ORIGINAL ARTICLE

Comparison of Clinical Characteristics and Frequencyof Adverse Outcomes in Patients with Marfan SyndromeDiagnosed in Adulthood Versus Childhood

Lisa Willis Æ Genie E. Roosevelt Æ Anji T. Yetman

Received: 29 October 2008 / Accepted: 12 November 2008 / Published online: 30 January 2009

� Springer Science+Business Media, LLC 2009

Abstract Patients with Marfan syndrome (MFS) continue

to elude diagnosis until well into adulthood. The purpose of

this study was to compare the clinical characteristics and

outcomes of adult survivors with MFS diagnosed during

adulthood (age, C18 years) with those of adult survivors

with MFS diagnosed in childhood (\18 years). We con-

ducted a retrospective review of 66 adult (age, [18 years)

MFS patients seen at a combined pediatric and adult

multidisciplinary MFS clinic from 2004 to 2006. Demo-

graphic, clinical, and cardiac variables were collected and a

comparative analysis was performed between the two

groups: patients diagnosed with MFS during childhood and

patients diagnosed in adulthood. The primary outcome

measures were the presence of aortic dissection and the

need for urgent cardiovascular surgery. Despite a similar

incidence of clinical characteristics, 39 of the 66 MFS

patients were not diagnosed until adulthood. The overall

incidence of major cardiac involvement was comparable

between the two groups, although the patients diagnosed at

a younger age were found to have a reduced need for aortic

surgery (33% vs. 59%; P \ 0.04) and fewer adverse

cardiac outcomes (0% vs. 46%; P \ 0.001). Moreover, the

patients diagnosed with MFS in adulthood were more

likely to require repeated surgical intervention for distal

aortic disease (13% vs. 0%; P = 0.07). In conclusion,

patients with MFS who remain undiagnosed until adult-

hood have well-established cardiovascular pathology

frequently requiring surgical intervention. Due to this delay

in diagnosis and management, they often suffer from a

suboptimal clinical outcome. Our research demonstrates

the importance of educating pediatric clinicians in early

MFS diagnosis in hopes of improving the long-term out-

come of all MFS patients.

Keywords Marfan syndrome � Aorta

The phenotypic features of Marfan syndrome (MFS) typi-

cally manifest in late childhood, and as a result, diagnosis

is usually made during early life [5]. Diagnosis in adult-

hood is considered a relative rarity in our current era of

heightened awareness of MFS. We sought to compare the

clinical characteristics and outcome of adult survivors with

MFS diagnosed during adulthood (age, C18 years) with

those of adult survivors diagnosed in childhood.

