Familial Sarcoidosis Research Articles

Whole exome sequencing of a German sarcoidosis family with four affected and one spontaneous remission case.

To analyse genetic mechanisms triggering familial sarcoidosis, whole exome screening of a family of six persons with four cases of sarcoidosis and two healthy controls was performed integrating progressive and spontaneous remission cases and evaluating involved genetic alterations that could potentially determine the individual course of the disease. Clinical diagnostic criteria in patients of the selected sarcoidosis family were according to American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders guidelines. Exome screening of four patients and the two intrafamilial healthy relatives was performed by paired-end (2 × 100 bp) sequencing. We then selected the gene variants considered pathogenic on the basis of a series of prediction software applications and presence only in members of the family affected by sarcoidosis, after subtracting the common variations observed in healthy subjects. Four persons out of six family members were affected by sarcoidosis. Fifty genes with uncommon in silico pathogenic variants could be identified that differentiated affected and healthy family members. One patient with sarcoidosis showed spontaneous remission whereas the remaining three patients required immunosuppressive treatment. Subtraction analysis revealed 18 genes that distinguished the three progressive cases from the patient with spontaneous remission. The genetic analysis of these cases with familial sarcoidosis identified several involved genes and functional pathways that could help in understanding the basic mechanisms that determine the development of the disease and that discriminate spontaneously regressive and progressive forms.

Whole Exome Sequencing Identified Two Single Nucleotide Polymorphisms of Human Leukocyte Antigen-DRB5 in Familial Sarcoidosis in China.

Sarcoidosis is a multisystem granulomatous disorder whose etiology is related to genetic and immunological factors. Familial aggregation and ethnic prevalence suggest a genetic predisposition and inherited susceptibility to sarcoidosis. This study aimed to identify suspected risk loci for familial sarcoidosis patients. We conducted whole exome sequencing on two sarcoidosis patients and five healthy family members in a Chinese family for a case-control study. The two sarcoidosis patients were siblings who showed chronic disease. The Gene Ontology results showed single nucleotide polymorphisms in three genes, including human leukocyte antigen (HLA)-DRB1, HLA-DRB5, and KIR2DL4, associated with both 'antigen processing and presentation' and 'regulation of immune response.' Sanger sequencing verified two nonsynonymous mutations in HLA-DRB5 (rs696318 and rs115817940) located on 6p21.3 in the major histocompatibility complex (MHC) class II beta 1 region. The structural model simulated on Prot- Param protein analysis by the Expert Protein Analysis System predicted that the hydropathy index changed at two mutation sites (rs696318: p.F96L, -1.844 to -1.656 and rs115817940: p.T106N, -0.322 to -0.633), which indicated the probability of changes in peptide-binding selectivity. Our results indicated that two nonsynonymous mutations of HLA-DRB5 have been identified in two sarcoidosis siblings, while their healthy family members do not have the mutations. The two HLA-DRB5 alleles may influence genetic susceptibility and chronic disease progression through peptide mutations on the MHC class II molecule among the two affected family members.

Serum amyloid A-A potential therapeutic target for hyper-inflammatory syndrome associated with COVID-19.

Serum amyloid-A (SAA) is associated with inflammatory disorders such as rheumatoid arthritis, Familial Mediterranean Fever, sarcoidosis, and vasculitis. There is accumulating evidence that SAA is a reliable biomarker for these autoinflammatory and rheumatic diseases and may contribute to their pathophysiology. Hyperinflammatory syndrome associated with COVID-19 is a complex interaction between infection and autoimmunity and elevation of SAA is strongly correlated with severity of the inflammation. In this review we highlight the involvement of SAA in these different inflammatory conditions, consider its potential role and discuss whether it could be a potential target for treatment of the hyperinflammatory state of COVID-19 with many potential advantages and fewer adverse effects. Additional studies linking SAA to the pathophysiology of COVID-19 hyper-inflammation and autoimmunity are needed to establish the causal relationship and the therapeutic potential of inhibitors of SAA activity.

