Clinical Variability in Two Macedonian Families with Arterial Tortuosity Syndrome.

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder caused by mutations in the solute carrier family 2 member 10 (SLC2A10) gene encoding a glucose/ascorbic acid transporter. The clinical features of ATS are mild-to-severe tortuosity of the large and medium arteries throughout the body, accompanied by dysmorphisms and joint laxity. Vascular changes in different parts of the body lead to stenosis and/or aneurysms requiring difficult surgical procedures. Here we present two new patients with ATS from two unrelated families. Patient 1 presented at 10 years of age with headache and typical physical appearance, delicate skeleton, large visible pulsation of the carotid arteries in the neck, and joint laxity. On computed tomography (CT) angiography she had severe tortuosity of the aortal branches and cerebral arteries, but no significant tortuosity of the pulmonary arteries. Two cousins of the girl carried the same homozygous c.254T>C, p.(Leu85Pro) mutation in SLC2A10, however, they additionally had a severe involvement of the pulmonary vessels. Patient 2 was a 9-year-old girl diagnosed with severe tortuosity and stenosis of the pulmonary arteries and progressive myocardiopathy. Her physical appearance was very similar to Patient 1, except that she also had growth retardation. After long-term follow-up by cardiologists, she underwent cardiac surgery abroad, with an unfavorable outcome. Homozygosity for the c.685C>T, p.(Arg229*) mutation in the SLC2A10 gene was detected. Consanguinity was disclosed within both families. Our findings confirm the intrafamilial phenotype variability of ATS. A novel finding is the severe tortuosity of cerebral arteries causing migraine that has not been described before in a child with ATS.

Spectrum of mucocutaneous, ocular and facial features and delineation of novel presentations in 62 classical Ehlers-Danlos syndrome patients.

Classical Ehlers-Danlos syndrome (cEDS) is characterized by marked cutaneous involvement, according to the Villefranche nosology and its 2017 revision. However, the diagnostic flow-chart that prompts molecular testing is still based on experts' opinion rather than systematic published data. Here we report on 62 molecularly characterized cEDS patients with focus on skin, mucosal, facial, and articular manifestations. The major and minor Villefranche criteria, additional 11 mucocutaneous signs and 15 facial dysmorphic traits were ascertained and feature rates compared by sex and age. In our cohort, we did not observe any mandatory clinical sign. Skin hyperextensibility plus atrophic scars was the most frequent combination, whereas generalized joint hypermobility according to the Beighton score decreased with age. Skin was more commonly hyperextensible on elbows, neck, and knees. The sites more frequently affected by abnormal atrophic scarring were knees, face (especially forehead), pretibial area, and elbows. Facial dysmorphism commonly affected midface/orbital areas with epicanthal folds and infraorbital creases more commonly observed in young patients. Our findings suggest that the combination of ≥1 eye dysmorphism and facial/forehead scars may support the diagnosis in children. Minor acquired traits, such as molluscoid pseudotumors, subcutaneous spheroids, and signs of premature skin aging are equally useful in adults.

High prevalence of radiological vertebral fractures in adult patients with Ehlers-Danlos syndrome.

Previous studies have reported an increased prevalence of osteoporosis in Ehlers­Danlos syndrome (EDS), but these were limited by a small number of patients and lack of information on fragility fractures. In this crosssectional study, we evaluated the prevalence of radiological vertebral fractures (by quantitative morphometry) and bone mineral density (BMD, at lumbar spine, total hip and femoral neck by dual-energy X-ray absorptiometry) in 52 consecutive patientswith EDS (10 males, 42 females; median age 41 years, range: 21­71; 12with EDS classic type, 37 with EDS hypermobility type, 1 with classic vascular-like EDS, and 2 without specific classification) and 197 control subjects (163 females and 34 males; median age 49 years, range: 26­83) attending an outpatient bone clinic. EDS patients were also evaluated for back pain by numeric pain rating scale (NRS- 11).Vertebral fractures were significantly more prevalent in EDS as compared to the control subjects (38.5% vs. 5.1%; p b 0.001) without significant differences in BMD at either skeletal sites. In EDS patients, the prevalence of vertebral fractures was not significantly (p = 0.72) different between classic and hypermobility types. BMD was not significantly different between fractured and non-fractured EDS patients either at lumbar spine (p = 0.14), total hip (p=0.08), or femoral neck (p=0.21). Severe back pain(≥7 NRS)was more frequent in EDS patients with vertebral fractures as compared to thosewithout fractures (60% vs. 28%; p=0.04). Inconclusion, this is the first study showing high prevalence of vertebral fractures in a relatively large population of EDS patients. Vertebral fractures were associated with more severe back pain suggesting a potential involvement of skeletal fragility in determining poor quality of life. The lack of correlation between vertebral fractures and BMD is consistent with the hypothesis that bone quality may be impaired in EDS.