Materials and Methods

Clinical records of all adult (age, [18 years) survivors

with MFS seen at a combined pediatric and adult multi-

disciplinary MFS clinic during the period 2004–2006 were

reviewed. Demographic variables including gender, age at

diagnosis, year of diagnosis, reason for initial referral for

evaluation of MFS, and presence of an antecedent or

L. Willis

Department of Pediatrics, Section of Pediatric Cardiology,

The Children’s Hospital, 13123 East 16th Avenue, Aurora,

CO 80045, USA

G. E. Roosevelt (&)

Department of Pediatrics, Section of Emergency Medicine,

B251, The Children’s Hospital, 13123 East 16th Avenue,

Aurora, CO 80045, USA

e-mail: roosevelt.genie@tchden.org

A. T. Yetman

Department of Pediatrics, Division of Pediatric Cardiology,

Primary Children’s Medical Center, Salt Lake City, UT, USA

123

Pediatr Cardiol (2009) 30:289–292

DOI 10.1007/s00246-008-9346-5

subsequent family history of MFS were recorded. Clinical

variables including the presence of lens subluxation or

dislocation, pectus deformity, scoliosis, other musculo-

skeletal abnormalities, and spontaneous pneumothoraces

were recorded. Radiographic evidence of dural ectasia was

recorded when available. Cardiac variables including aortic

diameter on initial echocardiogram (as an absolute and a

percentage predicted value for age), presence of aortic

dilation, dissection, or insufficiency, need for cardiac sur-

gery, need for urgent cardiac surgery (defined as surgical

intervention within 2 months of initial visit), presence of

mitral valve prolapse, and presence of mitral insufficiency

were recorded. For the purposes of comparative analyses,

patients were divided into two groups: those diagnosed

with MFS in childhood (age, \18 years) and those diag-

nosed in adulthood (age, C18 years). In order to determine

whether those patients not diagnosed with MFS until

adulthood had adequate clinical characteristics to make the

diagnosis of MFS, the Ghent criteria [3] were applied to

each patient’s clinical profile. Applying the Ghent criteria

allowed us to assess whether each patient fulfilled the

diagnostic criteria independent of a clinical family history

and/or genetic test results obtained because of a clinical

suspicion of an affected family member in a subsequent

generation. In order to assess the impact of late diagnosis,

the presence of an adverse clinical outcome was noted and,

for the purposes of this study, was defined as the presence

of aortic dissection or the need for urgent cardiovascular

surgery as defined above. Continuous variables were ana-

lyzed with the Mann–Whitney U test, as all distributions

were found to be nonnormal. Categorical variables were

analyzed with a chi-square test or with Fisher’s exact

test if there were fewer than 10 patients in a cell. A

P-value \0.05 was considered statistically significant. This

study was approved by the Colorado Multiple Institutional

Review Board. Calculations were performed using SPSS

for Windows, (version 16.0, 2007; SPSS Inc, Chicago, IL).

Results

Of the 66 adult patients currently receiving medical care in

our clinic (and thus known to be alive), 27 were diagnosed

in childhood and 39 patients in adulthood. Demographic

and clinical variables for the two groups are reported in

Table 1. The incidence of diagnostic clinical characteris-

tics was not significantly different for the two groups with

the exception of ocular lens subluxation.

The most common reason for referral in both patient

cohorts was an antecedent family history of MFS

(Table 2). Patients diagnosed in adulthood were more

likely to present with aortic dissection. Patients diagnosed

in childhood were more likely to have lens dislocation.

Documentation of an affected family member in a sub-

sequent generation was the reason for referral in five

patients (13%) diagnosed in adulthood. Independent clini-

cal criteria (i.e., not utilizing affected offspring to establish

diagnosis) were manifest during childhood in 29 of the 39

(74%) patients diagnosed in adulthood. In the remaining 10

patients, there were inadequate clinical criteria to establish

a diagnosis prior to the offspring being diagnosed. Seven-

teen of the 28 women (61%) diagnosed in adulthood had

undergone at least one pregnancy without appropriate

medical and genetic counseling, as the diagnosis was

unknown at the time of pregnancy. There was documen-

tation of an affected family member in the subsequent

generation in 16 of the 29 (55%) patients diagnosed in

adulthood who had offspring.

All patients in both groups showed evidence of cardiac

involvement at the time of diagnosis (Table 3). Patients

diagnosed at a younger age had less significant aortic

involvement, demonstrated by a lower percentage pre-

dicted aortic dimension, a trend toward less aortic

insufficiency, and a significantly lower likelihood of pre-

senting with aortic dissection (Table 2). As previously

described, patients diagnosed in childhood had a greater

Table 1 Demographic and

clinical variables

Note: NS not significant

Variable Diagnosed at C18 yr

(n = 39)

Diagnosed at \18 yr

(n = 27)

P-value

Male (%) 11 (28) 13 (48) NS

Median age at diagnosis (range) 34 (18–67) 15 (0–16) \0.001

Median years since diagnosis (range) 4 (0–42) 18 (0–53) \0.001

Lens subluxation (%) 8 (20) 12 (44) 0.03

Pulmonary pneumothoraces (%) 4 (10) 3 (11) NS

Scoliosis [20� (%) 28 (72) 18 (67) NS

Pectus deformity (%) 26 (67) 21 (78) NS

Major musculoskeletal criteria (%) 34 (87) 25 (93) NS

Aortic dilation (%) 39 (100) 27 (100) NS

Dural ectasia (%) 11 (28) 14 (52) NS

290 Pediatr Cardiol (2009) 30:289–292

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incidence of mitral valve prolapse associated with mitral

insufficiency [6].

Clinical outcome was significantly different for the two

patient groups, with the patients diagnosed in adulthood

having significantly greater cardiac morbidity (Table 3).

