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CMAJ
CMAJ
9711805
CMAJ : Canadian Medical Association Journal
0820-3946
1488-2329
CMA Impact Inc.

10.1503/cmaj.240353
196e1006
Practice
Cases
A 43-year-old woman with a porcelain rash and recurrent bowel perforations
Wiens Jeremy BScN MN
Dunham Michael MD
Walker Simon MD
Au Selena MD MSc
Departments of Surgery (Wiens, Dunham), Critical Care Medicine (Dunham, Au), and Pathology and Laboratory Medicine (Walker), Alberta Health Services, University of Calgary, Calgary, Alta.
Correspondence to: Selena Au, Selena.Au@ahs.ca
9 9 2024
09 9 2024
196 29 E1006E1010
© 2024 CMA Impact Inc. or its licensors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
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pmcKEY POINTS

Köhlmeier–Degos (KD) disease, also known as atrophic papulosis, is a rare obliterative vasculopathy with both a benign, cutaneous variant and a highly fatal, malignant, multi-system variant that most commonly involves the gastrointestinal and central nervous systems.

Porcelain-white plaques with atrophic centres and erythematous borders are pathognomic for KD disease and should prompt urgent referral to a dermatologist and specialized centre, given the need for close follow-up for malignant transformation.

More than half of patients with KD experience malignant transformation of lesions within a year of diagnosis, and mortality is high if the disease is untreated.

Treatment for systemic disease is based on evidence from case series, with a combination of eculizumab and treprostinil treatment reported to have success.

A 43-year-old woman presented to the emergency department with 5 days of severe, generalized abdominal pain associated with nausea, vomiting, and non-bloody diarrhea. She had a history of hypothyroidism and amenorrhea. In the preceding 3 months, she had postprandial, intermittent abdominal discomfort, for which she had started a gluten-free diet. She had seen her family doctor 6 weeks previously for porcelain-white, punctate skin lesions on her trunk and extremities, and was awaiting referral to a dermatologist (Figure 1).

Figure 1: Erythematous papules (4–5 mm) with hypopigmented centres and erythematous borders, some with overlying crusts, on the trunk and extremities of a 43-year-old woman with Köhlmeier–Degos (KD) disease. The photograph shows the patient’s older lesions, with a central sclerotic porcelain centre and a circular rim of hyperpigmentation. These lesions are not showing the classic porcelain-white appearance for cutaneous KD.

In the emergency department, the patient’s vital signs included a heart rate of 128 beats/min, a blood pressure of 138/97 mm Hg, a respiratory rate of 20 breaths/min with 96% saturation on room air, and a temperature of 36.4°C. Her physical examination revealed diffuse abdominal peritonitis. A contrast computed tomography (CT) scan of the abdomen and pelvis showed scattered locules of free intraperitoneal gas, consistent with bowel perforation, as well as scattered ascites and nonspecific mural thickening of the small bowel and sigmoid colon (Figure 2).

Figure 2: Contrast computed tomography scan of the abdomen and pelvis of a 43-year-old woman with Köhlmeier–Degos disease, showing scattered locules of free intraperitoneal gas (arrow), compatible with perforation of a hollow viscus.

Our general surgery service was consulted, and we performed an emergency exploratory laparotomy, which found perforation of the jejunum and numerous white, plaque-like lesions diffusely scattered along the entire small bowel (Figure 3). The perforation in the jejunum appeared to arise from one of these thin-walled white plaques. During surgery, palpation between 2 fingertips revealed an abnormally thin small bowel wall, which we felt indicated high risk for rupture at any of the plaques. We considered an excisional biopsy and small bowel resection of the perforation, but this was deemed too high a risk for anastomotic leak given the poor quality of the entire small bowel. We performed a primary repair of the jejunal perforation and an appendectomy for tissue diagnosis of the underlying disorder.

Figure 3: Image captured during the exploratory laparotomy of a 43-year-old woman with Köhlmeier–Degos disease showing thin-walled white plaques throughout the small bowel (arrows) and a small bowel perforation (indicated with surgical instrument).

