twin and consisted of bicuspid aortic
valve and patent ductus arteriosus in the other. Lin et al. (1998) reported a second family in which
the proband was a 3.5-year-old girl with AOS and bicuspid aortic valve, whose father had AOS
consisting of ACC and small distal fingertips and fingernails; her sister and paternal grandfather
reportedly also had mild AOS features with ACC and digital hypoplasia. Lin et al. (1998) reviewed
published cases of AOS and stated that approximately 20% have associated cardiovascular
malformations, frequently involving obstructive lesions on the left side of the heart.
Swartz et al. (1999) reported a 4-year-old girl with AOS who also had double-outlet right ventricle,
pulmonary hypertension, and portal hypertension resulting from hepatoportal sclerosis.
Keymolen et al. (1999) reported a girl with congenital scalp and acral reduction limb defects,
consistent with the diagnosis of Adams-Oliver syndrome, who also showed constriction rings,
making the limb anomalies similar to those seen in the amniotic band disruption sequence (217100).
The report was further evidence that the Adams-Oliver syndrome may be a vascular disruption
sequence.
Savarirayan et al. (1999) described a boy with AOS whose sister was also mildly affected. Their
mother had hypoplastic fifth toenails, thought to represent very mild expression of the syndrome.
Computed tomography of the brain to investigate mild left hemiparesis in the boy demonstrated
severe cortical dysplasia of central, occipital, and anterior regions of the right cerebral hemisphere.
The boy and his sister had apparent constriction rings present on the toes.
Pereira-da-Silva et al. (2000) described 2 patients with AOS, one of whom had necrotic lesions of
the fingertips, generalized cutis marmorata telangiectatica, and localized ulceration of the
abdominal skin, indicative of a vascular abnormality.
Patel et al. (2004) described 2 children with AOS and additional features, including intrauterine
growth retardation, CMTC, pulmonary hypertension, intracranial densities (shown in 1 patient to be
sites of active bleeding), and osteopenia. Patel et al. (2004) concluded that the 2 patients they
described, in addition to those reported by Toriello et al. (1988) and Swartz et al. (1999), established
that a subset of AOS patients is at high risk for pulmonary hypertension.
Maniscalco et al. (2005) reported a father and son with AOS and pulmonary arteriovenous
malformations (PAVMs). Manifestations of AOS in this 3-generation family included scalp defect,
digital hypoplasia and/or syndactyly, and cutis marmorata telangiectasia. The authors suggested that
the occurrence of PAVM in AOS supported the hypothesis that endothelial-specific abnormalities
could be the pathophysiologic mechanism for the development of AOS.
Rodrigues (2007) reported a family in which 4 individuals spanning 4 generations had aplasia cutis
congenita and congenital heart lesions. In addition, affected individuals had craniofacial
abnormalities associated with frontonasal cysts. The proband presented at age 9 days with a midline
frontal cyst between the eyebrows. She also had small C-shaped ears, prominent nasal bridge, and a
V-shaped gingival notch. Other features included brachydactyly and ventricular septal defect. The
proband's mother and grandmother had similar features and a maternal grandfather was reportedly
affected. None of the affected members had neurologic or mental impairment.
Snape et al. (2009) described 3 cases of AOS and provided a detailed review of the available
literature, with tabulation of the clinical features of all reported AOS dominant and recessive
families as well as sporadic patients.
Papadopoulou et al. (2008) reported a 14-month-old boy with aplasia cutis congenita, distal limb
transverse defects, growth retardation, and a wide atrial septal defect. Central nervous system
abnormalities included central hypotonia, small corpus callosum, and developmental delay. MRI
showed periventricular leukomalacia and enlarged ventricles. Fetal MRI at 26 weeks' gestation had
shown bilateral dilatation of lateral ventricles and periventricular cysts at the site of the postnatal
lesions, as well as a hypoplastic corpus callosum. The patient's father and paternal grandfather also
had aplasia cutis congenita without mental defect or other anomalies. The antenatal and postnatal
MRI findings suggested to the authors that this patient's periventricular leukomalacia may represent
an unusual congenital feature of AOS, possibly due to vascular disruption and decreased perfusion
during critical periods of fetal brain development.
Citing previous studies that have shown the possible association between ACC of the scalp and
various congenital heart defects, including patent ductus arteriosus (Deeken and Caplan, 1970) and
ventricular septal defect (Dubosson and Schneider, 1978), and noting that such congenital heart
defects occur in approximately 20% of AOS patients (Lin et al., 1998), Digilio et al. (2008)
proposed that variability in clinical expression of AOS might include the association of congenital
heart defect and ACC without limb defects. Digilio et al. (2008) pointed to families in which some
members exhibit classic AOS and other members have only ACC and congenital heart defect
(Santos et al., 1989; Lin et al., 1998) to substantiate their hypothesis.
Reviews
Sybert (1985) and Frieden (1986) provided reviews.

