Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

BACKGROUND: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. METHODS: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. MAIN RESULTS: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC. CONCLUSIONS: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

A Genetic Association Study of a Specific Gene and Severe Form of Resorption in the Edentulous Mandible in the Egyptian Population.

PURPOSE: To investigate for the first time in Egypt and the Middle East the relationship between a specific gene and the presence of severely resorbed edentulous mandibular ridges in a sample of the Egyptian population. MATERIALS AND METHODS: The study was conducted on 50 subjects divided into case and control groups according to the residual ridge height. Saliva was used as a convenient source of DNA in the dental clinic. A certain genetic variation (1772C>T) in an important gene related to bone healing (hypoxia-inducible factor-1 alpha [HIF1-α] gene) was selected. The genetic variation 1772C>T is a single nucleotide polymorphism (SNP) that occurs when corresponding sequences of DNA from different individuals differ at one base. Then, we have 2 forms of the gene (2 alleles): C and T. SNPs typically have 3 genotypes; in this study, they are the CC, CT, and TT genotypes. Polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) was the method performed for genotyping. The statistical significance of the results was evaluated by the Chi-square test and Fisher Exact test. RESULTS: A statistically significant difference in the distribution of the TT genotype between both groups was detected with p-value = 0.049. There was also a difference in the distribution of the CC and CT genotypes, but it was not statistically significant, since the p-values were 0.733 and 0.145, respectively. The T alleles were more abundant in the case group, while the control group showed more frequency of the C allele with no statistical significance. CONCLUSION: The TT genotype of the 1772C>T polymorphism of HIF1-α gene is related to the presence of severely atrophied residual ridges in completely edentulous Egyptians. This can be used as a marker to predict the future condition of the ridge using saliva samples. Further studies on larger scale are recommended.

11p13 microduplication: a differential diagnosis of Silver-Russell syndrome?

BACKGROUND: Silver-Russel syndrome (SRS) is a congenital disorder which is mainly characterized by intrauterine and postnatal growth retardation, relative macrocephaly, and characteristic (facial) dysmorphisms. The majority of patients shows a hypomethylation of the imprinting center region 1 (IC1) in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat), but in addition a broad spectrum of copy number variations (CNVs) and monogenetic variants (SNVs) has been reported in this cohort. These heterogeneous findings reflect the clinical overlap of SRS with other congenital disorders, but some of the CNVs are recurrent and have therefore been suggested as SRS-associated loci. However, this molecular heterogeneity makes the decision on the diagnostic workup of patients with SRS features challenging. CASE PRESENTATION: A girl with clinical features of SRS but negatively tested for the IC1 hypomethylation and upd(7)mat was analyzed by whole genome sequencing in order to address both CNVs and SNVs in the same run. We identified a 11p13 microduplication affecting a region overlapping with a variant reported in a previously published patient with clinical features of Silver-Russel syndrome. CONCLUSIONS: The identification of a 11p13 microduplication in a patient with SRS features confirms the considerable contribution of CNVs to SRS-related phenotypes, and it strengthens the evidence for a 11p13 microduplication syndrome as a differential diagnosis SRS. Furthermore, we could confirm that WGS is a valuable diagnostic tool in patients with SRS and related disorders, as it allows CNVs and SNV detection in the same run, thereby avoiding a time-consuming diagnostic testing process.

Clinical reappraisal of the composite international diagnostic interview version 3.3 in Qatar's National Mental Health Study.

