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R E S E A R C H Open Access
Prevalence, incidence, and age at diagnosis
in Marfan Syndrome
Kristian A. Groth
1,2*
, Hanne Hove
3,4
, Kasper Kyhl
5
, Lars Folkestad
6,7
, Mette Gaustadnes
2
, Niels Vejlstrup
5
,
Kirstine Stochholm
8,9
, John R. Østergaard
8
, Niels H. Andersen
1
and Claus H. Gravholt
2,9
Abstract
Background: Marfan syndrome is a genetic disorder with considerable morbidity and mortality. Presently, clinicians
use the 2010 revised Ghent nosology, which includes optional genetic sequencing of the FBN1 gene, to diagnose
patients. So far, only a few studies based on older diagnostic criteria have reported a wide range of prevalence and
incidence. Our aim was to study prevalence, incidence, and age at diagnosis in patients with Marfan syndrome.
Method: Using unique Danish patient-registries, we identified all possible Marfan syndrome patients recorded by
the Danish healthcare system (1977–2014). Following, we confirmed or rejected the diagnosis according to the
2010 revised Ghent nosology.
Results: We identified a total of 1628 persons with possible Marfan syndrome. We confirmed the diagnosis in 412,
whereof 46 were deceased, yielding a maximum prevalence of 6.5/100,000 at the end of 2014. The annual median
incidence was 0.19/100,000 (range: 0.0–0.7) which increased significantly with an incidence rate ratio of 1.03
(95 % CI: 1.02–1.04, p< 0.001). We found a median age at diagnose of 19.0 years (range: 0.0–74). The age at diagnosis
increased during the study period, uninfluenced by the changes in diagnostic criteria. We found no gender differences.
Conclusion: The increasing prevalence of Marfan syndrome during the study period is possibly due to build-up of a
registry. Since early diagnosis is essential in preventing aortic events, diagnosing Marfan syndrome remains a task for
both pediatricians and physicians caring for adults.
Keywords: Epidemiology, Rare diseases, Aortic aneurism, Lens subluxation, Aortic dissection
Background
Since the first description of Marfan syndrome (MFS),
decades of research in the syndrome [1] have contrib-
uted to the knowledge about the phenotypical presenta-
tion and the genetic background. In 1986, the definition
of MFS described by the Berlin criteria [2], was purely
based on the clinical phenotype. Later on, Dietz et al.
found a connection between MFS and FBN1, the gene
coding for the fibrillin protein [3]. The first Ghent criteria
from 1996 (Ghent-I) [4], which were a revision of the
Berlin criteria, used the newly discovered FBN1 mutations
as a component in the diagnostic criteria. In 2010, the re-
vised Ghent criteria (Ghent-II) [5] highlighted FBN1
mutation, aortic dilatation and ectopia lentis as corner-
stones in the MFS diagnosis [5].
The most frequently quoted prevalence of MFS is 20/
100,000 [6, 7]. The source is an early version of the text-
book of Emery and Rimoins: Principles and practice of
Medical Genetics [8], but the latest version only refers to
a crude calculation of 4–6/100,000 based on MFS pa-
tients found in the catchment area of Johns Hopkins
Hospital in Baltimore. During the last 70 years, only five
studies report MFS prevalence, all but one based on the
Berlin criteria. In 1958, Lynas et al. reported a preva-
lence of 1.5/100,000 in a population from Northern
Ireland [9]. Sun et al. reported a prevalence of 17.2/
100,000 in China in 1990 [10]. Gray et al. [11] reported
a prevalence of 6.8/100,000 in the north-east Scottish
population. A Danish study from 1997 by Fuchs et al.
showed a prevalence of 4.6/100,000 [12]. Here the diag-
nosis was based on data from medical records and all
* Correspondence: kristian.groth@ki.au.dk
1
Department of Cardiology, Aarhus University Hospital, DK-8200 Aarhus N,
Denmark
2
Department of Molecular Medicine, Aarhus University Hospital, Palle
Juul-Jensens Boulevard 99, DK-8200 Aarhus N, Denmark
Full list of author information is available at the end of the article
© 2015 Groth et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Groth et al. Orphanet Journal of Rare Diseases (2015) 10:153
DOI 10.1186/s13023-015-0369-8
cases were diagnosed before 1993. Chiu et al. in 2014 re-
ported a much higher prevalence of 10.2/100,000, but
the figures were solely based on data collected from
2000–2012 and without any regard to diagnostic criteria
or clinical presentation [13]. Thus, there are no publica-
tions on the prevalence of clinically verified MFS based
on the Ghent-I or the Ghent-II criteria and no preva-
lence studies report data including FBN1 mutations. As
the clinical manifestations of MFS may vary even within
families with the same genetic background, it is not only
difficult to diagnose MFS but also to assess the true
prevalence of MFS based on clinical phenotyping of pa-
tients [14]. However, use of FBN1 genotyping may repre-
sent a new dimension in diagnosing MFS and thereby
provide a more accurate identification and classification
of MFS [15].
