Overlap of familial Mediterranean fever and autoinflammatory PLCG2-associated antibody deficiency and immune dysregulation in a Turkish patient

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While familial Mediterranean fever (FMF) is a common example prevalent in Mediterranean regions, autoinflammatory phospholipase C gamma 2 ( PLCG2 )-associated antibody deficiency and immune dysregulation (APLAID) is extremely rare. We aim to report the first case of co-occurrence of FMF and APLAID and discuss the clinical manifestations, immunological findings, and medical approach of the patient by reviewing the medical literature. A 36-year-old male patient visited our dermatology clinic with a history of recurrent pustular eruptions since childhood, aggravated in the last month. He had bronchiectasis, emphysema, and a diagnosis of FMF. Colchicine helped to control arthritis but did not resolve the pustular eruptions. Histopathological examination of the pustules revealed neutrophilic exudation, and microbial cultures were negative. The patient exhibited high C-reactive protein levels, mild lymphopenia, mildly low IgM levels, and a decreased CD4/CD8 ratio. Genetic analysis revealed a heterozygous c.2120C > A (Ser707Tyr) mutation in the PLCG2 gene. Daily anakinra 100 mg therapy regressed subsequent relapses of pustules within two months. In 28-month treatment, the patient experienced two relapses of pustular eruption, which resolved with short-term low-dose systemic corticosteroid treatment. In conclusion, we point out that a thorough immunological evaluation of patients with recurrent pustular eruptions and associated systemic symptoms is essential, even if a patient has already been diagnosed with an autoinflammatory disease. Albeit rare, it is important to consider the possibility of another coexisting autoinflammatory disease. hereditary autoinflammatory diseases phospholipase C gamma familial Mediterranean fever genetic testing Figures Figure 1 Figure 2 Figure 3 Introduction Autoinflammatory diseases (AID) are usually rare inherited disorders resulting from genetic defects in innate immunity, leading to uncontrolled systemic or organ-specific inflammation [ 1 ]. Among the spectrum of AIDs, de novo or dominant mutations in the phospholipase C gamma 2 ( PLCG2 ) gene cause two exceptionally rare syndromes: PLCG2-associated antibody deficiency and immune dysregulation (PLAID) [ 2 ] and autoinflammatory PLCG2-associated antibody deficiency and immune dysregulation (APLAID) [ 3 ]. In contrast, familial Mediterranean fever (FMF) is the most frequent monogenic AID, much more common in countries in Mediterranean and Middle Eastern regions, and is characterized by mutations in the MEFV gene [ 4 ]. Phosphoinositide-specific phospholipase C (PLC) refers to a group of Ca2 + dependent enzymes that consist of various isoform families such as PLCβ, γ, δ, ϵ, η, and ζ [ 5 ]. PLCs are involved in catalysis hydrolysis of the phosphatidylinositol 4,5 bisphosphate (PI (4,5) P2) into diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (Ins (1,4,5) P3). Both of these products function as secondary messengers. Ins (1,4,5) P3 interacts with its associated receptor in the endoplasmic reticulum and triggers the opening of Ca2 + channels. This results in an elevation in the concentration of intracellular calcium ions, leading to the activation of calcium-reactive enzymes [ 6 ]. Ins (1,4,5) P3 and DAG interact with the receptors for neurotransmitters, antigens, hormones and growth factors [ 5 ]. Therefore, PLCs are required for signal transduction and regulation of cellular processes such as cellular mobilization and sensory transduction. There are two forms of PLCG enzymes, namely PLCG1 and PLCG2. PLCG2 is highly expressed in hematopoietic derived lymphoid cells and plays crucial role in regulation of immune responses. PLCG2 knockout mouse model demonstrated impaired B cell differentiation, platelet dysfunction and defective NK cell FcγRIII function [ 7 ]. Exon deletions and loss-of-function mutations of the PLCG2 gene result in PLAID as cold urticaria, immunodeficiency, and autoimmunity [ 2 ]. In contrary, substations and gain of function mutations in the gene PLCG2 gene result in the hyperactive PLCG2 protein due to the dysfunction of the regulatory region in APLAID. The increase of intracellular calcium as a second messenger, NLRP3 inflammasome activation [ 8 ], high IgE levels [ 3 , 9 ], and increased granulocyte colony-stimulating factor [ 10 ] are suggested drive the autoinflammation in APLAID although the exact mechanism is not clear. The manifestations of the autoinflammation phenotype of APLAID are heterogeneous among patients, from dominant inheritance without any manifestations to severe multisystemic involvement [ 3 , 9 , 11 – 21 ]. Here, we report and discuss the clinical manifestations, immunological findings and medical approach of patient diagnosed with APLAID and FMF for the first time. Methods and Results The Patient A 36-year-old Turkish male patient was admitted to the dermatology outpatient clinic with widespread non-itchy pustules, painful limb swelling lasting for about four weeks, and coughing. He had been experiencing pustules on his body since he was 12 years old, along with swellings of foot and knee joints since early infancy. He had no attacks of abdominal pain, fever, or mucosal ulcer. Medical files showed that he was diagnosed with Familial Mediterranean Fever (a compound heterozygous mutation, M694V (c.2080A>G p.Met694Val) and M680I (c.2040G>C p.Met680IIe). He was on colchicine therapy for years which helped with arthritis but the therapy did not resolve pustular eruption attacks. He has been experiencing coughs, expectorations, and shortness of breath for about ten years and was diagnosed with bronchiectasis and emphysema. He was a non-smoker and had been hospitalized twice for pneumonia and a preliminary diagnosis of asthma and was on inhaled steroids and bronchodilator therapy, providing no significant benefit. His parents were not consanguineous, and his family medical history was unremarkable. Dermatological examination revealed multiple papulopustules on his face, trunk, and limbs. Additionally, an erythematous and oedematous plaque with tiny pustules was found on the lateral lower side of his left shin (Figure 1 a-c). The patient did not have a fever, and his mucosal regions and nails appeared normal. The patient gave informed consent for performing further laboratory tests and genetic analyses. Laboratory analyses Histopathological examination of the pustules showed neutrophilic exudation, and microbial cultures were negative. To evaluate the T and B cell subgroups, flow cytometry analysis was performed. The patient had high levels of C-reactive protein (36.8 mg/L; normal range: 0-5 mg/L) and erythrocyte sedimentation rate (33 mm/h; normal range: 0-20 mm/h), mild lymphopenia, mildly low IgM levels, a decreased CD4/CD8 ratio, various T and B cell subgroup abnormalities. There was a prominent decrease in naïve T cells, along with an increase in effector memory CD4+ T cells and plasmablasts (Table 1). Fasting glucose and lipids, liver, kidney, and thyroid function tests, urine analysis, and serum electrolytes were all normal. Additionally, serological markers for hepatitis B and C, serum anti-nuclear antibody, alpha-1 antitrypsin antibody, anti-HIV antibody, and rheumatoid factor were all negative. The chest X-ray revealed increased linear opacities in the bilateral upper zones, as well as flattening and inferior displacement in both diaphragms (Figure 2a). Genetic Analysis Whole exome sequencing (WES) was performed on Illumina NextSeq 500 system using an Illumina v2 reagent kit, following the manufacturer’s protocol. We filtered rare variants (MAF<0.01) for presence in a comprehensive list of genes known to be involved in Human Inborn Errors of Immunity [22]. Variants present in the gnomAD as homozygous were ruled out. Along with these filters also synonymous variants were filtered out. Finally, disease related mutations were determined using in-silico pathogenicity prediction tools such as SIFT, PolyPhen2, and Mutation Taster. In addition, variants with a CADD Phred score higher than 20 were chosen. The pathogenicity of disease-attributable gene variants was evaluated using the American College of Medical Genetics and Genomics (ACMG) criteria also. In PLCG2 gene, a previously reported heterozygous missense c.2120C>A mutation is identified in the patient by WES analysis and confirmed by Sanger sequencing [3]. Heterozygous c.2120C>A mutation in the patient results in a serine to tyrosine substitution at the position 707 in the PLCG2 protein (Figure 3). Treatment Clinical features and symptoms were indicative of an autoinflammatory disease. While waiting for the results of the WES analysis, the patient was initially treated with systemic corticosteroid therapy, which resulted in rapid regression of all skin lesions within a week. Tocilizumab, an IL-6 blocker, at a dosage of 560 mg per month was prescribed, but the patient was considered unresponsive due to mild to moderately severe pustular rash that continued to emerge in three months of treatment. After validation of the PLCG2 mutation, the therapy was switched to 100 mg of anakinra therapy daily, which provided the regression of all pustules within two months (Figure 1d-f). After three months of treatment, chest X-ray revealed the disappearance of linear opacities (Figure 2b). Over the 28-month follow-up period, the patient experienced only