OBJECTIVES: Lifetime DSM-5 diagnoses generated by the lay-administered Composite International Diagnostic Interview for DSM-5 (CIDI) in the World Mental Health Qatar (WMHQ) study were compared to diagnoses based on blinded clinician-administered reappraisal interviews. METHODS: Telephone follow-up interviews used the non-patient edition of the Structured Clinician Interview for DSM-5 (SCID) oversampling respondents who screened positive for five diagnoses in the CIDI: major depressive episode, mania/hypomania, panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder. Concordance was also examined for a diagnoses of post-traumatic stress disorder based on a short-form versus full version of the PTSD Checklist for DSM-5 (PCL-5). RESULTS: Initial CIDI prevalence estimates differed significantly from the SCID for most diagnoses ( χ 1 2 ${\chi }_{1}^{2}$  = 6.6-31.4, p = 0.010 < 0.001), but recalibration reduced most of these differences and led to consistent increases in individual-level concordance (AU-ROC) from 0.53-0.76 to 0.67-0.81. Recalibration of the short-form PCL-5 removed an initially significant difference in PTSD prevalence with the full PCL-5 (from χ 1 2 ${\chi }_{1}^{2}$  = 610.5, p < 0.001 to χ 1 2 ${\chi }_{1}^{2}$  = 2.5, p = 0.110) while also increasing AU-ROC from 0.76 to 0.81. CONCLUSIONS: Recalibration resulted in valid diagnoses of common mental disorders in the Qatar National Mental Health Survey, but with inflated prevalence estimates for some disorders that need to be considered when interpreting results.

Design and field procedures for the clinical reappraisal of the Composite International Diagnostic Interview version 3.3 in Qatar's national mental health study.

BACKGROUND: The Composite International Diagnostic Interview (CIDI) has been clinically reappraised in several studies conducted mainly in the US and Europe. This report describes the methodology used to conduct one of the Middle East's largest clinical reappraisal studies. The study was carried out in conjunction with the World Mental Health Qatar-the first national psychiatric epidemiological study of common mental disorders in the country. This study aimed to evaluate the diagnostic consistency of core modules of the newly translated and adapted Arabic version of the CIDI 5.0 against the independent clinical diagnoses based on the Structured Clinical Interview for DSM-5 (SCID-5). METHODS: Telephone follow-up interviews were administered by trained clinicians using the latest research edition of the SCID for DSM-5. Telephone administered interviews were key in the data collection, as the study took place during the COVID-19 pandemic. RESULTS: Overall, within 12 months, 485 interviews were completed. The response rate was 52%. Quality control monitoring documented excellent adherence of clinical interviews to the rating protocol. CONCLUSIONS: The overall methods used in this study proved to be efficient and effective. For future research, instrument cultural adaptation within the cultural context is highly recommended.

Red cell distribution width and mean platelet volume in rheumatoid arthritis patients: Its association with disease activity.

INTRODUCTION: Hemogram parameters have been recently proposed as markers of inflammation in various studies from different parts of the world. Two of these hemogram parameters are red cell distribution width (RDW) and mean platelet volume (MPV). AIM: To evaluate the relation between RDW and MPV with disease activity of rheumatoid arthritis. To assess whether RDW and MPV can be used to follow disease activity in RA patients. METHODS: This is an observational cross-sectional study that was carried out on 60 rheumatoid arthritis patients who fulfilled the ACR/EULAR2010 classification criteria of RA attending to Rheumatology and Rehabilitation inpatient and outpatient clinics at Zagazig University Hospitals. All cases were subjected to full history taking, clinical examination, and laboratory investigations; differential complete blood picture (CBC), acute phase reactants (CRP and ESR), rheumatoid factor (RF) and anti-cyclic-citrullinated peptide (anti-CCP) antibodies. Disease activity was measured by disease activity score 28 (DAS28). RESULTS: The cut-off levels of RDW and MPV were 14.85 and 11.25. Patients with RDW>14.85 had higher Disease Activity Score 28 (DAS28; p=0.0003), ESR (p=0.0001) and CRP (p=0.0001). RDW was positively correlated with disease activity markers (ESR, CRP and DAS28) in rheumatoid arthritis patients. But, DAS28 was not different between patients with MPV>11.25 and <11.25. CONCLUSION: RDW was strongly correlated with disease activity. Also, RDW was better than ESR and CRP in detecting RA disease activity. According to these findings we suggest that RDW can be used in clinics to follow disease activity. In addition, RDW is widely available; as it's usually included in routine complete blood picture and there will be no need for further cost.

Mosaic Variegated Aneuploidy Syndrome and Noonan Syndrome in the Same Family.