RF18 | PSAT166 Hypercalcemia and hypocalcemia during pregnancy are associated with worse maternal and fetal outcomes

Abstract Background Hypercalcemia during pregnancy is rare. The true incidence, however, is difficult to estimate as routine calcium screening is not recommended. Hypercalcemia is linked with various maternal and fetal outcomes but overall, the literature is conflicting. Aims Aim of this study is to determine the frequency of hypercalcemia in pregnancy and to determine association with early maternal and fetal outcomes. Methods This retrospective cohort study included all confirmed gestations with expected date of delivery (EDD) between 2017-2019 at a large tertiary maternity unit. Baseline demographic, biochemical, and clinical data collected as part of a clinical-administrative dataset was retrieved. Maternal and fetal outcomes studied were incidence of fetal loss (miscarriage/stillbirth), pre-term delivery, emergency C-section, hypertension, blood loss during delivery, neonatal intensive care unit (NICU) admission, and fetal birth weight (for term deliveries). Results Total number of gestations and livebirths recorded between 2017-2019 were 33,118 and 20,969, respectively, with median age of 30.1 [IQR 25.6-34.3] years. Two-thirds of pregnancies were in Caucasian women (65.9%) followed by Asians (9.6%), Afro-Caribbean (5%), and others (19.5%). 15.7% (n=5195) of all gestations had calcium tested in the preceding ten months of EDD. Of these, the hypercalcemia and hypocalcemia were noted in 42 (0.81%) and 499 gestations (9.61%) respectively. The median adjusted calcium in the hypercalcemic group was 2.75 mmol/L [IQR 2.65-2.88] and underlying diagnoses were primary hyperparathyroidism (n=17), transient hypercalcemia (n=12), suspected familial hypocalciuric hypercalcemia (n=2), sarcoidosis (n=1), and unknown (n=10). Of maternal and fetal outcomes, the incidence of pre-term delivery (20.0% v 9.2%; P=0.042), emergency C-section (42.4% v 21.4%; P=0.021), neonatal intensive care unit (NICU) admission (19.4% v 8.2%; P=0.024), and blood loss during delivery (1252 v 526 mL; P<0.001) was higher in the hypercalcemic group. The incidence of fetal loss (22.5% v 18.9%; P=0.560) and hypertension (0% v 1%; P =0.561) was not different between hyper and normocalcemic groups. Interestingly, the hypocalcemic group also demonstrated higher incidence of pre-term delivery (24.2% v 9.2%; P=<0.001), emergency C-section (28.6% v 21.4%; P=0.025), NICU admission (15.9% v 8.2%; P<0.001), and blood loss (627 v 526 mL; P<0.001), but not of fetal loss (21.0% v 18.9%; P=0.281) or hypertension (2.2% v 1.0%; P =0.054) compared to the eucalcemic group. Conclusion The incidence of hypercalcemia in pregnancy is low (0.81%). However, abnormal calcium levels are associated with worse maternal and fetal outcomes. Research needs to focus on whether routine calcium estimations are necessary and if treatment of these conditions improves maternal and fetal outcomes. We recommend that calcium testing should be considered in women who are at risk of worse outcomes during current or previous pregnancies. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:54 p.m. - 12:59 p.m.

Whole exome sequencing and analysis of a Chinese family with familial pulmonary sarcoidosis

