Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene

<p>Abstract</p> <p>Background</p> <p>Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.</p> <p>Methods</p> <p>Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the <it>EVC/EVC2 </it>locus. The results did not exclude linkage, so samples were sequenced for mutations.</p> <p>Results</p> <p>We identified a c.1868T>C mutation in <it>EVC</it>, which predicts p.L623P, and was homozygous in affected individuals.</p> <p>Conclusion</p> <p>We conclude that this <it>EVC </it>mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. <it>EVC </it>mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.</p

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene

<p>Abstract</p> <p>Background</p> <p>Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.</p> <p>Methods</p> <p>Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the <it>EVC/EVC2 </it>locus. The results did not exclude linkage, so samples were sequenced for mutations.</p> <p>Results</p> <p>We identified a c.1868T>C mutation in <it>EVC</it>, which predicts p.L623P, and was homozygous in affected individuals.</p> <p>Conclusion</p> <p>We conclude that this <it>EVC </it>mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. <it>EVC </it>mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.</p

Molecular and clinical analysis of Ellis-van Creveld syndrome in the United Arab Emirates

<p>Abstract</p> <p>Background</p> <p>Ellis-van Creveld (EvC) syndrome is an autosomal recessive chondrodysplastic condition with clinical manifestations that include short-limbs and ribs, postaxial polydactyly and dysplastic nails and teeth. In about two thirds of patients, mutations in either <it>EVC </it>or <it>EVC2 </it>genes have been found to be the underlying cause.</p> <p>Methods</p> <p>In this paper, we describe the molecular (DNA sequencing) and clinical analysis of six children diagnosed with EvC from four different families from the United Arab Emirates (UAE).</p> <p>Results</p> <p>All the children had the common clinical and radiological features of this syndrome. However, DNA sequence analysis of the genes shown to be involved (<it>EVC </it>and <it>EVC2</it>) revealed a novel splice site mutation (c.2047-1G>T) in intron 13 of <it>EVC2 </it>gene in one family. In addition, we confirm previous mutational analyses that showed a truncating mutation in exon 13 of <it>EVC </it>gene (c.1813C>T; p.Q605X) in the second family and a single nucleotide deletion (c.981delG; p.K327<it>fs</it>) in exon 8 of <it>EVC2 </it>gene in the third family. No mutations in the exons, splice sites or the promoter regions of either gene have been found in the index case of the fourth family who exhibited "EvC-like" features.</p> <p>Conclusions</p> <p>Given the small population size of UAE, our data illustrates further the molecular heterogeneity observed in EvC patients and excludes the possibility of a common founder effect for this condition in the UAE reflecting the current ethnic diversity of the country.</p

Auditory dysfunction in type 2 Stickler Syndrome.

PURPOSE: To present the extent and site of lesion of auditory dysfunction in a large cohort of individuals with type 2 Stickler Syndrome. Type 2 Stickler Syndrome results from a mutation in the gene coding for α-1 type XI pro-collagen, which has been identified in the human vitreous, cartilage and the cochlea of the mouse. The condition is characterised by classic ocular abnormalities, auditory dysfunction, osteoarthropathy and oro-facial dysplasia. METHODS: This is a population study which used a combination of audiometric, tympanometric, and self-report measures on a series of 65 individuals (mean age 29.2 years, range 3-70, female 63.1%) with genetically confirmed type 2 Stickler Syndrome. RESULTS: Hearing impairment was identified in at least one ear for 69% of individuals. Analysis against age-matched normative data showed that reduced hearing sensitivity was present across all test frequencies. Sensorineural hearing loss was most common (77% of ears), with conductive (3%), mixed (7%) and no hearing loss (13%), respectively. The proportion of hypermobile tympanic membranes (24%) was less than previously documented in type 1 Stickler Syndrome. When present, this appears to arise as a direct result of collagen abnormalities in the middle ear. Self-report measures of speech and spatial hearing in sound were comparable to a non-syndromic cohort with similar audiometric thresholds. CONCLUSIONS: Auditory impairment in type 2 Stickler Syndrome is predominantly associated with cochlear hearing loss of varying severities across affected individuals. The impact on hearing thresholds can be seen across the frequency range, suggesting a contribution of defective collagen throughout the cochlea. Self-report questionnaires showed that difficulties understanding speech, and spatial information in sound (such as that used for localisation), were worse than a young, normal-hearing population but comparable to a non-syndromic cohort with similar audiometric thresholds. Therefore, it is likely that hearing loss in type 2 Stickler Syndrome arises in the auditory periphery, without significant central processing deficits

SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma.

