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

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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