Introduction: Mosaic variegated aneuploidy syndrome 2 (MVA2) and Noonan syndrome (NS) are 2 genetic disorders with overlapping clinical features, including intrauterine growth retardation, dysmorphic features, and heart defects. Whereas NS is a well-known congenital entity, MVA2 is rare, and only a few cases have been reported in the literature. Case Presentation: We report on the molecular findings in 3 patients with short stature phenotypes from the same family. By considering the clinical overlap between the patients, a common cause for the small stature was assumed in the beginning, but by whole exome analysis (WES) it turned out that the phenotypes were caused by different pathogenic variants in CEP57 and PTPN11, respectively. As a result, both MVA2 and NS occurred in the same family. Conclusion: As our example shows, the parallel occurrence of pathogenic alterations in different genes in the same family constitutes a challenge for the interpretation of WES data and has to be considered. The diagnostic workup illustrates the need for a careful anamnesis and molecular documentation in affected and healthy family members. The knowledge on the different molecular causes underlying the features of the affected family members is the basis for personalised therapeutic managements and can avoid unnecessary burden and even contraindicated therapies; while in patients with NS carrying PTPN11 variants growth hormone treatment leads to height increase, patients with MVA2 carrying CEP57 probably do not benefit from it.

Red Cell Distribution Width and Mean Platelet Volume in Rheumatoid Arthritis Patients: Its Association With Disease Activity.

INTRODUCTION: Hemogram parameters have been recently proposed as markers of inflammation in various studies from different parts of the world. Two of these hemogram parameters are red cell distribution width (RDW) and mean platelet volume (MPV). AIM: To evaluate the relation between RDW and MPV with disease activity of rheumatoid arthritis. To assess whether RDW and MPV can be used to follow disease activity in RA patients. METHODS: This is an observational cross-sectional study that was carried out on 60 rheumatoid arthritis patients who fulfilled the ACR/EULAR2010 classification criteria of RA attending to Rheumatology and Rehabilitation inpatient and outpatient clinics at Zagazig University Hospitals. All cases were subjected to full history taking, clinical examination, and laboratory investigations; differential complete blood picture (CBC), acute phase reactants (CRP and ESR), rheumatoid factor (RF) and anti-cyclic-citrullinated peptide (anti-CCP) antibodies. Disease activity was measured by disease activity score 28 (DAS28). RESULTS: The cut-off levels of RDW and MPV were 14.85 and 11.25. Patients with RDW>14.85 had higher Disease Activity Score 28 (DAS28; p=0.0003), ESR (p=0.0001) and CRP (p=0.0001). RDW was positively correlated with disease activity markers (ESR, CRP and DAS28) in rheumatoid arthritis patients. But, DAS28 was not different between patients with MPV>11.25 and <11.25. CONCLUSION: RDW was strongly correlated with disease activity. Also, RDW was better than ESR and CRP in detecting RA disease activity. According to these findings we suggest that RDW can be used in clinics to follow disease activity. In addition, RDW is widely available; as it's usually included in routine complete blood picture and there will be no need for further cost.

Efficacy of two actinomycete extracts in the amelioration of carbon tetrachloride-induced oxidative stress and nephrotoxicity in experimental rats.

Actinomycetes are a group of the Gram-positive bacteria famous for their antimicrobial, anticancer, anti-parasitic, and anti-inflammatory activities. This study aimed to investigate the efficacy of two bacterial extracts derived from two soil actinomycete strains (S19 and G30) against carbon tetrachloride (CCl4)-induced nephrotoxicity in experimental rats. Sixty-four male rats were assigned to four groups of 16 rats in each group. The 1st group was kept as a normal (control) group and given corn oil combined with the used production medium, while the 2nd group received only CCl4 (CCl4 group). On the other hand, the 3rd group (CCl4+S19) was administered CCl4 and the extract of the actinomycete strain S19 and the 4th group (CCl4+G30) received CCl4 and the extract of the actinomycete strain G30, both treatments for 8 weeks. The results revealed that the two actinomycete extracts S19 and G30 could significantly (p < 0.01) lower the elevated levels of serum creatinine, urea, and uric acid caused by the CCl4 administration. Additionally, the two actinomycete extracts improved the decreased serum total protein. Interestingly, treatment of the CCl4-intoxicated rats with S19 and G30 extracts remarkably reversed the lowered renal glutathione (GSH), glutathione peroxidase (GSH-Px), peroxidase (Px) and superoxide dismutase (SOD) activities, and the elevated lipid peroxidation (LPO) levels. The histopathological examination of the treated kidney revealed that the two actinomycete extracts improved rats against CCl4-induced kidney lesions. The present results suggested that the protective effect of the two actinomycete extracts may rely on its effect on reducing the oxidative stress and improving the antioxidant defense system.

