A homozygous mutation in the PSMB8 gene in a case

Scandinavian Journal of Rheumatology

ISSN: 0300-9742 (Print) 1502-7732 (Online) Journal homepage: http://www.tandfonline.com/loi/irhe20

A homozygous mutation in the PSMB8 gene in a case with proteasome-associated autoinflammatory syndrome C Contreras-Cubas, A Cárdenas-Conejo, A Rodríguez-Velasco, H García-Ortiz, L Orozco & V Baca To cite this article: C Contreras-Cubas, A Cárdenas-Conejo, A Rodríguez-Velasco, H GarcíaOrtiz, L Orozco & V Baca (2017): A homozygous mutation in the PSMB8 gene in a case with proteasome-associated autoinflammatory syndrome, Scandinavian Journal of Rheumatology, DOI: 10.1080/03009742.2017.1342273 To link to this article: http://dx.doi.org/10.1080/03009742.2017.1342273

Published online: 12 Sep 2017.

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Date: 12 September 2017, At: 11:19

Scand J Rheumatol 2017;00:1–4

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A homozygous mutation in the PSMB8 gene in a case with proteasomeassociated autoinflammatory syndrome C Contreras-Cubas1, A Cárdenas-Conejo2, A Rodríguez-Velasco3, H García-Ortiz1, L Orozco1, V Baca4 1

Immunogenomics and Metabolic Diseases Laboratory, National Institute of Genomic Medicine, SS, Mexico City, Mexico Departament of Genetics, Pediatric Hospital Medical Center SXXI, IMSS, Mexico City, Mexico 3 Anatomic Pathology Service, Pediatric Hospital Medical Center SXXI, IMSS, Mexico City, Mexico 4 Department of Rheumatology, Pediatric Hospital Medical Center SXXI, IMSS, Mexico City, Mexico

Downloaded by [Australian Catholic University] at 11:19 12 September 2017

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The term proteasome-associated autoinflammatory syndrome (PRAAS) has been proposed to encompass a group of disorders caused by autosomal recessive mutations in the inducible proteasome subunit β type 8 (PSMB8) gene, which encodes the β5i subunit (1). However, PRAAS has recently been associated with mutations in other proteasome genes, such as PSMA3, PSMB4, PSMB9, and proteasome maturation protein (POMP) (2). PRAAS includes joint contractures, muscle atrophy, microcytic anaemia, panniculitis-induced lipodystrophy syndrome (3), Nakajo–Nishimura syndrome (4), Japanese autoinflammatory syndrome with lipodystrophy (5), and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome (6). These syndromes are characterized by early-onset skin eruptions, recurrent fever, joint contractures, muscular atrophy, lipodystrophy, hepatosplenomegaly, and basal ganglia calcifications. Laboratory abnormalities include anaemia, elevated acute-phase reactants, high levels of interleukin-6, hypergammaglobulinaemia, and autoimmune abnormalities (7). Here, we report the first case homozygous for the c.274G > A, p.A92T mutation previously reported in a compound heterozygous Hispanic patient who also had the founder mutation c.224C > T, p.T75M (1). A 2-year-old female Mexican patient with non-consanguineous parents was referred to our institution without diagnosis. The mother previously had a spontaneous abortion and a repaired cleft lip and palate. The patient was delivered by caesarean section and had a cleft-lip repair at 5 months of age. At 3 months of age the patient developed papular and nodular erythematous skin lesions associated with recurrent fever. The skin lesions were painful and itchy, presenting first in the lower extremities and then generalized, and resulted in a hyperpigmented macule upon healing. At 18 months of age, the patient developed hepatosplenomegaly, and liver biopsy showed steatosis with moderate portoportal fibrosis. Upon physical examination, we found erythematous papules and nodules on her palms and face and ulceration on her fingertips in addition to multiple residual

