HOIL-1 Deficiency

In 2012, Boisson et al. (2012) described three children who developed very early recurrent fever episodes with a strong acute phase reaction, hepatosplenomegaly and lymphadenopathy. Serositis or inflammatory dermatoses, which are usually found in autoinflammatory diseases, were absent. All children were abnormally susceptible to bacterial infections, two out of three also to viral infections. The polysaccharide response to Pneumovax® was impaired. The overall clinical picture was thus characterized by immunodeficiency and autoinflammation. In addition, all three children had amylopectin-like intracellular deposits in the heart, smooth and skeletal muscles, which in combination defined a new clinical picture.

HOIL-1 deficiency is an autosomal recessive disease caused by mutations in the HOIL1 gene, which encodes HOIL1, a component of the linear ubiquitination chain assembly complex (LUBAC). These mutations lead to destabilization of the LUBAC complex with impaired IL-1β-dependent NF-κB activation in fibroblasts. However, myeloid cells, especially monocytes, are hyperreactive to IL-1β. Therefore, the consequences of human HOIL-1 and LUBAC deficiency for IL-1β responses differ between cell types

Mutations in the RBCK1 gene have been identified as the genetic cause. The encoded enzyme HOIL-1 is a component of LUBAC (linear ubiquitin chain assembly complex). The LUBAC complex in turn is necessary for the linear attachment of ubiquitin molecules to intracellular proteins such as NEMO. Ubiquitination, in turn, is a prerequisite for proteasomal degradation or translocation of proteins, for example, but also for protein-protein interactions.

Clinically, HOIL-1 deficiency is characterized by early-onset, recurrent febrile episodes with gastrointestinal symptoms such as abdominal pain, vomiting and diarrhea with blood and mucus, as well as lymphadenopathy, respiratory distress, failure to thrive and muscular amylopectinosis (storage of abnormal glycogen leading to intracellular glycogen inclusions) complicated by myopathy and cardiomyopathy. Recurrent bacterial infections associated with immunodeficiency have been reported, including hyper-IgA syndrome and B-cell memory defects with deficient antibody production and impaired response to vaccines. Inflammatory symptoms are accompanied by increased acute phase reactants during relapses (Aksentijevich I et al. 2017).

Dermatologic manifestations: Eczematous lesions, erythroderma and exfoliative dermatitis occurred in various patients with HOIL-1 deficiency. Vaccine-induced subcutaneous inflammatory lesions have also been described (Aksentijevich I et al. 2017; Boisson B et al. 2012).

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