Mosaic Tetrasomy 9p: A Mendelian Condition Associated With Pediatric-Onset Overlap Myositis
Pediatric-onset inflammatory myositis (IM) and systemic lupus erythematosus (SLE) are rare inflammatory diseases. Both result from the complex interaction of genetic and environmental factors. An increasing number of Mendelian conditions predisposing to the development of SLE have been recently identified. These include monogenic conditions, referred to as the type I interferonopathies, associated with a primary upregulation of type I interferon (IFN), a key cytokine in the pathogenesis of SLE and some cases of IM. Here, we report on a pediatric-onset inflammatory overlap phenotype in a 6-year-old girl who was shown to carry mosaic tetrasomy 9p. The patient presented with myositis overlapping with lupuslike features. Myositis was characterized by a proximal muscular weakness and HLA class I antigen myofiber overexpression on muscle biopsy. Lupus-like manifestations consisted of pericarditis, pleuritis, and positive antinuclear and anti-SSA (Sjögren-syndrome A) antibodies. Complete remission was achieved with corticosteroids and mycophenolate mofetyl. Analysis of tetrasomy 9p showed mosaic tetrasomy in the 9p24.3q12 region, including the type I IFN cluster, and increased expression of IFN-stimulated genes. These data suggest that mosaic tetrasomy 9p can be associated with an upregulation of type I IFN signaling, predisposing to inflammatory myositis and lupus-like features. Thus, unexplained muscle or other organ involvement in patients carrying mosaic tetrasomy of the type IFN cluster of chromosome 9p should lead to the search for IM and/or lupuslike disease, and karyotype should be performed in patients with SLE or IM with mental retardation.
- ANA —
- antinuclear antibody
- IFN —
- IM —
- inflammatory myositis
- SLE —
- systemic lupus erythematosus
- SSA —
- Sjögren-syndrome A
Pediatric-onset inflammatory myositis (IM) and systemic lupus erythematosus (SLE) are rare inflammatory phenotypes. These disorders result from the complex interaction between genetic and environmental factors. An increasing number of Mendelian conditions predisposing to the development of pediatric SLE have been identified.1,2 These include a number of so-called type I interferonopathies,3 which are Mendelian diseases associated with a primary upregulation of type I interferon (IFN), a key cytokine in SLE and some IM pathophysiology.4 Herein, we report for the first time that mosaic forms of tetrasomy 9p5 can predispose to the development of overlap myositis associated with type I IFN upregulation.
A 6-year-old girl was born at 35 weeks to unrelated parents. There was no family history of autoimmunity. She had moderate mental retardation, pervasive developmental disorder, hypertelorism, strabismus, and severe myopia. She had normal weight, height (+1 SD), and cranial perimeter growth. Her standard karyotype, performed after her parents’ informed consent, was mos47,XX,+i(9)(p10)/46,XX . Confirmation of isochromosome 9p was performed by interphase fluorescence in situ hybridization (FISH) by using commercial chromosome 9 centromeric probes. Parental conventional karyotypes were normal. The patient was referred to the pediatric cardiology department because of respiratory and cardiac failure. Physical examination revealed facial edema and rash, erythema of the soles of the feet, livedo reticularis of the legs, proximal muscular weakness, and an enlargement of liver and spleen in addition to polypnea and tachycardia. Chest radiograph revealed bilateral pleural effusions and echocardiography showed a large circumferential pericardial effusion. Laboratory investigations revealed an elevation of erythrocyte sedimentation rate of 33 mm/h (normal values: <25 mm/h), C-reactive protein of 52 mg/L (normal values: <5 mg/L), and platelet count of 590 × 109/L (normal values: <400 × 109/L). Serum creatine kinase, glutamine oxaloacetic transaminases, lactate dehydrogenase, and aldolase levels were normal. Positivity for antinuclear antibodies (ANAs; 1:800) and anti-Ro/SSA was found. Anti-DNA and antiphospholipid antibodies were absent, and serum complement levels were within the normal range. Deltoid muscle biopsy revealed some myofibers with ischemic, punched-out vacuoles and a heterogeneous major histocompatibility complex (MHC) class I antigen (human leukocyte antigen [HLA]-ABC) myofiber overexpression (Fig 1). A cerebral computed tomodensitometry scan was normal. Three pericardiocenteses were required because of recurrences of her pericardial effusion within the first 3 weeks, in addition to 1 pleural thoracentesis. Pleural and pericardial fluid analysis found an exudate containing a majority of lymphocytes and an increased number of macrophages and mesothelial cells, respectively. Pericardial biopsy revealed lymphocytic infiltration. There was no evidence of infection. Three pulses of methylprednisolone, followed by an oral course of steroids in combination with mycophenolate mofetyl, resulted in a complete clinical remission.
