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(DNASE 1, DNASE1L3) mutations and complement deficiencies.7,18–20. Patients with C1q deficiency had marked variability in clinical presentation; they are at ...
International Journal of Rheumatic Diseases 2018; 21: 207–212

ORIGINAL ARTICLE

Monogenic interferonopathies: Phenotypic and genotypic findings of CANDLE syndrome and its overlap with C1q deficient SLE. Sulaiman M. AL-MAYOUF,1 Alhanouf ALSALEEM,1 Nora ALMUTAIRI,1 Abdullah ALSONBUL,1 Tariq ALZAID,2 Anas M. ALAZAMI3 and Hamoud AL-MOUSA4 Departments of 1Pediatric Rheumatology, 2Pathology, 3Genetics, and 4Allergy and Immunology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Abstract Objective: To report the clinical and genetic features of the first cases of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome in an Arab population and to compare them with patients of C1q deficient systemic lupus erythematosus (SLE). Materials and Methods: This is a retrospective case series of patients with CANDLE syndrome and C1q deficient SLE seen at a single tertiary hospital. Medical records were reviewed for demographic data, clinical and laboratory features, histopathology and imaging findings, and response to therapeutic intervention. Descriptive data were summarized. Results: Three patients from unrelated families fulfilled the clinical manifestations of CANDLE syndrome. The disease onset was within the first 4 months of age. Two patients had uncommon features including uveitis, pulmonary involvement, aseptic meningitis and global delay. Skin biopsy showed heterogeneous findings. Genomic DNA screening was homozygous for mutation in PSMB8, (NM_004159.4:c.212C>T, p.T71M) in one patient and inconclusive for the other two patients. The comparison group was three patients with familial C1q deficient SLE from three unrelated families, who were born to consanguineous parents with at least one affected sibling. They presented with extensive mucocutaneous lesions, discoid rash and scarring alopecia. They required frequent admissions due to infections. Conclusion: This is the first report of CANDLE syndrome in an Arab population; our patients had heterogeneous phenotypic and genetic features with overlap manifestations with C1q deficient SLE. Both are monogenic interferonopathies. However, C1q deficient SLE had more systemic inflammatory disease. Key words: CANDLE interferonopathies.

syndrome,

C1q

deficiency,

systemic

lupus

erythematosus,

autoinflammatory,

INTRODUCTION Correspondence: Prof. Sulaiman M. Al-Mayouf, Professor of Pediatrics, College of Medicine, Alfaisal University, Consultant and Section Head, Rheumatology, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Saudi Arabia. Email: [email protected]

The concept of monogenic autoinflammatory disorders has evolved from the clinical and pathogenic description to include new, rare diseases and syndromes. Typically, these disorders present in infancy and probably share common clinical manifestations and laboratory findings. The main pathogenesis

© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd

S. M. Al-Mayouf et al.

results from the innate immunodysregulation, particularly, the interleukin-1 (IL-1) pathway defects.1,2 Furthermore, recent suggestion classifies the monogenic autoinflammatory disorders based on the response to IL-1 blockage into IL-1 mediated and non-IL-1 mediated autoinflammatory disorders.3 Interestingly, non-IL-1-mediated autoinflammatory disorders are Mendelian inherited disorders linked to type I interferonopathies.3–5 Among these disorders is chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, which is a newly described disorder caused by mutations in proteasome subunit beta type 8 (PSMB8).6 The spectrum of clinical manifestations seen in monogenic autoinflammatory disorders varies from common cutaneous and musculoskeletal features to infrequent findings, such as cardiopulmonary involvement; these manifestations can certainly overlap with those seen in patients with Mendelian inherited autoimmune diseases such as the monogenic form of systemic lupus erythematosus (SLE).3,4,7,8 Furthermore, an increase in type I interferon (IFN) activity was documented in family members of SLE patients, suggesting a key role in its pathogenesis.9,10 Based on the similarities and differences in phenotypes and immunopathogenesis of numerous monogenic autoinflammatory disorders, including CANDLE syndrome and monogenic form SLE, recent suggestion argues for grouping these disorders as interferonopathies.11,12 This work demonstrates the heterogeneity of phenotypic and genotypic features of the first three cases of CANDLE syndrome in an Arab population and the overlap with some features of monogenic form of SLE, namely C1q deficient SLE.

