Prevalence data on all Ghent features in a cross-sectional study of 87 adults with proven Marfan syndrome

Abstract

The prevalence of each single feature in the Ghent criteria in patients with Marfan syndrome (MFS) is not known. To elucidate this, a cross-sectional study of 105 adults with presumed MFS was carried out. All patients were examined by the same group of investigators with standardized and complete assessment of all features in the Ghent criteria. Eighty-seven (83%) fulfilled the criteria in 56 different variants. The most prevalent major criterion in Ghent-positive persons was dural ectasia (91%), followed by major genetic criterion (89%) and ectopic lenses (62 %). In 14 persons (16%), the diagnosis was dependent on the dural findings. In all, 79% fulfilled both major dural and major genetic (positive family history and/or FBN1 mutation) criteria, suggesting that most patients with MFS might be identified by investigating these criteria. A history or finding of ascending aortic disease was present in 46 patients (53%). This low prevalence might partly reflect a high number of diagnosed patients encompassing the whole spectrum of the syndrome. The study confirms the need to examine for the complete set of features in the Ghent criteria to identify all patients with MFS. The majority of persons with MFS might be identified by the combined assessment of dura mater and family history, supplemented with DNA analysis in family-negative cases. The low prevalence of ascending aortic disease might indicate better future prospects in an adult population than those traditionally considered.

Full text

ARTICLE
Prevalence data on all Ghent features in a
cross-sectional study of 87 adults with proven Marfan
syndrome
Svend Rand-Hendriksen*
1,7
, Rigmor Lundby
2,7
, Lena Tjeldhorn
3
, Kai Andersen
4
,
Jon Offstad
5
, Svein Ove Semb
6
, Hans-Jrgen Smith
2,7
, Benedicte Paus
3
and Odd Geiran
4,7
1
TRS National Resource Centre for Rare Disorders, Sunnaas Rehabilitation Hospital, Nesoddtangen, Norway;
2
Department of Radiology, Rikshospitalet University Hospital, Oslo, Norway;
3
Department of Medical Genetics, Ulleval
University Hospital, Oslo, Norway;
4
Department of Thoracic and Cardiovascular Surgery, Rikshospitalet University
Hospital, Oslo, Norway;
5
Department of Cardiology, Rikshospitalet University Hospital, Oslo, Norway;
6
Department of
Ophthalmology, Center for Eye Research, Ullevaal University Hospital, University of Oslo, Oslo, Norway;
7
Faculty
Division Rikshospitalet, University of Oslo, Oslo, Norway
The prevalence of each single feature in the Ghent criteria in patients with Marfan syndrome (MFS) is not
known. To elucidate this, a cross-sectional study of 105 adults with presumed MFS was carried out. All
patients were examined by the same group of investigators with standardized and complete assessment of
all features in the Ghent criteria. Eighty-seven (83%) fulfilled the criteria in 56 different variants.The most
prevalent major criterion in Ghent-positive persons was dural ectasia (91%), followed by major genetic
criterion (89%) and ectopic lenses (62 %). In 14 persons (16%), the diagnosis was dependent on the dural
findings. In all, 79% fulfilled both major dural and major genetic (positive family history and/or FBN1
mutation) criteria, suggesting that most patients with MFS might be identified by investigating these
criteria. A history or finding of ascending aortic disease was present in 46 patients (53%). This low
prevalence might partly reflect a high number of diagnosed patients encompassing the whole spectrum of
the syndrome. The study confirms the need to examine for the complete set of features in the Ghent
criteria to identify all patients with MFS. The majority of persons with MFS might be identified by the
combined assessment of dura mater and family history, supplemented with DNA analysis in family-
negative cases. The low prevalence of ascending aortic disease might indicate better future prospects in an
adult population than those traditionally considered.
European Journal of Human Genetics (2009) 17, 1222–1230; doi:10.1038/ejhg.2009.30; published online 18 March 2009
Keywords: dural ectasia; FBN1; lens dislocation; Marfan syndrome; protrusio acetabuli
Introduction
Marfan syndrome (MFS) is an autosomal dominant genetic
connective tissue disorder diagnosed by the Ghent criteria.
