Lethal Restrictive Dermopathy with ZMPSTE24 Mutation

Lethal restrictive dermopathy is genodermatoses associated with lamin protein defects resulting in connective tissue abnormalities of skin, musculoskeletal, and adipose tissue. We report one such case with a mutation in the ZMPSTE24 gene which is involved in lamin protein synthesis, resulting in fetal akinesia or hypokinesia deformation sequence. Early recognition in the perinatal period of distinctive clinical and skin histological features followed by molecular diagnosis enabled genetic counseling for the affected family.

An Emergent Nexus between Striae and Thoracic Aortic Dissection

Current approaches to stratify the risk for disease progression in thoracic aortic aneurysm (TAA) lack precision, which hinders clinical decision making. Connective tissue phenotyping of children with TAA previously identified the association between skin striae and increased rate of aortic dilation. The objective of this study was to analyze associations between connective tissue abnormalities and clinical endpoints in adults with aortopathy. Participants with TAA or aortic dissection (TAD) and trileaflet aortic valve were enrolled from 2016 to 2019 in the setting of cardiothoracic surgical care. Data were ascertained by structured interviews with participants. The mean age among 241 cases was 61 ± 13 years. Eighty (33%) had history of TAD. While most participants lacked a formal syndromic diagnosis clinically, connective tissue abnormalities were identified in 113 (47%). This included 20% with abdominal hernia and 13% with skin striae in atypical location. In multivariate analysis, striae and hypertension were significantly associated with TAD. Striae were associated with younger age of TAD or prophylactic aortic surgery. Striae were more frequent in TAD cases than age- and sex-matched controls. Thus, systemic features of connective tissue dysfunction were prevalent in adults with aortopathy. The emerging nexus between striae and aortopathy severity creates opportunities for clinical stratification and basic research.

415 Correlation between tissue abnormalities and myocardial deformation indices in arrhythmogenic cardiomyopathy: a pilot study

Aims To evaluate the correlation between cardiac magnetic resonance (CMR) tissue abnormalities and impairment of myocardial deformation indices in patients with definite diagnosis of arrhythmogenic cardiomyopathy (AC). Methods and results 41 AC Patients with available CMR study were enrolled. Myocardial deformation indices (i.e. global longitudinal strain -GLS-; global circumferential strain -GCS-; global radial strain -GRS-) for both ventricles were calculated using feature tracking analysis. Quantification of tissue abnormalities (i.e. late gadolinium enhancement -LGE- extension expressed as percentage of total ventricular mass) was performed. Spearman’s rho correlation was evaluated. Mean age was 44 ± 13 years and 26 (63%) patients were male. Mean left ventricular (LV) ejection fraction (EF) was 54 ± 10% and mean right ventricular (RV) EF was 49 ± 12%. Median LV LGE extension was 8.9% (1.05–21) and median RV LGE extension was 0 (0–6.92). All myocardial deformation indices were moderately associated with LGE extension (for LV 3D GLS Spearman’s Rho 0.423, P 0.016; 2D GCS Spearman’s Rho 0.388, P 0.028; 3D GCS 0.362, P 0.042; 2D GRS Spearman’s Rho −0.417, P 0.018; 3D GRS −0.396, P 0.025; for RV 2D GLS Spearman’s Rho 0.385, P 0.030; RV GCS Spearman’s Rho 0.450, P 0.010; RV GRS Spearman’s Rho −0.459, P 0.008). Conclusions All myocardial deformation indices showed a moderate association with LGE extension in a cohort of patients with definite AC. Further studies are needed to validate this observation and understand its implications.

Molecular Mechanisms of the RECQ4 Pathogenic Mutations

The human RECQ4 gene encodes an ATP-dependent DNA helicase that contains a conserved superfamily II helicase domain located at the center of the polypeptide. RECQ4 is one of the five RECQ homologs in human cells, and its helicase domain is flanked by the unique amino and carboxyl termini with sequences distinct from other members of the RECQ helicases. Since the identification of the RECQ4 gene in 1998, multiple RECQ4 mutations have been linked to the pathogenesis of three clinical diseases, which are Rothmund-Thomson syndrome, Baller-Gerold syndrome, and RAPADILINO. Patients with these diseases show various developmental abnormalities. In addition, a subset of RECQ4 mutations are associated with high cancer risks, especially for osteosarcoma and/or lymphoma at early ages. The discovery of clinically relevant RECQ4 mutations leads to intriguing questions: how is the RECQ4 helicase responsible for preventing multiple clinical syndromes? What are the mechanisms by which the RECQ4 disease mutations cause tissue abnormalities and drive cancer formation? Furthermore, RECQ4 is highly overexpressed in many cancer types, raising the question whether RECQ4 acts not only as a tumor suppressor but also an oncogene that can be a potential new therapeutic target. Defining the molecular dysfunctions of different RECQ4 disease mutations is imperative to improving our understanding of the complexity of RECQ4 clinical phenotypes and the dynamic roles of RECQ4 in cancer development and prevention. We will review recent progress in examining the molecular and biochemical properties of the different domains of the RECQ4 protein. We will shed light on how the dynamic roles of RECQ4 in human cells may contribute to the complexity of RECQ4 clinical phenotypes.