Patients diagnosed in adulthood were more likely to require

aortic root replacement and, in addition, were more likely

to require such surgery on an urgent basis because of

associated dissection or severe aortic insufficiency. Only

three (7%) of the patients diagnosed in adulthood who

required surgical intervention were able to undergo a

valve-sparing procedure, in contrast to two (33%) of the

patients diagnosed in childhood who required surgical

intervention. Despite a shorter duration of follow-up, the

need for repeat surgical intervention for distal aortic dis-

ease was greater in the patients diagnosed in adulthood

(Table 3). Surgical complications occurred in those

patients diagnosed later, including a cerebrovascular acci-

dent in two patients and dissection of a reimplanted

coronary artery with associated myocardial infarction in

one patient. One patient required concomitant mitral valve

replacement. There was no significant perioperative mor-

bidity in those patients diagnosed with MFS in childhood.

Discussion

MFS is a relatively common genetic disorder, with an

incidence of one in 5000 [4]. We have demonstrated that

despite the presence of manifest clinical features during

childhood, the disorder is often not diagnosed in a timely

manner. While it had been thought that young age at

diagnosis conferred an adverse prognosis, we have previ-

ously shown that children diagnosed in the preschool years

fare better than those diagnosed subsequently in childhood

[8]. In the present study we have demonstrated that patients

who remain undiagnosed until adulthood have well-estab-

lished cardiovascular pathology and a suboptimal clinical

outcome.

While elective aortic root replacement, in both children

and adults, has been shown to be a safe procedure with a

low mortality, aortic replacement in the setting of an

aortic dissection continues to carry a high morbidity and

mortality rate [1]. In addition, survivors of aortic

replacement performed in the setting of an aortic dissec-

tion have been shown to have a significantly higher

incidence of progressive aortic pathology in the remaining

native aorta requiring further surgical interventions [1].

As we were only looking at adult survivors with MFS, we

cannot determine the difference in mortality rate between

those diagnosed in childhood and those diagnosed in

adulthood. However, we note that despite being of similar

age at the time of surgical intervention, patients diagnosed

in adulthood underwent a much riskier surgical procedure

because of the presence of aortic dissection or aortic

valvar insufficiency. The presence of operative compli-

cations and need for subsequent cardiovascular surgery

were only seen in the patients diagnosed in adulthood.

Table 2 Reason for referral

Note: NS not significant

Diagnosed at C18 yr

(n = 39)

Diagnosed at \18 yr

(n = 27)

P-value

Antecedent family history (%) 9 (23) 14 (52) 0.02

Aortic dissection (%) 9 (23) 0 0.008

Other cardiac abnormalities (%) 7 (18) 2 (7) NS

Musculoskeletal abnormalities (%) 5 (13) 3 (11) NS

Child with MFS (%) 5 (13) 0 0.07

Pulmonary abnormalities (%) 3 (8) 0 NS

Lens dislocation (%) 1 (3) 8 (30) 0.003

Table 3 Clinical cardiac

characteristics and outcomes

a Presence of aortic dissection

or need for urgent

cardiovascular surgery

Diagnosed at C18 yr

(n = 39)

Diagnosed at \18 yr

(n = 27)

P-value

Median aortic root, mm (range) 45 (31–100) 35 (18–60) 0.009

Median percentage predicted aortic

root diameter at diagnosis (range)

125% (102–270) 117% (105–160) 0.03

Need for aortic surgery (%) 23 (59%) 9 (33%) 0.04

Adverse cardiac outcomea (%) 18 (46%) 0 \0.001

[Mild AI (%) 19 (49%) 7 (26%) 0.08

MVP with Cmild MR (%) 23 (59%) 23 (85%) 0.03

Repeat aortic surgery (%) 5 (13%) 0 0.07

Pediatr Cardiol (2009) 30:289–292 291

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Recent evidence suggests that patients undergoing a

valve-sparing procedure may have a lower risk of surgical

reintervention [2]. In order for such a procedure to be

performed, the aortic valve must be competent and the

aorta intact [2]. We have demonstrated that patients pre-

senting in adulthood have limited surgical options because

of the extent of their disease.

MFS is a treatable disease with preventable life-threat-

ening complications [1, 7]. The major impediment to an

optimal outcome continues to be lack of timely diagnosis.

Pediatricians and general practitioners caring for children

must maintain a high level of suspicion, particularly in

those patients with ocular lens subluxation, musculoskel-

etal features, auscultatory findings of mitral valve prolapse,

and a family history. As a number of adult patients will be

diagnosed only after their offspring is diagnosed, a high

level of suspicion on the part of the pediatrician may save

more than one life. Ongoing educational efforts need to be

made to improve early diagnosis of MFS. Routine

screening of both parents when evaluating a child with

MFS is worthwhile, given the autosomal dominant pattern

of this disease.

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