EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder.

Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele as the principal mechanism for decreased levels of EFEMP1 mRNA. We provide strong clinical and genetic evidence for the haploinsufficiency of EFEMP1 due to nonsense-medicated decay to cause severe kyphoscoliosis, generalized hypermobility of joints, high and narrow arched palate, and potentially severe diverticulosis. To the best of our knowledge, this is the first report of an autosomal dominant EFEMP1-associated hereditary connective tissue disorder and therefore expands the phenotypic spectrum of EFEMP1 related disorders.

Histopathological significance of connective tissue disease-associated interstitial lung disease in transbronchial lung cryobiopsy specimens.

Differentiating between idiopathic interstitial pneumonia (IIP) and secondary interstitial pneumonia, particularly connective tissue disease-associated interstitial lung disease (CTD-ILD), can be challenging histopathologically, and there may be discrepancies among pathologists. While surgical lung biopsy has traditionally been considered the gold standard for diagnosing interstitial pneumonia, the usefulness of transbronchial lung cryobiopsy (TBLC) has been reported. If TBLC could effectively distinguish between primary and secondary diseases, it would provide a less invasive option for patients. The aim of this study was to identify specific pathologic findings in TBLC specimens that could assist in distinguishing CTD-ILD from IIP. A total of 93 underwent TBLC at Tenri Hospital between 2018 and 2022. We retrospectively reviewed cases of CTD-ILD exhibiting a nonspecific interstitial pneumonia (NSIP) pattern (CTD-NSIP) and cases of NSIP with an unknown etiology (NSIP-UE), as determined through multidisciplinary discussion. Nineteen patients with CTD-NSIP and 26 patients with NSIP-UE were included in the study for clinicopathological analysis. The CTD-NSIP group had a significantly higher proportion of female patients compared to the NSIP-UE group (79% vs. 31%; p = 0.002). The presence of both fresh and old intraluminal fibrosis within the same TBLC specimen was significantly more frequent in CTD-NSIP group than in the NSIP-UE group (p = 0.023). The presence of an NSIP pattern with co-existing fresh and old intraluminal fibrosis in TBLC specimens raised suspicion for CTD-ILD.

Annular dermatoses with rheumatologic implications.

A wide variety of cutaneous disorders present with annular (ringlike) skin lesions, and some of them carry rheumatologic implications because they may involve the joints or belong to the spectrum of connective tissue diseases. The diagnosis of an annular rheumatologic skin disease is possible with a correct clinicopathologic correlation, with a correct anamnesis of the patient, with the evaluation of systemic symptoms, laboratory and instrumental investigations, and finally with a cutaneous biopsy.

Spectrum of high-resolution computed tomography pattern in lungs in patients with connective tissue disorders.

Background: Connective tissue disease associated with interstitial lung disease, or CT-ILD, is a lung condition that affects a large number of patients with a connective tissue disease. Objective: Our aim in this study is to correlation between images of high-resolution computed tomography (HRCT) of different connective tissue diseases associated interstitial lung diseases (CTD-ILDs). Methods: We shall be aiming to investigate the feasibility of HRCT imaging and thereby avoid lung biopsy in such patients. Results: Rheumatoid arthritis predominantly presented with usual interstitial pneumonia (UIP) (47.8%), followed by nonspecific interstitial pneumonia (NSIP) (30.4%). Mixed connective tissue disorder predominantly presented with NSIP and UIP (42.8%), followed by organizing pneumonia (OP) (14.2%). Systemic lupus erythematosus predominantly presented with UIP (38.8%), followed by NSIP (27.7%). Sjogren's syndrome predominantly presented with lymphocytic interstitial pneumonia (40%), followed by UIP (26.6%). Scleroderma predominantly presented with UIP (45.4%), followed by NSIP (36.4%). Sarcoidosis predominantly presented with UIP (75%), followed by NSIP (25%). Dermatomyositis predominantly presented with NSIP (50%), followed by UIP and OP each (25%). Conclusion: Both clinicians and radiologists should be aware of the expected evolution of HRCT changes in a variety of CT-ILDs.