The patient had a 1-day postoperative stay in the intensive care unit as she required vasopressor support for hypotension. The hypotension was secondary to bacteremia caused by Escherichia coli, for which she received intravenous pipercillan–tazobactam (4.5 g every 8 h). After improvement, she was transferred to the surgical ward on postoperative day 2 to continue her recovery. Pathology on the appendix revealed serositis and incidental endometriosis. We consulted specialists in infectious diseases, gastroenterology, and rheumatology to assist with making a unifying diagnosis. We completed laboratory tests for infectious and autoimmune causes, which were negative with the exception of a weakly positive antinuclear antibody of 1:80 and positive antiphosphatidylserine–prothrombin immunoglobulin (Ig) G (Table 1).

Table 1: Laboratory tests from a 43-year-old woman with Köhlmeier–Degos disease and recurrent bowel perforations

Investigation	Laboratory value	Reference range	
General	
Leukocyte (on admission), × 109 g/L	1.9	4.0–11.0	
CRP, mg/L		< 8.0	
 On admission	85.5		
 Day 11	77.5		
 Day 17	33.0		
 Day 37	214.0		
 Day 40	233.0		
Inflammatory	
ESR, mm/h	Not done during admission	≤ 20	
Autoimmune	
ANA	1:80	Negative	
ENA screen	Negative	Negative	
ANCA	Negative	Negative	
Anti-PR3, AI	< 0.2	< 1.0	
Anti-MPO, AI	< 0.2	< 1.0	
Anti-cardiolipin, U/mL	< 1.6 (negative)	≤ 19.9	
Anti-PS–PT IgM	Negative	Negative	
Anti-PS–PT IgG	Positive	Negative	
Anti-PLA2R	Negative	Negative	
Anti-β-2 glycoprotein, U/mL	< 1.4 (negative)	≤ 19.9	
Anti–double-strand DNA, kIU/L	4 (negative)	0–9	
dRVVT (lupus)	Not detected	Not detected	
MxA staining	Not done as not available in Alberta	Negative	
Anti-GBM, AI	< 0.2	< 1.0	
Rheumatoid factor, kU/L	13	< 21	
C3, g/L	1.71	0.60–1.60	
C4, g/L	0.49	0.10–0.40	
C5b-9 (skin)	Negative (perhaps from inactive lesion or sampling error)	Negative	
C5b-9 (bowel)	Not done at autopsy as no frozen bowel samples	Negative	
Infectious	
IgM, g/L	0.53	0.40–3.00	
IgG, g/L	9.04	6.80–18.00	
IgA, g/L	1.11	0.60–4.20	
EBV VCA IgM	Nonreactive	Nonreactive	
EBV VCA IgG	Reactive	Nonreactive	
EBV anti-EBNA-1 IgG	Reactive	Nonreactive	
Strongyloides stool culture	Negative	Negative	
HIV	Negative	Nonreactive	
QuantiFERON-TB	Indeterminate	Nonreactive	
AFB stain	Negative	Negative	
Mycobacteria culture — stool	Negative	Negative	
Mycobacteria culture — colon, tissue	Negative	Negative	
Hepatitis B surface antibody, IU/L	> 1000	≥ 10	
Hepatitis B surface antigen	Nonreactive	Nonreactive	
Hepatitis C antibody	Nonreactive	Nonreactive	
Herpes type 1 IgG	Positive	Negative	
Herpes type 2 IgG	Negative	Negative	
Varicella IgG	Positive	Negative	
CMV IgM	Nonreactive	Nonreactive	
Note: AFB = acid-fast bacteria, ANA = antinuclear antibody, ANCA = antineutrophil cytoplasmic antibody, CMV = cytomegalovirus, CRP = C-reactive protein, dRVVT = dilute Russell viper venom time, EBV = Epstein–Barr virus, EBNA = Epstein–Barr nuclear antigen, ENA = extractable nuclear antigen, ESR = erythrocyte sedimentation rate, GBM = glomerular basement membrane, Ig = immunoglobulin, MPO = myeloperoxidase, MxA = myxovirus-resistance protein A, PLA2R = phospholipase A2 receptor, PR3 = proteinase 3, PS = phosphatidylserine, PT = prothrombin, TB = tuberculosis, VCA = virus capsid antigen.