two relapses of generalized pustular eruption, both of which resolved with short-term low-dose systemic corticosteroid treatment. Discussion APLAID is one of the highly infrequent AIDs, and as far as we know, 29 cases have been reported in the literature [3, 9, 11-21] (Table 2). This report presents a unique coexistence of two monoalleic autoinflammatory diseases, APLAID and FMF. The patient was diagnosed with FMF due to recurrent arthritis and pathogenic MEFV gene mutations. However, the patient also suffered from recurrent pustular eruptions, a skin manifestation different from the typical erysipelas-like erythema of FMF and inconsistent with this diagnosis. These discordant skin lesions, along with long-standing lung disease and joint swellings since the patient’s early years of life prompted us to investigate the potential coexistence of another AID. The AIDs typically present with recurrent or persistent sterile systemic inflammation affecting multiple organs, especially skin, lungs, and joints, along with variable immune deficiencies. The inflammasomopathies, interferonopathies, proteoasomopathies, and diseases with nuclear kappa B pathway activation are common AIDs and lead to aberrant secretion of inflammatory cytokines, such as IL1 and TNF-α. Hereditary monogenic defects or multifactorial polygenic disorders result in the dysfunction of inflammation, especially in the innate response of the immune system [1, 4]. When skin is the target, patients may present with recurrent pustules, abscesses, urticarial-like plaques, angioedema, erythema nodosum, aphthae, or neutrophilic dermatosis with or without fever and several systemic involvements. FMF is the most common monogenic AID and presents with attacks of fever, erysipelas-like erythema, erythema nodosum, along with joint, abdominal, or chest pain due to serositis caused by pyrin inflammasome dysfunction and overproduction of the pro-inflammatory cytokine IL1. The pathogenic MEFV gene mutations, occurring in exon 10, including M694V and M680I, cause the typical gain of function in the regulatory protein, pyrin. Colchicine is the most commonly used treatment that prevents FMF attacks [4]. When the present patient was initially evaluated, the most remarkable finding was the colchicine-unresponsive pustular attacks and accompanying recurrent respiratory infections, which were potentially suggestive of an additional immunosuppression. The WES analyses helped to find the mutated PLCG2 gene and to explain the exact pathogenesis underlying the coexisting AIDs phenotype. The autoinflammation of APLAID may involve skin, eye, lung, joint, gastrointestinal system. Interstitial pneumonitis, recurrent sinopulmonary infections, arthritis, inflammatory eye and bowel diseases, and various skin manifestations are common [3, 9, 11-21] (Table 2). Vesicles/ blisters and pustular eruptions are the most frequent skin lesions, followed by granulomas, papules and plaques (Table 3). Our case demonstrated severe chronic relapsing pustular eruptions of autoinflammation in APLAID and chronic recurrent pulmonary infections, caused by Ser707Tyr gain-of function mutation in the SH2 domain of the PLCG2 gene. The SH2 domain is the most mutated one among the 30 patients, including the present case. However, a clear phenotype and genotype correlation could not be established in APLAID cases due to the rarity of the disease and distinct involvement of systems. Remarkably, the onset of disease ranges from the birth to the age of 50. Although data of most of the patients are missing, the age of diagnosis seems to be as late as 5 th decade. PLCG2 is known to be required for B cell receptor signalling, which is critical for B cell development and maturation. Patients with APLAID can have mild to severe immunodeficiency because PLCG2 activation causes impairment in B cell differentiation and myelopoiesis, and affects mature B cell survival and antibody production [23]. It has been previously described that APLAID patients have varying degrees of B cell lymphopenia and antibody deficiency, but no significant impairment of T or NK function [11, 13, 15]. Our patient had mild lymphopenia, mildly low IgM levels and a reduced CD4/CD8 ratio. Contrary to previous reports, while B lymphocyte counts and subgroups were normal, T cell subgroup abnormalities were present; naive T cell decrease, effector memory CD4+ T cells and plasmablast increase were prominent. The changes observed in T cells may be secondary to the patient's treatments. Decreased numbers of dendritic cells have also been found in several studies [18]. In this group of diseases with variable clinical findings, there may be different changes in immune cells, T and B cell subgroups. The treatment of APLAID aims to suppress excessive harmful autoinflammation and regulation of immunity. However, there is no consensus on the management of the disorder. Systemic corticosteroids, cyclosporine, methotrexate, IL1beta inhibitors, and tumour necrosis alfa inhibitors were used to treat suffering skin lesions with variable response [3, 9, 11-19, 21]. In the present case, the patient was initially treated with tocilizumab before the results of genetic analyses. Although tocilizumab is a treatment choice for FMF, it did not work to suppress the autoinflammation of APLAID. On the contrary, a subsequent switch to anakinra, the IL1beta receptor inhibitor, achieved total clearance and long-lasting control of the inflammatory skin lesions. The favorable continuous outcome in the present patient supports the possible role of IL1beta in the pathogenesis of APLAID. However, experience of anakinra in APLAID is rare and outcome is variable. Among three cases under anakinra treatment, one had improvement of skin lesions [13], one had partial control of autoinflammation [15], and one did not respond [11]. Conclusion Skin is potentially the most demonstrative and available target of AIDs. The present patient is unique. The patient was found to have two different AID since there were additional phenotype not explained only with FMF. The paper reports the first case of APLAID overlap with FMF and pays attention to the course, including the suspicion upon detailed history and examinations and subsequent WES analysis providing the correct diagnoses. Declarations Conflict of interest The authors declare no conflicts of interest. Funding sources: None. Patient consent: Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article. The patient gave informed consent for performing genetic analyses and laboratory tests. Author Contribution G.A. and D.C. designed the research study. G.A., I.Y., and S. E. performed the research. S.Y. and D.D.M. contributed essential reagents or tools. D.C. supervised the research study. G.A. wrote the manuscript. All authors have been involved in manuscript composition. All authors have read and approved the final manuscript. 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Parameters Patient’s value Reference Hemoglobin (g/dL) 14.7 13.6-17.2 Leukocyte (/μl) 9100 4300-10300 Absolute neutrophil count (/μl) 6850 Absolute lymphocyte count (/μl) 1310 1400-3300 Absolute eosinophil count (/μl) 260 <500 Platelets (/μl) 271000 156000-373000 IgA (mg/dL) 221 139-378 IgG (mg/dL) 1670 913-1884 IgM (mg/dL) 62.2 88-322 Total IgE (UI/ml) 5.17 - ANA titer (positivity)/staining patterns 1:100(+) Speckled-AC-4, AC-5, Nucleolar-AC-8, AC-9, AC-10 - Anti A/B titer Anti A: 1:512 Anti B: 1:32 - Dihydrorhodamine (DHR) test Normal - CD3 + T cells (%) 85 56-84 CD4 + T cells (%) 43 31-52 Naive T helper cell (CD4 + CCR7 + CD45RA + ) (%) 24.4 57.1-84.9 Central memory T helper cell (CD4 + CCR7 + CD45RA - ) (%) 29.2 11.3-26.7 Effector memory T helper cell (CD4 + CCR7 - CD45RA - ) (%) 34 3.3-15.2 TEMRA (CD4 + CCR7 - CD45RA + ) (%) 12.4 0.4-2.6 Recent thymic emigrants (CD4 + CD45RA + CD31 + ) (%) 7 7-100 CD8 + T cells (%) 42 18-35 Naive T cytotoxic cells (CD8 + CCR7 + CD45RA + ) (%) 20.5 28.4-80.6 Central memory T cytotoxic cells (CD8 + CCR7 + CD45RA - ) 0.2 1.0-4.5 Effector memory T cytotoxic cells (CD8 + CCR7 - CD45RA - ) 2.5 6.2-29.3 TEMRA (CD8 + CCR7 - CD45RA + ) 76.7 9.1-49.1 CD19 + B cells (%) 9 6-23 Transitional B cells (CD19 + CD38 High IgM High ) (%) 0 0.9-5.7 Naïve B cells (CD19 + CD27 − IgD + ) (%) 69.8 48.4-79.7 Activated B cells (CD19 + CD21 low CD38 - ) (%) 69.8 1.6-10 Marginal zone B cells (CD19 + CD27 + IgD + ) (%) 7.5 7-23.8 Memory B cells (CD19 + CD27 + ) (%) 18.8 17.5-46.5 Switched memory B cells (CD19 + CD27 + IgD − ) (%) 11.3 8.3-27.8 Plasmablasts (CD19 + CD38 High IgM − ) (%) 13.3 0.4-2.4 CD16 + 56 + NK cells (%) 4 3-22 CD25 (%) 73 69.9-98 CD69 (%) 82 70.6-83.2 CD3CD25 (%) 50 46.3-88.5 CD3CD69 (%) 70 50.3-75.6 Table 2. Summary of phenotypic and genotypic characteristics of cases with APLAID published in the literature. Zhou et al. Neves et al. Moran-Villasenor et al. Novice et al. Khabbazi et al. Martin-Nalda et al. Wu et al. Park et al. Itakura et al. Peng et al. Wang et al. Baysac et al. Yang et al. Our case Year of report 2012 2018 2019 2020 2020 2020 2021 2022 2023 2023 2024 2024 2024 2025 Origin (ethnicity/country) USA Porteguese Mexican USA Iran Spain Spain Chinese Korea Japan Chinese Chinese USA Russian Turkish Number of cases reported 2* 1 1 3** 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Age at onset infancy 1st week birth 2 infancy, 1 ND 8 yrs birth 1st week 5 yrs birth 32 yrs N/A birth 4 yrs 14 yrs 2 yrs 12 yrs 2 mo. 25 yrs 7 yrs 1 yrs birth 50 yrs 2.5 yrs 6 yrs 6 yrs 1 mo. infancy Age at diagnosis ND 11 yrs 3 yrs 2 yrs, 6 yrs, 