1
To obtain proper counselling and care of individuals with
MFS, a precise diagnosis is mandatory, prolonging life
expectancy and reducing disability.
2
The prevalence of MFS
is disputed. Two MFS prevalence studies reports 6.81/
100.000
3
and 4.6/100.000 inhabitants, respectively,
4
whereas
the usually cited prevalence is 1-2/10.000 inhabitants.
5
The Ghent criteria describe a number of variably
well-defined symptoms and signs. They are categorized as
‘major criteria’, ‘manifestations’ (in the skeletal system)
and ‘minor criteria’, which alone or combined indicate the
Received 6 May 2008; revised 16 December 2008; accepted 6 February
2009; published online 18 March 2009
*Correspondence: Dr S Rand-Hendriksen, TRS, National Resource Centre
for Rare Disorders, Sunnaas Rehabilitation Hospital, Bjornemyrveien,
Nesoddtangen N. 1450, Norway.
Tel: þ476 696 9000; Fax: þ476 691 2576;
E-mail: svend.rand-hendriksen@sunnaas.no
European Journal of Human Genetics (2009) 17, 1222 – 1230
&
2009 Macmillan Publishers Limited All rights reserved 1018-4813/09
$32.00
www.nature.com/ejhg

‘involvement of an organ system’ or the ‘fulfilment of a
major criterion’. Fulfilment of at least two major criteria in
two different organ systems and the involvement of a third
organ system are required to give the diagnosis.
Although FBN1 is the only gene included in the Ghent
nosology,
1
FBN1 mutations are also found in individuals
not fulfilling the Ghent criteria,
6,7
and mutations in
TGFBR1 and TGFBR2 have recently been reported
in individuals fulfilling the Ghent criteria.
8,9
The resources needed and the logistic challenge in the
examination of all organ systems may explain why clinical
papers do not commonly present complete data for all
variables. Furthermore, some may consider it appropriate
to stop the investigations when data sufficient for a
diagnosis of MFS have been acquired. This is illustrated
by the fact that less than 30% of the individuals were
investigated for dural ectasia and protrusio acetabuli in
recent collective reviews on the basis of the FBN1 mutation
database, presenting genotype– phenotype correla-
tions.
10,11
Moreover, various prevalences of ‘major criteria’
and ‘organ involvement’ are presented. The various results
might in part be owing to the features being age
dependent,
12
as most studies present results for children
or mixed age groups whereas reports for adults are rare.
13,14
The need for sensitivity and specificity of the ‘major
criteria’ and ‘organ involvement’ has been pointed out.
1,15
However, neither prevalences nor sensitivity and specifi-
city are known.
Thus, the purpose of this study was to explore the
phenotype, the prevalence of each ‘major criterion’ and
‘organ involvement’ through a prospective and complete
investigation of all features of the Ghent criteria in an adult
cohort with a proven diagnosis of MFS.
Patients and methods
This study was approved by the regional ethics committee.
In 2002, Norway had 4.5 million inhabitants, the majority
being Caucasians. By October 2002, 179 individuals had
reported themselves to the National Resource Centre for
MFS (TRS) as having MFS; 134 of them were 18 years of age
or older and all were citizens of Norway.
The participants in the Norwegian Marfan Syndrome
Study were recruited either by an invitation letter sent to
the 134 individuals above 18 years of age in the TRS
database, who had registered as having MFS, where by 80
persons signed in for participation, or by an advertisement
in the journal of the Norwegian Association for MFS
asking for persons who have been diagnosed with MFS,
or through invitations distributed in the Department of
Thoracic and Cardiovascular Surgery, Rikshospitalet
University Hospital to patients suspected for MFS, thereby
recruiting an additional 19 persons, although the number
of persons informed about the study is unknown. A total
of 109 individuals thus gave their informed consent to
participate, but one died before the study started, one
was not able to attend while living abroad and
two participants withdrew, one before and one during the
study.
Consequently, the study population consisted of 105
individuals, 67 women (64%) of median age 42 years
(range 20– 69 years) and 38 men (36%) of median age 33
years (range 19– 62 years).
Ninety of the 105 had earlier been given a diagnosis of
MFS; 15 persons entered the study because of suspicion of
MFS. All participants were Caucasian.
