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ARTICLE
Clinical and molecular analysis of nine families
with Adams–Oliver syndrome
Pieter Verdyck
1
, Muriel Holder-Espinasse
2
, Wim Van Hul
1
and Wim Wuyts*
,1
1
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium;
2
Department of Clinical and Molecular
Genetics, Institute of Child Health, London, UK
Adams–Oliver syndrome (AOS) is defined by the combination of limb abnormalities and scalp defects,
often accompanied by skull ossification defects. We studied nine families affected with AOS, eight of which
have not been clinically described before. In our patients, scalp abnormalities were most often found,
followed by limb and skull defects. The most common limb abnormalities appeared to be brachydactyly,
syndactyly of toes 2 and 3 and hypoplastic toenails. Additional features observed were cutis marmorata
telangiectatica congenita, cryptorchidism and cardiac abnormalities. In an attempt to identify the disease-
causing mutations in our families, we selected two genes, ALX4 and MSX2, which were considered serious
candidates based on their known function in skull and limb development. Mutation analysis of both genes,
performed by direct sequencing, identified several polymorphisms, but no disease-causing mutations.
Therefore, we can conclude that the AOS in our set of patients is not caused by mutations in ALX4 or MSX2.
European Journal of Human Genetics (2003) 11, 457–463. doi:10.1038/sj.ejhg.5200980
Keywords: Adams–Oliver syndrome; MSX2; ALX4; mutation analysis
Introduction
Adams–Oliver Syndrome (AOS) is characterized by the
combined occurrence of aplasia cutis congenita (ACC) and
transverse limb abnormalities. The former are scalp lesions
most frequently found on the vertex of the skull that are
variable in depth as well as in size.
1,2
Often, skull defects
underlying the scalp lesions are found. The most fre-
quently observed limb malformations in this disorder
include syndactyly (bony/cutaneous), brachydactyly, poly-
dactyly, oligodactyly and hypoplastic finger/toenails.
3
There is, however, a great variability in severity ranging
from the complete absence of the foot or hand to only mild
manifestations or normal appearance, as seen in obligate
AOS carriers.
2
AOS is mostly inherited as an autosomal
dominant trait but also a suggestive autosomal recessive
mode of inheritance has been described.
4–7
Several genes implicated in skull and limb development
have already been identified and animal models in which
these genes are knocked out or overexpressed have been
generated to gain more insight in their exact function and
regulation. Two genes, ALX4 and MSX2, have previously
been shown to be crucial for proper skull and limb
development. Both are homeobox transcription factors
and inactivating mutations in either gene results in
foramina parietalia permagna (FPP).
8–11
This is a relatively
rare disorder characterized by ossification defects in the
parietal bones resulting in (large) foramina, which can
persist in the calvaria far beyond childhood.
12 – 14
An
activating MSX2 mutation on the other hand is known
to be responsible for the Boston type craniosynostosis.
15
Mouse models have been generated for both transcrip-
tion factors further supporting their important role in skull
and limb development.
16,17
The functional importance
of the ALX4 and MSX2 genes in these processes and
similarities between the AOS phenotype and the KO mouse
models for these genes, make both genes strong candidates
for this disorder. To evaluate the role of these genes in the
pathogenesis of AOS, we performed molecular analysis of
MSX2 and ALX4 in our set of families with AOS.
Received 2 October 2002; revised 24 January 2003; accepted 5 February
2003
*Correspondence: Dr W Wuyts, Department of Medical Genetics,
University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Tel: +32-3-820.26.77; fax: +32-3-820-25-66; wwuyts@uia.ua.ac.be
European Journal of Human Genetics (2003) 11, 457–463
&
2003 Nature Publishing Group All rights reserved 1018-4813/03
$25.00
www.nature.com/ejhg
Patients, materials and methods
Patients
Nine AOS families were included in this study (Figure 1).
Family 1 originates from Canada, while family 9 is a
Northern American family that has previously been
described.
18
The remaining seven families come from the
United Kingdom. Diagnosis of the patients was made after
detailed examination of hands, feet and skull.
Mutation analysis
Mutation analysis of ALX4
10
and MSX2
9
was performed
using primers previously described. For amplifications of
Figure 1 Pedigrees of the nine AOS families. * indicates that no DNA was available for study. Unknown disease status is indicated
by a ‘?’.