The potential protective effect of two actinomycete extracts against carbon tetrachloride-induced hepatotoxicity in rats.

The aim of this study was to investigate the potential protective effect of two extracts derived from two soil actinomycete strains, designated S19 and G30, against CCl4-induced hepatotoxicity in male rats. Sixty-four male rats were divided into four groups of 16 rats per group. The first group was a control group given corn oil and the nutritive medium which is composed of a mixture of the two used media. The second group received CCl4 only, the third group was administered CCl4 and the extract S19, and the fourth group was administered CCl4 and the extract G30. The results were taken after a treatment period of 8 weeks. Our data demonstrated that the two actinomycete extracts significantly (P < 0.01) lowered the CCl4-induced elevation of serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) after 8 weeks of treatment. The extract S19 had no effect on serum lactate dehydrogenase (LDH) and total bilirubin, whereas the extract G30 significantly decreased (P < 0.01) the elevated levels of these parameters in the serum, especially after 4 weeks of treatment. The levels of hepatic glutathione (GSH), glutathione peroxidase (GSH-Px), peroxidase (Px), catalase (CAT), and superoxide dismutase (SOD) significantly increased (P < 0.01), while those of malondialdehyde (MDA) markedly decreased in rats treated with the two extracts. Furthermore, histopathological lesions in the liver, including necrosis, inflammatory cell infiltration, hydropic degeneration, and congestion of the central vein, were partially reversed by treatment with the two microbial extracts. Our results provided evidence for the protective effect of the two used actinomycete extracts against CCl4-induced liver damage occurred through the reduction of oxidative stress and improvement of antioxidant defense markers.

Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes.

LBR (Lamin B Receptor) encodes a bifunctional protein important for cholesterol biosynthesis and heterochromatin organization on the inner nuclear membrane. Pathogenic variants in LBR are associated with marked phenotypic variability, ranging from the benign Pelger-Huët anomaly to lethal Greenberg Dysplasia. We performed trio exome sequencing (ES) on two patients with atypical variants of skeletal dysplasia and their unaffected parents. Patient 1 exhibited frontal bossing, mid-face hypoplasia, short stature with rhizomelic limb shortening, and relative macrocephaly at birth. Although remained short, Patient 1 later showed spontaneous improvement in her skeletal findings. Exome sequencing revealed two novel variants in LBR, c.1504C > G (p.Arg502Gly) in exon 12 and c.1748G > T (p.Arg583Leu) in exon 14, which were inherited from her unaffected father and mother, respectively. Sterol analysis revealed an increased level of cholesta­8,14­dien­3ß­ol to 2.9% of total sterols, consistent with a functional deficiency of 3ß­hydroxysterol Δ14­reductase. Patient 2 presented at birth with short stature and marked rhizomelic limb shortening but later exhibited decreasing severity of shortening of the long bones and improvement in the radiographic skeletal abnormalities although he continued to be significantly short at age 10 years. Exome sequencing revealed that Patient 2 is homozygous for a pathogenic variant c.1534C > T (p.Arg512Trp) in exon 12 of LBR, which was inherited from his unaffected consanguineous parents. This report provides further evidence for a phenotypic spectrum of LBR-associated disorders and expands the genotypic spectrum by describing 3 novel disease-causing variants that have not been previously associated with a disease. Moreover, our data on Patient 1 demonstrate that variants throughout the gene appear to influence both the sterol reductase and nuclear functions of LBR.