The 105 individuals represented 66 families. Forty-five
individuals were the only representatives of their family,
whereas 60 individuals were from 21 families.
To obtain valid results, the same group of investigators,
using the same methods for all patients, carried out all
examinations. All participants were assessed for all Ghent
criteria.
1
The methods of assessment of clinical and
radiological examinations and cutoff limits are presented
in Table 1.
16 – 18
Details of the mutation analysis have been
published.
19,20
As recommended by the authors of the Ghent criteria,
the serum concentration of homocysteine was measured in
all 105 individuals to exclude homocystinuria.
1
When all data were present, the status for each
individual was assessed with regard to each organ system
(major criteria fulfilled and organ systems involved).
Adding up, the number of major criteria fulfilled and
organ systems involved was registered, and the individual
was classified as fulfilling the Ghent criteria or not.
Statistics
All data were stored in a customized database (SPSS for
Windows version 13). Descriptive statistics are reported as
medians (ranges). Owing to the low number of individuals,
results are reported as fractions and percentages.
Results
Of the 105 individuals, 87 persons from 57 families fulfilled
the Ghent criteria (83%), whereas 18 individuals (17%)
from 9 families did not. Of those individuals fulfilling the
Ghent criteria, 77 had earlier been diagnosed with MFS,
whereas MFS was suspected in 10 individuals. The
summary and interpretation of all examinations and the
prevalences of fulfilled major criteria and involved organ
systems are presented in Table 2 and Figure 1.
The prevalence of the major criteria in the other four
organ systems did not show significant differences in
accordance to gender.
The 87 persons fulfilled the Ghent criteria through
56 different combinations of major criteria and
organ involvement; the highest number of individuals
having the same combination of criteria was 5. Ten persons
Ghent evaluation of 105 Norwegian adults
S Rand-Hendriksen et al
1223
European Journal of Human Genetics

Table 1 Diagnostic criteria for Marfan syndrome (MFS) according to the Ghent nosology
Confirmation of the diagnosis requires the presence of at least two major criteria in two different organ systems and involvement of a third organ
system. Family history/genetic is counted as an organ system
System
Method Major criteria Criterion for involvement
Skeletal Requires four of the eight manifestations listed
below
Requires two of the eight manifestations in the left
column or one manifestation plus two minor criteria
Clinical investigation;
CT scan of thoracic cage;
scout view of spine,
CT scan of acetabuli
Manifestations: Minor criteria
Pectus carinatum Pectus excavatum of moderate severity
Pectus excavatum requiring surgery Joint hypermobility (Beighton score X4)
Reduced upper to lower segment ratio
o0.85
a
or Arm span to height ratio greater
than 1.05
Highly arched palate with crowding of teeth
Facial appearance (dolicocephaly
b
, malar
hypoplasia, enophthalmos, retrognathia, down-
slanting palpebral fissures)Wrist and thumb signs
Scoliosis of 4201or spondylolisthesis
Reduced extension at the elbows (o1701)
Medial displacement of the medial malleolus
causing pes planus
Protrusio acetabuli
c
of any degree
Ocular Ectopia lentis
d
Requires two of the following three minor criteria
Slit lamp investigation,
keratometry and ultrasound
Minor criteria
Abnormally flat cornea (o41.5 dioptres)
Increased axial length of the ocular globe
(423.5 mm)
Hypoplastic iris or ciliary body
Cardiovascular Dilatation of the ascending aorta with or
without aortic regurgitation and involving at
least the sinuses of Valsalva
e
Requires the presence of at least one major criterion or
one minor criterion
Echocardiography, MRI of
thoracic aorta. If MRI was not
possible, CT of thoracic aorta
Dissection of the ascending aorta Minor criteria
Mitral valve prolapse with or without mitral valve
regurgitation
Dilatation of the main pulmonary artery in the
absence of valvular or peripheral pulmonic
stenosis or any other obvious cause below the
age of 40 years
f
Calcification of the mitral annulus before the age
of 40 years
Dilatation or dissection of the descending
thoracic or abdominal aorta below the age of 50
years
Pulmonary None Requires at least one minor criterion
History, CT scan of thoracic cage Minor criteria
Spontaneous pneumothorax
Apical blebs
g
Skin and integument None Requires at least one minor criterion
History, inspection Minor criteria
Striae athrophicae (stretch marks) not associated
with marked weight changes, pregnancy or
repetitive stress
h
Recurrent or incisional herniae
Dura mater Major criterion: None
MRI of lumbosacral spine.If MRI
was not possible: CT of
lumbosacral spine
Lumbosacral dural ectasia
i
Ghent evaluation of 105 Norwegian adults
S Rand-Hendriksen et al
1224
European Journal of Human Genetics

fulfilled all five possible major criteria, three of them also
having lungs and skin and integument involved.