MATERIALS AND METHODS This is a retrospective case series of Arab patients with CANDLE syndrome and C1q deficient SLE. Medical records were reviewed for demographic data, clinical and laboratory features, including genetic studies, histopathology and imaging findings and response to therapeutic intervention. Descriptive data were summarized. Appropriate informed consent was obtained from the patients. The work was approved by our institutional ethics committee and the research advisory council.

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RESULTS CANDLE syndrome Three patients from unrelated families fulfilled the clinical manifestations of CANDLE syndrome; they were born with normal antenatal history and the parents were non-consanguineous, although they hailed from the same tribe. All three patients had early onset disease with recurrent fever and skin lesions associated with progressive facial lipodystrophy. There was evidence of systemic inflammatory involvement as manifested by high inflammatory markers and abnormal liver function tests.

First patient A 15-year-old girl presented at the age of 3 months with recurrent high-grade fever and skin rash, which appeared as diffuse erythematous nodular lesions all over the body, lymphadenopathy and hepatosplenomegaly. Follow-up assessment revealed progressive facial lipodystrophy with diffuse muscular wasting and weakness, global developmental delay and bilateral posterior uveitis. She had pancytopenia, (white cell count 2.5 9 109/L, hemoglobin 75 g/L and platelets 50 9 109/L). However, bone marrow aspiration and biopsy revealed reactive marrow with no granuloma or malignant cells. Other results revealed high erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) 125 mm/h and 85 mg/L, respectively. In addition, she had weakly positive antinuclear antibodies (ANA 1 : 160) with negative antibodies to extractable nuclear antigens. Immunological investigations including immunoglobulins, lymphocytes subsets and lymphocytes response to mitogens stimulation were normal. Skin biopsy showed mixed dermal and subcutaneous infiltrate, composed of mononuclear cells, T-lymphocytes, histiocytes and neutrophils. The histiocytes-rich nature and presence of some fragmented neutrophils, is suggestive of Sweet syndrome. Brain magnetic resonance imaging (MRI) showed non-obstructive hydrocephalus with no other abnormalities. In addition, chest computed tomography (CT) scan showed diffuse pulmonary nodules. Subsequently, use of a targeted next-generation primary immunodeficiency panel (PID) revealed no genetic mutation in PSMB8. Furthermore, genetic study sent for nucleotide-binding domain, leucine-rich family, pyrin domain containing 3 gene (NLRP3) and nucleotide binding oligomerization domain containing 2 gene (NOD2) came back negative for mutation. Unfortunately, she showed poor therapeutic response

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to all treatments, including corticosteroid, methotrexate, anti-tumor necrosis factor (TNF), anti-IL-1, and anti-IL-6 agents.

Second patient A 2-year-old boy presented at the age of 9 days with diffuse erythematous nodules and violaceous puffy eyelids accompanied by fever reaching 40°C. Progressively, the child had facial distortion with changes consistent with lipodystrophy. Laboratory evaluation showed normocytic normochromic anemia (hemoglobin 90 g/L); leukocyte and platelet counts were normal. He had liver enzymes (aspartate aminotransferase 71 U/L, alanine aminotransferase 60 U/L) as well as ESR 73 mm/h, and CRP 76 mg/ L. ANA was positive (1 : 640) but antibodies to extractable nuclear antigens were negative and complement levels were normal. Immunological work-up including immunoglobulins, lymphocytes subsets and lymphocytes response to mitogen stimulation were normal. Skin biopsy showed moderate-to-marked neutrophilic infiltrate with karyorrhectic debris involving superficial and deep dermis with extension to sub-cutis. There was no evidence of vasculitis. Genetic testing identified a previously reported homozygous PSMB8 mutation: NM_004159, c.212C>T, p.T71M.13 The patient was offered treatment in form of corticosteroid and anti-IL agent but the parents decided to seek medical advice in another institution. Unfortunately, the patient was lost to follow up.