Therefore, we set out to determine the prevalence and
incidence of Marfan syndrome in Denmark using the
current diagnostic approach as well as to describe the
age diagnostic as a marker for the diagnostic delay in
MFS defined as the time from birth until diagnosis.
Methods
Since 1968, all Danish citizens have a unique personal iden-
tification number (CPR-number) in the Danish Central
Person Register (www.cpr.dk) which is used in a number
of Danish registers, thus providing a unique opportunity
for record linkage, including The National Patient Register
(NPR) [16] and The Danish Register of Cause of Death
(DRCD) [17]. From 1977 and onwards, the NPR registered
all in-patient contacts with the Danish healthcare system
and from 1995, also registered all outpatient contacts. All
contacts were given an International Classification of
Diseases (ICD) code (ICD-8 until 1993 and ICD-10
from 1994 and onwards). DRCD record all death cer-
tificates since 1973 according to the ICD system, and
used ICD-8 in 1973–1983, and ICD-10 from 1984
and onwards. DRCD was updated through 2013.
We retrieved CPR-numbers from all persons recorded
in at least one of the two registries with the ICD-10
diagnosis Q87.4 “Marfan Syndrome”or ICD-8 759.80
“Arachnodactylia (syndroma Marfan)”.
As several persons were noted with an ICD-8 or ICD-
10 diagnosis of MFS only based on the suspicion of suf-
fering from MFS in the NPR register, all medical records
were manually evaluated, to confirm or reject the diag-
nosis. As the MFS diagnosis has evolved significantly
during the years with the changing criteria, Berlin [2],
Ghent-I [4] and II [5], we decided to perform the med-
ical record evaluation according to the Ghent-II criteria
[5]. Medical records were accessed via a central elec-
tronic patient journal system (E-journal) provided by the
Danish Healthcare System. If E-journal material was
insufficient to determine whether the person had MFS
or not, the original paper medical file was retrieved.
If we, during the evaluation, found other persons such
as family members that could also have MFS, we evalu-
ated their MFS status as well (Fig. 1).
There are seven ways a person can meet the Ghent-II
criteria (Table 1). All who fulfilled at least one of the
seven principal diagnostic features were classified as
“MFS”, whereas all who did not fulfill any of the seven
possible diagnostic criteria were classified as “not MFS”.
If medical records were insufficient (or non-existing)
in both electronic and non-electronic versions, or if for
some reason (ex. deceased or emigrated) it was not pos-
sible to fully determine the persons MFS status, a com-
mittee of three MFS specialist physicians evaluated the
available persons data and determined the MFS status by
consensus. All persons with no clinical data were classi-
fied as “not MFS”.
The study was approved by the Scientific Ethical
Committee and the Danish Data Protection Agency.
Statistical analysis
Age at diagnosis was studied by median age at diagnosis
with range interval and time trends were studied with
quantile regression including 95 % confidence intervals
(CI). Time trends in incidence including 95 % confi-
dence intervals (CI) were analyzed using Poisson regres-
sion. To graphically illustrate time trends in incidence
we used linear regression lines. Gender difference and
difference between the cohort with MFS and without
MFS were studied using Mann-Whitney’s nonparametric
test. P<0.05 was considered significant. Stata 12.1 for
Windows (StataCorp LP, College Station, TX, USA) was
used for all calculations.
Results
From NPR and DRCD, we extracted all persons regis-
tered with a relevant ICD-8 or ICD-10 diagnosis, which
resulted in 1559 unique CPR-numbers (Fig. 1). During
the evaluation of their medical records, we found 69
additional potential MFS persons resulting in a total co-
hort of 1628. During the evaluation process, we found
22.5 % (n= 366) patients fulfilling one of the seven ways
to obtain the MFS diagnosis and rejected 1078 cases
(66.2 %). In 184 (11.3 %), it was not possible to accur-
ately determine whether the persons fulfilled the diag-
nostic criteria. Thus, sufficient data was present in 1444
(88.7 %) of the total cohort. 73 (4.5 %) had no clinical data
and were either deceased (n= 69) or emigrated (n=4).
