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\begin{document}

\title{MARFAN SYNDROME IN A GHANAIAN MALE: THE DIAGNOSTIC CHALLENGES}



\author[1]{Aba Folson}%
\author[2]{Kwabena Oteng Agyapong}%
\author[3]{Dzifa Dey}%
\author[4]{Philip Eghan}%
\author[5]{Billey Quaye}%
\affil[1]{University of Health and Allied Sciences}%
\affil[2]{Ridge Hospital}%
\affil[3]{Korle Bu Teaching Hospital}%
\affil[4]{University of Ghana Medical Centre}%
\affil[5]{VRA Hospital }%


\vspace{-1em}



  
  \date{May 29, 2024}


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\textbf{INTRODUCTION}

Marfan syndrome (MFS) is an inherited connective tissue disease that
occurs following an autosomal dominant gene mutation in the
fibrillin-1gene (FBN1) \textsuperscript{1}. The protein produced by this
mutated gene is an essential component of most connective tissue and
being structurally abnormal, results in a wide range of specific
ophthalmological, skeletal, and cardiovascular abnormalities that
characterize MFS \textsuperscript{1}. The disease was discovered when
Antoine - Bernard Marfan diagnosed a 5-year-old named Gabrielle who
presented with skeletal signs \textsuperscript{2}. Current studies
estimate the prevalence of MFS at 6.5/100,00 \textsuperscript{3}.
Experts, in 1986, at Berlin created the first clinical criteria for
diagnosing MFS known as the Berlin Nosology \textsuperscript{2}. A new
criterion was detailed in 1996 (Ghent I criteria) on account of high
false positive results. In 2010 the Ghent 1 criterion was modified to
include specifically FBNI mutation, aortic root dilatation, and ectopic
lentis as the mainstay of MFS diagnosis (Ghent II). The formulation of
this nosology was essential for the avoidance of inconclusive diagnosis
and differentiation from conditions presenting with similar
manifestations \textsuperscript{1, 2}. Clinical manifestations of this
disorder include cardiovascular, ophthalmic, musculoskeletal,
craniofacial, and cutaneous abnormalities \textsuperscript{4}. Amongst
the cardiovascular manifestations, aortic dilatation and mitral
regurgitation from mitral valve prolapse occur
frequently\textsuperscript{5, 6}.

In this case report we describe the incidental finding of a young
African male with classic Marfan's syndrome but initially diagnosed at
the age of 23years. We further explore the barriers to early diagnosis
in our part of the world.

\textbf{CASE REPORT}

The patient presented to the cardiologist for echocardiography after a
3-month history of palpitations. Prior to this, he had had no
significant medical complaints except for frequent visits to see the
optician over the past 5 years resulting in the need to use spectacles.
As part of the initial assessment for the palpitations, his general
practitioner has asked for an electrocardiogram and chest x-ray to be
done and subsequently referred to the cardiologist for the
echocardiogram. It was during the interaction with the cardiologist that
the strikingly tall physique and echocardiographic abnormalities
initiated the assessment for possible MFS.

The patient admitted to dull left-sided chest pain which was
non-radiating and not associated with exertion, meals, breathing or
movement. He had progressively worsening fatigue on moderate exertion of
a two-month duration but had no associated cough, dyspnea, or pedal
swelling. The palpitations were not associated with dizziness or loss of
consciousness.

He admitted to blurred vision for 5 years which had worsened over the
period requiring the use of glasses for short-sightedness but had no
noticeable eye discoloration, redness, dryness, or tearing.

Since his adolescence, he had been noticeably more flexible than his
peers, allowing him more fluidity as a drummer. He had no other joint
pain, rash, or dislocation.

There were no abdominal or neurological symptoms of note.

The patient was the tallest member of his family and there was no
history of heart disease among siblings or mother. The patient had not,
however, been in contact with his father. All family members were
bespectacled and had no distinguishing physical features.

He denied the use of alcohol, tobacco, or illicit drugs and was
currently studying computer science at the university.

\textbf{Physical exam}

The facial features revealed a narrow, anteroposteriorly elongated
cranium (dolichocephaly) and leptoprosopic (elongated) face with malar
hypoplasia (under development of the cheek bones), mandibular
retrognathia (small lower jaw) and macrostomia (figure 2A). There was
proptosis of the right eye, prominent eye ridges and no ophthalmoplegia.
Beighton's score was 8/10.

Intraoral examination revealed mild overcrowding of his dentition with
good oral hygiene but a high-arched palate. (Figure 2C).

