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

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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