They were classified as “not MFS”. A committee of three
physicians specialized in MFS (KAG, NHA and CHG),
evaluated every remaining case (n= 111) and reached con-
sensus on their MFS status. Forty-six were determined to
have MFS and the remaining 65 were registered as “not
Groth et al. Orphanet Journal of Rare Diseases (2015) 10:153 Page 2 of 10
MFS”. Thus, 1216 (74.7 %) had “not MFS”and 412 (male
n= 215) classified as “MFS”. Among the 412 classified as
MFS, 366 (male n= 189) were still alive at the end of 2014
(Fig. 2a).
Therewasnodifferenceingender(p= 0.3) and birth year
between persons classified with or without MFS (p=0.2).
Prevalence and incidence
As of January 1
st
2015, the population of Denmark was
5,659,715 inhabitants (www.dst.dk) yielding a point
prevalence of MFS of 6.5/100,000. We also calculated an
average prevalence increase of 0.17/100,000 per year
during the study period. The average number of MFS di-
agnosed patients annually was 11.1 with a significantly
increasing incidence during the study period (Fig. 2a, b).
The median annual incidence was 0.19/100,000 (0.0–
0.7) (Table 2). During the study period, the absolute
number of patients diagnosed with MFS annually in-
creased significantly with an incidence rate ratio (IRR)
of 1.03 (95 % CI: 1.02–1.04, p< 0.001) (Fig. 3). Since
this increase could be due to lack of access to patient
records early in the study period, we calculated the IRR
for the last 10 years of the study period (2004–2014)
resulting in an increasing IRR of 1.11 (95 % CI 1.01–1.21
p= 0.018). We identified no difference in IRR between the
two genders during the study period (p=0.47).
Based on the current prevalence of MFS in our data
and exploring different scenarios with different relative
risk of mortality of 1.1, 1.25, 1.5, 2.0 or 3.0 in compari-
son with the general population and using forecasts for
the development of the Danish population, we generated
future trajectories of the prevalence of MFS (Fig. 4).
Age at diagnosis
The median age at diagnosis for the entire MFS group
was 19.0 (0.0–74.5) years. There was no difference in
age at diagnosis between males and females (median age
at diagnosis: males 18.3 years (0.0–74.5) and females
19.9 years (0.0–72.1) (p= 0.3)). By the age of 1.5 years
10 %, 6.5 years 25 % and 38.8 years 75 % of the entire
cohort were diagnosed, respectively, but age at diagnosis
extended into the seventies (Fig. 5a). There was a ten-
dency towards an increasing age at diagnosis of 0.29
(95 % CI -0.03–0.60, p= 0.075) years per year of diagno-
sis during the study period (Fig. 5b).
FBN1 evaluation
Of the total cohort of 412 MFS patient 196 had been tested
for FBN1 mutations, with 193 having a FBN1 mutation
Fig. 1 The total cohort and evaluation process defining patients with MFS
Groth et al. Orphanet Journal of Rare Diseases (2015) 10:153 Page 3 of 10
Fig. 2 aObserved cumulated absolute number of Marfan syndrome patients alive per year during the study period from 1977 to 2014. The
dashed line (expected prevalence) indicates the expected number of Marfan syndrome patients assuming a prevalence of 6.5 per 100,000 Danish
inhabitants. The year of change of nosology is indicated by a horizontal line and marked with the nosology name. bNumber of Marfan syndrome
patients diagnosed per year during the study period from 1977 to 2014. Bars divided by sex. The year when the MFS nosology was changed, is
indicated by a horizontal line and marked with the nosology name
Groth et al. Orphanet Journal of Rare Diseases (2015) 10:153 Page 4 of 10
known to cause MFS. In three cases no known mutation
was found, however they fulfilled the Ghent-II nosology by
other criteria (aorta ascendens dilatation and minimum
seven systemic points (n= 2) or by a family history of MFS
and aorta ascendens dilatation (n=1)). One patient was
only evaluated for FBN1 mutations and could have a MFS
related disorder. One patient was evaluated with a wide
genetic panel spanning all Marfan related disorders. One
patient was evaluated for FBN1 mutations and collagen
anomaly. However, since the three patients fulfilled the cri-
teria for MFS, we included them in the study cohort.
