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Failure to Close: An Unexpected Surgical Complication

Jessica Nguyen, MD

Pediatric Rheumatology Fellow, PGY-6

Baylor College of Medicine

Texas Children’s Hospital

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Disclosure

  • I have no financial relationships to disclose.

In accordance with the ACCME Standards for Integrity and Independence in Accredited Continuing Education, ACR has implemented mechanisms prior to the planning and implementation of this CME activity to identify and mitigate all relevant financial relationships for all individuals in a position to control the content of this CME activity.

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Patient Case

  • 13-year-old female admitted for planned extensive orthopedic procedures to correct gait abnormalities impairing ambulation
  • PMH: Prematurity, spastic diplegic cerebral palsy
  • PSH: Prior less extensive orthopedic procedures at age 3 and 9 years without complication
  • Family History: Non-contributory

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Hospital Course

  • Day 0: Undergoes procedures without acute complications
  • Day 4: Develops fevers associated with tachycardia, hypoxia, and wound dehiscence
    • CT Chest: Bilateral consolidative pneumonia with adjacent parapneumonic effusions
    • Started on broad spectrum antibiotics

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Hospital Course

  • Day 10: Transferred to the ICU for respiratory failure, uncompensated shock, and surgical site dehiscence

Right knee

Left ankle

R 1st Toe

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Laboratory Data

  • All infectious evaluations (blood, urine, wounds) are negative
  • All immune evaluations (T and B cell subsets, lymphocyte proliferation, DHR) are unremarkable; primary immunodeficiency gene panel sent and pending

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Test

Result (Reference)

CBC

  • WBC

​

​

  • Hgb

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  • Platelets

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48.72 (4.19-9.43 x103/uL)

  • ANC 46.24 (1.82-7.47 x103/uL)
  • ALC 0.83 (1.16-3.33 x103/uL)

7.4 (10.8-13.3 g/dL)

  • MCV 72.7

430 (194-345 x103/uL)

C-reactive Protein

34.2 (<1 mg/dL) 

IgG

472 (641-1353 mg/dL)

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Hospital Course

  • Day 13-17:
    • Returned to OR for washout x 3 and partial closure of necrotizing wounds without significant improvement

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Left ankle

Left knee

Right ankle

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Hospital Course

  • Day 20: Skin biopsy demonstrates skin ulceration with acute neutrophilic inflammation

Superficial ulceration with neutrophilic infiltrate

Neutrophilic infiltrate extending into the dermis

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Hospital Course

  • Day 24: Fevers resolve, however surgical wounds are progressively ulcerative and necrotic without healing

Left ankle

Left knee

Right ankle

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Audience Response Slide

Q: Pathogenic variants in which gene results in this condition?

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A. CARD14

B. NOD2

C. OTULIN

D. PSTPIP1

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Gene panel returns….

OTULIN c.787C>T (p.Arg263Trp)

  • Sequence replaces arginine (basic and polar) with tryptophan (neutral and slightly polar)
  • Not present in the gnomAD population database
  • At the same amino acid location previously reported in the literature for OTULIN haploinsufficiency
  • In Silico Prediction Scores:
    • SIFT: deleterious
    • PolyPhen: probably damaging

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OTULIN Haploinsufficiency

  • OTULIN encodes a deubiquitinase involved in maintaining cellular homeostasis and regulating inflammation driven by NF-kB pathways.
  • Due to amorphic or hypomorphic variants in OTULIN
  • Life-threatening necrosis of the skin and lungs, often, but not exclusively, in response to infection
  • First identified during evaluation for genetic homogeneity in patients with life-threatening staphylococcal disease
  • Adolescent-onset with incomplete penetrance and variable expressivity
  • Phenotypic discrepancies may be the result of variable levels of naturally elicited antibodies

Spaan, A. N. et al. Science (2022)

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Case Resolution

  • Started on corticosteroids (day 31) and infliximab infusions (day 53)
  • Patient discharged once wound VAC therapy was complete and she demonstrated adequate wound healing

Day 77

Day 87

Day 102

Left knee

Day 24

Right foot

Day 24

Day 24

Left ankle

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Summary

  • Defects in the management of posttranslational modifications of the molecular components of critical signaling complexes results in disrupted cellular homeostasis and a range of clinical phenotypes
  • OTULIN haploinsufficiency due to amorphic or hypomorphic mutations results in increased susceptibility to infections and tissue-specific necrosis often triggered by infection
  • Take Home Message: Patients with OTULIN haploinsufficiency and severe necrosis may need combined antibiotic and immunomodulatory therapy

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Key References

  • Spaan, A. N. et al. Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin. Science 376, eabm6380 (2022). ​
  • Damgaard, R. B. et al. OTULIN deficiency in ORAS causes cell type-specific LUBAC degradation, dysregulated TNF signalling and cell death. EMBO Mol. Medicine 11, e9324 (2019). ​
  • Tao, P. et al. Deubiquitination of proteasome subunits by OTULIN regulates type I IFN production. Sci. Adv. 7, eabi6794 (2021). ​

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Thank You!

  • Andrea Ramirez, MD, MEd
  • Tiphanie Vogel, MD, PhD
  • Charlotte Kim, MD
  • Pui Lee, MD, PhD