1 ND 11 yrs 16 yrs 9 yrs 23 yrs 17 yrs 34 yrs 7 yrs 21 mo. ND ND ND ND ND ND ND ND ND ND ND ND ND 9 yrs 36 yrs Gender M, F F M F F F M M M M M M ND ND ND ND ND ND ND ND ND ND ND ND ND M M Parental consangu-inity -, - - - ND + - - - - ND - - ND ND ND ND ND ND ND ND ND ND ND ND ND ND - Mutation Ser707 Tyr Leu848 Pro Leu848 Pro Met1141 Lys His193 Asn Leu845_Leu848 del Ala708 Pro Ile169 Val Ser707 Pro Leu1012Val Leu845 Ser Leu848 Pro His494 Tyr Arg697Trp Gly699 Ser Thr706 Ile Ala708 Pro Arg742 Cys Arg742 His Leu845 Ser Leu848 Pro Arg956 Cys Pro1050Leu Glu1139del Glu1191Gln Asp993 Tyr Ser707 Tyr Skin + + + + (except one) + + + + + - + + + + + + + + - + + - - + - + + Eye + + + + - + + - - - - - + - - - - - - - - - - - - - - Lung + + - + - + + + - - + + - + - - - - + - - - - + - + Joint + - - + + - - + - - - - - - - + - - - - - - - - - + + Gastro-intestinal + + + + + - - - - - + + + - - + + + + - - - - - - + - Infections + + + + - + + - + - + + - + + - + + + - + + - + + + + Immuno-deficiency + + + + - + + + + - + + - + + - + + + - + + - + + + + Treat-ments SysS, antiTNF, antiIL1 SysS, HCQ, antiIL1, ruxolitinib MTX, antiTNF, IVIG SysS, OMA, antiIL1 SysS, MTX, anti-TNF SysS, antiTNF, antiIL1, IVIG IVIG SysS, MTX, CsA, antiTNF, IVIG SysS SysS, CsA SysS, antiTNF MTX, CsA, IVIG ND ND ND ND ND ND ND ND ND ND ND ND ND AntiTNF, IVIG SysS, antiIL6, antiIL1 Control of disease activity Partial Partial Yes Yes for one case (2 ND) No Partial Yes Yes Yes Yes No No, exitus ND ND ND ND ND ND ND ND ND ND ND ND ND Yes Yes *Cases are father and daughter, **Two cases are mother and daughter Abbreviations: CsA: cyclosporine A, F: female, HCQ: hydroxychloroquine, IL1: interleukin, IVIG: intravenous immunoglobulin, M: male, MTX: methotrexate 1, mo.: month, ND: no data, OMA: omalizumab, SysS: systemic corticosteroids, TNF: tumour necrosis alpha, yrs: years Table 3. Skin manifestations and associated PLCG2 mutations in 30 patients including published cases with APLAID and the present case. Skin lesions n % Mutation Domain Reference number Superficial fluid filled lesions 18 60.0 Vesicules +/- pustules, blisters 16 53.3 Met1141Lys C2 13 Ile169Val EF 9 Leu848Pro sPH 11, 12, 19 Leu845Ser sPH 18 Leu845_Leu848 del sPH 15 Ala708Pro SH2 15 Ser707Pro SH2 16 Ser707Tyr SH2 3, our case Epidermolysis bullosa-like eruption 2 6.7 Ser707Tyr SH2 3 Infiltrative lesions 16 53.3 Granulomas 9 30.0 Glu1139del C2 20 Asp993Tyr Y-Box 21 His494Tyr sPH 20 Leu848Pro sPH 11, 12, 20 Thr706Ile SH2 20 Ala708Pro SH2 15, 20 Papules / plaques 7 23.3 Leu845_Leu848 del sPH 15 Leu848Pro sPH 12 Ser707Tyr SH2 3 Ser707Pro SH2 16 Ala708Pro SH2 15 Urticarial rash 5 16.7 Met1141Lys C2 13 His193Asn EF 14 Ala708Pro SH2 15 Arg697Trp SH2 20 Gly699Ser SH2 20 Eczema 3 10.0 Glu1139del C2 20 Arg742Cys SH2 20 Thr706Ile SH2 20 Dermal changes 6 20.0 Cutis laxa 3 10.0 Leu848Pro sPH 11 Leu845_Leu848 del sPH 15 Ala708Pro SH2 15 Atrophic skin lesions 2 6.7 Met1141Lys C2 13 Loose skin 1 3.3 Leu845Ser sPH 18 Hyperpigmentation 2 6.7 Leu845_Leu848 del sPH 15 Ala708Pro SH2 15 Destructive lesions 4 13.3 Ulcer 2 6.7 Ala708Pro SH2 15 Leu848Pro sPH 7 Gangrenous pyoderma 1 3.3 Ile169Val EF 9 Nasal septum ulcer 1 3.3 Leu1012Val Y-Box 17 Stomatitis 1 3.3 Leu1012Val Y-Box 17 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6201807","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":427413643,"identity":"3a76a890-b9ee-44ad-9bf5-12e310c8013a","order_by":0,"name":"Gulsen Akoglu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABC0lEQVRIiWNgGAWjYFAC5gYwJcHAwHiAoYIhAcrBBxjhWhgOMJyBazEgUgtjGxFa5CMSmz983MEgL9nefuEw77y6PIMDzAdv8zD8ycelxfBGYpvkzDMMhrN5zhQc5t12uNjgAFuyNQ+DgWUDLi0zEtuYedsYGOdJ5CQAtRxI3HCAx0waqAWny4Bamj//bWOwh2iZUwfUwv8NrxZ5icQGaaCvE2dLpB84zNvADLKFDa8WA56HbZK9bRLJM3vOMBycc+xwseRhNmPLOQbGuG1pTz784Webje2M4+0PH7ypqcvjO9788MabCjncthwAU6BY4YEqYgaL49IAtKUBzmR/gFvZKBgFo2AUjGgAAOoSV9liqz8GAAAAAElFTkSuQmCC","orcid":"","institution":"University of Health Sciences, Gülhane Training and Research Hospital","correspondingAuthor":true,"prefix":"","firstName":"Gulsen","middleName":"","lastName":"Akoglu","suffix":""},{"id":427413647,"identity":"8ac5b80b-824c-4092-a7ba-652df4ca4d47","order_by":1,"name":"Ismail Yaz","email":"","orcid":"","institution":"Hacettepe University, Institute of Child Health","correspondingAuthor":false,"prefix":"","firstName":"Ismail","middleName":"","lastName":"Yaz","suffix":""},{"id":427413650,"identity":"c3919f2d-1423-4bd9-9f49-48ccfd3be8e0","order_by":2,"name":"Saliha Esenboga","email":"","orcid":"","institution":"Hacettepe University Medical School","correspondingAuthor":false,"prefix":"","firstName":"Saliha","middleName":"","lastName":"Esenboga","suffix":""},{"id":427413653,"identity":"0bb3785b-99b1-496d-a0fc-a173b71355a8","order_by":3,"name":"Sedat Yilmaz","email":"","orcid":"","institution":"University of Health Sciences, Gülhane Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sedat","middleName":"","lastName":"Yilmaz","suffix":""},{"id":427413657,"identity":"9d7fb72e-10eb-43a8-b388-0aa827b81f75","order_by":4,"name":"Deniz Dogan Mulazimoglu","email":"","orcid":"","institution":"University of Health Sciences, Gülhane Training and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Deniz","middleName":"Dogan","lastName":"Mulazimoglu","suffix":""},{"id":427413660,"identity":"c31ff00c-49b1-4cde-8832-3d43a6c94824","order_by":5,"name":"Deniz Cagdas","email":"","orcid":"","institution":"Hacettepe University, Institute of Child Health","correspondingAuthor":false,"prefix":"","firstName":"Deniz","middleName":"","lastName":"Cagdas","suffix":""}],"badges":[],"createdAt":"2025-03-11 09:38:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6201807/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6201807/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78663052,"identity":"78beecff-1d99-4525-9d2f-a38b1b80ca71","added_by":"auto","created_at":"2025-03-17 10:36:12","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":177107,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(a-c) \u003c/strong\u003eWidespread pustular rash of the patient at first visit; \u003cstrong\u003e(d-f)\u003c/strong\u003e regression of almost all lesions after 3 months of anakinra treatment.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6201807/v1/0daa965883da7c23b5d7bb8b.jpg"},{"id":78663051,"identity":"73bc36c8-f029-4ec7-a737-4efe5e884bfa","added_by":"auto","created_at":"2025-03-17 10:36:12","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":180228,"visible":true,"origin":"","legend":"\u003cp\u003eChest X-ray of the patient showing\u003cstrong\u003e (a)\u003c/strong\u003eincreased linear opacities in the bilateral upper zones, flattening and inferior displacement in both diaphragms before anakinra therapy.\u003cstrong\u003e (b) \u003c/strong\u003eOpacities disappeared after 3 months.\u003c/p\u003e","description":"","filename":"Figure2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6201807/v1/ba7026b669b0b45bae2efade.jpeg"},{"id":78663880,"identity":"3bfa9cef-d03b-4b04-8c97-11de6076d1a9","added_by":"auto","created_at":"2025-03-17 10:44:12","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":181805,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(a) \u003c/strong\u003eSchematic representation of PLCG2 protein showing its domains and localization of the mutation identified in the patient (p.Ser707Tyr). PH, pleckstrin homology domain; EF, EF hand motif; sPH, split PH domain; nSH2, N terminus, Src Homology 2 domain; cSH2, C terminus Src Homology 2 domain; SH3, SRC Homology 3 domain; C2, C2 domain.\u003cstrong\u003e (b) \u003c/strong\u003eMultiple sequence alignments by UniProt. The asterisks indicate fully conserved residues, whereas colons indicate conserved and periods indicate semi-conserved substitutions. Black frame indicates evolutionary conservation of the serine at position 707.\u003cstrong\u003e (c) \u003c/strong\u003eGibbs free energy calculation results for wild-type and mutant PLCG2 proteins. (*Predicted ΔΔG\u0026lt;0 is destabilizing in the case of DynaMut2, mCSM, SDM, DUET. **Predicted ΔΔG\u0026gt;0 is destabilizing in the case of PremPS.) \u003cstrong\u003e(d) \u003c/strong\u003e3D protein structures of wild-type and mutant PLCG2 proteins, respectively.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6201807/v1/e7437c2c5a313087de44afbf.jpg"},{"id":78990824,"identity":"8dbe2899-abf9-422c-9ca9-4b4b6d63c2ad","added_by":"auto","created_at":"2025-03-21 20:46:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1541206,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6201807/v1/e1078e03-2ea2-4ab1-a4de-6ee48be8b389.