Preimplantation and prenatal diagnostics
Since 2000, only extremely few patients have chosen
preimplantation diagnostics due to limited service and
long waiting times. A total of 24 MFS patients chose
prenatal diagnostics and of these, ten fetuses carried an
FBN1 mutation. In only three cases did the parents
choose an abortion before the 12
th
gestation week, indi-
cating that currently such low numbers of legal abor-
tions are unlikely to affect the prevalence and incidence
of MFS (unpublished data from the Danish Cytogenetic
Central Register).
Discussion
As the first study of MFS according to the Ghent-II nos-
ology, this report shows a prevalence of MFS to be 6.5/
100,000 in the uniform health care system in Denmark.
We also find that the diagnosis of MFS is made through-
out the entire lifetime, with only half of all diagnoses
confirmed before the age of 19 years. Importantly, it
seems as if the diagnostic vigilance is increasing during
the study period, illustrated by the significant increase in
incidence.
We identified the Danish MFS prevalence to be 41 %
higher than the previously reported Danish prevalence
of 4.6/100,000 published almost 20 years ago [12]. In the
1990’ies, patients were diagnosed according to the Berlin
nosology and the study primarily focused on ectopia len-
tis [12], whereas the present study subjected every single
patient file to close scrutiny including every aspect of
MFS. Interestingly, the nosology of MFS changed three
times (1986, 1996 or 2010) during the study period, but
we did not see any changes in incidence or prevalence
related to different diagnostic criteria (Fig. 2a, b).
It is difficult to estimate the true prevalence of MFS
and we are well aware that some patients with MFS in
Denmark still need to be diagnosed and identified. Based
on the present data, we expect that the prevalence of
MFS will increase by approximately 0.17 patients/
100.000 the next many years. The reasons behind the
imprecision are multifactorial –i.e. multiple factors
exert an effect and some may tend to decrease and
others may tend to increase the observed prevalence.
Thus mortality, and to a lesser extent diagnostic prac-
tice, will influence the absolute number of MFS in the
Danish population. Since the exact relative risk of death
is not known in MFS, we have illustrated this with a set
of different scenarios, where it can be appreciated that if
the relative risk of death is below 2.0, we will continue
to see an expanding population of MFS (Fig. 4). Newer
literature seems to suggest that mortality is decreasing
for contemporarily treated MFS [18, 19], which would
obviously increase the prevalence, as illustrated in our
future projections (Fig. 4). Another important compo-
nent in the increasing prevalence is the build-up of a
registry, where more patients are often diagnosed than
censured (deceased or emigrated) in the beginning of
the history of a registry. This phenomenon is seen in
many other studies of rare syndromes [20, 21]. More-
over, our data also illustrate a significantly increasing in-
cidence rate ratio, which was evident even during the
last 10 years of the study period. This increase in inci-
dence could be caused by an increased focus on the dis-
ease and better knowledge about the syndrome by
healthcare professionals, resulting in more patients being
diagnosed even at a high age. Better diagnostics and the
increased use of genotyping could also explain the in-
creasing incidence, as could more intense investigations
of affected families, currently recommended in guide-
lines [5]. Factors expected to decrease prevalence, such
as preimplantation diagnostics followed by induced
abortions currently only seem to play a very minor role.
On the other hand more surviving well-treated individ-
uals with a disease causing MFS mutation could also
lead to increased transmission of MFS mutations.
Since 1996 there have been two centers in Denmark
handling rare diseases including MFS. We believe that
the centralization of rare diseases has resulted in an in-
creased focus on examining pedigrees of MFS families,
and thereby diagnosing adult family members with MFS.
Given that MFS is a potentially life-threatening dis-
order due to aortic disease [22–24], an early diagnosis is
important and will provide better overall health for the
MFS patient [22, 25]. It is our impression that some
Table 1 The seven principal ways a person can meet the Ghent
II criteria in the Marfan syndrome diagnosis
1) Ascending aorta dilatation
a
& ectopia lentis
2) Ascending aorta dilatation
a
&aFBN1 mutation
3) Ascending aorta dilatation
a
& minimum seven systematic points
4) Ectopia lentis with a FBN1 mutation known to cause ascending
aorta dilatation
a
5) Family history of MFS & ectopia lentis
6) Family history of MFS & minimum seven systematic points
7) Family history of MFS & ascending aorta dilatation
a
a
Or dissection of the ascending aorta
Groth et al. Orphanet Journal of Rare Diseases (2015) 10:153 Page 5 of 10
Fig. 3 Yearly incidence of Marfan syndrome in Denmark during the study period 1977 to 2014. For clarity, the significant increase in incidence
during the study period is visualized by linear regression
Fig. 4 Absolute numbers of Marfan syndrome in Denmark during the study period 1977 to 2014 and the absolute theoretical numbers
extrapolated onwards to 2050. Extrapolation is based on the expected Danish population according to Statistical Denmark (www.dst.dk).