Résumé Contexte: La maladie du tissu conjonctif associée à la maladie pulmonaire interstitielle, ou CT ILD, est une affection pulmonaire qui affecte un grand nombre de patients atteints d'une maladie du tissu conjonctif. Objectif: Notre objectif dans cette étude est de mettre en corrélation des images de tomodensitométrie à haute résolution (HRCT) de différentes maladies du tissu conjonctif associées à des maladies pulmonaires interstitielles (CTD ILDs). Méthodes: Notre objectif sera d'étudier la faisabilité de l'imagerie HRCT et d'éviter ainsi la biopsie pulmonaire chez ces patients. Résultats: La polyarthrite rhumatoïde se présentait principalement avec une pneumonie interstitielle habituelle (PUI) (47,8 %), suivie d'une pneumonie interstitielle non spécifique (NSIP) (30,4 %). Trouble mixte du tissu conjonctif présenté principalement avec NSIP et UIP (42,8 %), suivi d'une pneumonie organisée (OP) (14,2 %). Le lupus érythémateux disséminé présentait principalement une UIP (38,8 %), suivie d'une NSIP (27,7 %). Le syndrome de Sjogren présentait principalement une pneumonie interstitielle lymphocytaire (40 %), suivie d'une PUI (26,6 %). La sclérodermie se présentait principalement avec l'UIP (45,4 %), suivi du NSIP (36,4 %). La sarcoïdose se présentait principalement avec l'UIP (75 %), suivi du NSIP (25 %). La dermatomyosite se présentait principalement avec NSIP (50 %), suivi par UIP et OP chacun (25 %). Conclusion: Les cliniciens et les radiologues doivent être conscients de l'évolution attendue des changements HRCT dans une variété d'ILD CT. Mots-clés: Tissu conjonctif, CT ILDs, tomodensitométrie haute résolution, poumon interstitiel.

Potential role of type I interferon/IP-10 axis in the pathogenesis of anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVES: Dermatomyositis (DM) patients with anti-melanoma differentiation-associated protein 5 (MDA5) antibodies are known for poor prognosis. This study was designed to identify humoral factors that are readily detectable in the disease and may reflect its activity and pathophysiology. METHODS: We first quantified the serum level expression of 28 cytokines in the serum of patients with collagen vascular diseases using bead-based multiplex immunoassays. We completed these evaluations at hospital admission and followed up with three DM patients with anti-MDA5 antibodies during hospitalisation. We also performed an immunohistochemical analysis of skin samples obtained from two patients. RESULTS: The serum level of interferon gamma-induced protein 10 (IP-10) was significantly higher in DM patients with anti-MDA5 antibodies than in those without the antibody, decreasing drastically upon treatment. Interestingly, this time course paralleled not that of interferon (IFN)-γ, which was originally reported to be the inducer of IP-10, but that of IFN-α2. Immunohistochemical analysis revealed that most of the IP-10-positive cells were macrophages. Furthermore, monocytes stimulated with type I IFN in vitro produced IP-10 in a dose-dependent manner. CONCLUSIONS: IP-10 is a potentially useful disease activity marker of DM with anti-MDA5 antibodies, correlating more with IFN-α2 then IFN-γ. IP-10 released from macrophages might prompt the infiltration of macrophages themselves. Thus, the type I IFN/IP-10 axis may play a pivotal role in the pathogenesis of this intractable disease.

Dominant Stickler Syndrome.

The Stickler syndromes are a group of genetic connective tissue disorders associated with an increased risk of rhegmatogenous retinal detachment, deafness, cleft palate, and premature arthritis. This review article focuses on the molecular genetics of the autosomal dominant forms of the disease. Pathogenic variants in COL2A1 causing Stickler syndrome usually result in haploinsufficiency of the protein, whereas pathogenic variants of type XI collagen more usually exert dominant negative effects. The severity of the disease phenotype is thus dependent on the location and nature of the mutation, as well as the normal developmental role of the respective protein.

Identification of three novel homozygous variants in COL9A3 causing autosomal recessive Stickler syndrome.

BACKGROUND: Stickler syndrome (STL) is a rare, clinically and molecularly heterogeneous connective tissue disorder. Pathogenic variants occurring in a variety of genes cause STL, mainly inherited in an autosomal dominant fashion. Autosomal recessive STL is ultra-rare with only four families with biallelic COL9A3 variants reported to date. RESULTS: Here, we report three unrelated families clinically diagnosed with STL carrying different novel biallelic loss of function variants in COL9A3. Further, we have collected COL9A3 genotype-phenotype associations from the literature. CONCLUSION: Our report substantially expands the molecular genetics and clinical basis of autosomal recessive STL and provides an overview about allelic COL9A3 disorders.

Cutis verticis gyrata: a cutaneous finding in acromegaly.

Acromegaly is a rare disease characterized by changes in the bone and soft tissue systems, induced by excess growth hormone and insulin-like growth factor type 1. Among the skin lesions associated with acromegaly is cutis verticis gyrata, an hypertrophic, and coarse folding of the skin of the scalp, an association of uncommon incidence and unknown prevalence. This case report describes the case of a patient diagnosed with acromegaly at age 60 with previously unidentified cutis verticis gyrata. This report aims to review the literature on cutis verticis gyrata and its unusual association with acromegaly.