He had disproportionately long arms and legs (dolichostenomelia) with an
arm span of 201 cm, a height of 182 cm and an index of 0.905. His
fingers were long and spidery (arachnodactyly) (figure 1A), and Walker
wrist sign and Steinberg thumb sign were positive (figure 1B and 1C
(respectively). He was flat-footed with elongated toes (Figure 1F).
There was mild swelling of the proximal and distal interphalangeal
joints with no tenderness noted. Also noted was mild kyphoscoliosis of
the thoracic spine, with a stooped posture. There was a prominent
right-sided scapula with pectus carinatum (figure 2D).

The patient had a regular pulse at the time of the exam with an
undisplaced apex beat and normal heart sounds but had a grade 2
mid-systolic murmur with no radiation. He had a normal respiratory,
abdominal, and neurological exam.

Chest X-ray showed scoliosis and cardiomegaly (cardio-thoracic ratio of
0.76) with normal lung fields (figure 4) and the electrocardiogram
showed sinus rhythm with high voltages and normal ST / T waves.\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

The Echocardiogram report revealed moderate anterior mitral valve
prolapse in the A2 region with moderate eccentric mitral valve
regurgitation. There was mildly dilated left ventricular and atrial
chamber size and a severely dilated aortic root (5.9cm) and 1.98 when
indexed to his body surface area (BSA). A plain CT scan of the chest
confirmed moderate aortic root dilatation.

The patient was referred to the ophthalmologist and the findings were as
follows:

Visual acuity: This was found to be myopic in both eyes and worse in the
left eye. The unaided vision was 6/18 and 6/60 in the right and left
eyes respectively.

Cornea: Found to be thinner than the average. Central corneal thickness
was 457 and 476 in the right and left eyes respectively.

Iris: There were no transillumination defects noticed in either eye.

Lens: The patient had ectopia lentis in both eyes. The lens in the right
eye was subluxated superiorly and superonasally in the left eye.

The patient was started on oral Carvedilol 6.25mg daily by the
cardiologist and is currently on 6 monthly reviews with both the
cardiologist and the opthalmologist. The palpitations have since
subsided and the easy fatigue improved.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}\selectlanguage{english}
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\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\textbf{Figure 4. anterior mitral valve leaflet prolapse}

\textbf{DISCUSSION}

We described the case of a young African male diagnosed with classical
MFS syndrome using the Ghent 11 nosology. The diagnosis of MFS using
this criterion involves the observation and imaging of distinct
ophthalmologic, musculoskeletal, and cardiovascular abnormalities.

MFS is an autosomal dominant disorder with a mutation in the FBN I gene
resulting in a broad spectrum of phenotypic expressions. Typically, the
condition presents with skeletal, ophthalmologic, and cardiovascular
abnormalities. Due to the varying extent of phenotypic expression and
rate of progression, the time of diagnosis varies and requires a high
index of suspicion especially in the younger age groups.

In a study by Faivre et al, the median age at diagnosis was 6.5 years in
a study that looked at 320 patients less than 18 years of age. In this
study, 14 \% had moderate MFS, 14\% severe MFS, and 35\%, had probable
MFS with skeletal abnormalities, showing up as positive thumb and wrist
signs (83\%) and high arched palate (70\%) \textsuperscript{7}

The diagnosis in childhood may be missed since most diagnostic features
are age-dependent hence the Ghent 11 Criterion may have limited
application in this population.

The Ghent 11 nosology for diagnosis among adults includes the detection
of any of the following:

\begin{enumerate}
\tightlist
\item
  Aortic root dilatation and ectopia lentis
\item
  Aortic root dilatation and FBN1 mutation
\item
  Aortic root dilatation and systemic abnormalities
\item
  Ectopia lentis and FBN1 defect in a known \textsuperscript{2}
\end{enumerate}

In LMIC the diagnosis of MFS will most likely be clinical using the
Ghent 11 criterion. This is due to the general
unavailability/inaccessibility of genetic testing to the majority of
patients. There may therefore be a diagnostic challenge in patients who
have features that are not very diagnostic \textsuperscript{1}. This is
clearly demonstrated in the limited availability of published data in
the age range among people of African descent.

MFS is sporadic in 25\% to 30\% of patients having no family history.
These patients tend to present with severe manifestations of the disease
and have worse outcomes \textsuperscript{8}. In this case, neither the
two siblings nor the mother had any typical features of MFS.