Clinical and molecular analysis of AOS
P Verdyck et al
458
European Journal of Human Genetics
ALX4 exons, 35 cycles were executed at an annealing
temperature of 651C, except for exon 2, which was
amplified at 601C. PCR-enhancer system (Invitrogen)
with 1 enhancer solution was used to obtain optimal
amplification. The coding region and intron exon bound-
aries of MSX2 were amplified using an annealing tempera-
ture of 521C during 35 cycles in 1 GC-melt solution
(Clontech). All PCR products were purified with Concert
rapid PCR purification system (Life Technologies) and
sequenced using Big-Dye terminator chemistry (Perkin-
Elmer) on an ABI 3100 automated sequencer.
In addition, linkage to the ALX4 locus on chromosome
11p11 was analyzed with ALX4 flanking markers D11S554
and D11S903 as described previously.
19
MSX2 linkage was
tested by analysis of the intragenic MSX2GT repeat
reported previously.
15
The PCR-amplification mixture
contained dNTPs (4 10 mM). A volume of 0.5 pmol of
the two locus-specific primers and an IRD800-labeled M13-
reverse primer (5
0
-GGATAACAATTTCACACAGG-3
0
), 1
PCR buffer and Taq DNA polymerase. After a denaturation
step of 5 min at 961C, 35 cycles of 1
0
at 961C, 45
00
at 571C
and 45
00
at 721C a final elongation step at 721C for 10 min
was performed. Amplification products were analyzed on a
LI-COR IRD800 detection system.
Results
Clinical analysis
Patients and relatives from nine families (Figure 1) with
AOS were clinically investigated for the presence of scalp,
skull and limb abnormalities. Results of this clinical
analysis are summarized in Table 1.
Family 1 In this family, which originates from Canada,
two boys (II-1 and II-2) with similar defects were born out
of healthy parents. The boys both show major scalp and
cranial defects (Figure 2a), brachydactyly and syndactyly of
second and third toes. Patient II-2 also had tapering
phalanges. Both parents showed no defects of scalp, skull
or limbs.
Family 2 Clinical analysis of patient II-6 of this family
revealed a combination of scalp, hand and foot defects. He
Table 1 Summary of clinical data of the affected members of the families
Family ID Scalp
defect
Skull
defect
Brach
(hand)
Abnormal
fingernails
Syn
(toes)
Brach
(toes)
Abnormal
toenails
Other findings
Family 1 II-1 X X X X
II-2 X X X X X
Family 2 I-2 X Bicuspid aortic valve
II-5 X X
II-6 X X X X X X
Family 3 I-2 X Cutis marmorata
II-1 X X X X Cutis marmorata
Family 4 III-1 X X X X Cryptorchidism and small penis
III-2 X Severe developmental delay
Family 5 I-1 ? ? X X
II-1 X ? ? ? ? ? ?
II-2 ? ? X
III-1 X ? X
Family 6 I-1 X X X X Symphalangism of toes 2/3/4,
clinodactyly of fifth fingers
II-2 X X X
III-4 X X X X X Epilepsy
Family 7 II-3 X Hallux valgus
III-1 X X
III-2 X X X X
Family 8 II-1 X X X X
Family 9 II-2 ? ? ? ? ? ? ?
III-2 X Cardiovascular malformations
a
IV-1 X X X X
IV-2 X Cardiovascular malformations
a
Question marks indicate that no data was available. X indicates presence of the clinical symptom. Brach:brachydactyly; Syn:syndactyly.
a
Lin et al.
18
Clinical and molecular analysis of AOS
P Verdyck et al
459
European Journal of Human Genetics
had a large scalp defect over the crown and short left
fingers with small phalanges. His nails on the third and
fourth fingers of the right hand were hypoplastic. The
terminal phalanges of both feet were hypoplastic as well
with missing toenails on toes 2,3,4 and 5 of the left foot
and of toes 2 and 3 of the right. On the left foot, also
syndactyly of toes 2/3 was observed (Figure 2b). His brother
(II:5) also showed extensive ACC over the crown. In this
patient, no hand or foot defects were observed, except for a
hypoplastic second toenail on the right foot. Their mother
showed 2/3 syndactyly on both feet and a bicuspid aortic
valve. Two other children of this woman from another
marriage (II-1 and II-2) did not show any clinical features of
AOS. The father of the affected children was not examined.