Objective: To analyze the clinical features and the results of the whole exome sequencing (WES) of a Chinese family containing both pulmonary sarcoidosis patients and healthy members, and to find potent genes and variants that may be involved in the pathogenesis of sarcoidosis. Methods: Three patients with pulmonary sarcoidosis and 1 healthy member was included from a Chinese Han family in the north of China diagnosed in November 2016, which characterized as 2 consecutive generations including 2 males and 1 female, aged from 23 to 69 years old. The proband is Ⅱ-6. Pulmonary sarcoidosis was diagnosed by clinical features, imaging and pathological findings, and clinical data such as family history were collected. Whole blood samples were taken and WES (Illumina NovaSeq S2) was performed. The pathogenicity analysis and gene annotation analysis were performed by ExAC, SIFT, Polyphenv2, Metascape databases. Results: It was found that 27 genes were highly pathogenic in the database filtering result. After gene annotation analysis, we found that ZC3H12A gene can negatively regulate the differentiation of Th17 cells, which may be involved in the onset of pulmonary sarcoidosis. Sanger sequencing confirmed the c.1361 A>G variant in 3 sarcoidosis patients but normal in healthy member. Conclusions: In patients with familial pulmonary sarcoidosis, the genetic background could regulate immune response which is one of the pathogenic mechanisms of sarcoidosis. The whole exome test and gene ontology analysis showed that Ⅱ-2, Ⅱ-6 and Ⅲ-1 pulmonary sarcoidosis patients in this family were all shared the same variant on ZC3H12A gene, which played a pivotal role in differentiation of Th17 cells and is a potent pathogenesis gene in this Chinese pulmonary sarcoidosis family.

Clinical epidemiology of familial sarcoidosis: A systematic literature review.

Although the presence of familial sarcoidosis has been confirmed, clinical and epidemiological data on its characteristics are scattered and sometimes paradoxical. The objective of this review is to assess what is known on the clinical epidemiology of familial sarcoidosis, by combining data from early case reports with recent population based data; aiming to support in clinical decision making and providing information to patients. A systematic review of the literature in PubMed was done and 27 studies with clinical or epidemiological data on familial sarcoidosis, published between 1947 and 2017, were included. The pooled prevalence proportion of familial sarcoidosis, based on twelve study populations, was 9.5% (CI 4.6-16.1), highest in French, African American, Dutch and Irish patients. A heritability of 60-70% was estimated in diverse studies. Relative types and relationships most often reported in familial sarcoidosis were siblings and mother-child relationships. Familial risk is heterogeneous. In African Americans specific environmental factors have been associated with familial sarcoidosis (OR between 1.5 and 3.2). European American and African American subjects had different relative risks for first degree familial relationships (OR of 16.6 vs 3.1) and relative risk differed between relative types. Clinical findings in familial sarcoidosis are still obscure. Prevalence of familial sarcoidosis is high in specific study populations from countries worldwide. The estimated heritability of 60-70%, suggests a shared determinant, and the heterogeneous familial risk, associated with both genetic and environmental factors. Familial relative risks and clinical phenotypes may differ between ethnic groups and relative types, but require further study.

A Case of TINU Syndrome Difficult to Differentiate from Familial Sarcoidosis

A Case of TINU Syndrome Difficult to Differentiate from Familial Sarcoidosis

Whole-exome sequencing identifies rare genetic variations in German families with pulmonary sarcoidosis.

Genome-wide and candidate gene studies for pulmonary sarcoidosis have highlighted several candidate variants among different populations. However, the genetic basis of functional rare variants in sarcoidosis still needs to be explored. To identify functional rare variants in sarcoidosis, we sequenced exomes of 22 sarcoidosis cases from six families. Variants were prioritized using linkage and high-penetrance approaches, and filtered to identify novel and rare variants. Functional networking and pathway analysis of identified variants was performed using gene ontology based gene-phenotype, gene-gene, and protein-protein interactions. The linkage (n = 1007-7640) and high-penetrance (n = 11,432) prioritized variants were filtered to select variants with (a) reported allele frequency < 5% in databases (1.2-3.4%) or (b) novel (0.7-2.3%). Further selection based on functional properties and validation revealed a panel of 40 functional rare variants (33 from linkage region, 6 highly penetrant and 1 shared by both approaches). Functional network analysis implicated these gene variants in immune responses, such as regulation of pro-inflammatory cytokines including production of IFN-γ and anti-inflammatory cytokine IL-10, leukocyte proliferation, bacterial defence, and vesicle-mediated transport. The KEGG pathway analysis indicated inflammatory bowel disease as most relevant. This study highlights the subsets of functional rare gene variants involved in pulmonary sarcoidosis, such as, regulations of calcium ions, G-protein-coupled receptor, and immune system including retinoic acid binding. The implicated mechanisms in etiopathogenesis of familial sarcoidosis thus include Wnt signalling, inflammation mediated by chemokine and cytokine signalling and cadherin signalling pathways.

