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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CASE REPORTS
Patient 1 (P1). This 10-year-old Macedonian
female was born to a healthy consanguineous
couple following an uneventful pregnancy and
delivery. Birth weight was 2600 g and birth length
48 cm. A congenital diaphragmatic hernia was successfully
treated at 15 days of age; subsequently,
failure to thrive and poor suckling were noticed.
At the age of 10 years, the patient was brought in
for medical attention because of migraine, easy
fatigability, and visible large carotid pulsations
in the neck. Height and weight were within the
normal range (–1 and –1.5 SD), respectively);
a post-surgical atrophic scar on the abdominal
wall was noticed as a residue of the surgical treatment
in the neonatal period. Generalized joint
hypermobility (Beighton score 6/9), high palate
and dental crowding, flexible flat feet, and facial
dysmorphisms, i.e., narrow, elongated face with
beaked nose and long philtrum, were observed.
Heart ultrasound was appropriate for sex and age
(pulmonary pressure 20 mm Hg).
Magnetic resonance angiography (MRA),
performed to investigate the migraine, brain and
supra-aortic branches disclosed marked tortuosity
of several vessels, including cerebral, carotid, and
vertebral arteries (Figure 1). Computed tomography
(CT) angiography revealed an aberrant origin and tortuosity of the three branches of the aortic arch
(Figure 2); no evident tortuosity of the pulmonary arteries
was detected. Given the presence of widespread arterial
tortuosity and peculiar facial dysmorphisms, ATS was suspected
and confirmed by SLC2A10 molecular analysis that
revealed the homozygous c.254T>C, p.(Leu85 Pro) missense
mutation (Figure 3). This mutation was previously
found in a homozygous state in two Macedonian brothers,
8 and 6 years old, with a full-blown clinical presentation
of ATS including severe pulmonary arteries tortuosity
(patients 2 and 3) [3]. Subsequently, a family pedigree
reconstruction disclosed that the patients described by
Ritelli et al. [3] and the present patient were second cousins
(Figure 4).
Patient 2 (P2). This 9-year-old Macedonian female
was born to consanguineous parents (second cousins) following
an uneventful pregnancy and delivery. Weight and
length at birth were appropriate for sex and age (3100
g and 50 cm, respectively). Cyanosis after feeding was
noticed in the first year of life and in-depth vascular studies
with cardiac catheterization were performed that disclosed
pulmonary hypertension (65 mm Hg) due to PAS.
Heart ultrasound showed right ventricular dilatation and
hypertrophy with mild tricuspid regurgitation and mild
mitral stenosis. Computed tomography angiography revealed
dilatation of the pulmonary trunk (29 mm) and
the left pulmonary artery (32 mm) and stenosis of the
intra-parenchymal pulmonary arteries accompanied by severe
tortuosity. The patient was followed by a cardiologist
without any intervention until consultation at our hospital.
On examination, the 9-year-old girl presented with short
stature (–2 SD), low weight for sex and age (–3 SD), generalized
joint hypermobility (Beighton score 8/9), facial
dysmorphisms, e.g., elongated face, widely-spaced eyes, beaked nose and micrognathia. She had systolic ejection
murmur (4/6) in the precordium. This clinical presentation
and previous cardiac findings were strongly suggestive of
ATS. Molecular analysis of the SLC2A10 gene concluded
the diagnostic process disclosing the previously described
homozygous c.685C>T, p.(Arg229*) nonsense mutation
(Figure 3) [6,7]. Heart MRI confirmed severe right and
moderate left pulmonary artery stenosis with severe dilatations
and multiple stenoses of medium size arteries in the
lung. The patient was sent to a cardiology hospital abroad
for the second catheterization and surgical treatment. The
catheterization was performed with the aim of balloon
dilatation of the right pulmonary artery, however, due to
the severe pulmonary arteries tortuosity and myocardiopathy
with tricuspid regurgitation, she was scheduled for
surgery. Tube graft of a decellularized patch was adapted
to the right orifice of the pulmonary artery and side anastomosed
to the common pulmonary artery. No intervention
on the left pulmonary artery was performed. Intraoperative examination also disclosed a major tricuspid failure and
severe right ventricular dilatation; therefore, combined
heart-lung transplantation was proposed. Unfortunately,
the patient did not recover after surgery and died on the
second postoperative day, after several resuscitation attempts,
due to impaired contractile function of the heart,
hemorrhagic event and cardiac arrest.
Informed Consent. Informed consent was obtained
from all participants included in this study.
Ethical Approval. All procedures performed in studies
involving human participants were in accordance with
the ethical standards of the institutional and/or national
research committee and with the 1964 Helsinki declaration
and its later amendments or comparable ethical standards.
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