Abstract

The Inhibitor of Kappa-B Kinase Regulatory Subunit Gamma (IKBKG) is located on chromosome Xq28 and encodes the NF-κB essential modulator (NEMO), a critical molecule upstream of NF-kB activation. Though large deletions in IKBKG cause immunodeficiency, specific splice variants resulting in loss of exon 5 were recently described as causing autoinflammatory disease with a nodular rash. A 1-year-old full-term African male with asymptomatic sickle cell trait presented with episodes of transient erythematous subcutaneous nodules all over the body except the face since 2 weeks of age. The skin lesions evolved to areas of lipoatrophy and hyperpigmentation. At 4 months of age, he developed fever, a new rash, significant periorbital edema, and failure to thrive concerns. An extensive workup showed leukocytosis, hypercalcemia, elevated inflammatory markers, hypertriglyceridemia, and transaminitis. His syndrome, including fever, systemic inflammation, and lipodystrophy (initially mistaken for subcutaneous fat necrosis) was felt to be consistent with the autoinflammatory disease Chronic Atypical Neutrophilic Dermatosis, Lipodystrophy, and Elevated temperature (CANDLE) syndrome. A new skin biopsy of the eyelid revealed heavy mixed acute and chronic inflammation of subcutaneous adipose tissue with necrotic adipocytes and mild dermal perivascular and interstitial infiltrate, diagnosed as neutrophilic lobular panniculitis. A clinical whole-exome sequencing did not identify any causative mutations. However, targeted research re-analysis revealed a mosaic intronic mutation in IKBKG c. 671+3G>C. This mutation produces an mRNA that lacks exon 5 resulting in NEMO Delta-exon 5 Autoinflammatory Syndrome (NDAS), a recently-described disorder with less than 10 reported patients. In conclusion, adipose tissue necrosis in young infants does not necessarily indicate “fat necrosis of the newborn”. A differential diagnosis of autoinflammatory disorders should be considered.

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