CLINICAL VARIABILITY IN TWO MACEDONIAN FAMILIES
WITH ARTERIAL TORTUOSITY SYNDROME
Kocova M, Kacarska R, Kuzevska-Maneva K, Prijic S,
Lazareska M, Dordoni C, Ritelli M, Colombi M
*Corresponding Author: Professor Dr. Mirjana Kocova, University Pediatric Clinic, Str Majka Tereza 17, 1000 Skopje,
Republic of Macedonia. Tel: +389-70-242-694. Fax: +389-2-311-1713. E-mail: mirjanakocova@ yahoo.com
page: 47
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DISCUSSION
Arterial tortuosity syndrome is a rare and poorly characterized
connective tissue disorder caused by recessive
SLC2A10 gene mutations [1,2]. The estimated incidence
ranges from 1:100,000 to 1:500,000 live births. To date, approximately
100 patients have been reported carrying some
of the fewer than 30 described mutations [8]. Diagnostic
criteria have not been standardized, however, widespread
arterial tortuosity, PAS and specific facial dysmorphisms
have been reported in the large majority of the patients, and
are suitable to be considered as hallmarks of the disease
[3]. The usual presenting symptom of ATS is PAS-induced
cyanosis/respiratory failure in the first months of life. In the
large majority of cases, the disease diagnosis is made in the
first few years of life. In adulthood, life-threatening events
appear to be rare; in elderly patients, chronic systemic and
pulmonary hypertension, cardiac conductive defects, aortic
root dilatation, stroke and intracranial aneurysms can be
observed [1,3]. Some ATS patients require catheterization
and/or surgery of severe PAS and/or progressive aortic
root dilatation. Based on published data, in general, these
procedures are well tolerated if performed in a timely
manner, and surgery-related fatal events are rare.
Regarding prognosis, Wessels et al. [9] described a
high infant mortality rate (40.0% before the age of 5) in
ATS patients. Recent evidence suggests that life-expectancy
in ATS is higher than initially reported [3,9]. The initial
bias towards low life-expectancy/high mortality rate might
be caused by the absence of molecular confirmation and the
high rate of consanguinity in the studied families. Indeed,
SLC2A10 molecular analysis is mandatory to conclude the
diagnostic process and to distinguish ATS from other connective
tissue disorders with common clinical signs and
with high rates of life-threatening cardiovascular events,
such as Loeys-Dietz syndromes or autosomal recessive
Cutis laxa. Finally, in recent years, increased knowledge
about the disease has facilitated targeted follow-up and
timely cardiovascular surgery when needed, leading to an
improved prognosis [3].
However, the clinical variability and range of severity
in ATS patients is wide; the present cases exemplified
a mild (P1) and a severe (P2) ATS clinical presentation.
Patient 1 had an atypical presenting symptom, i.e., congenital
diaphragmatic hernia. Diaphragmatic hernia has
been reported in patients with connective tissue defects
including ATS [10], but a definite suspicion/diagnosis of
ATS in P1 was given only at 10 years of age, after in-depth
vascular studies performed to investigate migraine. To the
best of our knowledge, migraine has never been reported
in ATS patients and the present data are not sufficient to
conclude if this symptom is a result of the disease per se or
has a different pathogenesis. Nevertheless, we can speculate
that migraine might be part of the ATS spectrums, as cerebral
hypo-perfusion and blood flow velocity changes are
mechanisms involved in the pathogenesis of migraine and
it is known that the tortuosity of cerebral arteries might lead
to the above-mentioned brain blood flow changes [11,12].
The report by Pelaez et al. [13] of carotid artery, vertebral
artery, and vertebro-basilar junction tortuosity on MRA
imaging among patients with recurrent headache further
supports the idea that tortuosity of the arteries responsible
for brain perfusion may lead to migraine/headache. Furthermore,
arterial tortuosity has been shown to be a risk
factor for cerebral ischemic events and extracerebral dissection
of arteries [14]. Moreover, several patients with ATS
and stroke have been reported [1,15]. Pulmonary artery
stenosis was not present in P1, justifying the absence of
neonatal cyanosis and the delay of the diagnosis. The two
Macedonian brothers described by Ritelli et al. [3], second
cousins of P1, presented with a complete phenotype with
cyanosis in the first months of life due to PAS, widespread
arterial tortuosity, right ventricular dilatation or hypertrophy,
facial dysmorphisms and joint hypermobility. The
intra-familial variability in the presentation suggests interactions
with other modifiers. Furthermore, the c.254T>C,
p.(Leu85Pro) mutation found in this family seems to be a
recurrent Macedonian SLC2A10 mutation, as at least three
unrelated families are carriers of this specific pathogenetic
variant (Figure 3). Keeping in mind the recessive nature of
ATS, the other parents of the three children in this family
are putative relatives.
Patient 2 had a full-blown clinical presentation with
cyanosis related to severe PAS detected in the first year of
life. She had multiple cardiac consultations with progres sion of myocardiopathy, however, the intervention was
considered impossible until the age of 9 years when she
had severe cardiac failure and was referred immediately for
cardiac surgery in a specialized center. Major cardiac surgery
involved stent insertions and patching to correct the
numerous pulmonary arteries stenoses, however, she died
postoperatively due to severe myocardiopathy and heart
failure. Callewaert et al. [6] reported a 12-year-old Belgian
boy (family A) without PAS, with widespread arterial
tortuosity, dermal dysplasia, facial dysmorphisms, skeletal
abnormalities and joint laxity and the same homozygous
mutation of P2. Ritelli et al. [7] reported an 8-month-old
male baby (Patient 1) with the same mutation, in compound
heterozygosity with a second nonsense mutation,
who presented with severe PAS, pulmonary hypertension,
marked tortuosity of the aortic arch, bilateral congenital
scrotal-inguinal hernia and facial dysmorphisms.
Severe ventricular hypertrophy was described in
some of the largest studies [9] and the delay of the surgical
procedure might have been the reason for myocardiopathy
and lethal outcome in P2. Both of our patients received a
delayed diagnosis due to the rarity of the syndrome and
unavailability of molecular testing. It seems that whenever
a connective tissue disorder is detected, or early cardiac
features appear, the diagnostic process should include
SLC2A10 molecular analysis, since this syndrome might
be more common that previously considered.
In conclusion, our report suggests that migraine may
be part of the ATS spectrum and that further studies are
needed to investigate the cerebral perfusion in patients
with cerebral arterial tortuosity. Our data emphasizes the
clinical variability and different outcomes of ATS, ranging
from uncomplicated arterial tortuosity to early death
due to cardiovascular complications. Further studies are
needed to better define the natural history and guidelines
for management of these patients.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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