Arterial tortuosity syndrome: phenotypic and cardiovascular features in 4 newly identified patients

doi:10.21203/rs.3.rs-2594978/v1

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Arterial tortuosity syndrome: phenotypic and cardiovascular features in 4 newly identified patients

https://doi.org/10.21203/rs.3.rs-2594978/v1

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Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disease caused by biallelic variants in the SLC2A10gene and characterized by tortuosity and elongation of the aorta and medium-sized arteries. It’s considered an extremely rare disease; only 106 individuals with genetically confirmed ATS have been identified to date. The aim of this study is to contribute to the phenotypic, cardiovascular and genetic characterization of this disease.

Four cases of ATS from two families are described, contributing to the clinical delineation of the entity. Two cases with diaphragmatic hernia and a case with complex uropathy, reported in the literature only 11 times, are highlighted. Regarding the vascular involvement, a predominant supra-aortic affectation stands out and only 1 case of focal stenosis is detected (renal artery). All presented severe intracranial tortuosity. To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking treatment was prescribed.

A not previously described mutation (c.899T>G (p.Leu300Trp)) is presented in a proband; it has an allegedly deleterious effect in compound heterozygosis with the pathogenic variant c.417T>A (p.Tyr139Ter). The 3 other patients, siblings born from healthy consanguineous parents, had an homozygous variant in SLC2A10: c.510G>A (p.Trp170Ter).

Aortopathy

SLC2A10

GLUT10

Genotype

Pyelectasis

Arterial tortuosity syndrome (ATS) (OMIM #208050) is an autosomal recessive connective tissue disease caused by biallelic variants in the SLC2A10 gene. [1, 2] It is characterized by tortuosity of the aorta and medium-sized arteries with propensity to focal stenosis and aneurysm formation. Ischemic events, involving cerebrovascular and abdominal circulation, are of concern. Patients usually present characteristic dysmorphic features and connective tissue involvement that leads to joint hyperlaxity, skin hyperextensibility, inguinal hernia, and diaphragmatic hernia. [1–4]

The SLC2A10 gene (OMIM #606145) encodes the facilitative glucose transporter 10 (GLUT10) [5], an intracellular transporter of dehydroascorbic acid allegedly associated with upregulation of the TGFβ pathway in the arterial wall. Different but not mutually exclusive hypotheses to understand ATS pathophysiology have been considered, in which dehydroascorbic acid may participate in many physiologic processes in different cellular organelles. In the endoplasmic reticulum, dehydroascorbic acid is a cofactor for prolyl and lysyl hydroxylases for the crosslinking of collagen and elastin monomers. In the mitochondria, it maintains redox homeostasis and scavenges reactive oxygen species, whereas in the nucleoplasm it activates Fe2+/2-oxoglutarate-dependent dioxygenases that participate in epigenetic regulation of gene expression via histone and DNA demethylation. This process may lead to fragmentation of the inner elastic membrane and the elastic lamellae of the tunica media of the large arteries [1, 4, 6].

ATS is considered an extremely rare disease (incidence < 1:1,000,000 live births) [1] although no reliable estimates of prevalence exist [4]. To date, only 106 individuals with genetically confirmed ATS have been identified [2, 7–9]. As its natural history is incompletely studied, no clinical practice guidelines have been published and management mainly relies on expert opinion [1, 2]. Initial reports show mortality rates up to 40% before the age of 5 years [10], but subsequent cohorts of patients reveal a milder disease course. [2, 4].

The aim of the present study is to contribute to the phenotypic and cardiovascular delineation of this rare condition, as well as its natural history and genotypic spectrum.

At the time of diagnosis, all patients were evaluated by clinical geneticists and pediatric cardiologists. Clinical information and MRI (magnetic resonance imaging) data were retrospectively obtained. MRI studies from head to pelvis were performed using a 1.5T Magnetom Avanto (Siemens Medical System, Erlangen, Germany) with cardiac synchronization. Approval was granted by the local’s Ethics Committee and informed consent for publication was obtained.

