Alternative titles; symbolsOTULIN-RELATED AUTOINFLAMMATORY SYNDROME; ORASOTULIPENIA▼ DescriptionAutoinflammation, panniculitis, and dermatosis syndrome (AIPDS) i...
Alternative titles; symbols
Autoinflammation, panniculitis, and dermatosis syndrome (AIPDS) is an autosomal recessive autoinflammatory disease characterized by neonatal onset of recurrent fever, erythematous rash with painful nodules, painful joints, and lipodystrophy. Additional features may include diarrhea, increased serum C-reactive protein, leukocytosis, and neutrophilia in the absence of any infection. Patients exhibit no overt primary immunodeficiency (Damgaard et al., 2016 and Zhou et al., 2016).
▼ Clinical Features
Damgaard et al. (2016) described 3 patients, 2 sisters and their male cousin, from a highly consanguineous family with a severe inflammatory syndrome evident soon after birth. The infants were born prematurely and exhibited repeated episodes of systemic inflammation with diarrhea, increased serum C-reactive protein, leukocytosis, and neutrophilia without evidence of infection. All 3 developed relapsing nodular neutrophil-rich panniculitis, recurrent fevers, failure to thrive, and painful swollen joints. Despite treatment with steroids and other immunosuppressive agents, the sisters died at ages 16 months and 5 years. The male patient was born at 28 weeks' gestation and exhibited repeated episodes of increased CRP levels, leukocytosis, and neutrophilia; he developed relapsing nodular panniculitis at 8 weeks of age. Skin biopsy showed inflammatory infiltrates of lymphocytes and neutrophils within the subcutis, associated with foci of fat necrosis. No vasculitis was identified. He was treated with systemic steroids and a recombinant IL1R antagonist (Anakinra) until age 3 when he was switched to a TNF-alpha monoclonal antibody (Infliximab), which successfully controlled his disease. Damgaard et al. (2016) called the disorder 'OTULIN-related autoinflammatory syndrome (ORAS).'
Zhou et al. (2016) described 3 unrelated families segregating an autosomal recessive autoinflammatory disorder which they called 'otulipenia.' 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 within the 10th to 25th percentile. The other 2 patients were born to consanguineous Turkish parents with no family history of a similar disease. Patient 2 was born at 38 weeks of gestation and exhibited failure to thrive. She presented at the age of 4.5 months with prolonged fevers, lipodystrophy, arthralgias, and pustular, scarring rashes. Skin biopsy revealed panniculitis and neutrophilic dermatosis. Patient 3 presented with neonatal onset of fever and prominent cutaneous lesions including an erythematous rash with painful skin nodules. Skin biopsy showed a predominantly septal panniculitis with vasculitis of small- and medium-sized blood vessels. She exhibited arthralgias and myalgias as well as lymphadenopathy and lipodystrophy. Zhou et al. (2016) noted that all 3 patients had adequate specific antibody responses to vaccines or natural infections when tested.
▼ Clinical Management
Damgaard et al. (2016) described successful remediation of symptoms in an AIPDS patient by administration of a TNF inhibitor (Infliximab). Zhou et al. (2016) described treatment of Turkish patients with AIPDS with an IL1R antagonist (Anakinra) in Patient 2 and a TNF inhibitor (Etanercept) in Patient 3.
The transmission pattern of AIPDS in the consanguineous families reported by Damgaard et al. (2016) and Zhou et al. (2016) were consistent with autosomal recessive inheritance.
▼ Molecular Genetics
By homozygosity mapping followed by candidate gene and exome sequencing in a consanguineous family segregating AIPDS, Damgaard et al. (2016) identified a homozygous missense mutation (L272P; 614712.0001) in the OTULIN gene in all 3 affected individuals. The mutation segregated with the disease in the family and was not found in the Exome Variant Server or ExAC databases. Patient blood samples showed slightly reduced levels of OTULIN and strongly increased levels of M1-linked polyUb chains compared to control samples.
By exome sequencing and candidate gene screening in patients with AIPDS, Zhou et al. (2016) identified homozygous mutations in the OTULIN gene. They identified the L272P mutation in affected members of the same Pakistani family reported by Damgaard et al. (2016) and a missense (Y244C, 615712.0002) and a frameshift (Gly174AspfsTer2; 615712.0003) mutation in unrelated Turkish patients. By luciferase assay analysis, Zhou et al. (2016) demonstrated that the L272P and frameshift mutations enhanced signaling of the NF-kappa-B and MAPK (see 176872) pathways. Zhou et al. (2016) also demonstrated that loss-of-function mutations in OTULIN resulted in increased linear ubiquitination of signaling molecules and led to enhanced TNFR1 (191190)-, NF-kappa-B-, and ASC (606838)-dependent inflammation.