\textbf{OCULAR MANIFESTATIONS}

The FBN 1 gene produces microfibrils that support the lens and keep it
in position, the microfibrils are also found in the iris, Schlemm canal
and cornea. The defect in these microfibrils is associated with ectopia
lentis (lens subluxation), the development of miosis, wider corneal
diameter, and pupillary hypoplasia \textsuperscript{9-11}

Myopia is the commonest ocular manifestation of the disease, being
associated with elongation of the globe with 60\% of these having
concomitant lens dislocation \textsuperscript{12, 13}. The incidence of
ectopia lentis in Marfan syndrome varies from 30\% to 72\% in different
studies it may however be first seen in the second decade of
life\textsuperscript{14-16}.

Less common ocular manifestations are early cataracts, retinal
detachment, and glaucoma. ~Ocular abnormalities such as myopia,
astigmatism, anisometropia, ectopia lentis, and retinal pathologies may
result in amblyopia. The earlier the onset and the longer it goes
untreated, the harder amblyopia is to correct \textsuperscript{17}.
Therefore, patients with MFS should be screened annually and examined
for refractive errors and other ocular pathologies. Eyeglasses are the
first step to correct blurred vision caused by subluxated
lenses\textsuperscript{18}. Removal of a dislocated lens and the
possible insertion of an artificial one may be considered but not
usually required \textsuperscript{14}.

The indications for surgery in lens dislocation are inability to achieve
good corrected visual acuity, risk of amblyopia in children, posterior
dislocation of the lens into the vitreous cavity, anterior dislocation
of the lens with or without secondary glaucoma, impending to complete
lens dislocation, lens induced glaucoma or uveitis, and
cataract\textsuperscript{19}.

Glaucoma may develop at a later age and may be as a result of phacolytic
glaucoma from dislocation of a matured lens \textsuperscript{20, 21}.

\textbf{SKELETAL ABNORMALITIES}

The system with the largest variety of clinical manifestations is the
skeletal system though scored less in the Ghent nosology compared to
cardiovascular or ophthalmologic manifestations. This is likely due to
their non-specific nature and the possibility of varied differential
diagnoses to explain their presence.

Skeletal abnormalities include craniofacial, ribcage, limb, and
vertebral defects with differing levels of impact on the patient. In one
study, typical foot deformities such as hindfoot deformities were not
limiting compared to controls despite the fact that the cases had longer
and narrower feet \textsuperscript{22, 23}. In the same study, Lindsey
et al note however the social limitation of patients with MFS finding
well-fitted shoes on account of the associated claw and hammer toes.

Two major chest wall abnormalities have been documented in MFS. Pectus
carinatum also called the pigeon chest, is thought to be more specific
for MFS \textsuperscript{8} and scores higher in the Ghent nosology than
the pectus excavatum (funnel chest). The impact of chest wall
abnormalities on cardiovascular signs and symptoms in patients with MFS
included increased chest pain attributable to mediastinal compression.
The significance of this can be evaluated by imaging
studies\textsuperscript{24, 25}. For, these patients, however, cosmesis
tends to be the more common reason for surgical
intervention\textsuperscript{26}.

Scoliosis is the lateral deviation of the vertebra with axial rotation
and vertebral body compression \textsuperscript{27}. Management remains
a challenge with outcomes of bracing, (the mainstay and initial
treatment option) showing varied outcomes and impact on rates of
progression \textsuperscript{28-30}. Factors that affect the rate of
progression rates adversely include earlier age of onset, intolerance of
braces, and increases in the rigidity of the curve \textsuperscript{31,
32}. Surgical interventions are reserved for severe scoliosis.

The usefulness of craniofacial abnormalities in making a diagnosis is
subjective, being dependent on the experience of the examiner. These
features include enophthalmos, down slanting of the external palpebral
fissures compared to the internal, malar hypoplasia, and dolichocephaly
(long skull) \textsuperscript{33}. Other orthodontic abnormalities, not
incorporated into the Ghent nosology are a high-arched palate and dental
overcrowding.

It is important to note that despite the reduction in the bone mineral
density reduction noted in the wrist, hip, and femur of patients with
MFS, its impact on the occurrence of fractures is not fully understood.

