NEMO-NDAS: A Panniculitis in the Young Representing an Autoinflammatory Disorder in Disguise

Abstract

:A 15-month-old full-term boy of African descent with an asymptomatic sickle cell trait presented with episodes of transient erythematous subcutaneous nodules involving the entire body except the face, since 2 weeks of age. The skin lesions evolved to areas of lipoatrophy and hyperpigmentation. An initial skin biopsy, studied at a different department at 2 months, was initially misinterpreted as subcutaneous fat necrosis of the newborn, despite the lack of the typical radiated crystals and needle-shaped clefts characterizing that entity. At 4 months of age, he developed systemic inflammatory manifestations, including fever, a new rash, significant periorbital edema, and failure to thrive. An extensive workup showed leukocytosis, hypercalcemia, elevated inflammatory markers, hypertriglyceridemia, and transaminitis. A new skin biopsy of the eyelid was diagnosed as neutrophilic lobular panniculitis with necrotic adipocytes. An initial whole-exome sequencing did not identify any causative mutations, but a WES reanalysis focused on autoinflammatory disorders was requested based on additional clinicopathologic data and revealed a mosaic intronic mutation in IKBKG c. 671+3 G > C. This mutation encodes an mRNA missing exon 5 resulting in NF-kB essential modulator (NEMO) Δ-exon 5–autoinflammatory syndrome (NDAS). NEMO-NDAS is one of the systemic autoinflammatory diseases that may appear as an unexplained panniculitis in young children, who should be monitored for immunodeficiency and/or autoinflammatory diseases. The differential diagnosis of autoinflammatory disorders should be considered in such cases incorporating the use of the whole-genome/exome sequencing in the investigation. The inhibitor of kappa-B kinase regulatory subunit gamma (IKBKG) is located on chromosome Xq28 and encodes the NEMO, a critical molecule upstream of NF-kB activation.

New primary immunodeficiencies 2023 update

“…Non-inflammasome-related conditions C2orf69 deficiency AR C2orf69 FTT, developmental delay, fevers, microcytic anemia, brain atrophy, septic inflammation [39] SYK GOF AD GOF SYK Fever, rash, colitis, arthritis, FTT, recurrent infections [38] HCK GOF AD GOF HCK Cutaneous vasculitis, pulmonary fibrosis, hepatosplenomegaly [37] PSMB9 GOF AD GOF PSMB9 Fever, rash myositis, pulmonary hypertension, hypogammaglobulinemia, variable lymphopenia [35,36] IKBKG (NEMO exon 5 deletion) XL IKBKG Fever, panniculitis, splenomegaly, liver inflammation, FTT [34] TBK1 deficiency AR TBK1 Polyarthritis, cutaneous vasculitis, intellectual disability, seizures, fever, autoinflammation [33] IUIS Table IX Mutations in IKZF3 encode in an aberrant AIO-LOS transcription factor whose homodimerization and heterodimerization with IKAROS, which result in impaired DNA binding and subsequent B cell developmental defects. Interestingly, IKAROS can still function normally and result in normal B cell development if the inhibitory AIOLOS protein were to be removed [15].…”

“…The newly added variants in the SYK, HCK, PSMB9, IKBKG, TBK1 genes all confer a gain of function phenotype resulting in increased signaling resulting in autoinflammation and immune dysregulation [33][34][35][36][37][38]. C2ORF69, which previously had no known function, has been shown to interact with the mitochondria to affect mitochondrial membrane potential and oxidative respiration in neurons and the reported variants are thought to account for the degenerative central nervous system (CNS) disease as well as a glycogen storage disease-like phenotype in these patients [39].…”

Update on autoinflammatory diseases

“…Following the discovery of genes mutated in FMF and TRAPS genes (MEFV and TNFRSF1A) [1,29], there are now more than 50 monogenic SAIDs. A new disease is described almost every month [30,31,32 ▪ ,33 ▪ ].…”