Incidence is set to 0.19 per 100,000 as found in this study. Since there has been no studies reporting mortality ratios in comparison with
general population, we have for illustration plotted five different relative risks (RR) of mortality compared to the general Danish population
Groth et al. Orphanet Journal of Rare Diseases (2015) 10:153 Page 6 of 10
physicians expect diagnosing MFS to be mainly a task
for pediatricians. However, our data clearly indicate that
many MFS patients are not diagnosed until late in life
which means that all medical specialties should focus on
even subtle clinical signs [26] and not hesitate to refer
potential undiagnosed MFS patients, even from an elderly
population. Early diagnosis should be the goal since this
could reduce health expenditures and possibly avoid cases
of dissection and sudden death [27]. The significant in-
crease in age at diagnosis in the current cohort and
Fig. 5 aNumber of Marfan syndrome patients by age at diagnosis. Patients diagnosed during the study period 1977 to 2014. Dashed lines
indicating the age when 10, 25, 50 and 75 % of MFS patients are diagnosed. bAge at diagnosis versus year of diagnosis during the study period
1977 to 2014. The non-significant increase in age at diagnosis is visualized by quantile regression
Groth et al. Orphanet Journal of Rare Diseases (2015) 10:153 Page 7 of 10
especially the diagnosis of quite old individuals, may well
illustrate diagnosis of less affected individuals, a factor that
could also lead to an increased prevalence of the MFS.
Phenotyping patients can be difficult and time-
consuming and clinical manifestations resulting in MFS
will sometimes only be evident when the patient reaches
Table 2 Yearly incidence per 100,000 of Marfan syndrome in Denmark
Year of
diagnosis
Male Female Total
Diagnosed Population Incidence Diagnosed Population Incidence Diagnosed Population Incidence
1977 6 2,513,000 0.24 1 2,567,000 0.04 7 5,079,879 0.12
1978 1 2,520,000 0.04 1 2,577,000 0.04 2 5,096,959 0.04
1979 1 2,526,000 0.04 4 2,586,000 0.15 5 5,111,537 0.10
1980 2 2,529,053 0.08 1 2,593,012 0.04 3 5,122,065 0.06
1981 0 2,528,225 0.00 2 2,595,764 0.08 2 5,123,989 0.04
1982 5 2,523,825 0.20 4 2,595,330 0.15 9 5,119,155 0.18
1983 3 2,521,220 0.12 1 2,595,244 0.04 4 5,116,464 0.08
1984 3 2,517,942 0.12 3 2,594,188 0.12 6 5,112,130 0.12
1985 3 2,517,072 0.12 4 2,594,036 0.15 7 5,111,108 0.14
1986 2 2,520,563 0.08 1 2,595,710 0.04 3 5,116,273 0.06
1987 1 2,526,020 0.04 1 2,598,774 0.04 2 5,124,794 0.04
1988 3 2,527,996 0.12 3 2,601,258 0.12 6 5,129,254 0.12
1989 5 2,528,165 0.20 1 2,601,613 0.04 6 5,129,778 0.12
1990 2 2,530,597 0.08 2 2,604,812 0.08 4 5,135,409 0.08
1991 3 2,536,391 0.12 7 2,610,078 0.27 10 5,146,469 0.19
1992 2 2,544,454 0.08 8 2,617,672 0.31 10 5,162,126 0.19
1993 8 2,554,594 0.31 5 2,626,020 0.19 13 5,180,614 0.25
1994 18 2,563,442 0.70 15 2,633,200 0.57 33 5,196,642 0.64
1995 9 2,573,324 0.35 9 2,642,394 0.34 18 5,215,718 0.35
1996 7 2,592,222 0.27 9 2,658,805 0.34 16 5,251,027 0.30
1997 5 2,604,937 0.19 3 2,670,184 0.11 8 5,275,121 0.15
1998 10 2,615,669 0.38 5 2,679,191 0.19 15 5,294,860 0.28
1999 7 2,625,421 0.27 6 2,688,156 0.22 13 5,313,577 0.24
2000 7 2,634,122 0.27 5 2,695,898 0.19 12 5,330,020 0.23
2001 7 2,644,319 0.26 3 2,704,893 0.11 10 5,349,212 0.19
2002 10 2,654,146 0.38 9 2,714,208 0.33 19 5,368,354 0.35
2003 8 2,662,423 0.30 15 2,721,084 0.55 23 5,383,507 0.43
2004 9 2,670,135 0.34 10 2,727,505 0.37 19 5,397,640 0.35
2005 5 2,677,292 0.19 6 2,734,113 0.22 11 5,411,405 0.20
2006 3 2,685,846 0.11 9 2,741,613 0.33 12 5,427,459 0.22
2007 4 2,696,662 0.15 5 2,750,422 0.18 9 5,447,084 0.17
2008 6 2,712,666 0.22 3 2,763,125 0.11 9 5,475,791 0.16
2009 7 2,732,020 0.26 4 2,779,431 0.14 11 5,511,451 0.20