Of the 87 fulfilling the diagnostic criteria, 76 fulfilled the
Ghent criteria on the basis of the individual examinations
alone, without considering family history or mutation
analyses.
Another nine individuals did fulfil one major organ
criterion and had a first-degree relative independently
fulfilling the Ghent criteria (positive family history) as
the second major criterion and a third organ system
involved.
Two individuals, both being the first in their family to be
diagnosed with MFS, fulfilled one major organ criterion,
had an FBN1 mutation as their second major criterion and
had a third organ system involved. These two persons were
the only ones to be dependent on mutation analysis to be
diagnosed with MFS.
Of the 87 persons fulfilling the Ghent criteria, 14 were
dependent on the dural criterion for the diagnosis.
Of the 87 individuals fulfilling the diagnostic criteria, an
FBN1 mutation was found in 73 individuals, representing
44 families.
19,20
No FBN1 mutations were found in
individuals not fulfilling the Ghent criteria.
Of the 18 individuals not fulfilling the diagnostic
criteria, 13 had been diagnosed with MFS earlier, including
a person with a highly elevated serum concentration of
homocysteine (320mmol/l), one person in whom a muta-
tion in the Collagen 3 gene (COL3A1) was found and five
persons from one family in whom a TGFBR2 mutation was
found.
The prevalence of the features in the Ghent criteria
among the 87 individuals fulfilling the diagnostic criteria
in our study is presented in Table 3 for comparison with
prevalences from other studies reporting the prevalence of
two or more major criteria.
11,21 – 29
The prevalence of having at least two major criteria
fulfilled in our study is presented in Figure 2.
Discussion
This study confirms the need for the complete Ghent
criteria to identify all patients with MFS, although the
majority of them might be identified by combined
assessment of dura and family history, supplemented with
DNA analysis in family-negative cases.
Table 1 (Continued)
Confirmation of the diagnosis requires the presence of at least two major criteria in two different organ systems and involvement of a third organ
system. Family history/genetic is counted as an organ system
System
Method Major criteria Criterion for involvement
Family history/genetic Having a parent, child or sib who meets
these diagnostic criteria independently
j
None
Sequencing of coding sequences
of FBN1
Presence of a mutation in FBN1 known to
cause the Marfan syndrome
k
Presence of a FBN1 haplotype around FBN1,
inherited by descent, known to be associated
with unequivocally diagnosed Marfan
syndrome in the family
Our methods of investigation are indicated in italics in the first column. Where no limit for normality is given in the Ghent criteria, our chosen values
are presented, where possible with references.
Our chosen limits are as follows:
a
(see reference Roman et al).
18
b
Cephal index o0.76 (Hall et al., 1995).
16
c
On the CT monitor, an ellipse is adapted aligning the inner border of the pelvis over the acetabulum. We defined protrusio acetabuli to be present
when the bottom of the acetabulum protrudes into the ellipse.
d
Ectopia lentis was noted when (1) the lenses had been removed due to luxation, (2) luxation; the centre of the lens is displaced from the centre of the
pupil, (3) subluxation; horizontal tilt of the lens, usually the caudal part of the lens tilted posteriorly leaving space between the lens and the iris.
e
Plotting body surface area (BSA) versus echocardiographic aortic diameter in sinus valsalva into age relevant normograms (from Roman et al
17
), the
result lies higher than the normal upper border or graft due to dilated/dissected ascending aorta.
f
Plotting BSA versus MRI or CT measured diameter of pulmonary artery into age relevant aorta normograms (from Roman et al
17
), the result lies higher
than the normal upper border.
g
Blebs in the lungs on CT.
h
Striae from puberty/before pregnancy.