Comparative genomic hybridization arrays were used to better specify the breakpoints of the tetrasomy. The comparative genomic hybridization platform used was a single-nucleotide polymorphism microarray analysis performed by using the Illumina HumanHap300 BeadChips platform (Illumina, Inc, San Diego, CA). Data were analyzed with Genome Studio software (Illumina, Inc, San Diego, CA). Probe positions were established for all cases by using the Genome Browser Assembly hg19 (National Center for Biotechnology Information Build 37; http://genome.ucsc.edu/cgi-bin/hgGateway). Mosaic tetrasomy concerns a 42-Mb region in 9p24.3q12 including 495 genes, among them 26 encoding for IFN (Fig 2A). Relative mosaicism in cultured lymphocytes and buccal smear was seen (Fig 2B). Single-nucleotide polymorphism array favored maternal origin of i(9p) with partial uniparental disomy of chromosome 9. An increased expression of IFN-stimulated genes, a so-called IFN signature, was observed on 2 occasions (Fig 2C); specifically, the expression of 6 genes known to be IFN-stimulated was assessed from total RNA extracted from whole blood by using a PAXgene RNA isolation kit (PreAnalytix GmbH, Switzerland).
We report on a patient carrying a mosaic tetrasomy of 9p who presented with an overlap myositis. Myositis was characterized by a proximal muscular weakness and HLA class I antigen myofiber overexpression on muscle biopsy. Overlap features consisted of lupus manifestations comprising pericarditis, pleuritis, and positive ANAs and anti-SSA antibodies.
Tetrasomy 9p has a highly variable phenotype due to the position of the breakpoints and number of cell lineages affected, resulting in differential levels and distribution of mosaicism.5 Tetrasomy 9p mosaicism commonly leads to facial dysmorphy associated with moderate to severe mental disability, mild growth retardation, renal and skeletal abnormalities, and congenital heart disease. However, normal phenotypes are also possible.6–8 This report identifies, for the first time to our knowledge, mosaic tetrasomy of 9p as predisposing to the development of IM, which is associated with an upregulation of type I IFN activity.
Type I IFN plays a key role in the pathogenesis of SLE and some forms of IM.4 In both diseases, type I IFN genes are upregulated, and serum IFN-α is a biomarker of disease activity.4,9–11 The genes encoding for the 13 different IFN-α protein isoforms are found together in a cluster on chromosome 9p22. In our patient, mosaic tetrasomy 9p resulted in a triplication of the 9p24.3q12 region, which includes a cluster of 17 genes encoding for type I IFN.12 As shown by the observation of an IFN signature, it appears that mosaic tetrasomy 9p results in an increased expression of genes induced by IFN, which is in accordance with the findings of Zhuang et al13 who reported SLE-like disease associated with elevated levels of IFN-α/β in 2 patients with a trisomy of 9p–containing type I IFN cluster. Our report supports the hypothesis that several copies of the type I IFN cluster result in high levels of type I IFN due to a gene-dosage effect, and hence an increased susceptibility to some autoimmune diseases. Thus, we hypothesize that the presence of overlap myositis in our patient with tetrasomy of 9p reported here was related to the presence of 4 copies of the type I IFN gene cluster, and was not coincidental. However, the observation of a single patient is a limitation of our study, and additional reports are required to confirm the relationship between the chromosomal aneuploidy and autoimmunity.
Pediatric-onset overlap myositis is characterized by the association of juvenile DM (dermatomyositis) or polymyositis with another autoimmune disease, such as SLE, scleroderma, juvenile idiopathic arthritis, inflammatory bowel disease, type 1 diabetes mellitus, or celiac disease.14 An increasing number of Mendelian conditions predisposing to the development of pediatric SLE have been identified.1,2 To date, 3 major molecular pathways have been involved in the development of monogenic SLE: (1) a disturbed clearance of apoptotic material in complement deficiencies, leading to lupus in association with a predisposition to infections15; (2) an upregulated production of type I IFN in type I interferonopathies, including Aicardi-Goutières syndrome, ACP5 gene mutations causing SLE associated with a skeletal dysplasia, mutations in DNASE1L3 associated with lupus nephritis, and STING (Stimulator of interferon genes)-associated vasculopathy with onset in infancy (SAVI)3,16; and (3) defective T-cell apoptosis coupled with dysregulated B-cell proliferation, which results from protein kinase Cδ deficiency, leading to Mendelian lupus in association with lymphoproliferative syndrome due to increased B-cell proliferation.17 Until now, ACP5 gene mutation was the only known monogenic condition associated with the development of IM.18 The present report suggests that mosaic tetrasomy of 9p might also predispose to this disease.
In conclusion, our report suggests that mosaic tetrasomy 9p predisposes to IM and lupuslike features. Our data implicate a dysregulation of type I IFN signaling due to the chromosomal aneuploidy. These observations emphasize that lupuslike disease and/or IM should be considered in patients with tetrasomy of 9p presenting with an acquired muscle or other organ involvement and that genetic studies should be performed in patients with mental retardation who develop IM and/or lupuslike features.
We thank Dr Gillian I. Rice for her help and contribution, in particular for performing expression analyses of type I IFN–stimulated genes.
- Accepted May 6, 2015.
- Address correspondence to Marie-Louise Frémond, MD, Service de Pédiatrie, Université Paris 13, Sorbonne Paris Cité, Hôpital Jean Verdier, AP-HP, F-93143 Bondy Cedex, France. E-mail:
Drs Frémond and Gitiaux conceptualized and designed the study and drafted the initial manuscript; Drs Bonnet and Guiddir carried out the initial analyses and reviewed and revised the manuscript; Drs Crow, Bader-Meunier and de Pontual coordinated and supervised the study and critically reviewed the manuscript; and all authors approved the final manuscript as submitted.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- George S,
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- Crow MK
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- Copyright © 2015 by the American Academy of Pediatrics