Inherited connective tissue diseases highlight macromolecular network interdependences in skin extracellular matrix: a histomorphometric study.

Mutation of just a single extracellular matrix protein, a receptor or enzyme involved in connective tissue metabolism is sufficient to cause systemic pathologies and failure of tissues that are subjected to strong mechanical stresses. Skin histological and computerized image analyses can provide a good qualitative and quantitative indication of these inherited connective tissue diseases. In this study, skin biopsies from young (10 to 25 years) and middle-aged patients (26 to 50 years) suffering from Ehlers-Danlos syndromes (EDS), Marfan syndrome (MS) or pseudoxanthoma elasticum (PXE) were studied after specific staining of both the collagen and elastic networks. Findings from the histomorphometric analyses conducted on skin sections of the patients with EDS, MS and PXE were compared to skin sections of healthy subjects from the same age groups. Our results show that both the collagen and the elastic networks were affected in all the studied pathological cases, but that the adverse changes to the elastic network in older patients were distinct from the physiological changes observed during aging process for healthy subjects. This degenerative process may be explained by an added phenomenon involving a general connective tissue proteolysis.

Capillaroscopy: a useful tool in the early diagnosis of connective tissue disease and non-scleroderma spectrum disorders.

BACKGROUND: Detection of early capillaroscopic alterations in the preclinical phase may prove useful in patients with non-scleroderma connective tissue disease (CTD). We aimed to verify whether certain capillaroscopic alterations, alone or in combination, might be predictive of CTD. METHODS: We retrospectively collected data on patients with Raynaud's phenomenon who underwent capillaroscopy conducted by highly expert examiners with a degree in vascular medicine at our institutions. Included subjects were divided in two groups: those developing rheumatic disease during follow-up, and those without subsequent diagnosis of CTD. Notably, we excluded subjects who presented with an evident scleroderma pattern or rheumatic disease during their initial examination. RESULTS: We included a total of 76 patients, 60 of whom developed CTD during follow-up, which spanned in this group 23±7 months, and 16 who did not develop CTD during follow-up, which spanned 23±9 months. The following features were significantly associated with Raynaud's phenomenon: 1) angiotectonic disorder (P<0.001); 2) nonhomogeneous loop morphology (P<0.001); 3) avascular areas (P<0.001); 4) pseudo-avascular areas (P<0.001), and, albeit to a lesser degree; and 5) ectasias (P<0.050). Notably, the initial capillaroscopic pattern did not undergo any changes in subsequent tests. CONCLUSIONS: Although certain pathological characteristics of the capillaroscopic pattern are non-specific and not diagnostic if considered individually, they can be significantly suggestive for latent CTD when found in combination. At the very least, they warrant an in-depth diagnostic analysis and a lengthy follow-up.

Molecular characterization of xerosis cutis: A systematic review.

BACKGROUND: Xerosis cutis or dry skin is a highly prevalent dermatological disorder especially in the elderly and in patients with underlying health conditions. In the past decades, numerous molecular markers have been investigated for their association with the occurrence or severity of skin dryness. The aim of this review was to summarize the molecular markers used in xerosis cutis research and to describe possible associations with different dry skin etiologies. METHODS: We conducted a systematic review of molecular markers of xerosis cutis caused by internal or systemic changes. References published between 1990 and September 2020 were searched using 'MEDLINE', 'EMBASE' and 'Biological abstracts' databases. Study results were summarized and analyzed descriptively. The review protocol was registered in PROSPERO database (CRD42020214173). RESULTS: A total of 21 study reports describing 72 molecules were identified including lipids, natural moisturizing factors (NMFs), proteins including cytokines and metabolites or metabolic products. Most frequently reported markers were ceramides, total free fatty acids, triglycerides and selected components of NMFs. Thirty-one markers were reported only once. Although, associations of these molecular markers with skin dryness were described, reports of unclear and/or no association were also frequent for nearly every marker. CONCLUSION: An unexpectedly high number of various molecules to quantify xerosis cutis was found. There is substantial heterogeneity regarding molecular marker selection, tissue sampling and laboratory analyses. Empirical evidence is also heterogeneous regarding possible associations with dry skin. Total free fatty acids, total ceramide, ceramide (NP), ceramide (NS), triglyceride, total free amino acids and serine seem to be relevant, but the association with dry skin is inconsistent. Although the quantification of molecular markers plays an important role in characterizing biological processes, pathogenic processes or pharmacologic responses, it is currently unclear which molecules work best in xerosis cutis.