i
Visualization by CT or MRI of anterior meningocele (ie: dura covered spinal fluid inside the pelvic cavity); dural sac diameter S1 or distally larger than
dural sac diameter L4; one or more herniations of dura along lumbosacral nerve roots; dural sac ratio L5 40.48 or dural sac ratio S1 40.57 (from
Oosterhof et al
34
).
j
On the basis of the probands knowledge about their relatives: Lens (sub)luxation and/or operation, dilatation/dissection or operation of ascending
aorta and documented FBN1 mutations.
k
A mutation in FBN1 resulting in amino acid shift and not reported to represent a genetic polymorphism, or a large duplication/deletion in FBN1.
Ghent evaluation of 105 Norwegian adults
S Rand-Hendriksen et al
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European Journal of Human Genetics

Using the full version of the Ghent criteria on 105
individuals refuted the MFS diagnosis in 13 of 90 patients
who had been diagnosed earlier, and verified the diagnosis
in 10 of 15 persons with suspected MFS. The 56 different
ways of fulfilling the Ghent criteria in this cohort illustrate
the need for the complete set of criteria and the problems
with differential diagnosis versus other genetic connective
tissue disorders. Our cohort represents persons with given
or suspected diagnosis of MFS; the primary clinical result of
our investigations is the separation of individuals fulfilling
the Ghent criteria from individuals suspected for MFS, not
fulfilling the Ghent criteria.
The Ghent criteria require at least two major criteria to
be fulfilled. The major criteria in five organ systems have
equal value and validity in the diagnostic process. Even so,
the concept of severity of Marfan phenotypes has been
presented.
30 – 32
‘Severe Marfan syndrome’ often seems
to be understood as ‘severe cardiovascular pathology’,
irrespective of age, not as a person fulfilling many major
criteria. The term ‘severity’ in accordance with the MFS has
yet to be defined.
In spite of the great diversity of combinations, a
combination of the dural major criterion and the presence
of genetic major (positive family history and/or mutation
Table 2 Prevalence of the individual features.
Total,
N¼105
Fulfilling
Ghent,
N¼87
Not Ghent,
N¼18
Pectus carinatum 60 57 3
Pectus excavatum requiring surgery 6 6 –
Reduced upper to lower segment ratio (o0.85) or arm span to height ratio greater than 1.05 48 43 5
Wrist and thumb signs 21 20 1
Scoliosis of 4201or spondylolisthesis 24 23 1
Reduced extension at the elbows (o1701)29263
Medial displacement of the medial malleolus causing pes planus 37 32 5
Protrusio acetabuli of any degree 56 52 4
Fulfilling skeletal major 34 33 1
Skeletal system involved 90 82 8
Abnormally flat cornea (o41.5 dioptres) 47 46 1
Increased axial length of the ocular globe (423.5 mm) 71 62 9
Hypoplastic iris or ciliary body (transillumination of the iris, loss of iris crypts) 3 3 –
Fulfilling ocular major ¼ectopia lentis 56 54 2
Ocular system involved 37 36 1
Mitral valve prolaps with or without mitral valve regurgitation 14 12 2
Dilatation of the main pulmonary artery below the age of 40 years, see reference Roman et al
17
–– –
Calcification of the mitral annulus below the age of 40 years 1 1 –
Dissection of the descending thoracic or abdominal aorta below the age of 50 years (B-dissection) 5 5 –
Dilatation of the descending thoracic or abdominal aorta below the age of 50 years – – –
Fulfilling cardiovascular major ¼dilatation or dissection of ascending aorta 51 46 5
Cardiovascular system involved 57 51 6
A-dissection before the study 55 –
Graft in ascending aorta before the study 31 30 1
Apical blebs 22 16 6
Spontaneous pneumothorax 65 1
Lungs involved 24 18 6
Recurrent or incisional herniae 10 8 2
Striae atrophicae (stretch marks) from puberty 70 60 10
Skin and integument involved 74 63 11
Dural sac diameter S1 or distal 4dural sac diameter L4 43 42 1
DSR L5 40.48 and/or DSR S1 40.57 65 64 1
One or more herniations of dura along lumbosacral nerve roots 65 63 2
Anterior meningocele 29 29 –
Fulfilling dural major 82 79 3
Having a parent, child or sibling who meets these diagnostic criteria independently 58 56 2
The presence of a mutation in FBN1 known to cause the Marfan syndrome 73 73 –
Fulfilling genetic major 79 77 2
N¼105. Major criteria and affected organ systems are indicated in italics.