Red cell distribution width and mean platelet volume in rheumatoid arthritis patients: Its association with disease activity / Ancho de distribución de glóbulos rojos y volumen plaquetario medio en pacientes con artritis reumatoide; su asociación con la actividad de la enfermedad

Introduction: Hemogram parameters have been recently proposed as markers of inflammation in various studies from different parts of the world. Two of these hemogram parameters are red cell distribution width (RDW) and mean platelet volume (MPV). Aim: To evaluate the relation between RDW and MPV with disease activity of rheumatoid arthritis. To assess whether RDW and MPV can be used to follow disease activity in RA patients. Methods: This is an observational cross-sectional study that was carried out on 60 rheumatoid arthritis patients who fulfilled the ACR/EULAR2010 classification criteria of RA attending to Rheumatology and Rehabilitation inpatient and outpatient clinics at Zagazig University Hospitals. All cases were subjected to full history taking, clinical examination, and laboratory investigations; differential complete blood picture (CBC), acute phase reactants (CRP and ESR), rheumatoid factor (RF) and anti-cyclic-citrullinated peptide (anti-CCP) antibodies. Disease activity was measured by disease activity score 28 (DAS28). Results: The cut-off levels of RDW and MPV were 14.85 and 11.25. Patients with RDW>14.85 had higher Disease Activity Score 28 (DAS28; p=0.0003), ESR (p=0.0001) and CRP (p=0.0001). RDW was positively correlated with disease activity markers (ESR, CRP and DAS28) in rheumatoid arthritis patients. But, DAS28 was not different between patients with MPV>11.25 and <11.25. Conclusion: RDW was strongly correlated with disease activity. Also, RDW was better than ESR and CRP in detecting RA disease activity. According to these findings we suggest that RDW can be used in clinics to follow disease activity. In addition, RDW is widely available; as it's usually included in routine complete blood picture and there will be no need for further cost.(AU)

Introducción: Los parámetros del hemograma se han propuesto recientemente como marcadores de inflamación en varios estudios de diferentes partes del mundo. Dos de estos parámetros del hemograma son el ancho de distribución de glóbulos rojos (RDW) y el volumen plaquetario medio (MPV). Objetivo: Evaluar la relación entre RDW y MPV con la actividad de la enfermedad de la artritis reumatoide (AR). Evaluar si RDW y MPV se pueden utilizar para seguir la actividad de la enfermedad en pacientes con AR. Métodos: Se trata de un estudio transversal observacional que se llevó a cabo en 60 pacientes con AR que cumplieron con los criterios de clasificación ACR/EULAR2010 de AR que acudieron a consultas hospitalarias y ambulatorias de reumatología y rehabilitación en los Hospitales Universitarios de Zagazig. Todos los casos fueron sometidos a una anamnesis completa, un examen clínico e investigaciones de laboratorio; imagen diferencial arterial completa, reactivos de fase aguda (CRP y ESR), factor reumatoide y anticuerpos antipéptido cíclico-citrulinado. La actividad de la enfermedad se midió mediante la puntuación de actividad de la enfermedad 28 (DAS28). Resultados: Los niveles de corte de RDW y MPV fueron 14,85 y 11,25. Los pacientes con RDW>14,85 tenían mayor puntuación de DAS28 (p=0,0003), ESR (p=0,0001) y CRP (p=0,0001). RDW se correlacionó positivamente con marcadores de actividad de la enfermedad (ESR, CRP y DAS28) en pacientes con AR. Sin embargo, DAS28 no era diferente entre los pacientes con MPV>11,25 y <11,25. Conclusión: RDW estaba fuertemente correlacionado con la actividad de la enfermedad. Además, RDW fue mejor que ESR y CRP en la detección de la actividad de la enfermedad de AR. De acuerdo con estos hallazgos, sugerimos que el RDW se puede utilizar en clínicas para seguir la actividad de la enfermedad. Además, RDW está ampliamente disponible, ya que por lo general se incluye en la imagen de sangre completa de rutina y no habrá necesidad de costos adicionales.(AU)