Bi-allelic Loss-of-Function Mutations in the NPR-C Receptor Result in Enhanced Growth and Connective Tissue Abnormalities

Abstract Sneddon syndrome is a rare disorder affecting small and medium-sized blood vessels that is characterized by the association of livedo reticularis and stroke. We performed whole-exome sequencing (WES) in 2 affected siblings of a consanguineous family with childhood-onset stroke and identified a homozygous nonsense mutation within the epidermal growth factor repeat (EGFr) 19 of NOTCH3, p.(Arg735Ter). WES of 6 additional cases with adult-onset stroke revealed 2 patients carrying heterozygous loss-of-function variants in putative NOTCH3 downstream genes, ANGPTL4, and PALLD. Our findings suggest that impaired NOTCH3 signaling is one underlying disease mechanism and that bi-allelic loss-of-function mutation in NOTCH3 is a cause of familial Sneddon syndrome with pediatric stroke.

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Labour outcomes in siblings with channelopathy associated insensitivity to pain due to bi-alleleic SCN9A mutations

Obstetric Medicine ◽

10.1258/om.2012.110096 ◽

2012 ◽

Vol 5 (4) ◽

pp. 181-182 ◽

Cited By ~ 2

Author(s):

A Haestier ◽

S Hamilton ◽

R J Chilvers

Keyword(s):

Pelvic Fractures ◽

Sensory Loss ◽

Uneventful Recovery ◽

Allelic Loss ◽

Loss Of Function ◽

Case Histories ◽

Experienced Pain ◽

Caucasian Family ◽

Postpartum Outcomes ◽

Insensitivity To Pain

The gene SCN9A encodes for the voltage-gated sodium channel Nav1.7, which is highly expressed in pain sensing neurons. Bi-allelic ‘loss of function’ mutations result in a channelopathy associated with insensitivity to pain and anosmia. This is the first report of the labour and postpartum outcomes of two sisters who belong to a non-consanguineous Caucasian family with homozygous SCN9A mutations. Neither sister experienced pain during labour; this had major implications for the staff titrating the syntocinon for labour augmentation and contributed towards their ultimate delivery by caesarean section. During the postpartum period, one of the sisters developed lower limb sensory loss and investigations revealed a spinal haematoma and unrecognized bilateral pelvic fractures. The other sister had an uneventful recovery and both babies are well. These case histories underline the importance of pain in labour management and its function in alerting patients and staff to problems during the puerperium.

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Recurrence of cervical artery dissection

Neurology ◽

10.1212/wnl.0000000000005324 ◽

2018 ◽

Vol 90 (16) ◽

pp. e1372-e1378 ◽

Cited By ~ 11

Author(s):

Manja Kloss ◽

Caspar Grond-Ginsbach ◽

Peter Ringleb ◽

Ingrid Hausser ◽

Werner Hacke ◽

...

Keyword(s):

Connective Tissue ◽

Recurrent Events ◽

Clinical Symptoms ◽

Artery Dissection ◽

Cervical Artery Dissection ◽

Consecutive Series ◽

Initial Event ◽

Cervical Artery ◽

Tissue Abnormalities

ObjectiveTo explore the recurrence of cervical artery dissection (CeAD).MethodsA single-center consecutive series of 282 CeAD patients was prospectively recruited during first admission from 1995 to 2012. Patients with a follow-up of at least 1 year (n = 238) were eligible for the current analysis. All patients with clinical symptoms or signs of recurrent CeAD on ultrasound were examined by MRI. Dermal connective tissue morphology was studied in 108 (45.4%) patients.ResultsMedian follow-up was 52 months (range 12–204 months). In all, 221 (92.8%) patients presented with monophasic CeAD, including 188 (79.0%) patients with a single CeAD event, 11 (4.6%) with simultaneous dissections in multiple cervical arteries, and 22 (9.2%) with subsequent events within a single phase of 4 weeks. Seventeen patients (7.1%) had late (>1 month after the initial event) recurrent CeAD events, including 5 (2.1%) with multiple recurrences. Patients with late recurrences were younger (37.5 ± 6.9 years) than those without (43.8 ± 9.9; p = 0.011). Ischemic stroke occurred in 164 (68.9%) patients at first diagnosis, but only 4 of 46 (8.7%) subsequent events caused stroke (p < 0.0001), while 19 (41.3%) were asymptomatic. Connective tissue abnormalities were found in 54 (56.3%) patients with monophasic and 8 (66.7%) with late recurrent dissections (p = 0.494).ConclusionTwenty-two (9.2%) patients had new CeAD events within 1 month and 17 (7.1%) later recurrences. The risk for new events was significantly higher (about 60-fold) during the acute phase than during later follow-up. Connective tissue abnormalities were not more frequent in patients with late recurrent events than in those with monophasic CeAD.

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