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Overlap of familial Mediterranean fever and autoinflammatory PLCG2-associated antibody deficiency and immune dysregulation in a Turkish patient","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAutoinflammatory diseases (AID) are usually rare inherited disorders resulting from genetic defects in innate immunity, leading to uncontrolled systemic or organ-specific inflammation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Among the spectrum of AIDs, de novo or dominant mutations in the phospholipase C gamma 2 (\u003cem\u003ePLCG2\u003c/em\u003e) gene cause two exceptionally rare syndromes: PLCG2-associated antibody deficiency and immune dysregulation (PLAID) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and autoinflammatory PLCG2-associated antibody deficiency and immune dysregulation (APLAID) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In contrast, familial Mediterranean fever (FMF) is the most frequent monogenic AID, much more common in countries in Mediterranean and Middle Eastern regions, and is characterized by mutations in the \u003cem\u003eMEFV\u003c/em\u003e gene [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePhosphoinositide-specific phospholipase C (PLC) refers to a group of Ca2\u0026thinsp;+\u0026thinsp;dependent enzymes that consist of various isoform families such as PLCβ, γ, δ, ϵ, η, and ζ [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. PLCs are involved in catalysis hydrolysis of the phosphatidylinositol 4,5 bisphosphate (PI (4,5) P2) into diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (Ins (1,4,5) P3). Both of these products function as secondary messengers. Ins (1,4,5) P3 interacts with its associated receptor in the endoplasmic reticulum and triggers the opening of Ca2\u0026thinsp;+\u0026thinsp;channels. This results in an elevation in the concentration of intracellular calcium ions, leading to the activation of calcium-reactive enzymes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Ins (1,4,5) P3 and DAG interact with the receptors for neurotransmitters, antigens, hormones and growth factors [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Therefore, PLCs are required for signal transduction and regulation of cellular processes such as cellular mobilization and sensory transduction.\u003c/p\u003e \u003cp\u003eThere are two forms of PLCG enzymes, namely PLCG1 and PLCG2. PLCG2 is highly expressed in hematopoietic derived lymphoid cells and plays crucial role in regulation of immune responses. PLCG2 knockout mouse model demonstrated impaired B cell differentiation, platelet dysfunction and defective NK cell FcγRIII function [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eExon deletions and loss-of-function mutations of the \u003cem\u003ePLCG2\u003c/em\u003e gene result in PLAID as cold urticaria, immunodeficiency, and autoimmunity [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In contrary, substations and gain of function mutations in the gene \u003cem\u003ePLCG2\u003c/em\u003e gene result in the hyperactive PLCG2 protein due to the dysfunction of the regulatory region in APLAID. The increase of intracellular calcium as a second messenger, NLRP3 inflammasome activation [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], high IgE levels [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and increased granulocyte colony-stimulating factor [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] are suggested drive the autoinflammation in APLAID although the exact mechanism is not clear. The manifestations of the autoinflammation phenotype of APLAID are heterogeneous among patients, from dominant inheritance without any manifestations to severe multisystemic involvement [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHere, we report and discuss the clinical manifestations, immunological findings and medical approach of patient diagnosed with APLAID and FMF for the first time.\u003c/p\u003e"},{"header":"Methods and Results","content":"\u003cp\u003e\u003cstrong\u003eThe Patient\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 36-year-old Turkish male patient was admitted to the dermatology outpatient clinic with widespread non-itchy pustules, painful limb swelling lasting for about four weeks, and coughing. He had been experiencing pustules on his body since he was 12 years old, along with swellings of foot and knee joints since early infancy. He had no attacks of abdominal pain, fever, or mucosal ulcer. Medical files showed that he was diagnosed with Familial Mediterranean Fever (a compound heterozygous mutation, M694V (c.2080A\u0026gt;G p.Met694Val) and M680I (c.2040G\u0026gt;C p.Met680IIe). He was on colchicine therapy for years which helped with arthritis but the therapy did not resolve pustular eruption attacks. He has been experiencing coughs, expectorations, and shortness of breath for about ten years and was diagnosed with bronchiectasis and emphysema. He was a non-smoker and had been hospitalized twice for pneumonia and a preliminary diagnosis of asthma and was on inhaled steroids and bronchodilator therapy, providing no significant benefit. His parents were not consanguineous, and his family medical history was unremarkable. Dermatological examination revealed multiple papulopustules on his face, trunk, and limbs. Additionally, an erythematous and oedematous plaque with tiny pustules was found on the lateral lower side of his left shin (Figure 1 a-c). The patient did not have a fever, and his mucosal regions and nails appeared normal. The patient gave informed consent for performing further laboratory tests and genetic analyses.\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eLaboratory analyses\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHistopathological examination of the pustules showed neutrophilic exudation, and microbial cultures were negative. To evaluate the T and B cell subgroups, flow cytometry analysis was performed.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe patient had high levels of C-reactive protein (36.8 mg/L; normal range: 0-5 mg/L) and erythrocyte sedimentation rate (33 mm/h; normal range: 0-20 mm/h), mild lymphopenia, mildly low IgM levels, a decreased CD4/CD8 ratio, various T and B cell subgroup abnormalities. There was a prominent decrease in na\u0026iuml;ve T cells, along with an increase in effector memory CD4+ T cells and plasmablasts (Table 1). Fasting glucose and lipids, liver, kidney, and thyroid function tests, urine analysis, and serum electrolytes were all normal. Additionally, serological markers for hepatitis B and C, serum anti-nuclear antibody, alpha-1 antitrypsin antibody, anti-HIV antibody, and rheumatoid factor were all negative. The chest X-ray revealed increased linear opacities in the bilateral upper zones, as well as flattening and inferior displacement in both diaphragms (Figure 2a).\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eGenetic Analysis\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhole exome sequencing (WES) was performed on Illumina NextSeq 500 system using an Illumina v2 reagent kit, following the manufacturer\u0026rsquo;s protocol. We filtered rare variants (MAF\u0026lt;0.01) for presence in a comprehensive list of genes known to be involved in Human Inborn Errors of Immunity [22]. Variants present in the gnomAD as homozygous were ruled out. Along with these filters also synonymous variants were filtered out. Finally, disease related mutations were determined using in-silico pathogenicity prediction tools such as SIFT, PolyPhen2, and Mutation Taster. In addition, variants with a CADD Phred score higher than 20 were chosen. The pathogenicity of disease-attributable gene variants was evaluated using the American College of Medical Genetics and Genomics (ACMG) criteria also. In \u003cem\u003ePLCG2\u003c/em\u003e gene, a previously reported heterozygous missense c.2120C\u0026gt;A mutation is identified in the patient by WES analysis and confirmed by Sanger sequencing [3]. Heterozygous c.2120C\u0026gt;A mutation in the patient results in a serine to tyrosine substitution at the position 707 in the PLCG2 protein (Figure 3).\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTreatment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical features and symptoms were indicative of an autoinflammatory disease. While waiting for the results of the WES analysis, the patient was initially treated with systemic corticosteroid therapy, which resulted in rapid regression of all skin lesions within a week. Tocilizumab, an IL-6 blocker, at a dosage of 560 mg per month was prescribed, but the patient was considered unresponsive due to mild to moderately severe pustular rash that continued to emerge in three months of treatment. After validation of the \u003cem\u003ePLCG2\u003c/em\u003e mutation, the therapy was switched to 100 mg of anakinra therapy daily, which provided the regression of all pustules within two months (Figure 1d-f). After three months of treatment, chest X-ray revealed the disappearance of linear opacities (Figure 2b). Over the 28-month follow-up period, the patient experienced only two relapses of generalized pustular eruption, both of which resolved with short-term low-dose systemic corticosteroid treatment.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAPLAID is one of the highly infrequent AIDs, and as far as we know, 29 cases have been reported in the literature [3, 9, 11-21] (Table 2). This report presents a unique coexistence of two monoalleic autoinflammatory diseases, APLAID and FMF.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe patient was diagnosed with FMF due to recurrent arthritis and pathogenic MEFV gene mutations. However, the patient also suffered from recurrent pustular eruptions, a skin manifestation different from the typical erysipelas-like erythema of FMF and inconsistent with this diagnosis. These discordant skin lesions, along with long-standing lung disease and joint swellings since the patient\u0026rsquo;s early years of life prompted us to investigate the potential coexistence of another AID. The AIDs typically present with recurrent or persistent sterile systemic inflammation affecting multiple organs, especially skin, lungs, and joints, along with variable immune deficiencies. The inflammasomopathies, interferonopathies, proteoasomopathies, and diseases with nuclear kappa B pathway activation are common AIDs and lead to aberrant secretion of inflammatory cytokines, such as IL1 and TNF-\u0026alpha;. Hereditary monogenic defects or multifactorial polygenic disorders result in the dysfunction of inflammation, especially in the innate response of the immune system [1, 4]. When skin is the target, patients may present with recurrent pustules, abscesses, urticarial-like plaques, angioedema, erythema nodosum, aphthae, or neutrophilic dermatosis with or without fever and several systemic involvements.