Family 3 In this English family, mother and daughter are
affected. The mother shows a scalp defect and cutis
marmorata teleangiectatica congenita. The daughter is
more severely affected and also shows syndactyly and
brachydactyly with absent nails on left toes 2,3 and 4. The
father was not affected.
Family 4 Two affected children, brother and sister, have
been identified in this family. The girl (III-2) had a large
scalp defect with extensive vascular damage and short toes
without toenails. Apart from the typical symptoms of AOS,
also severe developmental delay was observed. Her younger
brother showed a persistent open anterior fontanel, a
subdural hematoma and a bald streak over the sagittal
suture. He also suffered from cryptorchidism and a small
penis. The father and maternal grandfather showed no
grand abnormalities. The patients mother had short toes.
Family 5 In this English family, three generations are
affected, with male to male transmission of the disorder.
The youngest member (III-1) suffers from ACC and has
small toes. Her father (II-2) was diagnosed to have short 3,4
and 5 toes with short phalanges. His brother (II:1) also had
a bald patch, similar to the ACC of his niece. The
grandfather (I-1) shows syndactyly of second and third
toes and short third and fourth toes.
Family 6 Family 6 comprises three patients in three
generations. The proband (III:4) is severely affected with a
large scalp defect, an underlying skull ossification defect
(Figure 2c) and amputated toes. He had a short left index
finger with a small nail. He also suffered from epilepsy. His
mother had a milder phenotype, with a scalp defect and
short fingers/toes with normal nails. The probands’
maternal grandfather was also affected, with a scalp defect
and a mild depression in the mid-line in the region of the
fused coronal suture. He suffered from clinodactyly of the
hands as well, and from bony syndactyly of the middle and
distal phalanges of toes 3, 4 and 5. Furthermore, he had
small middle phalanges of the second toes and small distal
phalanges of the first (big) toes. The father, aunts and
maternal grandmother were also examined but this
revealed no abnormalities.
Family 7 Three patients, an affected mother (II:3) and
her two affected (III:1, III:2) children, have been identified
in this family. The boy was born with an open patch on his
Figure 2 Characteristic features of Adams – Oliver syndrome
present in our set of AOS patients. (a) Patient II2 (family 1)
showing severe skull and scalp defects. (b) foot abnormalities
including syndactyly, shortening of the digits and missing
toenails in patient II6 (family 2) (c) scalp and underlying skull
defect in patient III4 (family 6).
Clinical and molecular analysis of AOS
P Verdyck et al
460
European Journal of Human Genetics
scalp, which healed two days later, with a large bald area
remaining. He also has foot abnormalities with absent
distal phalanges of the fifth toes and very small distal
phalanges of the other toes with minute epiphyses. His
younger sister showed a major scalp defect and hypoplastic
phalanges of both hands and feet. The mother was more
mildly affected, with an area of furrowing over the crown
and bilateral hallux valgus.
Family 8 The only known patient of this family was born
with a large scalp defect. Under this, a large bony defect
was observed. She had shortened first toes (bilaterally) and
no nails on toes 1 and 5. Clinical examination of her
parents revealed no abnormalities.
Family 9 This family has been reported before as family 1
in Lin et al.
18
DNA from four patients was studied. Typical
scalp defects were observed in three of them, two twin boys
and their mother. Hypoplasia of the fingertips and all nails
was observed in one of the twin boys. In addition, all these
patients and the maternal grandmother showed cardiovas-
cular malformations. DNA from three apparently unaf-
fected sibs of the mother was also available.
Molecular analysis of ALX4
To analyze the ALX4 gene, we sequenced all four exons
including the intron –exon boundaries. Four sequence
variations were found (Table 2). A 63C4T change in
exon 1 was detected in patient III-2 of family 4.
This substitution at the third position in the tyrosine
codon causes no amino-acid change (TAC-TAT) at
the protein level and was not detected in 100 control
chromosomes. The second sequence variance, a 104C4G
transversion, was found in several individuals of families
1,2,3,4,5 and 9. At the amino-acid level this results in
the substitution of an arginine (AGG) for a threonine
(ACG). This substitution was also frequently found in
a control population of 100 chromosomes with 47%
possessing the C-allele and 53% having the G-allele.
