Mosaic Tetrasomy 9p: A Mendelian Condition Associated With Pediatric-Onset Overlap Myositis

Abstract

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.

Mosaic Tetrasomy of 9p24.3q21.11 postnatally identified in an infant born with multiple congenital malformations: a case report

“…Although the affected population is small, males seemed to be slightly more affected than females [ 5 ]. The clinical severity of tetrasomy 9p varies from neonatal death to mild developmental delay and minor anomalies [ 9 , 18 , 19 ]. Furthermore, when the tetrasomic segment extend to 9q22-9q32 it is common to observe intrauterine growth retardation, skeletal anomalies, cleft lip/palate, and heart defects [ 15 ].…”

Case presentation: persistent adenovirus B3 infections associated with bronchiolitis obliterans treated with cidofovir in a child with mosaic tetrasomy 9p

“…It is likely that chronic AdV B3 infection contributed to persistent inflammation which may have contributed to the development of BO. This may have been further exacerbated by a dysregulated IFN-1 response, which has been described previously in association with tetrasomy 9p [ 12 ]. The relatively benign course and response to steroid therapy suggests a mild disease, and it is possible that cidofovir therapy acted as a disease modifying agent by reducing the viral load and associated immune stimulus during the active inflammation phase.…”

“…An array comparative genomic hybridisation (CGH) revealed mosaic tetrasomy of short arm of chromosome 9. There are no reports yet of immunodeficiency in association with mosaic tetrasomy 9p, nor any specific vulnerability to any particular viral infections [ 13 ], but has previously been associated with auto-immune conditions associated with IFN-1 dysregulation (predisposing to inflammatory myositis and lupus-like syndrome) [ 12 ].…”

“…In patients living with this genotype, the two forms are usually present in a mosaic state, hence the term mosaic tetrasomy 9p [ 11 ]. More recently, it has been associated with some degree of immune dysregulation [ 12 ], which may demonstrate a potential to impact on host responses to infections, though no specific immunodeficiency syndrome has yet been linked to this mutation [ 13 ].…”

9p24 triplication in syndromic hydrocephalus with diffuse villous hyperplasia of the choroid plexus

“…Tetrasomy 9p occurs from either isodicentric 9p (as in our patient) or pseudodicentric 9p duplications. There have been fewer than 70 reported cases of tetrasomy 9p ( El Khattabi et al 2015 ; Fremond et al 2015 ). Patients are typically mosaics for the chromosomal aberration and demonstrate considerable clinical heterogeneity, ranging from impaired physical and mental development to severe intellectual disability and growth delay ( El Khattabi et al 2015 ).…”