Third patient An 11-year-old girl presented at the age of 4 months with a history of persistent fever associated with diffuse painful subcutaneous nodular skin rash. Laboratory evaluation showed normal leukocyte counts, normocytic normochromic anemia (hemoglobin 75 g/L) and thrombocytosis (550 9 109/L) with persistent high inflammatory markers (ESR = 48 mm/h, CRP = 61 mg/L). A few months later, she developed knee arthritis and seizure associated with aseptic meningitis. All work-up infectious causes and bone marrow were unremarkable. She underwent extensive immunological work up, including lymphocyte markers, blastogenesis and oxidative burst assay: all reported as unremarkable. Furthermore, she had negative ANA and normal complement levels. Skin biopsy was suggestive of subcutaneous histiocytoid Sweet syndrome with mixed lobular and septal atypical lymphoid infiltrate septal

International Journal of Rheumatic Diseases 2018; 21: 207–212

panniculitis, and reactive lymphomatoid CD8+ epitheliotrpic lymphocytic infiltrate. MRI of the brain revealed the presence of high-intensity white matter changes, which were non-specific findings. Follow-up assessment revealed progressive facial lipodystrophy with diffuse muscular wasting and weakness. The targeted next-generation sequencing assay revealed no genetic mutation in PSMB8, NLRP3 or NOD2. She was treated with different immunosuppressive medications including corticosteroid, methotrexate, azathioprine, anti-TNF, anti-IL-1 and anti-IL-6 agents but with poor therapeutic response.

Monogenic form SLE Three patients with familial C1q deficient SLE from three unrelated families were reviewed. All were born to consanguineous parents and had strong family history of SLE due to C1q deficiency. Two families lost three affected siblings with C1q deficient SLE. All patients had early-onset disease and characterized by recurrent fever, extensive mucocutaneous lesions and diffuse erythematous rash, facial discoid rash and scarring alopecia. They had multi-system involvement including nephritis with persistent elevated inflammatory markers. The targeted next-generation sequencing assay of PID panel confirmed a homozygous missense variant of C1qA (C1qA:NM_015991:exon3:c.470G>A:p.G157D) in all patients. Treatment regimens included pulse and maintenance of corticosteroids, hydroxychloroquine and cyclic intravenous immunoglobulin infusion in addition to sequential immunosuppressive medications, namely methotrexate, azathioprine, mycophenolate mofetil and cyclophosphamide, and lately rituximab. Unfortunately, they showed only partial response. In comparison with CANDLE syndrome, patients with monogenic form SLE had a strong family history of lupus and mucocutaneous lesions in addition to profound autoantibodies. Table 1 illustrated the differences in clinical presentation and laboratory features between CANDLE syndrome and C1q deficient SLE.

DISCUSSION We describe herein the first three patients of CANDLE syndrome in an Arab population. One patient had the characteristic phenotypic and genotypic features; he was homozygous for mutation in the PSMB8 gene (c.212C>T,p.T71M) while the other patients had

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Table 1 Difference in clinical and laboratory features of CANDLE syndrome and C1q deficiency systemic lupus erythematosus CANDLE Case I Family history Consanguinity Fever Lipodystrophy Diffuse skin rash Mucosal ulceration Scarring alopecia Discoid rash Violaceous/puffy eyelids Nail changes Nephritis Arthritis Joint contractures Uveitis Lung involvement Developmental delay Recurrent infection Aseptic meningitis White cell count Hemoglobin level Platelet count C1q/C3/C4 levels ANA Anti-dsDNA Anti-Sm APL ESR/CRP Targeted next-generation sequencing assay