A third polymorphism in exon 1, 304C4T, was identified
in families 1,2,3,4,5 and 9. It causes a change from serine
into proline at amino-acid position 102. Analysis of
100 control chromosomes revealed an allele frequency
of 37% for the G allele and 63% for the C allele. The
fourth polymorphism, 1074C4T (His358His) is located in
exon 4. This silent mutation was detected in families 1,3,7
and 9, but it is also frequent in the control population
with 71% possessing the C-allele, and 29% possessing the
T-allele.
Analysis of ALX4 flanking markers D11S903 and
D11S554in all families (excluding families 3 and 8, which
were too small), further revealed that no recombination
between these two flanking markers and AOS could be
observed in families 1, 2, 6 and 9. However, in the latter
family, the unaffected individual III-4 inherited the same
D11S903/D11S554 alleles from his affected mother as his
affected sister. A recombination was observed with at least
one of these two markers in the remaining families.
Molecular analysis of MSX2
To analyze the MSX2 gene, both exons were sequenced
using intronic primers. One polymorphism, 386 C4T
located in the beginning of exon 2, was found hetero-
zygously in members of families 5 (II-1) and 6 (III-4) and
causes an amino-acid substitution of threonine for methio-
nine. Allele frequencies were determined at 0.10 for the T-
allele and 0.90 for the C-allele in the control population
(Table 2). No further molecular abnormalities were
detected.
Analysis of the intragenic MSX2 CA repeat revealed
recombination with AOS in families 4 and 5. In family 9,
healthy individual III-4 again inherited the same MSX2CA
allele from his affected mother as his affected sister. The
remaining families were not informative for this marker.
Discussion
We describe here nine AOS families with 27 affected
individuals, 24 of whose detailed clinical data were
available (Table 1). Consistent with previous reports,
3,20,21
we also observed a great intrafamilial clinical variability
that is characteristic for AOS. A total of 20 patients were
diagnosed having scalp defects and eight also had under-
lying skull defects. Limb abnormalities were also very
frequent with seven of the patients having hand abnorm-
alities and seventeen having abnormalities of one or both
feet. In the limb abnormalities brachydactyly, syndactyly
of toes 2 and 3 and hypoplastic toe/fingernails were most
common. In all families at least one patient is found with
both scalp defect and limb abnormalities, the main
characteristic features of AOS.
Apart from skull, scalp and limb defects, several addi-
tional features were observed in some of our AOS patients.
In family 3, cutis marmorata telangiectatica congenita was
found in both patients. This symptom has frequently been
Table 2 Polymorphisms found in the ALX4 and MSX2
genes
Exon Frequency in controls (%)
ALX4
63C-T (Y21Y) 1 100/0
104C-G (T35R) 1 53/47
304 T-C (S102P) 1 63/37
1074C-T (H158 H) 4 71/29
MSX2
386C-T (T129 M) 2 90/10
Clinical and molecular analysis of AOS
P Verdyck et al
461
European Journal of Human Genetics
found in AO patients and suggests a mechanism of early
embryonic vascular disruption as one of the underlying
causes of this syndrome.
20,22 – 29
Various intracranial abnormalities have been described
in AOS patients. They include encephalocele,
2
microce-
phaly,
21
hypoplasia of the left arteria cerebri media and
right spastic hemiplegia 27 and dysplasia of the cerebral
cortex.
30
As a consequence, secondary symptoms, such as
epilepsy are frequently found in AOS patients. One severely
affected patient in our study (III-4, family 6) was also
reported to be epileptic, but unfortunately no CT scans
were available to gain information about possible causative
structural brain abnormalities in this patient.
In a previous study which included family 9, Lin et al
18
estimated the occurrence of cardiovascular malformation
in AOS patients to be about 20%. In our remaining eight
families, one case of biscupid valve (patient I2, family 2)
was noted. However, this may be an underpresentation as
not all patients had extensively been screened for cardio-
vascular abnormalities.
In the literature both autosomal dominant and recessive
modes of inheritance have been described for AOS.
4–7
Six of the families described here show clear autosomal
dominant segregation with male-to-male transmission
in family 5, excluding an X-linked pattern of inheritance.
The remaining families (1,4 and 8) are too small to
be conclusive on this subject but we could not find
any suggestion for a recessive form of AOS. Indeed, none
of the families were consanguineous and in family 1
an autosomal dominant mode of inheritance was
suspected with an anamnestic positive history of unde-
fined ‘skin-defects’ in a maternal relative. Therefore, the
segregation pattern in these small families can perfectly be
explained by reduced penetrance or ‘de novo’ mutations
that have arisen.