G908R NOD2 variant in a family with sarcoidosis

BackgroundSarcoidosis is a systemic disease characterized by the formation of immune granulomas in various organs, mainly the lungs and the lymphatic system. Exaggerated granulomatous reaction might be triggered in response to unidentified antigens in individuals with genetic susceptibility. The present study aimed to determine the genetic variants implicated in a familial case of sarcoidosis.MethodsSarcoidosis presentation and history, NOD2 profile, NF-κB and cytokine production in blood monocytes/macrophages were evaluated in individuals from a family with late appearance of sarcoidosis.ResultsIn the present study, we report a case of familial sarcoidosis with typical thoracic sarcoidosis and carrying the NOD2 2722G > C variant. This variant is associated with the presence of three additional SNPs for the IL17RA, KALRN and EPHA2 genes, which discriminate patients expressing the disease from others. Despite a decrease in NF-κB activity, IL-8 and TNF-A mRNA levels were increased at baseline and in stimulated conditions.ConclusionsCombination of polymorphisms in the NOD2, IL17RA, EPHA2 and KALRN genes could play a significant role in the development of sarcoidosis by maintaining a chronic pro-inflammatory status in macrophages.

Familial sarcoidosis: Report of a mother and her son.

Sarcoidosis is a chronic, multisystemic inflammatory disease, characterized with noncaseating granulomas. The pathogenesis of the disease is not yet clear, however, the main hypothesis is impaired and inadequate immune response developing against different environmental triggers in genetically predisposed people. The role of genetic factors in the development of sarcoidosis is well known. Over many years, familial sarcoidosis cases have been reported in various studies. In this report, we present familial sarcoidosis cases in a mother and her son.

Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.

BackgroundThe occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition. The involvement of butyrophilin-like 2 (BTNL2) gene (rs2076530 variant) has to be investigated.ResultsThe study performed independent analyses of BTNL2 polymorphism, clinical phenotypes, and outcomes in familial vs. sporadic presentations in 256 sporadic and 207 familial cases from 140 families. The logistic multivariate model showed that a young age at diagnosis and the combination of lung and skin involvement at diagnosis may distinguish sporadic from familial sarcoidosis (p = 0.016 and p = 0.041). We observed also that Sarcoid Clinical Activity Classification (SCAC) profiles were significantly different between familial and sporadic cases (p = 0.0497).Variant rs2076530 was more frequent in patients than in controls (OR = 2.02; 95% CI: [1.32–3.09]) but showed no difference between sporadic and familial cases and no difference according to the clinical phenotype or the outcome.ConclusionDespite a significant difference in BTNL2 polymorphism between sarcoid patients and controls, there was no such difference between familial and sporadic sarcoidosis cases and no correlation between BTNL2 polymorphism and disease severity or outcome. Thus, BTNL2 difference cannot be considered as a key marker for disease classification or patient management.

Üst Göz Kapağında Asemptomatik Nodüler Lezyona Eşlik Eden Kronik Osteomyeliti Olan Ailesel Subkutan Sarkoidoz Olgusu

Üst Göz Kapağında Asemptomatik Nodüler Lezyona Eşlik Eden Kronik Osteomyeliti Olan Ailesel Subkutan Sarkoidoz Olgusu

Sarcoidosis with uveitis occurring in Taiwanese sisters

Sarcoidosis is a multisystem granulomatous inflammatory disease, and uveitis is the most common ocular manifestation. Herein we report a female sibling pair both having sarcoidosis with uveitis. A 59-year-old woman presented with chronic panuveitis in both eyes lasting for one year. Enlarged mediastinal lymph nodes were demonstrated on computed tomography, and mediastinoscopic biopsy revealed chronic non-caseating granulomatous inflammation. Sarcoidosis was diagnosed. Eight months later, her younger sister developed bilateral anterior and intermediate uveitis. She was also diagnosed with sarcoidosis confirmed by intrathoracic lymph node biopsy. This is the first report of familial sarcoidosis presented with uveitis in Taiwan.

