Otulin-Related Autoinflammatory Syndrome M79.3

The autoinflammation-panniculitis-dermatosis syndrome is a very rare, genetically defined clinical picture, which manifests itself already in the first weeks of life, characterized by abnormal inflammations in the entire body, especially of the gastrointestinal system, the joints and the skin.

Autoinflammation is caused by a homozygous mutation in the OTULIN gene (615712) on chromosome 5p15.

First inflammatory signs and symptoms usually begin within the first weeks of life

Recurrent attacks of fever, diarrhea, painful, swollen joints, lymphadenopathy and inflammatory nodular skin lesions. These are caused by painful panniculitis.

Some patients suffer from an abnormal distribution of fatty tissue (lipodystrophy). Affected infants have growth difficulties and failure to thrive. Other features may include elevated serum C-reactive protein, leukocytosis and neutrophilia. The patients have no obvious primary immunodeficiency (Damgaard et al. 2016; Zhou et al. 2016).

Treatments with TNF-alpha blockers have proven to be effective (Aksentijevich I et al. 2017).

If left untreated, the damage to body tissues and organs caused by inflammation is life-threatening.

Damgaard et al (2016) described three patients, two sisters and their cousin, with an autoinflammatory panniculitis-dermatosis syndrome that appeared shortly after birth. The children showed repeated episodes of systemic inflammation with diarrhea, elevated serum C-reactive protein, leukocytosis, and neutrophilia without evidence of infection. All 3 developed recurrent nodular neutrophilic panniculitis, recurrent episodes of fever, failure to thrive, and painful swollen joints. Despite treatment with steroids and other immunosuppressive agents, the sisters died at 16 months and 5 years of age. The male patient was born at 28 weeks' gestation and had repeated episodes of elevated CRP, leukocytosis, and neutrophilia; at 8 weeks of age, he developed recurrent nodular panniculitis. Skin biopsy showed inflammatory infiltrates of lymphocytes and neutrophils in the subcutis associated with fat necrosis. He was treated with systemic steroids and a recombinant IL1R antagonist (anakinra) until he was switched to a TNF-alpha monoclonal antibody (infliximab) at 3 years of age. Among them, decrease in symptomatology.

Zhou et al (2016) described three unrelated families with this disease. Patient 1 was the surviving male in the Pakistani family described by Damgaard et al. (2016). Zhou et al (2016) noted additional features, including lipodystrophy and lymphadenopathy. At age 11 years, his height was between the 10th and 25th percentiles. The other two patients were born to consanguineous Turkish parents. Patient 2 was born at 38 weeks of gestation and had failure to thrive. She had persistent fever at 4.5 months of age. Furthermore: lymphadenopathy, lipodystrophy, arthritides, pustular scarring skin rash. Skin biopsy revealed panniculitis and neutrophilic dermatosis. The 3rd patient presented with fever in the first weeks of life as well as papular painful exanthema with painful skin nodules. Skin biopsy: ptal panniculitis with vasculitis of small and medium blood vessels. She had arthralgias and myalgias as well as lymphadenopathy and lipodystrophy. All 3 patients had adequate specific antibody responses to vaccines on testing.

1. Aksentijevich I et al. (2017) NF-κB pathway in autoinflammatory diseases: dysregulation of protein modifications by ubiquitin defines a new category of autoinflammatory diseases. Front Immunol 8:399.

2. Damgaard RB et al. (2016) The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity. Cell 166: 1215-1230.

3. Hoste E et al. (2021) OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity. Nat Commun 12:5913.

4. Zhou A et al. (2016) Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Nat Acad Sci 113: 10127-10132.