OTULIN-Related Autoinflammatory Syndrome With a Novel Mutation Treated With Tumor Necrosis Factor Inhibitor Therapy: A Rare Case Report

Vildan Güngörer; İlknur Külhaş Çelik; Hasibe Artaç; Banu Çelikel Acar

doi:10.3899/jrheum.2024-1141

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Figure 1.
Skin manifestations, treatment response, and familial pedigree of the patient. (a) Livedo racemosa and opisthotonic posture (arrows) and (b,c) hyperemic nodular rashes (arrows). (d) Skin biopsy showing dense neutrophilic infiltration in subcutaneous fat tissue. (e) The pedigree of the patient shows that both parents are carriers for OTULIN^Lys160Ter. (f) Treatment response. CRP: C-reactive protein.

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Table.

Clinical and genetic characteristics of patients with ORAS.

Reference (Year)	Patient	Gestational Age/Weight	Symptom Onset Age/Sex	Gene; AA Alteration	Mutation	Origin	Consanguinity	Symptoms	Treatment	Outcome
Damgaard¹ (2016)	1	34 wks	3 wks/F	c.815T>C; Leu272Pro homozygous	Missense	Pakistani	2nd cousins	• Protracted diarrhea, failure to thrive, nodular erythematous rash, severe pneumonia	• PSL, azathioprine, MTX	• Died at age 16 mos from pneumococcal septicemia
	2	36 wks/2000 g	3 d/F	c.815T>C; Leu272Pro homozygous	Missense	Pakistani	2nd cousins	• Relapsing nodular panniculitis, diarrhea, vomiting, fever, painful swollen joints, failure to thrive, bilateral cataracts	• PSL, anakinra	• Died at age 5 yrs from acute renal failure, pulmonary edema
	3	28 + 6 wks/1230 g	8 wks/M	c.815T>C; Leu272Pro homozygous	Missense	Pakistani	2nd cousins	• Relapsing nodular panniculitis, fever, vomiting, diarrhea (sometimes bloody), inflamed painful joints, swollen feet, weight loss, juvenile cortical cataracts	• Systemic CS, anakinra, IFX, prophylactic azithromycin, acyclovir	• At age 11 yrs, successfully controlled with IFX for 8 yrs (> 5 mg/kg)
Zhou² (2016)	4	38 wks	4.5 mos/F	c.731A>G; Tyr244Cys homozygous	Missense	Turkish	Yes	• Prolonged fevers and pustular, scarring rashes	• CS, anakinra	• Symptoms improved on treatment with anakinra
Zhou² (2016)	5	NA	Neonatal/F	c.517delC; Glyl74Aspfs*2 homozygous	Frameshift	Turkish	Yes	• Erythematous rash with painful skin nodules, progressive lipodystrophy, failure to thrive	• CS, ETN	• CS-dependent
Damgaard⁴ (2019)	6	NA	3 d/F	c.841G>A; p.Gly281Arg homozygous	Missense	Arab	1st cousins	• Recurrent fever, widespread panniculitis, diarrhea, failure to thrive, severe splenomegaly, bilateral cataracts	• Prednisone, colchicine, anakinra, HSCT	• Relapse at age 9 mos after HSCT, under control with ETN (0.4 mg/kg, twice weekly)
Nabavi³ (2019)	7	35 wks/NA	Neonatal/F	c.864+2T> chomozygous	Frameshift	Iranian	1st cousins	• Erythematous nodules, abscesses without fever, highgrade fever with respiratory distress, mild hepatosplenomegaly	• Antibiotic therapy, IFN-γ	• Died at age 8.5 mos from pulmonary edema
Zinngrebe⁵ (2022)	8	NA	7 yrs/M	c.25SG>A; p.M86I/c.500G>C; P.W167S compound heterozygous	Missense	Greek	No	• Late-onset, sterile abscess formation in different organs (skin, lung, spleen)	• Antibiotic therapy, CS	• Alive and in good condition
Caballero-Oteyza⁶ (2024)	9	NA	Neonatal/M	c.595T>A; p.Trpl99Arg homozygous	Missense	Moroccan	Yes	• Failure to thrive, severe, sterile systemic inflammation	• Antibiotic therapy, CS	• Died soon after the neonatal period
Takeda⁹ (2024)	10	NA	Neonatal/F	c.917G>A; p.Arg306Gln heterozygous	De novo	Japanese	No	• Persistent fever, erythema nodosum-like skin eruptions, unresolving omphalitis and ARDS	• CS, ETN	• CS-free remission, catching up in physical growth
Davidson⁸ (2024)	11	31 wks/NA	4 d/M	c.386G>C; p.Cys129Ser heterozygous	De novo	Caucasian	No	• Periumbilical abscess (positive culture with methicillin-Sensitive S. aureus), ARDS, sterile pustular abscesses	• CS, ADA, ruxolitinib, broad-spectrum antibiotic prophylaxis	• At age 2 yrs, controlled with low-dose CS, ADA weekly, and ruxolitinib
Davidson⁸ (2024)	12	Term/NA	7 mos/F	c.38ST>A; p.Cys129Ser heterozygous	De novo	Saudi	No	• Multiple tender skin lesions, fever, generalized edema, necrotizing fasciitis with ulceration	• Antibiotic therapy, IFX, MTX, CS	• At age 3 yrs, in clinical and biochemical remission since starting TNFi 2 yrs prior

AA: amino acid.; ADA: adalimumab; ARDS: acute respiratory distress syndrome; CS: corticosteroid; ETN: etanercept; HSCT: hematopoietic stem cell transplantation; IFN: interferon; IFX: infliximab; MTX: methotrexate; NA: not applicable; ORAS: OTULIN-related autoinflammatory syndrome; PSF: prednisolone; S. aureus: Staphylococcus aureus, TNFi: tumor necrosis factor inhibitor.