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFMF is the most common monogenic AID and presents with attacks of fever, erysipelas-like erythema, erythema nodosum, along with joint, abdominal, or chest pain due to serositis caused by pyrin inflammasome dysfunction and overproduction of the pro-inflammatory cytokine IL1. The pathogenic MEFV gene mutations, occurring in exon 10, including M694V and M680I, cause the typical gain of function in the regulatory protein, pyrin. Colchicine is the most commonly used treatment that prevents FMF attacks [4]. When the present patient was initially evaluated, the most remarkable finding was the colchicine-unresponsive pustular attacks and accompanying recurrent respiratory infections, which were potentially suggestive of an additional immunosuppression. The WES analyses helped to find the mutated \u003cem\u003ePLCG2\u003c/em\u003e gene and to explain the exact pathogenesis underlying the coexisting AIDs phenotype.\u003c/p\u003e\n\u003cp\u003eThe autoinflammation of APLAID may involve skin, eye, lung, joint, gastrointestinal system. Interstitial pneumonitis, recurrent sinopulmonary infections, arthritis, inflammatory eye and bowel diseases, and various skin manifestations are common [3, 9, 11-21] (Table 2). Vesicles/ blisters and pustular eruptions are the most frequent skin lesions, followed by granulomas, papules and plaques (Table 3). Our case demonstrated severe chronic relapsing pustular eruptions of autoinflammation in APLAID and chronic recurrent pulmonary infections, caused by Ser707Tyr gain-of function mutation in the SH2 domain of the PLCG2 gene. The SH2 domain is the most mutated one among the 30 patients, including the present case. However, a clear phenotype and genotype correlation could not be established in APLAID cases due to the rarity of the disease and distinct involvement of systems. Remarkably, the onset of disease ranges from the birth to the age of 50. Although data of most of the patients are missing, the age of diagnosis seems to be as late as 5\u003csup\u003eth\u003c/sup\u003e decade. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePLCG2 is known to be required for B cell receptor signalling, which is critical for B cell development and maturation. Patients with APLAID can have mild to severe immunodeficiency because PLCG2 activation causes impairment in B cell differentiation and myelopoiesis, and affects mature B cell survival and antibody production [23]. It has been previously described that APLAID patients have varying degrees of B cell lymphopenia and antibody deficiency, but no significant impairment of T or NK function [11, 13, 15]. Our patient had mild lymphopenia, mildly low IgM levels and a reduced CD4/CD8 ratio. Contrary to previous reports, while B lymphocyte counts and subgroups were normal, T cell subgroup abnormalities were present; naive T cell decrease, effector memory CD4+ T cells and plasmablast increase were prominent. The changes observed in T cells may be secondary to the patient\u0026apos;s treatments. Decreased numbers of dendritic cells have also been found in several studies [18]. In this group of diseases with variable clinical findings, there may be different changes in immune cells, T and B cell subgroups. The treatment of APLAID aims to suppress excessive harmful autoinflammation and regulation of immunity. However, there is no consensus on the management of the disorder. Systemic corticosteroids, cyclosporine, methotrexate, IL1beta inhibitors, and tumour necrosis alfa inhibitors were used to treat suffering skin lesions with variable response [3, 9, 11-19, 21]. In the present case, the patient was initially treated with tocilizumab before the results of genetic analyses. Although tocilizumab is a treatment choice for FMF, it did not work to suppress the autoinflammation of APLAID. On the contrary, a subsequent switch to anakinra, the IL1beta receptor inhibitor, achieved total clearance and long-lasting control of the inflammatory skin lesions. The favorable continuous outcome in the present patient supports the possible role of IL1beta in the pathogenesis of APLAID. However, experience of anakinra in APLAID is rare and outcome is variable. Among three cases under anakinra treatment, one had improvement of skin lesions [13], one had partial control of autoinflammation [15], and one did not respond [11]. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSkin is potentially the most demonstrative and available target of AIDs. The present patient is unique. The patient was found to have two different AID since there were additional phenotype not explained only with FMF. The paper reports the first case of APLAID overlap with FMF and pays attention to the course, including the suspicion upon detailed history and examinations and subsequent WES analysis providing the correct diagnoses.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of interest\u003c/h2\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003ch2\u003eFunding sources:\u003c/h2\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003ch2\u003ePatient consent:\u003c/h2\u003e\n\u003cp\u003eWritten informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article. The patient gave informed consent for performing genetic analyses and laboratory tests.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eG.A. and D.C. designed the research study. G.A., I.Y., and S. E. performed the research. S.Y. and D.D.M. contributed essential reagents or tools. D.C. supervised the research study. G.A. wrote the manuscript. All authors have been involved in manuscript composition. All authors have read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMcDermott MF, Aksentijevich I, Galon J, et al (1999) Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97:133-144. https://doi.org/10.1016/s0092-8674(00)80721-7\u003c/li\u003e\n\u003cli\u003eOmbrello MJ, Remmers EF, Sun G, et al (2012) Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med 366:330-338. https://doi.org/10.1056/NEJMoa1102140\u003c/li\u003e\n\u003cli\u003eZhou Q, Lee GS, Brady J, et al (2012) A hypermorphic missense mutation in PLCG2, encoding phospholipase C\u0026gamma;2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet 91:713-720. https://doi.org/10.1016/j.ajhg.2012.08.006\u003c/li\u003e\n\u003cli\u003eFigueras-Nart I, Mascar\u0026oacute; JM Jr, Solanich X, Hern\u0026aacute;ndez-Rodr\u0026iacute;guez J (2019) Dermatologic and dermatopathologic features of monogenic autoinflammatory diseases. Front Immunol 10:2448. https://doi.org/10.3389/fimmu.2019.02448\u003c/li\u003e\n\u003cli\u003eEverett KL, Bunney TD, Yoon Y, et al (2009) Characterization of phospholipase C gamma enzymes with gain-of-function mutations. J Biol Chem 284:23083-23093. https://doi.org/10.1074/jbc.M109.019265\u003c/li\u003e\n\u003cli\u003eDrin G, Scarlata S (2007) Stimulation of phospholipase Cbeta by membrane interactions, interdomain movement, and G protein binding--how many ways can you activate an enzyme? Cell Signal 19:1383-1392. https://doi.org/10.1016/j.cellsig.2007.04.006\u003c/li\u003e\n\u003cli\u003eWang D, Feng J, Wen R, et al (2000) Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Immunity 13:25-35. https://doi.org/10.1016/s1074-7613(00)00005-4\u003c/li\u003e\n\u003cli\u003eChae JJ, Park YH, Park C, et al (2015) Connecting two pathways through Ca 2+ signaling: NLRP3 inflammasome activation induced by a hypermorphic PLCG2 mutation. Arthritis Rheumatol 67:563-567. https://doi.org/10.1002/art.38961\u003c/li\u003e\n\u003cli\u003eWu N, Zhang B, Wang T, Shen M, Zeng X (2021) Case report: a rare case of autoinflammatory phospholipase C\u0026gamma;2 (PLC\u0026gamma;2)-associated antibody deficiency and immune dysregulation complicated with gangrenous pyoderma and literature review. Front Immunol 12:667430. https://doi.org/10.3389/fimmu.2021.667430\u003c/li\u003e\n\u003cli\u003eMulazzani E, Kong K, Ar\u0026oacute;stegui JI, et al (2023) G-CSF drives autoinflammation in APLAID. Nat Immunol 24:814-826. https://doi.org/10.1038/s41590-023-01473-6\u003c/li\u003e\n\u003cli\u003eNeves JF, Doffinger R, Barcena-Morales G, et al (2018) Novel \u003cem\u003ePLCG2\u003c/em\u003e Mutation in a patient with APLAID and cutis laxa. Front Immunol 9:2863. https://doi.org/10.3389/fimmu.2018.02863\u003c/li\u003e\n\u003cli\u003eMor\u0026aacute;n-Villase\u0026ntilde;or E, Saez-de-Ocariz M, Torrelo A, et al (2019) Expanding the clinical features of autoinflammation and phospholipase C\u0026gamma;2-associated antibody deficiency and immune dysregulation by description of a novel patient. J Eur Acad Dermatol Venereol 33:2334-2339. https://doi.org/10.1111/jdv.15918\u003c/li\u003e\n\u003cli\u003eNovice T, Kariminia A, Del Bel KL, et al (2020) A germline mutation in the C2 domain of PLC\u0026gamma;2 associated with gain-of-function expands the phenotype for PLCG2-related diseases. J Clin Immunol 40:267-276. https://doi.org/10.1007/s10875-019-00731-3\u003c/li\u003e\n\u003cli\u003eKhabbazi A, Rahbar Kafshboran H, Nasiri Aghdam M, et al (2020) A new report of autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) with