Blood samples from venous puncture were obtained to extract DNA. Fragmentation, end-repair, adapter ligation and capture were performed using KAPA HyperPlus kit (Roche) and SeqCap EZ Exome V3.0 capture kit (Roche) or custom clinical exome using also SeqCap EZ probes (Roche). Enriched captured targets were sequenced on a NextSeq sequencing instrument (Illumina). Alignment and variant calling were carried out using standard methodologies. Sequence reads were aligned against the human reference genome (version GRCh37) using the Burrows-Wheeler Aligner (BWA, version 0.7.12) and Picard tool (version 2.18.21). Single nucleotide and in/del variants were detected using Genome Analysis Toolkit (GATK:version 4.1), while functional annotation was performed using ANNOVAR. Copy number variants (CNVs) were analysed through coverage assessment of sequence alignment files (.bam) using RStudio and the following packages: ExomeDepth_(version 1.1.10), GenomicRanges_ (version_1.30.1), GenomeInfoDb_(version 1.14.0) and IRanges_(version 2.12.0). Classification of the variants was made according to the American College of Medical Genetics and Genomics (ACMG) guidelines [11]. Co-segregation analyses in first-degree relatives were performed by Sanger sequencing.

Four cases of ATS from two families are described. Genetic information, clinical features and their corresponding Human Phenotype Ontology (HPO) terms [12] are presented in Table 1,

Table 1

Molecular and phenotypic features
Patient	Patient 1	Patient 2	Patient 3	Patient 4
Family	Family 1			Family 2
cDNA	c.510G > A			1. c.417T > A 2. c.899T > G
Protein change	p.Trp170Ter			1. p.Tyr139Ter 2. p.Leu300Trp
Variant type	Nonsense			1. Nonsense 2. Missense
Zygosity	Homozygous			Compound heterozygosity
Year and age at the time of diagnosis	2019 4 years old	2019 2 years old	2019 11 years old	2019 2 years old
Year of birth and age at last investigation	2015 7 years old	2017 5 years old	2008 14 years old	2017 5 years old
Dimorphism
Low set ears (HP:0000369)	+	+	+	+
Hypertelorism (HP:0000316)	+	+	+	+
Downslanted palpebral fissures (HP:0000494)	+	+	+	+
High narrow palate (HP:0002705)	+	+	+	+
Prominent forehead (HP:0011220)	+	+
Sagging cheeks (HP:0034273)	+	+
Microcephaly (HP:0000252)	+
Hypoplasia of facial musculature (HP:0004660)			+
High anterior hairline (HP:0009890)			+
Joint hypermobility (HP: 0001382)	+	+	+	+
Pes valgus (HP:0008081)	+			+
Pes planus (HP:0001763)	+			+
Pectus excavatum (HP:0000767)				+
Extravascular affection
Diaphragmatic hernia (HP:0000776)	+			+
Inguinal hernia (HP:0000023)	+			+
Abnormal esophagus morphology (HP:0002031)	+
Dilatation of the renal pelvis (HP:0010946)	+
Congenital megaureter (HP:0008676)	+
Cryptorchidism (HP:0000028)	+
Temporal cortical atrophy (HP:0007112)	+
Microcephaly (HP:0000252)	+
Hypoplasia of corpus callosum (HP:0002079)		+
Myopia (HP:0000545)	+			+
Exotropia (HP:0000577)	+
Myopic astigmatism (HP:0500041)				+
Pleural effusion (HP:0002202)			+
Cardiovascular findings
Arterial tortuosity (HP:0005116): Most affected arteries	Aortic root and aortic arch (mainly ascending aorta) Carotid and vertebral branches Subclavian, humeral and arm and forearm vessels Pulmonary arteries	Vertebral arteries Transverse aortic arch Descending aorta Common-external iliacs Posterior tibialis	Vertebral and carotid arteries Subclavian arteries	Very elongated and tortuous aortic root and arch, with bending causing mild stenosis Supraaortic trunks Pulmonary arteries Upper extremities, iliac and femoral arteries
Arterial stenosis (HP:0100545)	Absent	Absent	Absent	Stenosis in the middle of the aortic arch due to marked elongation Focal stenosis at the origin of the left renal artery Right pulmonary artery kinked at the origin
Arterial tortuosity (HP:0005116): cerebrovascular arteries	Vertebrobasilar circulation and circle of Willis Tortuous and dysplastic internal carotids with leptomeningeal collaterals	Arteries of the carotid and vertebro-basilar circulation	Especially carotid circulation, with loops Middle and anterior cerebral arteries and vertebro-basilar circulation	Loops in both carotid and circle of Willis arteries Prominent posterior communicating arteries Right vertebral dominance, hypoplasia on the left
Cardiomyopathy (HP:0001638)	Absent	Absent	Absent	Absent