Ghent evaluation of 105 Norwegian adults
S Rand-Hendriksen et al
1226
European Journal of Human Genetics

in FBN1) criteria could identify 69 out of 87 (79%) affected
individuals with MFS in our cohort.
The lack of investigations on the dura in many other
studies and the problems resulting from this have been
pointed out by Ade
`set al
33
Dural ectasia was the most frequent major criterion
present in individuals fulfilling the Ghent criteria (91%)
comparable with the prevalences found in other
studies.
15,21,34
It is noteworthy that 16 % of the individuals
fulfilling Ghent were dependent on this major criterion. If
dura had not been investigated, they would not have been
given the diagnosis.
In our study, a positive family history (64%) was found
less often than expected. This is probably because of the
high number of probands in our study and because
investigations of family members were not carried out for
relatives who had not signed in for the study; the
participants were asked about their relatives having
obvious major manifestations as known aortic dilatation
or operation, known ectopic lenses or lenses removed and
known mutations; see subtext to Table 1.
10
In spite of sequencing all coding parts of FBN1 and
searching for large deletions and duplications, the presence
of FBN1 mutations (44 probands out of 57 probands
fulfilling the Gent criteria, 77 %), is lower in our study
than in that commonly reported among individuals
fulfilling the Ghent criteria.
2,35
All patients with a muta-
tion in FBN1 did fulfil the Ghent criteria; thus, no other
‘type-1 fibrillinopathies’ were found.
7
Investigating dura in
all cases may be the reason for this discrepancy.
The prevalence of ascending aortic disease among
individuals fulfilling the Ghent criteria in our study
(53%) (Table 2), more often found in men than in women,
is among the lowest reported. We have not found papers
reporting different prevalences of major aortic pathology
depending on gender. However, families have been
observed in which the men are more likely to have earlier
onset aortic enlargement, more rapid enlargement and
earlier dissection than the women in the family.
36
One
might speculate whether our results represent a true
difference between genders or differences between recruit-
ing men and women. In our clinical work, it seems that a
man needs a serious organ affection as a trigger for
searching for help in their coping process. The prevalence
of mitral valve prolapse (MVP) was also low compared with
that in other studies, which, however, presents cohorts of
children or mixed age groups.
37 – 39,29
We did not encoun-
ter any patient with a dilated pulmonary trunk who was
below the age of 40 years, using the aortic normograms as
suggested in the Ghent paper. Using Nollen’s upper limit of
normality for the pulmonary trunk, 34.8 mm, 13 out of 87
persons fulfilling Ghent had enlarged pulmonary trunk
(median diameter 30 mm; range 23 – 38 mm).
40
As most studies that were found have emerged from
specialized 4th level cardiovascular centres serving indivi-
duals with severe aortic or cardiovascular disease, patient
selection may explain the high prevalence of cardio-
vascular pathology in other reports.
The acronym ‘MASS phenotype’ has been suggested to
emphasize the involvement of the mitral valve, aorta,
0
20
40
60
80
100
120
Skeletal Major
Skeletal involved
Ocular Major
Ocular involved
Cardiovascular Major
Cardiovascular
involved
Pulmonary involved
Skin and integument
involved
Dura Major
Genetic Major
Not fulfilling Ghent, n=18. Not fulfilling the feature
Not fulfilling Ghent, n=18. Fulfilling the feature
Fulfilling Ghent, n=87. Not fulfilling the feature
Fulfilling Ghent, n=87. Fulfilling the feature
N=105
Figure 1 Number of persons fulfilling major criteria and having organ systems involved. Over all, 105 persons with given or suspected diagnosis of
Marfan syndrome. Order as in the Ghent paper.
Ghent evaluation of 105 Norwegian adults
S Rand-Hendriksen et al
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European Journal of Human Genetics

skeleton and skin in persons who could not be classified in
accordance to the Berlin nosology.
41
In our study, no
patient fitted into the ‘MASS phenotype.’