Purpose: Affecting children by age 3, primary congenital glaucoma (PCG) can cause debilitating vision loss by the developmental impairment of aqueous drainage resulting in high intraocular pressure (IOP), globe enlargement, and optic neuropathy. TEK haploinsufficiency accounts for 5% of PCG in diverse populations, with low penetrance explained by variable dysgenesis of Schlemm's canal (SC) in mice. We report eight families with TEK-related PCG, and provide evidence for SVEP1 as a disease modifier in family 8 with a higher penetrance and severity. Methods: Exome sequencing identified coding/splice site variants with an allele frequency less than 0.0001 (gnomAD). TEK variant effects were assayed in construct-transfected HEK293 cells via detection of autophosphorylated (active) TEK protein. An enucleated eye from an affected member of family 8 was examined via histology. SVEP1 expression in developing outflow tissues was detected by immunofluorescent staining of 7-day mouse anterior segments. SVEP1 stimulation of TEK expression in human umbilical vascular endothelial cells (HUVECs) was measured by TaqMan quantitative PCR. Results: Heterozygous TEK loss-of-function alleles were identified in eight PCG families, with parent-child disease transmission observed in two pedigrees. Family 8 exhibited greater disease penetrance and severity, histology revealed absence of SC in one eye, and SVEP1:p.R997C was identified in four of the five affected individuals. During SC development, SVEP1 is secreted by surrounding tissues. SVEP1:p.R997C abrogates stimulation of TEK expression by HUVECs. Conclusions: We provide further evidence for PCG caused by TEK haploinsufficiency, affirm autosomal dominant inheritance in two pedigrees, and propose SVEP1 as a modifier of TEK expression during SC development, affecting disease penetrance and severity

Ellis-Van Creveld syndrome

Ellis-van Creveld syndrome (EVC) is a chondral and ectodermal dysplasia characterized by short ribs, polydactyly, growth retardation, and ectodermal and heart defects. It is a rare disease with approximately 150 cases reported worldwide. The exact prevalence is unknown, but the syndrome seems more common among the Amish community. Prenatal abnormalities (that may be detected by ultrasound examination) include narrow thorax, shortening of long bones, hexadactyly and cardiac defects. After birth, cardinal features are short stature, short ribs, polydactyly, and dysplastic fingernails and teeth. Heart defects, especially abnormalities of atrial septation, occur in about 60% of cases. Cognitive and motor development is normal. This rare condition is inherited as an autosomal recessive trait with variable expression. Mutations of the EVC1 and EVC2 genes, located in a head to head configuration on chromosome 4p16, have been identified as causative. EVC belongs to the short rib-polydactyly group (SRP) and these SRPs, especially type III (Verma-Naumoff syndrome), are discussed in the prenatal differential diagnosis. Postnatally, the essential differential diagnoses include Jeune dystrophy, McKusick-Kaufman syndrome and Weyers syndrome. The management of EVC is multidisciplinary. Management during the neonatal period is mostly symptomatic, involving treatment of the respiratory distress due to narrow chest and heart failure. Orthopedic follow-up is required to manage the bones deformities. Professional dental care should be considered for management of the oral manifestations. Prognosis is linked to the respiratory difficulties in the first months of life due to thoracic narrowness and possible heart defects. Prognosis of the final body height is difficult to predict

The C-Type Lectin of the Aggrecan G3 Domain Activates Complement

Excessive complement activation contributes to joint diseases such as rheumatoid arthritis and osteoarthritis during which cartilage proteins are fragmented and released into the synovial fluid. Some of these proteins and fragments activate complement, which may sustain inflammation. The G3 domain of large cartilage proteoglycan aggrecan interacts with other extracellular matrix proteins, fibulins and tenascins, via its C-type lectin domain (CLD) and has important functions in matrix organization. Fragments containing G3 domain are released during normal aggrecan turnover, but increasingly so in disease. We now show that the aggrecan CLD part of the G3 domain activates the classical and to a lesser extent the alternative pathway of complement, via binding of C1q and C3, respectively. The complement control protein (CCP) domain adjacent to the CLD showed no effect on complement initiation. The binding of C1q to G3 depended on ionic interactions and was decreased in D2267N mutant G3. However, the observed complement activation was attenuated due to binding of complement inhibitor factor H to CLD and CCP domains. This was most apparent at the level of deposition of terminal complement components. Taken together our observations indicate aggrecan CLD as one factor involved in the sustained inflammation of the joint

A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis

Background Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA). Methods Patients with moderate to severe RA who had received ≥12 weeks’ stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85. Results A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group (n = 3 b.i.d; n = 10 t.i.d.) and 20 (61%) in the GSK2982772 group (n = 3 b.i.d; n = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints–C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms. Conclusions These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA. Trial registration ClinicalTrials.gov Identifier: NCT02858492. Registered 8 August 2016.</p

In-utero epigenetic factors are associated with early-onset myopia in young children

10.1371/journal.pone.0214791PLoS One145e0214791POLNCGUSTO (Growing up towards Healthy Outcomes