hyperpigmented skin lesions. Her facial features included violaceous erythema and oedema of the eyelids, thick lips, and decreased fatty tissue in the face (Figure 1A B). Partial lipodystrophy was also found in the upper chest and upper limbs. She also had generalized lymphadenopathy, a protuberant abdomen with umbilical hernia, and hepatosplenomegaly. No joint contractures were observed, but bilateral knee arthritis and swollen fingers and toes were noted. The patient’s height and weight were below the third percentile and she was both physically and developmentally delayed. Abnormal laboratory findings included hypochromic microcytic anaemia (haemoglobin 8.5 g/dL), thrombocytosis (520 000 cells/mm3), and elevated serum aspartate aminotransferase (105 UI/L) and alanine aminotransferase (160 UI/L). High serum triglycerides (356 mg/dL) and low high-density lipoprotein cholesterol levels (14 mg/ dL) were measured. High levels of C-reactive protein (54 mg/L), serum globulin (5.19 g/dL), immunoglobulin G (IgG) (3513 mg/dL), IgM (292 mg/dL), IgE (851 IU/ mL), and thyroid stimulating hormone (6.3 mU/L) were also measured. Immunological tests revealed positive anti-nuclear, anti-cardiolipin, and anti-Sm antibodies. Initially, complement C3 levels were normal but decreased after disease progression. Skin biopsy revealed a mixed perivascular, periadnexal, and interstitial infiltrate composed of lymphocytes and plasma cells, leucocytoclasis, and vasculitis. Brain computed tomography revealed basal ganglia calcification (Figure 1C–F). Because PRAAS was suspected, direct DNA sequencing of PSMB8 was performed for the patient, mother, and maternal grandparents. The patient was homozygous for the previously reported missense mutation on exon 2 (c.274 G > A), whereas the mother and grandfather were heterozygous (Figure 1G). Because the father was not available, the relationship between the maternal grandfather and grandchild was confirmed by DNA testing. After genetic diagnosis of PRAAS, 1 mg/kg/day prednisone was started with a good response regarding the fever and skin lesions, but symptoms recurred

© 2017 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation DOI: https://doi.org/10.1080/03009742.2017.1342273

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Figure 1. Clinical photographs of the proteasome-associated autoinflammatory syndrome (PRAAS) patient. (A) Facial features revealed a heliotrope-like periorbital rash and oedema, erythematous papules, thick lips, and lipoatrophy. (B) Erythematous papules and nodules on her palms and wrists, and ulceration on her fingertips. (C) Calcification of basal ganglia on cranial computed tomography. Histological findings revealed (D) periadnexal inflammatory infiltrate and leucocytoclasis, (E) lymphocytic vasculitis with leucocytoclasis, and (F) an interstitial mixed infiltrate composed of lymphocytes and plasma cells, most prominently in the deep reticular dermis (hematoxylin and eosin stain). (G) PSMB8 sequencing for all family members. Nucleotide chromatograms of the affected region. The red arrow indicates the variation site on exon 2 (c.274 G > A).

following tapering. Thereafter, methotrexate and chloroquine were added without clinical improvement. At 4 years of age, she developed status epilepticus with generalized tonic–clonic seizures and was admitted to


another hospital, dying 3 days later in the intensive care unit from aseptic meningitis of unknown cause. To the best of our knowledge, this is the first PRAAS patient homozygous for the A92T mutation. Proteasomes

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Table 1. Comparison of clinical and laboratory findings in proteasome-associated autoinflammatory syndrome (PRAAS) patients harbouring the p.A92T mutation. Clinical and laboratory findings

Our patient

PRAAS patient reported in reference (1)