CANDLE Case II

CANDLE Case III

+ + +

+ + +

+ + + +

+

+

+

+

+ + + +

C1q SLE Case I

C1q SLE Case II

C1q SLE Case III

+ + +

+ + +

+ + +

+ + + +

+ + + +

+ + + +

+ + +

+ +

+ + +

+

+

+

Low Low Low Low + + + + High C1qA mutations

Low Low Low Low + + + + High C1qA mutations

Low Low Low Low + + + + High C1qA mutations

+

Low Low Normal Normal +

High Low Normal Normal +

High Negative PSMB8/ NLRP3/NOD2

High PSMB8 mutations

+ High Low Normal Normal

High Negative PSMB8/ NLRP3/NOD2

CANDLE, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; ANA, antinuclear antibody; Anti-Sm, anti-Smith antibody; anti-dsDNA, anti-double-stranded DNA; APL, antiphospholipid antibody; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; PID, primary immunodeficiency diseases.

episodic fevers, nodular violaceous skin lesions and progressive lipodystrophy. Additionally, they had unusual features in form of uveitis, aseptic meningitis, nonobstructive hydrocephalus, developmental delay and pulmonary nodular lesions without evidence of pulmonary hypertension, yet no mutations in PSMB8 were identified. The lack of PSMB8 mutations in two of the patients may account for the heterogeneity of CANDLE syndrome. Our patients had clinical features overlapping with cryopyrin-associated periodic syndrome (CAPS), namely chronic infantile neurological cutaneous and articular (CINCA) syndrome and early-onset sarcoidosis. However, no mutations in NLRP3 gene or NOD2 were detected. Moreover, they did not show any response to anti-IL-1 agent. Several reports expand the spectrum of the clinical and histological findings with more variables and novel gene mutations; one patient

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with CANDLE syndrome had no mutations, which probably emphasizes the phenotypic variation and genetic heterogeneity underlying this syndrome.14–17 SLE is the prototypical model of autoimmune diseases. It is a complex disease with heterogeneous presentations and chronic unpredictable, relapsingremitting course. Monogenic form SLE is a rare entity that has been reported in patients with different gene (DNASE 1, DNASE1L3) mutations and complement deficiencies.7,18–20 Patients with C1q deficiency had marked variability in clinical presentation; they are at high risk of developing familial lupus with multisystem involvement.19,21 CANDLE syndrome and C1q deficient SLE are rare genetic diseases characterized by early-onset presentation, inflammatory phenotypes and autoimmunity, which underline the complexity of pathogenic

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mechanisms responsible for the activation of both innate and adaptive immunity. Recent studies have linked the pathogenesis in CANDLE syndrome and C1q deficiency SLE and other Mendelian inherited disorders to dysregulation of type I IFN.12,16 Patients with C1q deficiency have high levels of type I IFN and correlate with elevations of autoantibodies and disease activity, which indicate that genetic factors might stimulate the type I IFN pathway.4,22 Similarly, mutations in PSMB8 are associated with increased type I IFN production.23 Type I IFN bridges the innate and adaptive immune systems, acts as an immune adjuvant and stimulates T cells and B cells, which all play an important role in the loss of tolerance and persistent autoimmune reaction in SLE.24 CANDLE syndrome and C1q deficiency SLE are under the umbrella of monogenic interferonopathies. We believe that C1q deficient SLE patients, at least our patients, had severe disease with strong family histories. They had scarring alopecia, discoid rash and nephritis, high levels of ANA, antibodies to extractable nuclear antigens and antiphospholipid antibodies. They required frequent hospitalizations because of severe mucocutaneous manifestations and recurrent infection. Unfortunately, patients with C1q deficient SLE have refractory disease and high mortality.21,25 Two families of our C1q deficient SLE lost three children with the same diagnosis; the cause of death was severe infection. At least, our limited results showed that C1q deficiency SLE had significant phenotypic differences that can differentiate it from other monogenic interferonopathies. Furthermore, this work demonstrates the heterogeneity of phenotypic and genotypic features of the first three cases of CANDLE syndrome in an Arab population. Studying these conditions can improve our understanding of the variable autoinflammatory and autoimmune interferonopathies and can provide a rational approach for therapy.

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