Monogenic Lupus with IgA Nephropathy Caused by Spondyloenchondrodysplasia with Immune Dysregulation

Abstract

Monogenic disorders causing systemic lupus erythematosus represent a small subset of cases. Type-1 interferonopathies, like spondyloenchondrodysplasia with immune dysregulation constitute an important functional category of monogenic lupus. Apart from autoimmune disorders, neurological and skeletal abnormalities are additional manifestations observed in this disorder. A young female presented with seizures due to acute hemorrhagic stroke secondary to malignant hypertension. On evaluating the cause for hypertension, there was evidence of glomerulonephritis and multiple autoantibodies positivity including dsDNA. A diagnosis of lupus was made based on clinical and laboratory findings. Kidney biopsy revealed mesangial proliferative glomerulonephritis with predominant IgA deposits favouring IgA nephropathy. Additional features in the form of short stature with vertebral abnormalities and bilateral basal ganglia calcification led to evaluation of Type-1 interferonopathies. Sanger sequencing identified a novel compound heterozygous variants c.550C>T (p.Q184*) in exon 3 and c.740T>G (p.L247R) in exon 4 of ACP5 gene. Parents were found to be carriers of the variants in ACP5 gene. Management included antihypertensive agents and symptomatic therapy. On follow-up, there was complete resolution of glomerulonephritis and normalization of blood pressure. This case report documents the classic phenotype comprising autoimmune, skeletal, and neurological abnormalities in spondyloenchondrodysplasia with immune dysregulation with a novel variant on Sanger sequencing in an Indian patient. This report also highlights the rare coexistence of IgA nephropathy in monogenic lupus.

Case report: Refractory Evans syndrome in two patients with spondyloenchondrodysplasia with immune dysregulation treated successfully with JAK1/JAK2 inhibition

“…Both parents were identified as heterozygous asymptomatic carriers of one of the variants ( Figures 2B, C ; Supplementary Materials ; Supplementary Table 1 ). Based on the favorable therapeutic response of other patients with type I interferonopathies to JAK inhibitors ( 3 , 4 , 12 , 19 – 21 ), and the shared pathophysiologic hallmarks of SPENCDI with other type I interferonopathies ( 14 , 22 ), a therapeutic trial with the JAK1/JAK2 inhibitor ruxolitinib was initiated (0.4 mg/kg/day). Within a week from initiation of therapy, the patient reported significantly improved energy levels.…”

“…The patient was subsequently referred to an oncologist and diagnosed with smoldering multiple myeloma. These findings prompted a review of the literature that revealed that approximately half of the patients with SPENCDI also report hypergammaglobulinemia ( 2 , 4 , 12 , 13 , 20 , 22 ).…”

“…In addition, SPENCDI can manifest with neurologic symptoms ( 1 , 2 , 4 , 6 , 8 ). Immune dyscrasias, most commonly manifesting as cytopenias and SLE-like symptoms ( 10 – 12 ), are often recalcitrant and refractory to conventional immunomodulatory therapies ( 1 , 2 , 6 , 10 , 13 ). SPENCDI is an autosomal recessive disease secondary to biallelic pathogenic variants in the ACP5 gene.…”

Nefropatía por IgA en una adolescente con lupus eritematoso sistémico juvenil. Reporte de caso

“…Existen casos reportados de asociación entre LESJ y (11)(12)(13)(14)(15) NIgA, aunque en su mayoría en adultos , reportándose un caso interesante de Lupus (16) monogénico y NIgA en una adolescente de 15 años . En GWAS, se describen los loci que demuestran asociación entre LES e NIgA: CFH, HLA-DRA, HLA- En este caso, la paciente presentó criterios para LESJ a la edad de 13 años, manifestados por artritis, poliserositis, anemia hemolítica autoinmune, leucopenia, ANA positivo, Anti-DNA positivo, c3 y c 4 b a j o s .…”

Novel Mutations in ACP5 and SAMHD1 in a Patient With Pediatric Systemic Lupus Erythematosus

“…Mutations in ACP5 and SAMHD1 are known to drive the pathogenesis of SPENCD and AGS, both of which are monogenic interferon diseases characterized by increased type I IFN signaling leading to vasculopathy, autoinflammation, and SLE-like disease (8,23,24). To date, 30 cases of SPENCD with SLE have been reported in the literature (23,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) (Figure 2A; Table 2), and 9 cases of SLE with SAMHD1 mutations have been reported in the literature (21,(36)(37)(38)(39)(40)(41) (Figure 2B; Table 3), including the patients in this article. Patients with SPENCD or AGS with SLE have a homogeneous clinical presentation, including autoantibody positivity, hematologic involvement, and neurologic symptomatic manifestations.…”