PSMB8 mutation Age at onset Outcome Low weight and height Recurrent fever Skin eruptions

p.A92T/p.A92T 3 months Died at 4 years of age Yes Yes Erythematous papules and nodules; violaceous erythema and oedema of eyelids; fingertip ulcers Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Normal to mild leucocytosis initially and leucopenia with lymphopenia after disease progression Thrombocytosis initially and thrombocytopenia after disease progression Yes Yes No Yes Yes ANA, ACL, and anti-Sm positive; anti-DNA, anti-Ro, anti-La, and anti-RNP negative C3 levels normal initially and low after disease progression High levels of IgG, IgM, and IgE ND

p.A92T/p.T75M 3 months Alive at 19 years old (age at diagnosis) Yes Yes Erythematous papules and nodules

Alopecia Vasculitis/leucocytoclasis Lipodystrophy Arthritis Swollen fingers and toes Perioral swelling Prominent abdomen Lymphadenopathy Hepatomegaly Splenomegaly Myositis/muscle atrophy Low IQ Seizures Basal ganglia calcification Anaemia White blood cells Platelet count Elevated AST and ALT Dyslipidaemia Elevated CPK Elevated TSH Elevated ESR/CRP Autoantibodies Complement levels Hypergammaglobulinaemia Cytokine levels

No No Yes Yes No No No No Yes Yes Yes Yes No Yes Yes Low normal range NS Yes No Yes Yes Yes ANA and ANCA positive NS High levels of IgG, IgM, and IgE High levels of IL-6 and IP-10

IQ, intelligence quotient; AST, aspartate aminotransferase; ALT, alanine aminotransferase, CPK, creatine phosphokinase; TSH, thyroid-stimulating hormone; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; ANA, anti-nuclear antibodies; ACL, anti-cardiolipin; Ig, immunoglobulin; ANCA, anti-neutrophil cytoplasmic antibodies; IL, interleukin; IP, interferon-gamma-inducible protein; ND, not determined; NS, not specified.

are protease complexes that play a critical role in maintaining cellular function through the selective degradation of ubiquitinated proteins. The p.A92T variant changes residues that define the conformation of the S1 substrate-specificity pocket, causing selective impairment of chymotrypsin-like activity but not affecting maturation of the β5i subunit and proteasome assembly (2). Mutations in proteasome genes cause proteasome dysfunction, which induces type I interferon transcription and drives an inflammatory response and autoimmunity (2). Although our case shared several clinical symptoms and laboratory findings with the previously reported compound heterozygous patient carrying the A92T mutation (Table 1), our patient’s outcome shows that homozygosity for this mutation is associated with a more severe clinical course.

References 1. McDermott A, Jesus AA, Liu Y, Kim P, Jacks J, Montealegre Sanchez GA, et al. A case of proteasome-associated auto-inflammatory syndrome with compound heterozygous mutations. J Am Acad Dermatol 2013;69:e29–32. 2. Brehm A, Liu Y, Sheikh A, Marrero B, Omoyinmi E, Zhou Q, et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest 2015;125:4196–211. 3. Agarwal AK, Xing C, DeMartino GN, Mizrachi D, Hernandez MD, Sousa AB, et al. PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet 2010;87:866–72. 4. Arima K, Kinoshita A, Mishima H, Kanazawa N, Kaneko T, Mizushima T, et al. Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc Natl Acad Sci USA 2011;108:14914–19.


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5. Kitamura A, Maekawa Y, Uehara H, Izumi K, Kawachi I, Nishizawa M, et al. A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J Clin Invest 2011;121:4150–60. 6. Liu Y, Ramot Y, Torrelo A, Paller AS, Si N, Babay S, et al. Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum 2012;64:895–907. 7. McDermott A, Jacks J, Kessler M, Emanuel PD, Gao L. Proteasomeassociated autoinflammatory syndromes: advances in pathogeneses,


clinical presentations, diagnosis, and management. Int J Dermatol 2015;54:121–9.

Vicente Baca, Department of Rheumatology, Pediatric Hospital Medical Center SXXI, Av Cuauhtemoc 330, Col Doctores, CP 06720, Mexico City, Mexico. E-mail: [email protected] Accepted 11 June 2017