Expanding the clinical and mutational spectrum of the Ehlers–Danlos syndrome,dermatosparaxis type

PurposeThe Ehlers–Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective tissue disorder caused by deficient activity of ADAMTS-2, an enzyme that cleaves the aminoterminal propeptide domain of types I, II, and III procollagen. Only 10 EDS dermatosparaxis patients have been reported, all presenting a recognizable phenotype with characteristic facial gestalt, extreme skin fragility and laxity, excessive bruising, and sometimes major complications due to visceral and vascular fragility.MethodsWe report on five new EDS dermatosparaxis patients and provide a comprehensive overview of the current knowledge of the natural history of this condition.ResultsWe identified three novel homozygous loss-of-function mutations (c.2927_2928delCT, p.(Pro976Argfs*42); c.669_670dupG, p.(Pro224Argfs*24); and c.2751-2A>T) and one compound heterozygous mutation (c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs26*)) in ADAMTS2 in five patients from four unrelated families. Three of these displayed a phenotype that was strikingly milder than that of previously reported patients.ConclusionThis study expands the clinical and molecular spectrum of the dermatosparaxis type of EDS to include a milder phenotypic variant and stresses the importance of good clinical criteria. To address this, we propose an updated set of criteria that accurately captures the multisystemic nature of the dermatosparaxis type of EDS.Genet Med 18 9, 882–891.     

Proprioceptive sensitivity in Ehlers–Danlos syndrome patients

Reaching movements are rapidly adapted following training with rotated visual feedback of the hand. Our laboratory has also found that this visuomotor adaptation results in changes in estimates of felt hand position (proprioceptive recalibration) in the direction of the visuomotor distortion (Cressman and Henriques in J Neurophysiol 102:3505–3518, 2009; Cressman et al. in Exp Brain Res 205:533–544, 2010). In the current study, we investigated proprioceptive acuity and proprioceptive recalibration in a group of individuals with Ehlers–Danlos syndrome (EDS), a degenerative condition associated with collagen malformation. Some studies have suggested that these patients may have proprioceptive impairments, but the exact nature of the impairment is unclear (Rombaut et al. in Clin Rheumatol 29:289–295, 2010a). In this study, we measured the ability of EDS patients to estimate their felt hand position and tested whether these estimates changed following visuomotor adaptation. We found EDS patients were less precise in estimating their felt hand position in the peripheral workspace compared to healthy controls. Despite this poorer sensitivity, they recalibrated hand proprioception to the same extent as healthy controls. This is consistent with other populations who experience proprioceptive deficits (e.g. the elderly, Parkinson’s disease patients), suggesting that sensory noise does not influence the extent of either motor or sensory plasticity.     

Frequency of de novo variants and parental mosaicism in vascular Ehlers–Danlos syndrome

PurposeVascular Ehlers–Danlos syndrome (vEDS) is a rare inherited autosomal dominant disorder caused by COL3A1 pathogenic variants. A high percentage of de novo cases has been suggested. Part of it could be due to parental mosaicism, but its frequency is unknown.MethodsThis retrospective study included a large series of COL3A1-confirmed vEDS probands with family information. The frequency of de novo cases was evaluated and the distribution of the type of variants was compared according to the mode of inheritance. The COL3A1 mosaicism was studied by deep targeted next- generation sequencing (NGS) from parental blood DNA.ResultsOut of 177 vEDS probands, 90 had a negative family history, suggesting a high rate (50.8%) of de novo pathogenic variants, enriched in the more severe COL3A1 variants (no null variant). Among those, both parental DNA were available in 36 cases and one parental DNA in 18 cases. NGS detected only one mosaicism from maternal blood DNA (allelic ratio 18%), which was confirmed in saliva (allelic ratio 22%).ConclusionvEDS is characterized by a high frequency of de novo pathogenic variants. Parental mosaicism is rare (2–3%), but should be systematically searched with targeted NGS, taking into account its importance in genetic counseling.     

Pregnancy-related deaths and complications in women with vascular Ehlers–Danlos syndrome

PurposeThe purpose of this study was to characterize the nature and magnitude of pregnancy risks in women with vascular Ehlers–Danlos syndrome.MethodsPregnancy-related death rate was determined by a review of pedigrees of families with vascular Ehlers–Danlos syndrome. Maternal morbidity was characterized through semistructured interviews with women with vascular Ehlers–Danlos syndrome or their next of kin.ResultsPregnancy-related deaths occurred in 30 of 565 deliveries (5.3%). There was no difference in Kaplan–Meier survival curves between parous versus nulliparous women with vascular Ehlers–Danlos syndrome. Interviews with 39 women indicated that 46% of deliveries were uncomplicated. The most common pregnancy-related complications were third-/fourth-degree lacerations (20%) and preterm delivery (19%). Life-threatening complications occurred in 14.5% of deliveries and included arterial dissection/rupture (9.2%), uterine rupture (2.6%), and surgical complications (2.6%). There were 5 maternal deaths in 76 deliveries (6.5%).ConclusionThe risk of pregnancy-related complications is increased in women with vascular Ehlers–Danlos syndrome compared with the general population; however, survival data indicate that pregnancy does not appear to affect overall mortality compared with nulliparous women with vascular Ehlers–Danlos syndrome. The data were insufficient to determine whether mode or timing of delivery influenced risk of complications. Women with vascular Ehlers–Danlos syndrome should be engaged in a shared decision-making process when contemplating pregnancy and pregnancy management.Genet Med16 12, 874–880.     

Evaluating perinatal and neonatal outcomes among children with vascular Ehlers–Danlos syndrome

PurposeBirth outcomes data for patients with vascular Ehlers–Danlos syndrome (VEDS) are limited.MethodsPatients with a pathogenic or likely pathogenic COL3A1 variant were included. Outcomes included gestational age (GA), birthweight (BW), and maternal complications. Birth outcomes were first compared with that of US population data, then compared by sex, maternal affected status, and COL3A1 genotype.ResultsA total of 41 children were included (70.7% male), including 32 with high-risk (missense and splice site) variants. Preterm birth (<37 weeks) was more common in patients with VEDS than in the US population (48.8% vs 12.2%, P < .0001). Low BW (<2.5 kg) was also more common in patients with VEDS than in the US population (P < .0001), although, it was appropriate after GA adjustment (median GA-adjusted z-score 0.01 vs z-score 0.0, P = .26). No differences in GA or BW were observed by sex or maternal affected status. Those with high-risk variants were more likely to be born preterm than those with haploinsufficient variants, although this did not meet significance criteria (53% vs 33%, P = .35). Of the 6 affected mothers, 5 had perinatal complications.ConclusionPreterm birth is more common in children with VEDS than in the general population. Maternal affected status is not associated with preterm birth, suggesting that risk is conferred by the fetal VEDS diagnosis alone.