Family 1

Proband 1 was born on term as the second child of healthy consanguineous parents from Morocco. Pregnancy was well controlled and without any medical problems nor teratogenic exposures.

Neonatal presentation included microcephaly and a complex uropathy: severe bilateral pyelectasis with non-obstructive non-refluxing megaureter and cryptorchidism. Subsequently, skin hyperextensibility and dysmorphic features were noticeable, suggesting an extracellular matrix related disorder. Brain MRI at 1 year of age detected vascular tortuosity of the vertebrobasilar circulation and the circle of Willis, with a tortuous and dysplastic appearance of both internal carotids with leptomeningeal collaterals. Vascular MRI findings are shown in Fig. 1 and Table 1.

During follow-up, inguinal and diaphragmatic hernia were observed, as well as mild esophageal dilatation. He also developed ophthalmological involvement consisting of severe myopia and intermittent angle exotropia. MRI revealed a mild bilateral temporal cortical atrophy.

A previously reported [2] homozygous variant in SLC2A10 was identified and subsequently validated by Sanger sequencing: c.510G > A (p.Trp170Ter). No other relevant variants were found in the proband’s exome. Co-segregation studies showed that the variant was also present in homozygous state in two siblings and in heterozygous state in both parents.

Both siblings presented similar dysmorphic features (Table 1). Retrospectively registered, patient 2 had presented mild hypoplasia of the corpus callosum in neonatal age and patient 3 had pleural effusion with pulmonary hypoplasia, which resolved spontaneously.

To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking treatment was prescribed (atenolol 2 mg/kg/day). Currently, all three are in school without major problems.

Family 2

Proband 2 is an only child born to healthy non-consanguineous parents. In neonatal age he was diagnosed with a diaphragmatic hernia that recurred after surgery. Since early infancy, he presented pectus excavatum along with hypertelorism, low-set ears, downslanting palpebral fissures, narrow palate and joint hyperlaxity; thus, screening for associated cardiovascular defects was performed. ATS was suspected when severe tortuosity and elongation of the aorta was found, also affecting supraaortic trunks and pulmonary arteries. Atenolol was prescribed. Subsequently he developped inguinal hernia, severe myopia and astigmatism. He has normal neurological development without major problems except for the presence of dyslalia, which got better with speech therapy.

Clinical exome identified two heterozygous variants in SLC2A10: The first was c.417T > A (p.Tyr139Ter) (ClinVar identifier #161095, rs572620317), originally described as pathogenic in compound heterozygosis in a 2-year-old Japanese boy with ATS presenting with early-onset pulmonary emphysema [13]. The second variant, c.899T > G (p.Leu300Trp) (rs771702107), not previously described in homozygosis, had been rarely described in heterozygosis in healthy individuals with a minor allele frequency of 0.00000657 in the population (one out of 152222 individuals) according to gnomAD v.3.1.1 [14]). Bioinformatic prediction algorithms were consistent in assigning it a deleterious effect on the function or structure of the protein encoded by the SLC2A10 gene (11 over 11 in silico predictors including SIFT, Polyphen2_HDIV, Polyphen2_HVAR, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, MetaSVM, MetaLR, M.CAP). Segregation study in parents revealed that both variants were in trans; therefore following ACMG guidelines, the second variant was reclassified as likely pathogenic.