2010 5 2,743,286 0.18 4 2,791,452 0.14 9 5,534,738 0.16
2011 10 2,756,582 0.36 3 2,804,046 0.11 13 5,560,628 0.23
2012 10 2,766,776 0.36 10 2,813,740 0.36 20 5,580,516 0.36
2013 9 2,778,852 0.32 9 2,823,776 0.32 18 5,602,628 0.32
2014 9 2,792,279 0.32 6 2,834,956 0.21 15 5,627,235 0.27
1977–2014 215 2,609,146 0.22 197 2,671,729 0.19 412 5,281,280 0.20
Data on gender only, with an accuracy of 1000 individuals for the years 1977–1979. For the line 1977–2014 the presented data are the summed number of
patients diagnosed with Marfan syndrome, mean values for the Danish population and mean values for Marfan syndrome incidence
Groth et al. Orphanet Journal of Rare Diseases (2015) 10:153 Page 8 of 10
adulthood and thereby “grows into the diagnosis”. Clinical
manifestations may also vary considerably and some pa-
tients have a milder phenotype making it difficult to ac-
curately assess the prevalence of MFS [28]. In theory,
FBN1 genotyping should help solve this problem, but dis-
covery of the FBN1-gene did not seem to have any imme-
diate effect on the age at diagnosis (Fig. 2a). However, of
the 412 patients diagnosed with MFS in our study cohort
approximately half of the population (n=196) had been
tested for FBN1 mutations, even that it is a snapshot it
may be the reason why genotyping did not have a major
impact in this cohort. It is our impression that access to
genetic sequencing is improving and we have not seen the
full impact of FBN1 screening on the prevalence of MFS.
FBN1 genotyping represents a new dimension in diagnos-
ing MFS that could accelerate the process, but still some
difficulties remain in the correct interpretation of FBN1
gene test results [29].
Strength and limitations
The present study is a nationwide register study, cover-
ing all subjects ever given a diagnosis of MFS. Further-
more, the study was performed in a uniform public
healthcare system making it possible to report precise
data on age at diagnosis. The rising incidence, preva-
lence and age at diagnosis during the study period could
be due to information bias in the early time period of
the study. Since Danish hospitals are only legally re-
quired to keep patient records 10 years after the latest
entry, many hospitals have destroyed records. Nonethe-
less, most Danish hospital records are computerized and
kept infinitely. Therefore, data collection from journals
may not be as good in the beginning of the study period
compared to the latest 10–15 years, resulting in some
bias in interpretation of data over time. Many of the eld-
erly persons registered in the first part of the study
period are dead before computerization of records and
for that reason their records were purely paper files and
often not available for evaluation. Consequently, some
persons had to be evaluated as “not MFS”due to lack of
journal data, while they in reality might have suffered
from MFS. This could obviously create a bias in the as-
sessment of the median age at diagnosis and the preva-
lence early in the study period. However, this problem
should not affect our data during the latter part of the
study period.
Conclusion
We found a MFS prevalence of 6.5/100,000 in the
Danish population but expect a growing prevalence dur-
ing the next years, since we saw an increasing prevalence
and incidence during the study period. We also found a
striking time span of patients age at diagnosis of zero to
seventy-four years and a median age at diagnosis of
19.0 years emphasizing that diagnosing MFS is a task for
both pediatricians as well as other clinicians.
Ethics approval and consent to participate
The study was approved by the Scientific Ethical
Committee of Region Midtjylland and the Danish
Data Protection Agency.