Mystery called sarcoidosis: Forty-four years follow-up of chronic systemic disease

This is a presentation of a 61-year-old female patient. Since 44 years have passed from the onset of her first symptoms until the final diagnosis of sarcoidosis, this was the reason of our decision to publish the case. During the follow-up period of 44 years the patient had ocassional polymorphic complains, such as adynamia, nausea, abdominal pains, myalgia, arthralgia, body weight loss (8-10 kg) etc. The clinical course was predominated by splenomegaly, hepatitis and arthralgia, and later chronic renal failure also developed. Laboratory findings showed elevated markers of acute inflammation and autoantibodies. The patient was hospitalized in different university internal hospitals (gastroenterology, allergology, rheumatology, nephrology and pulmology). Liver biopsy was performed three times, rectum and kidney biopsy once each and finally bronchoscopy and pulmonary biopsy was done. At last, about 40 years from the onset of the first symptoms, in 2006 the diagnosis of lung sarcoidosis was established. The final diagnosis of spleen sarcoidosis was confirmed by pathologically verified sarcoidosis of the lungs. This case is particularly interesting because of the presence of familial sarcoidosis (the patient's son also had recurrent pulmonary sarcoidosis).

Renal failure as first manifestation of familial sarcoidosis

To the Editors: Sarcoidosis is a systemic illness of unknown origin characterised by the presence of epithelioid, noncaseating granulomas in multiple organs, most commonly the lungs, eyes and skin. Renal disease is uncommon; however, it is an indication to perform a diagnostic and prognostic renal biopsy, and to put the patient on treatment with high and prolonged steroid doses. The presence of several cases in the same family is well known, as is the association with other chronic inflammatory disorders, favouring a genetic, environmental and/or immunological aetiology 1. We report a case of a 40-yr-old male referred to the nephrologist because of high levels of creatinine. He had been a 5 pack-yr smoker until 8 yrs previous and had worked as a salesperson in a large store. Except for mild asthenia, polyuria and polydipsia, he remained asymptomatic. Physical examination was entirely normal. Abdominal ultrasonography showed bilateral nephrocalcinosis and spleen enlargement, and the patient was admitted for further evaluation. Red and white blood cell counts were normal. Serum chemistry showed the following (normal ranges in parentheses): creatinine 3.2 mg·dL−1 (0.7–1.3 mg·dL−1); calcium 13.5 mg·dL−1 (8,2–10,6 mg·dL−1); 1,25-dihydroxyvitamin D 62,2 ng·dL−1 (10–50 ng·dL−1); parathyroid hormone 8.7 pg·mL−1 (11–72 pg·mL−1); angiotensine converting enzyme 178 IU·L−1 (18–55 IU·L−1); and 24-h urine calcium excretion 976 mg·day−1 (10–300 mg·day−1). Thyroid hormone levels, immunoglobulin (Ig) levels and antigliadin IgA levels were normal. Chest radiography showed bilateral diffuse interstitial infiltrates and a high-resolution computed tomography scan further showed hilar, mediastinal and axilar adenopathy. There were interlobar septal thickening and peripheral and subpleural small nodules related to pulmonary vessels. A 2-IU purified protein derivative RT-23 test showed no induration after 72 h. The ECG was normal, as was the ocular exam. Pulmonary function test results were …