With the genetic cause underlying AOS being unknown,
we selected several candidate genes implicated in cranio-
facial and limb development in order to identify the
AOS gene. Two of these candidate genes, encoding the
transcription factors ALX4 and MSX2, were analyzed in
the 9 AOS families. Haploinsufficiency of ALX4 is already
known to be related to FPP, a disorder characterized by
round-to-oval skull ossification defects on the vertex of
the skull. Alx4 is expressed in cells of the craniofacial and
limb bud mesenchyme. In the limb bud it is expressed
only anteriorly, where it suppresses the formation of a zone
of polarizing activity (ZPA) and so confines it to
the posterior part of the limb bud. In this way it helps to
define the anterior – posterior axis. In Alx4 knockout mice,
an ectopic anterior ZPA is formed with preaxial polydactyly
as a result. Apart from limb abnormalities, the knockout
mice show also a decreased size of the parietal skull
bones.
16
These similarities between Alx4 knockout and
AOS phenotype prompted us to analyze this gene in our
AOS families.
We used direct sequencing to investigate the ALX4 gene
in the nine families. In this way, four sequence variations
were found. Variations 104C4G, 304 C4T and 1074 C4T
are commonly found in the control population and thus
can be regarded as polymorphisms. Variation 63 C4T was
not found in 100 control chromosomes, but does not result
in an amino-acid substitution and does not segregate with
the disease in the family 4 since it only was found in one of
two affected siblings. In addition to the mutation analysis,
we analyzed ALX4 flanking markers to see whether we
could further exclude the ALX4 gene. Although most of the
families were too small to obtain fully conclusive results,
recombination with at least one of the analyzed markers
was observed in families 4, 5 and 7. As these markers are
located approximately 1 cM on each side of the ALX4 gene
this further suggests that ALX4 does not cause AOS in these
families. In the largest family (family 9) all patients from
which DNA was available and one of the not affected
individuals showed a common haplotype for D11S903/
D11S554. However, due to the reduced penetrance of AOS
linkage to ALX4 can not be excluded. It would be
interesting however, to genotype the remaining patients
from which no DNA was available to us, to obtain a
definite conclusion for this family.
MSX2 is another strong candidate since it is expressed in
many sites of epithelial and mesenchymal interactions,
including the calvaria and the limb bud, the tissues
affected in AOS patients. In the limb bud, Msx2 is
specifically expressed in parts of the mesenchym and in
the apical ectodermal ridge, one of the three signaling
centers of the hand and thought to regulate the proximo-
distal axis. In Msx2-knock-mice animals, limb abnormal-
ities include reduced appendicular skeletal lengths, with
femur and tibia lengths 83 and 88% that of wild-type
animals. The calvaria of Msx2 knockout mice show many
abnormalities of which a large mid-line foramen and small
abnormally shaped interparietal, and supraoccipital bones
are the most striking.
17
In humans, gain of function
mutations in MSX2 cause Boston-type craniosynostosis,
15
in which the cranial sutures fuse prematurely (and in
which sometimes hand abnormalities are seen). Loss of
function can lead to FPP, considered as an opposite effect.
Interestingly, a possible association between MSX2 muta-
tions and ACC (a feature of AOS) has already been
described in two patients with both ACC and FPP where
a MSX2- mutation has been identified.
9,31
To examine this
gene, we performed sequence analysis in the collected
families. However, no mutation was found, only one
polymorphism. Linkage analysis did not provide any
further suggestion for linkage to the MSX2 locus with even
exclusion of MSX2 in at least two families and again
a recombination event in an unaffected individual in
family 9. Therefore, we conclude that there are no
indications for MSX2 involvement in the pathogenesis of
autosomal dominant AOS.
Clinical and molecular analysis of AOS
P Verdyck et al
462
European Journal of Human Genetics
In general, we did not find any indications for involve-
ment of ALX4 or MSX2 in the pathogenesis of autosomal
dominant AOS. Further studies have to be performed to
identify the responsible gene(s) in AOS.
Acknowledgements
This study was supported by a NOI BOF UA grant to WW. We are
grateful to Dr W Reardon and Dr R Winter for collecting DNA and
providing clinical information of the AOS families.
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