a homozygous pattern from Iran. Immunol Lett 221:27-32. https://doi.org/10.1016/j.imlet.2020.01.008\u003c/li\u003e\n\u003cli\u003eMart\u0026iacute;n-Nalda A, Fortuny C, Rey L, et al (2020) Severe autoinflammatory manifestations and antibody deficiency due to novel hypermorphic PLCG2 mutations. J Clin Immunol 40:987-1000. https://doi.org/10.1007/s10875-020-00794-7\u003c/li\u003e\n\u003cli\u003ePark HS, Oh A, Keum CW, et al (2022) A novel likely pathogenic PLCG2 variant in a patient with a recurrent skin blistering disease and B-cell lymphopenia. Eur J Med Genet 65:104387. https://doi.org/10.1016/j.ejmg.2021.104387\u003c/li\u003e\n\u003cli\u003eItakura T, Sasaki H, Hosoya T, et al (2023) A novel gain-of-function missense variant in PLCG2 associated with autoinflammation and hypergammaglobulinaemia. Rheumatology (Oxford) 62:e319-e321. https://doi.org/10.1093/rheumatology/kead193\u003c/li\u003e\n\u003cli\u003ePeng Q, Luo D, Yang Y, et al (2023) Clinical and immunological features of an APLAID patient caused by a novel mutation in \u003cem\u003ePLCG2\u003c/em\u003e. Front Immunol 14:1014150. https://doi.org/10.3389/fimmu.2023.1014150\u003c/li\u003e\n\u003cli\u003eWang T, Wang X, Teng Y, et al (2024) APLAID complicated with arrhythmogenic dilated cardiomyopathy caused by a novel PLCG2 variant. Immunol Res 72:512-519. https://doi.org/10.1007/s12026-024-09455-y\u003c/li\u003e\n\u003cli\u003eBaysac K, Sun G, Nakano H, et al (2024) PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants. J Allergy Clin Immunol 153:230-242. https://doi.org/10.1016/j.jaci.2023.08.036\u003c/li\u003e\n\u003cli\u003eYang Z, Tao P, Han X, et al (2024) Characterization of a novel pathogenic PLCG2 variant leading to APLAID syndrome responsive to a TNF inhibitor. Arthritis Rheumatol https://doi.org/10.1002/art.42948.\u003c/li\u003e\n\u003cli\u003eTangye SG, Al-Herz W, Bousfiha A, et al (2022) Human inborn errors of immunity: 2022 Update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 42:1473-1507. https://doi.org/10.1007/s10875-022-01289-3\u003c/li\u003e\n\u003cli\u003eYu M, Chen Y, Zeng H, et al (2017) PLC\u0026gamma;-dependent mTOR signalling controls IL-7-mediated early B cell development. Nat Commun 8:1457. https://doi.org/10.1038/s41467-017-01388-5\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eImmunological profile of the patient.\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"860\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient\u0026rsquo;s value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReference\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eHemoglobin (g/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e14.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e13.6-17.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eLeukocyte (/\u0026mu;l)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e9100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e4300-10300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eAbsolute neutrophil count (/\u0026mu;l)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e6850\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eAbsolute lymphocyte count (/\u0026mu;l)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e1310\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e1400-3300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eAbsolute eosinophil count (/\u0026mu;l)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e260\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e\u0026lt;500\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003ePlatelets (/\u0026mu;l)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e271000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e156000-373000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eIgA (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e221\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e139-378\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eIgG (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e1670\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e913-1884\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eIgM (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e62.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e88-322\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eTotal IgE (UI/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e5.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eANA titer (positivity)/staining patterns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e1:100(+)\u003c/p\u003e\n \u003cp\u003eSpeckled-AC-4, AC-5, Nucleolar-AC-8, AC-9, AC-10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eAnti A/B titer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003eAnti A: 1:512\u003c/p\u003e\n \u003cp\u003eAnti B: 1:32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eDihydrorhodamine (DHR) test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eCD3\u003csup\u003e+\u0026nbsp;\u003c/sup\u003eT cells (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e56-84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eCD4\u003csup\u003e+\u0026nbsp;\u003c/sup\u003eT cells (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e31-52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eNaive T helper cell (CD4\u003csup\u003e+\u003c/sup\u003eCCR7\u003csup\u003e+\u003c/sup\u003eCD45RA\u003csup\u003e+\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e24.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e57.1-84.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eCentral memory T helper cell (CD4\u003csup\u003e+\u003c/sup\u003eCCR7\u003csup\u003e+\u003c/sup\u003eCD45RA\u003csup\u003e-\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e29.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e11.3-26.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eEffector memory T helper cell (CD4\u003csup\u003e+\u003c/sup\u003eCCR7\u003csup\u003e-\u003c/sup\u003eCD45RA\u003csup\u003e-\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e3.3-15.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eTEMRA (CD4\u003csup\u003e+\u003c/sup\u003eCCR7\u003csup\u003e-\u003c/sup\u003eCD45RA\u003csup\u003e+\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e12.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e0.4-2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eRecent thymic emigrants (CD4\u003csup\u003e+\u003c/sup\u003eCD45RA\u003csup\u003e+\u003c/sup\u003eCD31\u003csup\u003e+\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e7-100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eCD8\u003csup\u003e+\u0026nbsp;\u003c/sup\u003eT cells (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e18-35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eNaive T cytotoxic cells (CD8\u003csup\u003e+\u003c/sup\u003eCCR7\u003csup\u003e+\u003c/sup\u003eCD45RA\u003csup\u003e+\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e20.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e28.4-80.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eCentral memory T cytotoxic cells (CD8\u003csup\u003e+\u003c/sup\u003eCCR7\u003csup\u003e+\u003c/sup\u003eCD45RA\u003csup\u003e-\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e1.0-4.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eEffector memory T cytotoxic cells (CD8\u003csup\u003e+\u003c/sup\u003eCCR7\u003csup\u003e-\u003c/sup\u003eCD45RA\u003csup\u003e-\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e6.2-29.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eTEMRA (CD8\u003csup\u003e+\u003c/sup\u003eCCR7\u003csup\u003e-\u003c/sup\u003eCD45RA\u003csup\u003e+\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e76.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e9.1-49.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eCD19\u003csup\u003e+\u0026nbsp;\u003c/sup\u003eB cells (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e6-23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eTransitional B cells (CD19\u003csup\u003e+\u003c/sup\u003eCD38\u003csup\u003eHigh\u003c/sup\u003eIgM\u003csup\u003eHigh\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e0.9-5.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eNa\u0026iuml;ve B cells (CD19\u003csup\u003e+\u003c/sup\u003eCD27\u003csup\u003e\u0026minus;\u003c/sup\u003eIgD\u003csup\u003e+\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e69.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e48.4-79.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eActivated B cells (CD19\u003csup\u003e+\u003c/sup\u003eCD21\u003csup\u003elow\u003c/sup\u003eCD38\u003csup\u003e-\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e69.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e1.6-10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eMarginal zone B cells (CD19\u003csup\u003e+\u003c/sup\u003eCD27\u003csup\u003e+\u003c/sup\u003eIgD\u003csup\u003e+\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e7-23.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eMemory B cells (CD19\u003csup\u003e+\u003c/sup\u003eCD27\u003csup\u003e+\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e18.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e17.5-46.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eSwitched memory B cells (CD19\u003csup\u003e+\u003c/sup\u003eCD27\u003csup\u003e+\u003c/sup\u003eIgD\u003csup\u003e\u0026minus;\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e11.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e8.3-27.