Genetic Characteristics and Phenotype of Korean Patients with Stickler Syndrome: A Korean Multicenter Analysis Report No. 1.

Stickler syndrome is an inherited connective tissue disorder of collagen. There are relatively few reports of East Asian patients, and no large-scale studies have been conducted in Korean patients yet. In this study, we retrospectively analyzed the genetic characteristics and clinical features of Korean Stickler syndrome patients. Among 37 genetically confirmed Stickler syndrome patients, 21 types of gene variants were identified, of which 12 were novel variants. A total of 30 people had variants in the COL2A1 gene and 7 had variants in the COL11A1 gene. Among the types of pathogenic variants, missense variants were found in 11, nonsense variants in 8, and splice site variants in 7. Splicing variants were frequently associated with retinal detachment (71%) followed by missense variants. This is the first large-scale study of Koreans with Stickler syndrome, which will expand the spectrum of genetic variations of Stickler syndrome.

Expanding the phenotypic spectrum of Mendelian connective tissue disorders to include prominent kidney phenotypes.

Heritable connective tissue disorders are a group of diseases, each rare, characterized by various combinations of skin, joint, musculoskeletal, organ, and vascular involvement. Although kidney abnormalities have been reported in some connective tissue disorders, they are rarely a presenting feature. Here we present three patients with prominent kidney phenotypes who were found by whole exome sequencing to have variants in established connective tissue genes associated with Loeys-Dietz syndrome and congenital contractural arachnodactyly. These cases highlight the importance of considering connective tissue disease in children presenting with structural kidney disease and also serves to expand the phenotype of Loeys-Dietz syndrome and possibly congenital contractural arachnodactyly to include cystic kidney disease and cystic kidney dysplasia, respectively.

Predictors for progressive fibrosis in patients with connective tissue disease associated interstitial lung diseases.

BACKGROUND: Connective tissue disease associated interstitial lung disease (CTD-ILD) is associated with decreased quality of life and high mortality risk. Outcome and treatment response is unpredictable. This study aimed to identify clinical predictors for CTD-ILD with poor outcome. METHODS: We performed a retrospective single centre cohort study in outpatients with CTD-ILD seen between 2004 and 2018. Clinical and biochemical data, pulmonary function tests (PFT) and high-resolution computed tomography (HRCT) results were analysed. Overall survival and progressive fibrosing ILD (PF-ILD, defined as a significant deterioration of PFT or HRCT) after two years of follow-up were assessed. RESULTS: In total, 150 patients with CTD-ILD were included. Thirty (20%) deaths occurred during a median follow-up of 40 months (IQR 27.3-60.8), which were attributed to pulmonary infection in six (4%), respiratory failure due to PF-ILD in ten (7%) and due to other causes in fourteen patients. PF-ILD occurred in 76 (50.7%) patients and was associated with poor overall survival (adjusted HR 5.73, 95%CI 1.17-28.11). Age, smoking, C-reactive protein, and steroid-use were independently associated with increased mortality risk as well. Furthermore, patients with diabetes mellitus (adjusted OR 4.52, 95%CI 1.10-18.51), steroid-use (adjusted OR 2.26, 95%CI 1.04-4.93), and a fibrotic HRCT pattern at baseline (adjusted OR 3.11, 95%CI 1.15-8.38) had a higher risk of PF-ILD. CONCLUSION: PF-ILD is associated with increased mortality in patients with CTD-ILD. Patients with a fibrotic HRCT pattern at baseline, diabetes mellitus and steroid-use have a higher risk of developing PF-ILD.

Toward precision medicine in vascular connective tissue disorders.

Tremendous progress has been made in understanding the etiology, pathogenesis, and treatment of inherited vascular connective tissue disorders. While new insights regarding disease etiology and pathogenesis have informed patient counseling and care, there are numerous obstacles that need to be overcome in order to achieve the full promise of precision medicine. In this review, these issues will be discussed in the context of Marfan syndrome and Loeys-Dietz syndrome, with additional emphasis on the pioneering contributions made by Victor McKusick.

Prognostic role of NK cell percentages in bronchoalveolar lavage from patients with different fibrotic interstitial lung diseases.