Epidemiological features of Turkish patients with sarcoidosis

Epidemiological characteristics of sarcoidosis differ according to geographical distribution. The aim of our study was to disclose epidemiological characteristics in our country. The data was collected from investigators, who sent information on newly-diagnosed patients via internet. In 2 years 198 female and 95 male patients were enrolled to the study (f/m:2.08). Mean age of patients was 44+/-13 years (17-90). Mean age of male patients was 38+/-12 while mean age of female patients was 48+/-13 (p<0.001). 73.4% of patients were nonsmokers (85.4% of females; 48.4% of males; (p<0.001)). About 50% of our 293 patients were housewives. Familial sarcoidosis was found in 3 patients' first degree relatives. Estimated annual incidence of sarcoidosis for Turkey was calculated as 4 per 100,000 person. According to our study, 2/3 of sarcoidosis patients were women; mean age of patients was 45 and the disease began 10 years later in female patients. 80% of patients were nonsmokers; negative relation between sarcoidosis and smoking was evident especially in women. Familial sarcoidosis frequency was lower compared to other studies in the literature. There was no occupational exposure history in our patients. Our incidence rate, is similar with the results of other European studies.

A Case of Familial Sarcoidosis with Acute Onset of Fever and Arthralgia

A Case of Familial Sarcoidosis with Acute Onset of Fever and Arthralgia

Familial early onset sarcoidosis with bone cysts and erosions

Early onset sarcoidosis is a granulomatous disease which is characterized by synovitis, polyarthritis, skin and eye involvement. We report the skeletal features of one patient with a family history and clinical symptoms suggestive of early onset sarcoidosis (EOS) which was confirmed by skin biopsy. Radiographs reveal postarthritic deformities of the MCP joints, contractures, a coarsened trabecular pattern at the PIP joints and small bone cysts resembling osteitis cystoides multiplex. Similar lesions were described in radiographs of the older sister and an uncle of our patient. This is the first report demonstrating bone cysts and erosions which could be a diagnostic feature in this rare disease and may help to differentiate other rheumatoid disorders.

Familial Sarcoidosis in Taiwan

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology and is uncommon in Taiwan. No cases of familial sarcoidosis have been reported in Taiwan. In this article, we report a mother and son pair who had sarcoidosis. The 56-year-old mother sought medical help for chronic cough for 3 months in 1993. Enlarged mediastinal lymph nodes were demonstrated on chest computed tomography. Besides, two small erythematous papules on her face were observed. Mediastinoscopic biopsy and skin biopsy showed non-caseating granulomatous inflammation. Sarcoidosis was thus diagnosed. The human leukocyte antigen (HLA)-typing of the patient was HLA-A2, A11, B35, B39, CW4, CW7, DR8 and DQ6. Eleven years later, her son was also diagnosed with sarcoidosis proved by mediastinoscopic biopsy. His HLA-typing was HLA-A2, A24, B39, B48, CW7, CW8, DR8 and DQ6. This is the first report of familial sarcoidosis in Chinese people. More cases are needed for further investigation of genetic predisposition among Chinese people.

Sarcoidosis is associated with a truncating splice site mutation in BTNL2

Sarcoidosis is a polygenic immune disorder with predominant manifestation in the lung. Genome-wide linkage analysis previously indicated that the extended major histocompatibility locus on chromosome 6p was linked to susceptibility to sarcoidosis. Here, we carried out a systematic three-stage SNP scan of 16.4 Mb on chromosome 6p21 in as many as 947 independent cases of familial and sporadic sarcoidosis and found that a 15-kb segment of the gene butyrophilin-like 2 (BTNL2) was associated with the disease. The primary disease-associated variant (rs2076530; P(TDT) = 3 x 10(-6), P(case-control) = 1.1 x 10(-8); replication P(TDT) = 0.0018, P(case-control) = 1.8 x 10(-6)) represents a risk factor that is independent of variation in HLA-DRB1. BTNL2 is a member of the immunoglobulin superfamily and has been implicated as a costimulatory molecule involved in T-cell activation on the basis of its homology to B7-1. The G --> A transition constituting rs2076530 leads to the use of a cryptic splice site located 4 bp upstream of the affected wild-type donor site. Transcripts of the risk-associated allele have a premature stop in the spliced mRNA. The resulting protein lacks the C-terminal IgC domain and transmembrane helix, thereby disrupting the membrane localization of the protein, as shown in experiments using green fluorescent protein and V5 fusion proteins.