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003ePlasmablasts (CD19\u003csup\u003e+\u003c/sup\u003eCD38\u003csup\u003eHigh\u003c/sup\u003eIgM\u003csup\u003e\u0026minus;\u003c/sup\u003e)\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e0.4-2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eCD16\u003csup\u003e+\u003c/sup\u003e56\u003csup\u003e+\u003c/sup\u003e NK cells (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e3-22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eCD25 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e69.9-98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eCD69 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e70.6-83.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eCD3CD25 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e46.3-88.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 49.4761%;\"\u003e\n \u003cp\u003eCD3CD69 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25.2619%;\"\u003e\n \u003cp\u003e50.3-75.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Summary of phenotypic and genotypic characteristics of cases with APLAID published in the literature.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eZhou et al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeves et al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMoran-Villasenor et al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNovice et al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKhabbazi et al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMartin-Nalda\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eet al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWu et al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePark et al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eItakura et al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePeng et al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWang et al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"13\" style=\"width: 482px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaysac et al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYang et al.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOur case\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eYear of report\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"13\" style=\"width: 482px;\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrigin (ethnicity/country)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003ePorteguese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eMexican\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eIran\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eChinese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eKorea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eChinese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eChinese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"13\" style=\"width: 482px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eRussian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eTurkish\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of cases reported\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at onset\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003einfancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e1st week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003ebirth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2 infancy,\u003c/p\u003e\n \u003cp\u003e1 ND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e8 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003ebirth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e1st week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e5 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003ebirth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e32 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003ebirth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e4 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e14 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e12 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2 mo.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e25 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e7 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003ebirth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e50 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2.5 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e6 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e6 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1 mo.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003einfancy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e11 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e3 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2 yrs,\u003c/p\u003e\n \u003cp\u003e6 yrs,\u003c/p\u003e\n \u003cp\u003e1 ND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e11 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e16 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e9 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e23 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e17 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e34 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e7 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e21 mo.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e9 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e36 yrs\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eM, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParental consangu-inity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-, -\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMutation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eSer707\u003c/p\u003e\n \u003cp\u003eTyr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eLeu848\u003c/p\u003e\n \u003cp\u003ePro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eLeu848\u003c/p\u003e\n \u003cp\u003ePro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eMet1141\u003c/p\u003e\n \u003cp\u003eLys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eHis193\u003c/p\u003e\n \u003cp\u003eAsn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eLeu845_Leu848 del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eAla708 Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eIle169\u003c/p\u003e\n \u003cp\u003eVal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eSer707\u003c/p\u003e\n \u003cp\u003ePro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eLeu1012Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eLeu845 Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eLeu848\u003c/p\u003e\n \u003cp\u003ePro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eHis494\u003c/p\u003e\n \u003cp\u003eTyr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eArg697Trp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eGly699 Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eThr706 Ile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eAla708 Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eArg742 Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eArg742 His\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eLeu845\u003c/p\u003e\n \u003cp\u003eSer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eLeu848\u003c/p\u003e\n \u003cp\u003ePro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eArg956 Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003ePro1050Leu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eGlu1139del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eGlu1191Gln\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eAsp993\u003c/p\u003e\n \u003cp\u003eTyr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eSer707 Tyr\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSkin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+ (except one)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEye\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLung\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJoint\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGastro-intestinal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInfections\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmuno-deficiency\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreat-ments\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eSysS, antiTNF, antiIL1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSysS,\u003c/p\u003e\n \u003cp\u003eHCQ, antiIL1, ruxolitinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eMTX, antiTNF, IVIG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSysS, OMA, antiIL1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eSysS, MTX, anti-TNF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eSysS, antiTNF, antiIL1, IVIG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eIVIG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eSysS, MTX, CsA, antiTNF, IVIG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eSysS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eSysS, CsA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eSysS, antiTNF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eMTX, CsA, IVIG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eAntiTNF, IVIG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eSysS, antiIL6, antiIL1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl of disease activity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003ePartial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003ePartial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eYes for one case (2 ND)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003ePartial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eNo, exitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Cases are\u0026nbsp;father and daughter, **Two cases are mother and daughter\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Abbreviations: CsA: cyclosporine A, F: female, HCQ: hydroxychloroquine, IL1: interleukin, IVIG: intravenous immunoglobulin, M: male, MTX: methotrexate 1, mo.: month, ND: no data, OMA: omalizumab, SysS: systemic corticosteroids, TNF: tumour necrosis alpha, yrs: years\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Skin manifestations and associated PLCG2 mutations in 30 patients including published cases with APLAID and the present case.