Magnetic Resonance Imaging Findings of the Proximal Metacarpal Region in Warmblood Horses: 36 Lame and 26 Control Limbs (2015–2021)

Objectives: This study aims to evaluate the distribution and severity of bone and soft tissue lesions in the proximal metacarpal region of warmblood horses in lame and control groups. Correlation between lesions and ability to return to work was evaluated in the lame group.Methods: This restrospective analysis evaluated 62 horses with MRI examination of the proximal metacarpal region between Sept 2015 and Feb 2021. There were 36 lame limbs and 26 control limbs. The control group included seven contralateral limbs.Results: Proximal suspensory ligament (PSL) size was not different between the lame and control groups. Hyperintensity seen on T1W/T2*W GRE images within the dorsal collagenous part of the PSL and hyperintense Short-TI Inversion Recovery (STIR) signal within the dorsal collagenous part of the PSL or within the McIII were only present within the lame group. Palmar cortical McIII resorption and dorsal margin irregularity of the PSL and McIII sclerosis were more severe within the lame limbs, but mild gradations were also seen in control limbs. Intermediate gradings for a subset of lesions were commonly seen in the non-lame contralateral to lame limbs. Return to work in the lame group is not statistically different for any measured observation(s), and 19/33 of the lame horses returned to work at similar or higher levels.Conclusion and clinical importance: Fifty-eight percent in this group of warmblood horses returned to work within a variable time frame. The majority (81%) of lame limbs showed bone and soft tissue abnormalities, but no enlargement of the PSL was noted in lame horses, and no correlation was seen between the severity or type of lesions and the ability to return to work. The presence of STIR hyperintensity within the proximal McIII or dorsal collagenous part of the PSL and hyperintensity within the dorsal collagenous part of the PSL on T1W GRE and T2*W GRE images, as well as significant palmar cortical McIII resorption are considered clinically relevant lesions. Contralateral limbs may not truly represent the normal condition, showing nonclinical variations and adaptive remodeling.

JOB'S SYNDROME: A RARE CASE REPORT

Hyper IgE Syndrome (HIES) or Job's Syndrome is a complex primary immunodeciency disorder characterized by elevated serum IgE levels, recurrent skin rashes, eosinophilia, skeletal and connective tissue abnormalities. The patients also exhibit features of specic facies, retention of deciduous teeth and susceptibility to infections. HIES is a rare genetic disorder where some cases are inherited as autosomal dominant or autosomal recessive but most cases are supposedly sporadic. Hereby we present a case of 12-year-old male child admitted in the hospital with complaints of fever, skin rashes, intermittent abdominal pain and generalised lymphadenopathy. As there is no denite cure for HIES, the approach was directed towards conservative management. Due to the extreme paucity of reported cases in literature, this case report can help shed light on a syndrome of such rarity.

Advancing our understanding of genetic risk factors and potential personalized strategies in pelvic organ prolapse: largest GWAS to date reveals 19 novel associated loci

Objectives: To identify the genetic determinants of pelvic organ prolapse (POP) and assess the predictive ability of polygenic risk scores (PRS) alone or in combination with clinical risk factors. Design: Meta-analysis of genome-wide association studies (GWAS) and PRS construction and validation. Setting: GWAS summary statistics from three European datasets and individual-level data from Estonian Biobank, including phenotype questionnaire and measurement panel, together with follow-up data from linkage with national health-related registries. Participants: A total of 28,086 women with POP and 546,321 controls of European ancestry. Genetic risk scores were derived from a dataset of 20,118 cases and 427,426 controls of European ancestry and validated in a target dataset of 7,896 cases and 118,895 controls. Cases were defined using ICD codes and classical risk factors were derived from questionnaire data and ICD10 codes. Results: The identified novel loci reinforce the role of connective tissue abnormalities, urogenital tract development and point towards association with a range of cardiometabolic traits. A novel PRS combining 3,242,959 variants demonstrated that women in the top 5 % have 1.63 (95% CI: 1.37 to 1.93) times the hazard of developing POP compared to the rest of the women. When analyzing PRS in incident disease, it showed similar predictive ability (Harrell C-statistic 0.583, sd=0.007) than five established clinical risk factors (number of children, body mass index (BMI), ever smoked, constipation and asthma) combined (Harrell C-statistic 0.588, sd=0.007) and demonstrated its incremental value in combination with these (Harrell C-statistic 0.630, sd=0.007). Conclusions: The largest GWAS meta-analysis in POP to date identified 26 genetic loci which establish links between POP and connective tissue abnormalities, urogenital development and cardiometabolic health. We present a PRS for POP which provides the first potential tool for preventive strategies and early detection of higher risk susceptibility to POP including genetic risk factors.

CONGENITAL CUTIS LAXA: A RARE GENODERMATOSIS

Cutis Laxa (CL) / generalized elastolysis / dermatomegaly is a heterogeneous group of disorders which are related to elastic tissue abnormalities. Depending on extent of abnormal elastic tissue, it may be mild or severe. Severe form presents with loose, inelastic, wrinkled skin resembling ill tted suit. Infant has characteristic facial features like old man appearance, a hooked nose, a short columella, a long upper lip with long philtrum, and everted lower eyelids. CL is categorised as congenital or acquired and the inheritance can be autosomal dominant or recessive, or X linked. Occasionally a few metabolic disorders like Menkes disease, disorders of glycosylation are associated with Congenital CL. Acquired cutis laxa has developed after a febrile illness and various inammatory skin diseases. Here we present a case of a full-term SGA (small for gestational age) female child born with features of CL.