Abbreviations
CI: Confidence interval; CPR: Danish Central Personal Register; DRCD: The
Danish Register of Causes of Death; FBN1: Fibrillin-1 gene; Ghent-I: First
revised Ghent nosology [4]; Ghent-II: Second revised Ghent Nosology [5];
ICD: International classification of disease; IRR: Incidence rate ratio;
MFS: Marfan Syndrome; NPR: The National Patient Register; RR: Relative risk.
Competing interest
The authors declare that they have no competing interests.
Authors’contribution
All authors have participated in the writing of the manuscript. The following
specific areas where each author have an provide extra contribution. KG:
Main author of the manuscript, general data collection and evaluation. HH:
Provided access to data for patients living in the eastern part of Denmark.
Also provided expert knowledge on Marfan Syndrome and phenotyping the
patients. KK: Provided access to data from department of cardiology on
patients living in the eastern part of Denmark. Also collected data on
patients from the eastern part of Denmark. LF: Provided access to patient in
the southern part of Denmark as well expert knowledge on evaluation of
rare diseases. MG: Provided expert knowledge on genetics and gentypical
evaluation. NV: Provided access to data from department of cardiology on
patients living in the eastern part of Denmark. Also collected data on
patients from the eastern part of Denmark. KS: Provided expert knowledge
on statistical analysis and evaluation of rare diseases. JØ: Provided expert
knowledge on Marfan Syndrome. Also helped in accessing patient data from
patients in the western part of Denmark. NHA: Provided cardiological data
for patient from the western part of Denmark as well as expert knowledge
on Marfan Syndrome. CHG: Provided expert knowledge on scientific
handling of rare diseases. Also provided expert knowledge on Marfan
syndrome. All authors read and approved the final manuscript.
Acknowledgements
This study is supported by Department of Clinical Medicine, Aarhus
University Hospital and Aarhus University and the Novo Nordisk Foundation.
The funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
Author details
1
Department of Cardiology, Aarhus University Hospital, DK-8200 Aarhus N,
Denmark.
2
Department of Molecular Medicine, Aarhus University Hospital,
Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus N, Denmark.
3
Department
of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, DK-2100
Copenhagen, Denmark.
4
The RAREDIS Database, Section of Rare Diseases,
Department of Clinical Genetics, Copenhagen University Hospital,
Rigshospitalet, DK-2100 Copenhagen, Denmark.
5
Department of Cardiology,
Rigshospitalet, DK-2100 Copenhagen, Denmark.
6
Department of
Endocrinology, Odense University Hospital, DK-5000 Odense C, Denmark.
7
Institute of Clinical Reasearch, University of Southern Denmark, DK-5000
Odense C, Denmark.
8
Centre for Rare Diseases, Department of Paediatrics,
Aarhus University Hospital, DK-8200 Aarhus N, Denmark.
9
Department of
Endocrinology and Internal Medicine, Aarhus University Hospital, DK-8000
Aarhus C, Denmark.
Received: 21 September 2015 Accepted: 22 November 2015
References
1. von Kodolitsch Y, De Backer J, Schüler H, Bannas P, Behzadi C, Bernhardt
AM, et al. Perspectives on the revised Ghent criteria for the diagnosis of
Groth et al. Orphanet Journal of Rare Diseases (2015) 10:153 Page 9 of 10
Marfan syndrome. Appl Clin Genet. 2015;8:137–55. doi:10.2147/TACG.S60472.
eCollection@2015.:137–55.
2. Beighton P, de Paepe A, Danks D, Finidori G, Gedde-Dahl T, Goodman R,
et al. International nosology of heritable disorders of connective tissue,
Berlin, 1986. Am J Med Genet. 1988;29(3):581–94.
3. Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, et al.
Marfan syndrome caused by a recurrent de novo missense mutation in the
fibrillin gene. Nature. 1991;352(6333):337–9.
4. De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised
diagnostic criteria for the Marfan syndrome. Am J Med Genet. 1996;62(4):417–26.
5. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB,
et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet.
2010;47(7):476–85.
6. Pepe G, Lapini I, Evangelisti L, Attanasio M, Giusti B, Lucarini L, et al. Is
ectopia lentis in some cases a mild phenotypic expression of Marfan
syndrome? Need for a long-term follow-up. Mol Vis. 2007;13:2242–7.
7. Gillis E, Kempers M, Salemink S, Timmermans J, Cheriex EC, Bekkers SC, et al.
An FBN1 deep intronic mutation in a familial case of Marfan syndrome: an
explanation for genetically unsolved cases? Hum Mutat. 2014;35(5):571–4.