Our cohort represents persons recruited through all
medical specialities and through the patient organization.
In addition, the social security system in Norway does
prevent economical constraints for diagnosis and partici-
pation in the study. Our study cohort may therefore be
more representative for an adult population with MFS of
different phenotypes.
Table 3 Prevalence (%) of major criteria and affected organ systems in the Ghent criteria in papers presenting X2 organ
systems
Gent criteria
Skeletal Ocular Cardvasc Pulm
Sk and
int Dura Genetic Major
Study (criteria) Group N
Major
(%)
Involved
(%)
Major
(%)
Involved
(%)
Major
(%)
Involved
(%)
Involved
(%)
Involved
(%)
Major
(%)
First deg.
rel (%)
Mut. FBN1
(%)
Present study (G) Adult 87 38 94 62 41 53 59 21 72 91 64 84
Faivre et al
11
(G and
fibrilinopathies)
Ch+a? 1009
a
32 56 54 – 77 11 7 48 53
b
51 100
Ladouceur et al
25
(G) Child 155 – – 64 – B80 – 1 16 8 60 19
Knirsch et al
24
(G) Child 20 13 91 30 90 68 35 0 28 40 30 18
Garreau de Loubresse
et al
23
(G)
Ch+a 58 76 – 74 – 81 – 9 79 69 – –
Arbustini et al
21
(G) Ch+a 72 64 32 60 – 92 – – – 92 – 100
Loeys et al
26
(G) Ch+a 93 50 – 56 – 87 – – – – 57 91
van Karnebeek et al
29
(G) Child 52 – – 62 – 82 – – – – 63 –
Rose et al
27
(G) Ch+a 39 13 87 33 28 87 3 8 79 76 56 –
Rossi-Foulkes et al
28
(G) Child 53 – – 44 – 79 – – – – – –
Grahame and Pyeritz
13
(B) Child 27 – – 33 – 48 – – 7
c
–47 –
Adult 48 – – 37 – 62 – – 35
c
–37 –
Finkbohner et al
22
(B) Ch+a? 192 – – 41 – 100 – 16
d
60
c
65 60 –
G, Ghent criteria; B, Berlin criteria; Sk and int, skin and integument; first deg. rel., first-degree relative independently fulfilling the Ghent criteria; Mut.,
mutation.
a
Information about varying number of persons for different features.
b
154 persons out of 292 persons where dura mater was investigated.
c
only Striae athrophica.
d
Spontaneous pneumothorax.
0
20
40
60
80
100
120
Genetic
major
and dura
major
Genetic
major
and
ocular
major
Ocular
major
and dura
major
CV
major
and dura
major
Genetic
major
and CV
major
Genetic
major
and
skeletal
major
Skeletal
major
and dura
major
Ocular
major
and CV
major
Skeletal
major
and
ocular
major
CV
major
and
skeletal
major
Not fulfilling Ghent, n=18. Not fulfilling two major
Not fulfilling Ghent, n=18. Fulfilling two major
Fulfilling Ghent, n=87. Not fulfilling two major
Fulfilling Ghent, n=87. Fulfilling two major
N=105
Figure 2 Number of persons fulfilling two major criteria, organized after prevalence. N¼105.
Ghent evaluation of 105 Norwegian adults
S Rand-Hendriksen et al
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European Journal of Human Genetics

Most studies of cardiovascular pathology in MFS have
been carried out on groups with low mean age; therefore
the natural history of the aging Marfan aorta is not well
known. In our adult cohort, we expect the features of MFS,
including cardiovascular manifestations, to be present, and
it is unlikely that typical features would disappear during
life. Although a further development of aortic pathology in
our cohort in the next few decades cannot be excluded, our
study indicates that dilatation and dissection of the
ascending aorta and of MVP may be found more seldom
in adults than in cohorts including Marfan children and
adolescents. This underlines the more severe consequences
of manifest cardiovascular disorders in the lower age
groups, sometimes resulting in early cardiovascular death,
as illustrated by Gray et al.
42
Thus, a patient selection on
the basis of the natural history of the disease may have
taken place. However, if the low prevalence of cardiovas-
cular pathology is representative for adult persons with
MFS, it will influence the overall clinical outcome and,
consequently, the estimated individual prognosis when
counselling adult persons with MFS.