\textbf{CARDIOVASCULAR MANIFESTATIONS}

Mitral valve prolapse (MVP) and mitral valve regurgitation are common CV
complications in patients with MFS. Estimated at 40-68\% in adults
compared to about 30-38\% in children with MFS and 1-2\% in the general
population \textsuperscript{34}. Aortic regurgitation occurs following
the dilatation of the aortic root and also abnormal valve cusp structure
leading to aortic valve prolapse. Moderate to severe AR has been
documented in a study to be an independent predictor of CV events
including dilatation, dissection, and the need to have surgical
intervention \textsuperscript{35}. Eventually, the patient with MFS dies
from aortic complications such as dissection or heart failure following
volume overload from long-standing aortic and mitral regurgitation.

In the management of MFS, it has been documented that the impact of
prophylactic pharmacotherapy with B Blockers on the risk of complication
is not insignificant \textsuperscript{36}. Randomized controlled trials
(RCTs) that compared the impact of ARBs and BB found no statistically
significant difference in the rates of clinical outcomes such as aortic
regurgitation or the need for surgery. Some studies have found an added
benefit of concomitant use of BB and ARB therapies \textsuperscript{37,
38}

\textbf{SCREENING FOR MARFAN SYNDROME IN GHANA}

The reporting of diagnosed cases of MFS on the continent has been low.
The factors that fuel this pattern are likely multifaceted and may
include low detection rates, varying severities in disease expression
making the recognition difficult and the largely inaccessible means of
genetic testing should the need for that in diagnosis be required.

There is no single laboratory test that completely makes the diagnosis
of MFS, and other conditions also have the mutation in the FBN 1 gene.
The diagnosis therefore requires a thorough physical examination, a
family history of the condition and investigations that assess the
possible involved organ systems \textsuperscript{32}.

In Ghana, the detection of the clinical features may be the most
reliable means of screening for MFS. A high index of suspicion by a
well-trained clinician will help initiate further testing in order to
make the diagnosis. This is an inexpensive means of initial detection of
MFS but will probably be most effective in patients who have florid
phenotypic features. By default, the use of this means alone excludes
detection in neonates and children in whom these may be obscure.

Assessment of the extent of organ system involvement in MFS is another
crucial part of diagnosis and another potentially significant limitation
in Ghana. Cardiovascular involvement requires the use of
echocardiography and possibly CT scanning to not only detect but to
continually monitor patients and diagnose life-threatening complications
such as aortic dissection, should they occur. Across Ghana, these
services are limited to a few large cities and so in most instances
geographically, and very often financially inaccessible to patients.

Trained cardiologists, ophthalmologists, orthopaedic surgeons, and
various other specialities who form part of the multi-disciplinary team
needed to care for the patient with MFS, are inadequate in number and
found in only a few specialized centres.

The need for genetically detected FBNI gene, by the Ghent nosology, is
limited to special situations and therefore not mandatory in all cases
of MFS. Even though genetic testing is less available than diagnostic
tests in Ghana, it should not be a limitation in the detection of MFS
especially in patients with a typical phenotypic appearance and in whom
some further evaluation can lead to a diagnosis.

\textbf{CONCLUSION}

This case report shows how typical MFS presents and how the diagnosis
can be made with a high clinical index of suspicion and some level of
diagnostic testing. This is the first write-up on a Ghanaian patient
with MFS and highlights the fact that diligent assessment may uncover
several other patients in our society, with possibly, many of them not
requiring genetic testing to make the diagnosis. Following this we have
evaluated the limitations in the Ghanaian society that may fuel the low
rates of detection. In this report we emphasize on the meticulous use of
the physical exam primarily to detect possible MFS, and then supportive
tests for extent of organ involvement and further monitoring in low
resource settings.

\textbf{AUTHOR CONTRIBUTION}

\textbf{Aba Folson:} ~Conceptualization; formal analysis; investigation;
methodology; project administration; supervision; validation;
visualization; writing -- original draft; writing -- review and
editing.~ \textbf{Kwabena Oteng Agyapong:} ~Conceptualization;
investigation; methodology; writing -- original draft; writing -- review
and editing.~\textbf{Dzifa Dey:} ~ Supervision; visualization; writing
-- review and editing.~\textbf{Philip Eghan:} ~Conceptualization;
investigation; methodology; validation; writing -- review, and
editing.~\textbf{Billy Quaye:} ~Investigation; methodology; writing --
review, and editing.

\textbf{ACKNOWLEDGEMENT}

The authors would like to thank the patient for his cooperation during
the assessment and writing of this report.

\textbf{FUNDING INFORMATION}

There was no funding for this work.

\textbf{CONFLICT OF INTEREST}

The authors have no conflict of interest.

\textbf{CONSENT}

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy. A copy
of the written consent is available for review by the Editor-in-Chief of
this journal.

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