Normal salivary gland ultrasonography could rule out the diagnosis of Sjögren’s syndrome in anti-SSA-negative patients with sicca syndrome

Objective To evaluate the relevance of salivary gland ultrasound (SGUS) and its place in the diagnostic algorithm in patients referred with dry syndrome (DS) for a suspicion of Sjögren’s syndrome (SS).Methods We included all patients assessed at our dedicated DS clinic from June 2015 to September 2019 for which a SGUS has been carried out. Images were read blindly and the worst salivary gland was scored according to OMERACT classification. Clinical features, disease activity and treatments were collected.Results 337 patients were seen from June 2015 to September 2019. 269 patients underwent SGUS. 77 patients were diagnosed with SS and 192 did not meet the ACR/EULAR criteria for SS: non-Sjögren’s DS (NSDS). Of these 192 patients, 60 had another possible cause of DS, and 132 patients were diagnosed with SAPS (sicca, asthenia, polyalgia syndrome).SGUS abnormalities were significantly higher in patients with SS versus NSDS: 51% vs 8% for a score ≥2 (p<0.0001), and 43% vs 3% for a score ≥3 (p<0.0001). SGUS score ≥2 had a specificity (Sp) of 91%, sensitivity (Se) of 57%, positive predictive value (PPV) of 72% and negative predictive value (NPV) of 82% for SS diagnosis. SGUS’s characteristics in SSA-negative patients were similar to the whole population (Se=42%, Sp=91%, PPV=42%, NPV=92%). The high specificity and NPV in this population could avoid labial salivary gland biopsy (LSGB) in SSA-negative patients with normal SGUS (186 patients, 69%).Conclusion SGUS is useful for SS diagnosis. If anti-SSA antibodies are negative and SGUS score <2, the diagnosis of SS is very improbable and LSGB could be avoided

Comparison between primary Sjögren’s disease patients with high or low level of dryness

Objectives To describe primary Sjögren’s disease (SjD) patients presenting no or low level of dryness and to compare them with SjD patients with oral or ocular dryness features.Methods All patients diagnosed with SjD according to AECG or ACR/EULAR criteria in our tertiary reference centre were included. Patients with high or low subjective symptoms or objective signs of dryness were compared.Results Overall, 509 patients were included for the comparison of patients with high (n=456) or low (n=53) level of subjective dryness and 472 for the comparison of patients with (n=359) or without (n=113) high objective dryness. Compared with patients with subjective dryness, patients without high subjective dryness were significantly younger (median 49 (39–62) years vs 58 (47–67) years, p<0.01), diagnosed earlier (median time from first symptoms to diagnosis 2 (0.5–4.5) years vs 4 (1–9.25), p=0.0056), more frequently anti-SSA positive ((83% vs 64%, p=0.008) and had less focal sialadenitis in minor salivary gland biopsy (69% vs 83%, p=0.02).The patients without high level of objective dryness (n=113) were also younger (51 (41–60) vs 58 (47–67) years, p<0.001) and were more frequently anti-SSA positive (79% vs 63%, p=0.002).In both groups, no difference was observed regarding disease activity.Conclusions Among the patients with SjD, those without high subjective or objective dryness features had a younger profile, a faster diagnosis which may result from a more acute onset, were more frequently anti-SSA positive than patients with high dryness features

3-Dimensional CBCT analysis of mandibular asymmetry in unilateral condylar hyperplasia

Three-dimensional quantification of asymmetry in UCH has not been reported yet, but would be useful for diagnosing and evaluating the degree of deformity in this disease. It enables profound decision-making and timing of surgery. Unilateral condylar hyperplasia (UCH) can subjectively be classified in hemimandibular elongation (HE), hemimandibular hyperplasia (HH) and a combination of these two (hybrid form). The main purpose of this study was to quantify mandibular asymmetry in UCH patients with a reliable and reproducible method. Secondly, it was evaluated whether the existing classification can be confirmed. 37 UCH-patients with progressive mandibular asymmetry, supported by a positive bone scan and/or such clinical progression that condylectomy was performed, were included in this retrospective study. A group of healthy subjects, matched for age and gender, was used as the control group. Cone-beam computed tomography (CBCT) scans were imported in Maxilim(®) software. Each mandibular half was divided into three skeletal segments (condyle, ramus, and body). Linear and volumetric measurements were calculated for these skeletal units on the affected and unaffected side, for both patients and controls. Significant differences between affected and unaffected sides in the patient group were found in condylar, ramus, and body segments for linear (p < 0.01) as well as for volumetric quantitative measurements (p < 0.0040). A mean linear difference between affected and unaffected sides in the condylar region of the UCH patient group was found of 3.6 mm (sd 2.9) versus 0.2 mm (sd 1.5) in controls. For volumetric measurements there was a mean difference between the left and right condyle of 718 mm(3) (sd 638) in the patient group versus 8 mm(3) (sd 225) difference in the control group. The condyle was the most affected segment. Differences between sides were significantly larger in the patient group than in the control group (p < 0.001). It was not possible to objectify differences between HE and HH. CBCT is a useful and accurate modality for quantification and evaluation of mandibular asymmetry in UCH. It enables objective monitoring. The existing classification in HE and HH could not be confirme

Family-based association study of the MTHFR polymorphism C677T in patients with nonsyndromic cleft lip and palate from central Europe.

Item does not contain fulltextOBJECTIVE: The 677C-->T allele in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been implicated in the etiology of nonsyndromic cleft lip and palate (CL/P). This study involved a family-based association study of the MTHFR polymorphism. PATIENTS/PARTICIPANTS: We examined 181 patients with CL/P of central European descent and their parents for this variant. RESULTS: The transmission disequilibrium test (TDT) did not confirm an association between the MTHFR 677C-->T polymorphism and nonsyndromic CL/P as previously suggested (p = .36). When comparing the offspring of mothers with periconceptional use of folate to those without, no statistically significant differences were found (p = .708). CONCLUSION: Our data suggest that the MTHFR 677C-->T polymorphism does not make a major contribution to the occurrence of CL/P among central Europeans

Deletions and loss-of-function variants in TP63 associated with orofacial clefting

We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected

Novel IRF6 Mutations Detected in Orofacial Cleft Patients by Targeted Massively Parallel Sequencing

Common variants in interferon regulatory factor 6 (IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.status: publishe

AGORA, a data- and biobank for birth defects and childhood cancer

Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection.status: publishe

Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.status: publishe

Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

Purpose:We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.Methods:WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls.Results:We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo.Conclusion:Mutations in LRP6 cause TA in humans