ATS is an extremely rare disorder [1, 4] with only 106 individuals with biallelic pathogenic variants in SLC2A10 identified to date [2, 7–9]. Four novel pediatric cases are described, contributing to the delineation of the phenotype. A compilation of the clinical findings is shown in Table 1.

Regarding the vascular affectation, a predominant supra-aortic tortuosity stands out (4/4, 100%), being less severe in the abdominal aorta and visceral branches (severe tortuosity in 2/4). It should be noted that the aortic root presented significant dilation in 2 out of the 4 patients (z-score + 4.1 in both [15]). Literature on ATS population is sparse, but aortic root involvement has been published to be about 16–21% [1, 2], which contrasts with higher rates seen in other syndromic diseases with a more selective aortic affection such as Marfan, Loeys-Dietz or vascular Ehlers-Danlos syndromes [16–18]. Also, unlike these syndromes, and despite the progressive arterial tortuosity seen in ATS, no arterial dissections have been confirmed to date [2, 4], suggesting that an early surgical approach might not be the best option in cases of slowly progressive aortic root dilatation [2].

A greater extravascular affectation is noteworthy in both probands when compared to the siblings of proband 1, affected by the same mutation. This fact would reflect the variable expressivity as an attribute of the syndrome; to date, no genotype-phenotype correlation has been observed, difficulting prognosis assessment from early genotyping [1, 2, 4, 6].

The fact that the diagnosis is achieved from the most severe cases or from segregation analysis suggests that the disease is underdiagnosed [4], also because distinctive craniofacial features are less prominent at young ages [2] and because some diagnostic panels for inheritable thoracic aortic diseases still may not include SLC2A10 [6]. Furthermore, since the diagnosed patients are the ones with the most severe clinical presentation, false beliefs regarding the perspective of survival may exist [1], considering the high mortality rates presented in old reports [10].

Concerning the extravascular features, urinary tract anomalies seem more prevalent, but only 11 patients with urogenital anomalies have been described so far [2]. A new case (proband 1) is reported. Screening abdominal ultrasound would be recommended in patients with ATS. Current evidence indicates that diaphragmatic hernia (19/65, 29%) and inguinal hernia (35/92, 38%) are frequent [2, 19]. In this study 2 more cases with diaphragmatic hernia are registered.

Most individuals affected with ATS are identified in early childhood but no clinical practice guidelines have been published to date; recommendations are made in analogy with other heritable disorders of connective tissue [1, 2, 6]. The progressive identification of novel cases would make it possible to determine the clinical spectrum and the expected evolution of these patients, in order to guide the clinical management accurately. A multidisciplinary and individualized approach is advised.

Although efficacy of any treatment has not been established in ATS, in analogy with the therapeutic approach for other genetic connective tissue diseases, such as Marfan and Loeys–Dietz syndromes [16], the reported patients are receiving beta-adrenergic blockers to prevent aortic dilatation.

To conclude, ATS is an extremely rare disorder of which 4 novel pediatric cases are described, contributing to its clinical delineation. A case with complex uropathy is included. Moreover, a non- previously described mutation (c.899T > G, p.Leu300Trp) in the SLC2A10 gene is presented; it has an allegedly deleterious effect according to bioinformatic prediction algorithms and it would be the cause of the disease in homozygosis or in association with another pathogenic variable.

Competing interests: Authors have no relevant financial or non-financial interests to disclose. No funds, grants, or other support was received.

Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Vall d’Hebron Hospital Campus. Informed consent for publication was obtained.

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No competing interests reported.

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Arterial tortuosity syndrome: phenotypic and cardiovascular features in 4 newly identified patients

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