BAL cellularity and lymphocyte immunophenotyping offer insights into lung inflammatory status. Natural killer (NK) cells are efficient effector cells, producing pro-inflammatory cytokines. A better understanding of the biology of NK cells in BAL in the lungs is necessary to improve the pathogenesis of fibrotic ILD and develop prospective targeted treatments. Our aim was to analyse NK and NKT-like cell percentages in BAL from 159 patients with different ILD: f-HP, f-NSIP, IPF and CTD-ILD, to evaluate their potential diagnostic/prognostic role. BAL NK cell percentages showed significantly higher values in IPF than in f-HP and f-NSIP, while BAL NKT-like cells showed significantly lower values in the f-NSIP than the f-HP and IPF. A cut-off of 4%NK cells in BAL of IPF showed a significant difference in survival rate. It suggests a possible new marker of survival and raises the possibility of new targeted approach in treatment and management of IPF.

Cleft palate morphology, genetic etiology, and risk of mortality in infants with Robin sequence.

Robin sequence (RS) has many genetic and nongenetic causes, including isolated Robin sequence (iRS), Stickler syndrome (SS), and other syndromes (SyndRS). The purpose of this study was to determine if the presence and type of cleft palate varies between etiologic groups. A secondary endpoint was to determine the relationship of etiologic group, cleft type, and mortality. Retrospective chart review of patients with RS at two high-volume craniofacial centers. 295 patients with RS identified. CP was identified in 97% with iRS, 95% with SS, and 70% of those with SyndRS (p < .0001). U-shaped CP was seen in 86% of iRS, 82% with SS, but only 27% with SyndRS (p < .0001). At one institution, 12 children (6%) with RS died, all from the SyndRS group (p < .0001). All died due to medical comorbidities related to their syndrome. Only 25% of children who died had a U-shaped CP. The most common palatal morphology among those who died was an intact palate. U-shaped CP was most strongly associated with iRS and SS, and with a lower risk of mortality. RS with submucous CP, cleft lip and palate or intact palate was strongly suggestive of an underlying genetic syndrome and higher risk of mortality.

The role of interleukin-6 as a prognostic biomarker for predicting acute exacerbation in interstitial lung diseases.

BACKGROUND: Interstitial lung diseases (ILDs) are chronic, parenchymal lung diseases with a variable clinical course and a poor prognosis. Within various clinical courses, acute exacerbation (AE) is a devastating condition with significant morbidity and high mortality. The aim of this study was to investigate the role of interleukin-6 (IL-6) to predict AE and prognosis in patients with ILD. METHODS: Eighty-three patients who were diagnosed with ILD from 2016 to 2019 at the Haeundae Paik Hospital, Busan, South Korea, were included and their clinical data were retrospectively analyzed. RESULTS: The median follow-up period was 20 months. The mean age was 68.1 years and 65.1% of the patients were men with 60.2% of patients being ever-smokers. Among ILDs, idiopathic pulmonary fibrosis was the most common disease (68.7%), followed by connective tissue disease-associated ILD (14.5%), cryptogenic organizing pneumonia (9.6%), and nonspecific interstitial pneumonia (6.0%). The serum levels of IL-6 were measured at diagnosis with ILD and sequentially at follow-up visits. During the follow-ups, 15 (18.1%) patients experienced an acute exacerbation (AE) of ILD and among them, four (26.7%) patients died. In the multivariable analysis, high levels of IL-6 (OR 1.014, 95% CI: 1.001-1.027, p = 0.036) along with lower baseline saturations of peripheral oxygen (SpO2) were independent risk factors for AE. In the receiver operating characteristic curve analysis, the area under the curve was 0.815 (p < 0.001) and the optimal cut-off value of serum IL-6 to predict AE was 25.20 pg/mL with a sensitivity of 66.7% and specificity of 80.6%. In the multivariable Cox analysis, a high level of serum IL-6 (HR 1.007, 95% CI: 1.001-1.014, p = 0.018) was only an independent risk factor for mortality in ILD patients. CONCLUSIONS: In our study, a high level of serum IL-6 is a useful biomarker to predict AE and poor prognosis in patients with ILD.

Recognition and Management of Cutaneous Connective Tissue Diseases.

Connective tissue diseases (CTDs) encompass a broad spectrum of clinical presentations that involve multidisciplinary management. Cutaneous findings are common in CTD and careful examination of these features aids in appropriate diagnosis and subsequent evaluation. Thorough work-up of CTD is crucial to properly identify disease subtypes and systemic involvement. Management plans can be developed based on diagnosis and systemic manifestations of disease. Disease management often requires treatment with pharmacotherapies with potential for toxicities, further underscoring the importance of diagnostic accuracy in this patient population. Evolving research strives to better elucidate the pathogenic mechanisms of CTDs allowing for more targeted treatment modalities.