Population Genetics
Stittrich et al. (2014) stated that the incidence of AOS is approximately 1 in 225,000 individuals.
 Inheritance
Bonafede and Beighton (1979) reported a family in which 9 members spanning 4 generations had
congenital scalp defects associated with abnormalities of the hands and feet. Circumscribed defects
of the skull were an inconsistent finding. Inheritance was clearly autosomal dominant, with one
instance of male-to-male transmission.
Sybert (1989) concluded that ACC in association with limb defects is most often inherited in an
autosomal dominant pattern.

Pathogenesis
Toriello et al. (1988) suggested that the vascular changes in the skin may indicate that features of
Adams-Oliver syndrome result from vascular disruption sequences. Jaeggi et al. (1990) also noted
that cutis marmorata and dilated scalp veins in AOS suggested a probable vascular disruptive
pathogenesis.
Der Kaloustian et al. (1991) described 2 families having members affected with the Poland
anomalad (173800) and AOS. They hypothesized that the Poland anomalad and AOS result from
the interruption of early embryonic blood supply in the subclavian arteries, and that the gene
predisposing to this interruption follows an autosomal dominant pattern of inheritance. Hoyme et al.
(1992) reported that 2 additional individuals in family 2 of Der Kaloustian et al. (1991) had the
Poland sequence with no findings of Adams-Oliver syndrome.
Swartz et al. (1999) suggested that AOS should be considered not merely a syndrome consisting of
aplasia cutis congenita and terminal transverse limb defects, but rather a constellation of clinical
findings resulting from an early embryonic vascular abnormality.
Postmortem examination of an AOS patient with pulmonary hypertension reported by Patel et al.
(2004) showed defective vascular smooth muscle cell/pericyte coverage of the vasculature
associated with 2 blood vessel abnormalities. Pericyte absence correlated with vessel dilatation
whereas hyperproliferation of pericytes correlated with vessel stenosis. These findings suggested a
unifying pathogenic mechanism for the abnormalities seen in AOS.
Verdyck et al. (2006) reported a Belgian family in which 10 individuals over 4 generations had
Adams-Oliver syndrome, 6 of whom were available for study. Clinical symptoms were variable, as
reported in other families, and included large areas of alopecia on the vertex of the skull and serious
limb reduction defects with agenesis of all toes of 1 foot.

Mapping
Southgate et al. (2011) performed a genomewide screen in 22 members of 2 multigenerational
families segregating autosomal dominant Adams-Oliver syndrome, originally reported by Bonafede
and Beighton (1979) and Verdyck et al. (2006), respectively, and identified a locus for the disease
on chromosome 3q13.31-q13.33. Fine mapping defined a 5.53-Mb critical interval flanked by
markers rs714697 and D3S4523. A maximum multipoint lod score of 4.93 was obtained at marker
rs1464311.

Molecular Genetics
In 2 families with congenital scalp defects and distal limb reduction anomalies mapping to
chromosome 3q13, originally reported by Bonafede and Beighton (1979) and Verdyck et al. (2006),
respectively, Southgate et al. (2011) sequenced 4 candidate genes and identified heterozygosity for
2 different truncating mutations in the ARHGAP31 gene (610911.0001 and 610911.0002,
respectively) that segregated with disease in each family. Sequencing of ARHGAP31 in 3 additional
multiplex AOS kindreds as well as 43 sporadic patients with features of aplasia cutis congenita
and/or terminal transverse limb defects revealed no mutations.