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"765\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSkin lesions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMutation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDomain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReference number\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSuperficial fluid filled lesions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e60.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"8\" valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eVesicules +/- pustules, blisters\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"8\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"8\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e53.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eMet1141Lys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eC2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eIle169Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eEF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu848Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e11, 12, 19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu845Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu845_Leu848 del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eAla708Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eSer707Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eSer707Tyr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3, our case\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eEpidermolysis bullosa-like eruption\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eSer707Tyr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInfiltrative lesions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e53.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eGranulomas\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e30.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eGlu1139del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eC2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eAsp993Tyr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eY-Box\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eHis494Tyr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu848Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e11, 12, 20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eThr706Ile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eAla708Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e15, 20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003ePapules / plaques\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e23.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu845_Leu848 del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu848Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eSer707Tyr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eSer707Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eAla708Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUrticarial rash\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e16.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eMet1141Lys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eC2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eHis193Asn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eEF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eAla708Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eArg697Trp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eGly699Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEczema\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e10.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eGlu1139del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eC2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eArg742Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eThr706Ile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDermal changes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e20.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eCutis laxa\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e10.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu848Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu845_Leu848 del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eAla708Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eAtrophic skin lesions\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eMet1141Lys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eC2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eLoose skin\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu845Ser\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHyperpigmentation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu845_Leu848 del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eAla708Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDestructive lesions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eUlcer\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eAla708Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSH2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu848Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003esPH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eGangrenous pyoderma\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eIle169Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eEF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eNasal septum ulcer\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu1012Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eY-Box\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 274px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStomatitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eLeu1012Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eY-Box\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"hereditary autoinflammatory diseases, phospholipase C gamma, familial Mediterranean fever, genetic testing","lastPublishedDoi":"10.21203/rs.3.rs-6201807/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6201807/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAutoinflammatory diseases encompass a group of inherited disorders characterized by genetic defects in innate immunity, and leading to uncontrolled systemic or organ-specific inflammation. While familial Mediterranean fever (FMF) is a common example prevalent in Mediterranean regions, autoinflammatory phospholipase C gamma 2 (\u003cem\u003ePLCG2\u003c/em\u003e)-associated antibody deficiency and immune dysregulation (APLAID) is extremely rare. We aim to report the first case of co-occurrence of FMF and APLAID and discuss the clinical manifestations, immunological findings, and medical approach of the patient by reviewing the medical literature. A 36-year-old male patient visited our dermatology clinic with a history of recurrent pustular eruptions since childhood, aggravated in the last month. He had bronchiectasis, emphysema, and a diagnosis of FMF. Colchicine helped to control arthritis but did not resolve the pustular eruptions. Histopathological examination of the pustules revealed neutrophilic exudation, and microbial cultures were negative. The patient exhibited high C-reactive protein levels, mild lymphopenia, mildly low IgM levels, and a decreased CD4/CD8 ratio. Genetic analysis revealed a heterozygous c.2120C\u0026thinsp;\u0026gt;\u0026thinsp;A (Ser707Tyr) mutation in the \u003cem\u003ePLCG2\u003c/em\u003e gene. Daily anakinra 100 mg therapy regressed subsequent relapses of pustules within two months. In 28-month treatment, the patient experienced two relapses of pustular eruption, which resolved with short-term low-dose systemic corticosteroid treatment. In conclusion, we point out that a thorough immunological evaluation of patients with recurrent pustular eruptions and associated systemic symptoms is essential, even if a patient has already been diagnosed with an autoinflammatory disease. Albeit rare, it is important to consider the possibility of another coexisting autoinflammatory disease.\u003c/p\u003e","manuscriptTitle":"Overlap of familial Mediterranean fever and autoinflammatory PLCG2-associated antibody deficiency and immune dysregulation in a Turkish patient","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-17 10:36:07","doi":"10.21203/rs.3.rs-6201807/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"95535073-1a92-47cf-9318-aa02d3c69ae0","owner":[],"postedDate":"March 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-26T19:53:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-17 10:36:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6201807","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6201807","identity":"rs-6201807","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}