In the ensuing 2 weeks, the patient’s condition did not improve despite antibiotics and parenteral nutrition. On postoperative day 18, her abdominal pain worsened, with vitals concerning for sepsis (heart rate 143 beats/min, blood pressure 135/89 mm Hg, respiratory rate 30 breaths/min, oxygen saturation 95% on room air, temperature 38.3°C). Her leukocyte count was 15.8 (normal range 4.0–11.0) × 109 g/L. An enhanced CT scan of her abdomen and pelvis showed increasing free air and fluid. Given the concern for recurrent perforation, we performed an emergency laparotomy, and the small bowel was again noted to have numerous white plaque-like lesions. We identified 3 new perforations (Appendix 1, available at www.cmaj.ca/lookup/doi/10.1503/cmaj.240353/tab-related-content). We undertook a small bowel resection and primary repairs, and the patient returned to the intensive care unit for postoperative care.

Three days later, skin and bowel biopsies suggested Köhlmeier–Degos disease (KD) (Figure 4). We submitted an emergency application to the Short-Term Exceptional Drug Therapy program to gain access to eculizumab and treprostinil, the treatment with best supportive evidence in systemic KD. In the interim, we treated with intravenous immunoglobulin (IVIG) and a heparin infusion. Five days and an additional 2 operations later, her application was approved, and treprostinil and eculizumab were initiated. Three days after the administration of eculizumab, she underwent her seventh laparotomy. Again, we identified and repaired small bowel perforations. Her entire abdomen had developed dense adhesions, preventing further surgical interventions. We advised the patient and her family that further surgeries were not feasible, and her condition continued to decline. Twelve days later, she passed away peacefully and comfortably, surrounded by her family.

Figure 4: Hematoxylin and eosin stain of a small bowel specimen from a 43-year-old woman with Köhlmeier–Degos disease, showing (A) oblique intimal expansion, (B) a thrombosed artery, (C) intimal expansion and intimal arteritis, (D) and perivascular inflammation.

Discussion

Köhlmeier–Degos disease, also known as atrophic papulosis, is a rare obliterative vasculopathy that may present in either a benign or malignant form.1–8 Benign, cutaneous KD is characterized by pathognomonic lesions with porcelain-white plaques, atrophic centres, and erythematous borders, which may persist for several weeks or even years.1,2,5,6 These cutaneous lesions typically involve the trunk and upper extremities and often spare the face and hands.2,6 Benign, cutaneous KD may progress into a severe, multisystem, malignant variant; in three-quarters of people who have malignant progression, KD involves the gastrointestinal system. 4,6 Although case series describe visceral perforation as the dominant presentation, patients have preceding gastrointestinal symptoms of abdominal pain, cramping, anorexia or weight loss, vomiting, diarrhea, constipation, or fullness.2 Involvement of the central nervous system, heart, lung, eyes, or bladder has been described.4,6 Patients with systemic involvement who are left untreated have high mortality, most commonly from abdominal sepsis caused by bowel perforation or strokes caused by lesions of the central nervous system.2 In the largest case series to date, including 105 patients, the mean age of disease onset was 33 (range 15–50) years with a male-to-female ratio of 1 to 1.6.6,7 Although 41% of patients had cutaneous KD throughout the follow-up period, 59% of patients had malignant KD that progressed from cutaneous to multisystem involvement within a year of symptom onset.7 This series described a mortality of 22.6%, less than the 50%–75% reported in earlier case series and reviews.5,7