8. Pyeritz RE, Pye. Marfan Syndrome and Related Disorders. Sixthth ed.
2013. p. 1–51.
9. Lynas MA. Marfan’s syndrome in Northern Ireland; an account of thirteen
families. Ann Hum Genet. 1958;22(4):289–309.
10. Sun QB, Zhang KZ, Cheng TO, Li SL, Lu BX, Zhang ZB, et al. Marfan
syndrome in China: a collective review of 564 cases among 98 families.
Am Heart J. 1990;120(4):934–48.
11. Gray JR, Bridges AB, Faed MJ, Pringle T, Baines P, Dean J, et al.
Ascertainment and severity of Marfan syndrome in a Scottish population.
J Med Genet. 1994;31(1):51–4.
12. Fuchs J. Marfan syndrome and other systemic disorders with congenital
ectopia lentis. A Danish national survey. Acta Paediatr. 1997;86(9):947–52.
13. Chiu HH, Wu MH, Chen HC, Kao FY, Huang SK. Epidemiological profile of
Marfan syndrome in a general population: a national database study. Mayo
Clin Proc. 2014;89(1):34–42.
14. Faivre L, Collod-Beroud G, Adès L, Arbustini E, Child A, Callewaert BL, et al.
The new Ghent criteria for Marfan syndrome: what do they change? Clin
Genet. 2012;81(5):433–42.
15. Cañadas V, Vilacosta I, Bruna I, Fuster V. Marfan syndrome. Part 1:
pathophysiology and diagnosis. Nat Rev Cardiol. 2012;7(5):256–65.
16. Andersen TF, Madsen M, Jørgensen J, Mellemkjoer L, Olsen JH. The Danish
National Hospital Register. A valuable source of data for modern health
sciences. Dan Med Bull. 1999;46(3):263–8.
17. Helweg-Larsen K. The Danish Register of Causes of Death. Scand J Public
Health. 2011;39(7 Suppl):26–9.
18. Jondeau G, Detaint D, Tubach F, Arnoult F, Milleron O, Raoux F, et al. Aortic event
rate in the Marfan population: a cohort study. Circulation. 2012;125(2):226–32.
19. Silverman DI, Burton KJ, Gray J, Bosner MS, Kouchoukos NT, Roman MJ, et al.
Life expectancy in the Marfan syndrome. Am J Cardiol. 1995;75(2):157–60.
20. Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence,
diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol
Metab. 2006;91(10):3897–902.
21. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of
Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab.
2013;88(2):622–6.
22. Milewicz DM, Dietz HC, Miller DC. Treatment of aortic disease in patients
with Marfan syndrome. Circulation. 2005;111(11):e150–7.
23. Januzzi JL, Isselbacher EM, Fattori R, Cooper JV, Smith DE, Fang J, et al.
Characterizing the young patient with aortic dissection: results from the
International Registry of Aortic Dissection (IRAD). J Am Coll Cardiol. 2004;
43(4):665–9.
24. McKusick VA. The cardiovascular aspects of Marfan’s syndrome: a heritable
disorder of connective tissue. Circulation. 1955;11(3):321–42.
25. Cameron DE, Alejo DE, Patel ND, Nwakanma LU, Weiss ES, Vricella LA, et al.
Aortic root replacement in 372 Marfan patients: evolution of operative
repair over 30 years. Ann Thorac Surg. 2009;87(5):1344–9.
26. Stheneur C, Tubach F, Jouneaux M, Roy C, Benoist G, Chevallier B, et al.
Study of phenotype evolution during childhood in Marfan syndrome to
improve clinical recognition. Genet Med. 2014;16(3):246–50.
27. Grosse SD, Rogowski WH, Ross LF, Cornel MC, Dondorp WJ, Khoury MJ.
Population screening for genetic disorders in the 21st century: evidence,
economics, and ethics. Public Health Genomics. 2010;13(2):106–15.
28. Dietz HC, Pyeritz RE. Mutations in the human gene for fibrillin-1 (FBN1) in
the Marfan syndrome and related disorders. Hum Mol Genet. 1995;4 Spec
No:1799–809. 1799–809.
29. Groth KA, Gaustadnes M, Thorsen K, Østergaard JR, Jensen UB, Gravholt CH
et al. Difficulties in diagnosing Marfan syndrome using current FBN1
databases. Genet Med. 2015;10.
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