The prevalence of lens subluxation or luxation in our
study, 62%, is the average of what is reported,
43,4
whereas
the prevalence of fulfilling the major criteria for the
skeletal system was 38%; other reports show large varia-
tion.
23,24
The involvement of skin and integument is
comparable with the highest prevalence published.
23,27,44
Spontaneous pneumothorax has been rare in our
cohort, whereas blebs in the lungs were found more
often.
45
This can partially be explained by different
imaging techniques.
The patient with two major criteria, but not fulfilling
the Ghent criteria, had subluxation of one lens and a
mother independently fulfilling the Ghent criteria.
The mother had the family mutation, whereas the patient
did not.
Family history, aortic disease, loose lenses or Marfanoid
habitus usually raises the suspicion of MFS. Our results
indicate that at the time of suspecting the MFS in an adult,
an early investigation using MRI of the lumbosacral spine
to detect dural ectasia is appropriate. When MFS is
confirmed, the individual should be referred to a inter-
disciplinary ‘Marfan centre’ for individual counselling,
follow-up and care.
2
Even if close to 80% of our cohort
could have settled the diagnosis by dura and family/genetic
major criteria, a complete examination of all organ systems
in the Ghent criteria should be carried out.
The broad variety of ways of fulfilling the Ghent criteria
illustrates the need for individual counselling on the basis
of the individuals’ own signs and findings in all organ
systems.
Longitudinal studies of groups of persons fulfilling the
Ghent criteria might indicate whether some variants
may have more benign natural history than do others.
Until then, all persons fulfilling the Ghent criteria should
have ophthalmological and aortic controls for the rest of
their lives.
A strength of our study is the defined population from
which the participants are recruited (the Norwegian
population of 4.5 million inhabitants) and that the same
group of investigators using the same methods carried out
all the examinations with close to no missing data. The
complete investigation in all cases may have increased the
number of individuals fulfilling the Ghent criteria through
combinations of features not depending on the cardiovas-
cular system. The relatively small size of our cohort might
possibly influence our results. However, most commonly,
current papers provide incomplete clinical information as
compared with the extensive and complete investigations
performed in this study.
A limitation is that our study population was skewed for
gender, women being in surplus. This reflects the repre-
sentation of gender among individuals over 18 years of age
with MFS, who have registered themselves at the National
Resource Centre for Rare Disorders, TRS.
In conclusion, using the complete list of features in
the Ghent criteria, out of 105 adult individuals with given
or suspected diagnosis of MFS, 87 fulfilled the Ghent
criteria in 56 different variants.The large number of
variants shows the need for using the complete set of
features in the Ghent criteria. Dural ectasia is the major
criterion most often present in persons fulfilling the
Ghent criteria (91%), followed by FBN1 mutations (84%),
positive family history (64%) and ectopic lenses (62%).
Dilatation or dissection of the ascending aorta was only
found in 53% of Ghent-positive persons (30 of them
operated), one of the lowest prevalences published. The
gender difference observed in the prevalence of major
aortic pathology may be real or may represent a selection
bias. Having dural ectasia as well as fulfilling the major
genetic criterion (positive family history and/or FBN1
mutation) was the combination of fulfilling two major
criteria most often found, with 79% of persons fulfilling
the Ghent criteria, indicating an early investigation of
those systems when suspicion of MFS has been raised in
adults. The low prevalence of cardiovascular pathology
might indicate better future prospects in an adult popula-
tion than those traditionally considered. More studies are
needed describing the prevalence of all Ghent features,
thereby making it possible to calculate the sensitivity and
specificity for each feature.
Acknowledgements
We thank Finn Lillea
˚s, MD and Ina Ghisolfi, technologist, Diakonh-
jemmet Hospital, Oslo, Norway for performing the radiological
investigations. This study has been funded by (South-) Eastern
Norway Regional Health Authority (Helse (Sr-)Øst RHF); TRS, a
National Resource Centre for Rare Disorders; the Stokbaks Heart
Foundation and the Kirkevoll Memory Foundation.
Ghent evaluation of 105 Norwegian adults
S Rand-Hendriksen et al
1229
European Journal of Human Genetics

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