The exact cause and pathophysiology of KD remains unknown.6 In the large case series, 10% of the 105 patients reported familial occurrence, suggesting a possible genetic predisposition.7 The disease has also been described in the postinfection or autoimmune context.4 Pathologically, KD has features of thrombotic microangiopathy and distinctive obliterative arteriopathy.7 Histopathological studies show lymphocyte-mediated necrotizing vasculitis of the cutaneous venules and arterioles.4 Heavy deposition of membranolytic attack complex (i.e., C5b-9 complex) within cutaneous vasculature is noted on biopsy.4 Myxovirus-resistance protein A, a type I interferon–inducible protein, is expressed in the pattern of C5b-9 deposition, suggesting a role for interferon-α in the pathophysiology of KD.4 Endothelial cell dysfunction and coagulopathy have also been proposed as pathogenic mechanisms, as deep excessive endothelial proliferation — seen in the vessels — may lead to thrombosis and final distal necrosis.4 Conversely, thrombi may also cause endothelial damage, mucin deposition, and mononuclear cell aggregation.4 The C5b-9 immunohistochemical stain of frozen sections of our patient’s skin were negative; however, we may have sampled inactive areas, given the absence of thrombi. We did not have any frozen bowel tissue for C5b-9 staining. She also tested positive for antiphosphatidylserine–prothrombin IgG, but negative for IgM and antiphospholipid syndrome markers; the importance of these results is unknown.

The treatment for KD is currently empirical and based on case series data. We started IVIG based on a single case report of successful remission and its availability, although the results have been mixed in other reports.4,8 We also used heparin on the basis of case reports supporting the use of antiplatelets and anticoagulants, preferring an agent that could be immediately stopped to allow for emergency surgery.4 We specifically avoided steroids as they have been shown to increase the risk of complications.4 Similarly, cyclosporine, cyclophosphamide, and azathioprine have not been found effective.4 Eculizumab — a monoclonal antibody that binds to the C5 complement component to prevent the formation of the membranolytic attack complex and partially reverse complement deposition — has shown some promise.3,4 Several case series have shown the effectiveness of eculizumab during the acute phase of the disease, with more prolonged remission when coupled with treprostinil.2,4 Treprostinil is a prostacyclin analogue that inhibits platelet aggregation and causes vasodilation.4. The rare incidence and high fatality of systemic KD limits the feasibility of randomized controlled trials of treatments.

Eculizumab is approved by Health Canada to treat paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome.9 The use of eculizumab in the treatment of malignant KD is considered off label and is evaluated on a case-by-case basis. Applications to finance and access eculizumab for emergency use are submitted to and approved by local programs for exceptional access to drug therapies. Approval for using this 2-drug regimen is based on pathology results supporting the diagnosis of KD and provision of literature that demonstrates therapy correlation with prolonged survival.2

The time-sensitive nature of treatment and the need for a special application to access eculizumab and treprostinil highlight the importance of early recognition by providers. Given this context, diagnosing KD when it is still the benign, cutaneous variant is essential to allow for monitoring of disease progression and early identification of malignant transformation.

Patients with KD should be followed at a specialized centre according to a standardized protocol, including whole-skin exam, skin biopsy, fecal occult blood testing, and ocular fundus exam every 6 months.4 For patients with KD and any gastrointestinal symptoms, laparoscopy is more sensitive than endoscopy or colonoscopy and should be used to detect complications and confirm progression to malignant disease.10 Reversal of lesions upon treatment with eculizumab and treprostinil has been shown among patients who have undergone laparoscopy before catastrophic perforation.2 Further testing — such as esophagogastroduodenoscopy, colonoscopy, brain or spine magnetic resonance imaging, echocardiogram, and CT angiography — may be needed depending on patient symptomatology. Given that transformation of KD from benign to malignant forms most often occurs within the first 7 years of disease, review articles suggest that patients with cutaneous KD be followed up twice per year for the first 7 years, and once per year until the tenth year, after which the risk of malignant transformation is nearly nonexistent.4

The section Cases presents brief case reports that convey clear, practical lessons. Preference is given to common presentations of important rare conditions, and important unusual presentations of common problems. Articles start with a case presentation (500 words maximum), and a discussion of the underlying condition follows (1000 words maximum). Visual elements (e.g., tables of the differential diagnosis, clinical features or diagnostic approach) are encouraged. Consent from patients for publication of their story is a necessity. See information for authors at www.cmaj.ca.

Acknowledgement

The authors thank Dr. Lee Shapiro (Professor at Albany Medical College, NY) for his expertise as a rheumatologist with special interest in Köhlmeier–Degos disease.

Competing interests: None declared.

This article has been peer reviewed.

The authors have obtained patient consent.

Contributors: All of the authors contributed to the conception and design of the work, drafted the manuscript, revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.
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