Alternative titles; symbols
SNOMEDCT: 765435009; ORPHA: 500062; DO: 0080163; MONDO: 0014912;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p15.2 | Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive | 617099 | Autosomal recessive | 3 | OTULIN | 615712 |
A number sign (#) is used with this entry because of evidence that autosomal recessive autoinflammation, panniculitis, and dermatosis syndrome (AIPDSB) is caused by homozygous or compound heterozygous mutation in the OTULIN gene (615712) on chromosome 5p15.
Heterozygous gain-of-function mutation in the OTULIN gene causes an autosomal dominant form of the disorder (AIPDSA; 621030).
Heterozygous loss-of-function mutation in the OTULIN gene causes immunodeficiency-107 with susceptibility to invasive Staphylococcus aureus infection (IMD107; 619986). Evidence suggests that some heterozygous mutation carrier parents of patients with AIPDS may exhibit mild features of IMD107.
Autosomal recessive autoinflammation, panniculitis, and dermatosis syndrome (AIPDSB) is an 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 (CRP; 123260), leukocytosis, and neutrophilia in the absence of any infection. Patients exhibit no overt primary immunodeficiency (Damgaard et al., 2016 and Zhou et al., 2016).
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 (147810) antagonist (Anakinra) until age 3 when he was switched to a TNF-alpha (191160) 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.
Nabavi et al. (2019) reported a patient who developed abscesses without fever or sepsis soon after birth. Laboratory testing showed neutrophilia, leukocytosis, and elevated C-reactive protein, erythrocyte sedimentation rate, and total IgG. She was treated with interferon-gamma and her symptoms improved; however, she had recurrences at 2, 4, and 6 months of age, coinciding with vaccine administration. She died at 8.5 months of age in the setting of pulmonary edema.
Zinngrebe et al. (2022) reported a patient who had a history of pneumonia at 6 months of age, appendicitis at 6 years of age, and a gluteal abscess. He presented at 7 years of age with leukocytosis, elevated C-reactive protein, and fevers. He developed inflammatory lesions on his limbs and abscesses in his spleen, axilla, and lungs. The lesions were biopsied and were sterile. Examination of skin lesions demonstrated massive inflammatory infiltration. He was treated with corticosteroids and his temperature, CRP, and elevated liver transaminases improved.
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.
Damgaard et al. (2019) reported a patient who developed severe inflammatory symptoms after birth, including fever and panniculitis. At 7 months of age, she had fevers, diarrhea, panniculitis, cachexia, and cataracts. She underwent a hematopoietic stem cell transplantation at 17 months of age, and her symptoms resolved for 9 months, at which point she relapsed with fevers and panniculitis. It was found that she had a decrease in bone marrow chimerism and regrowth of native hematopoietic cells. At 29 months of age she was treated with etanercept and had resolution of symptoms.
The transmission pattern of AIPDSB in the consanguineous families reported by Damgaard et al. (2016) and Zhou et al. (2016) was consistent with autosomal recessive inheritance.
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 in the OTULIN gene (L272P; 615712.0001) 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 (see 164011) 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.
In an Iranian patient, born to consanguineous parents, with AIPDS, Nabavi et al. (2019) identified a homozygous splice site mutation in the OTULIN gene (615712.0007). The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents. Analysis of cDNA from PBMCs from the father demonstrated a fully spliced mRNA and smaller, abnormally spliced fragments, which were predicted to result in an unstable, truncated protein.
Damgaard et al. (2019) identified a homozygous missense mutation in the OTULIN gene (G281R; 615712.0008) in a patient with AIPDS. Purified OTULIN with the G281R mutation demonstrated reduced catalytic efficiency towards an M10-linked tetraUb substrate compared to wildtype. OTULIN expression was undetectable in patient fibroblasts. In addition, components of the linear ubiquitin chain assembly complex (LUBAC) were downregulated and the cellular response to TNF signaling was impaired in patient fibroblasts.
Zinngrebe et al. (2022) identified compound heterozygous mutations in the OTULIN gene (615712.0009; 615712.0010) in a patient with AIPDS. LUBAC components were increased in patient fibroblasts and B cells compared to controls. Analysis of linear ubiquitin linkages in EBV-transformed B-cell lines from the patient and his mutation carrier parents demonstrated a surplus of linear ubiquitination in all 3 cell lines, although to a greater extent in the patient.
Damgaard, R. B., Elliott, P. R., Swatek, K. N., Maher, E. R., Stepensky, P., Elpeleg, O., Komander, D., Berkun, Y. OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death. EMBO Molec. Med. 11: e9324, 2019. [PubMed: 30804083] [Full Text: https://doi.org/10.15252/emmm.201809324]
Damgaard, R. B., Walker, J. A., Marco-Casanova, P., Morgan, N. V., Titheradge, H. L., Elliott, P. R., McHale, D., Maher, E. R., McKenzie, A. N. J., Komander, D. The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity. Cell 166: 1215-1230, 2016. [PubMed: 27523608] [Full Text: https://doi.org/10.1016/j.cell.2016.07.019]
Nabavi, M., Shahrooei, M., Rokni-Zadeh, H., Vrancken, J., Changi-Ashtiani, M., Darabi, K., Manian, M., Seif, F., Meyts, I., Voet, A., Moens, L., Bossuyt, X. Auto-inflammation in a patient with a novel homozygous OTULIN mutation. J. Clin. Immun. 39: 138-141, 2019. [PubMed: 30796585] [Full Text: https://doi.org/10.1007/s10875-019-00599-3]
Zhou, A., Yu, X., Demirkaya, E., Deuitch, N., Stone, D., Tsai, W.-L., Kuehn, H. S., Wang, H., Yang, D., Park, Y. H., Ombrello, A. K., Blake, M., and 15 others. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc. Nat. Acad. Sci. 113: 10127-10132, 2016. [PubMed: 27559085] [Full Text: https://doi.org/10.1073/pnas.1612594113]
Zinngrebe, J., Moepps, B., Monecke, T., Gierschik, P., Schlichtig, F., Barth, T. F. E., Strauss, G., Boldrin, E., Posovszky, C., Schulz, A., Beringer, O., Rieser, E., and 9 others. Compound heterozygous variants in OTULIN are associated with fulminant atypical late-onset ORAS. EMBO Molec. Med. 14: e14901, 2022. [PubMed: 35170849] [Full Text: https://doi.org/10.15252/emmm.202114901]