Dermatology in General Medicine Familial Ulcerative Pyoderma Gangrenosum: A Report of 2 Kindred Jennifer H. Alberts, MD; Hunter H. Sams, MD; Jami L. Miller, MD; Lloyd E. King, Jr, MD, PhD Pyoderma gangrenosum is a rare, chronic ulcer- Case Reports ative skin disease. It is a diagnosis of exclusion, Patient 1—In 1993, a healthy 23-year-old white after ruling out other causes of cutaneous ulcer- man injured his right shin with a tow truck motor. ation. The etiology of pyoderma gangrenosum is The initial superficial injury subsequently ulcer- poorly understood but is likely multifactorial. We ated. Before presentation at our clinic, the patient describe 2 families affected by ulcerative pyo- had received multiple unsuccessful treatments, derma gangrenosum. This familial clustering including tetracycline, dapsone, prednisone, and suggests a possible genetic role in the develop- isoniazid. A split-thickness skin graft in August ment of pyoderma gangrenosum in some cases. 1997 failed. The patient reported a history of minor trauma precipitating small ulcers before Pyoderma gangrenosum is a rare, chronic ulcera- healing but denied a history of inflammatory bowel tive skin disease. No specific laboratory or histo- disease or arthritis. Additionally, there was no fam- logic tests confirm the diagnosis. Pyoderma ily history of inflammatory bowel disease, connec- gangrenosum is a diagnosis of exclusion, after rul- tive tissue diseases, or diabetes mellitus. However, ing out other etiologies of cutaneous ulceration family history was significant for pyoderma gan- such as infectious, malignant, vasculitic, and fac- grenosum, occurring in his brother, maternal uncle, titial. Four distinct clinical variants of pyoderma and maternal great uncle (Figure 1). On presenta- gangrenosum have been described: ulcerative tion in June 1998, an 11ϫ10-cm dry ulcer with a (classic), pustular, bullous, and vegetative.1 Ulcer- rolled violaceous border was present on the right ative pyoderma gangrenosum characteristically medial calf (Figure 2). The findings from anti- presents on the lower extremities or trunk, often nuclear antibody (ANA), rapid plasma reagin, and in sites of previous trauma (pathergy). The earliest hepatitis profile were normal. Results from complete lesion is a pustule that typically persists and devel- blood cell count, serum chemistries, protein C, ␣ ops into a large painful ulcer, with erythematous- 1-antitrypsin, CH50, and serum protein electro- to-violaceous undermined, rolled borders. phoresis were within normal limits. A culture of Satellite violaceous papules or pustules may fuse the ulcer grew coagulase-negative Staphylococcus. with the ulcer as it expands. Although pyoderma Despite aggressive treatment (eg, multiple skin gangrenosum has been reported in otherwise grafts, various intravenous and oral courses of antibi- healthy people, 50% of the cases are associated otics [dicloxacillin, levofloxacin, tetracycline, and with underlying hematologic, gastrointestinal, and rifampin], multiple immunomodulating medications arthritic disorders.2-4 To our knowledge, 3 families [colchicine, cyclosporine, azathioprine, cyclophos- with pyoderma gangrenosum, which was not asso- phamide, mycophenolate, high-dose pulse steroids, ciated with underlying systemic disorders, have thalidomide, leflunomide, and infliximab]), the been reported previously.5-7 We describe 2 addi- ulcer on the patient’s right medial calf persists. tional families affected by idiopathic ulcerative Patient 2—In 1994, the otherwise healthy pyoderma gangrenosum. 22-year-old brother of patient 1 developed non- healing ulcers on his lower extremities. The From the Vanderbilt University Medical Center Department of patient denied any trauma at the involved sites. Medicine, Division of Dermatology, Nashville, Tennessee. During the next 3 months, the ulcer on the right Dr. King is also from Nashville Veterans Administration lower extremity healed spontaneously, but the Medical Center. Reprints: Lloyd E. King, Jr, MD, PhD, 3900 The Vanderbilt left leg ulcer persisted. The patient reported a his- Clinic, Nashville, TN 37232-5227 tory of stable vitiligo on his hands and feet since (e-mail: [email protected]). 9 years of age but denied a history of hematologic, VOLUME 69, JUNE 2002 427 Dermatology in General Medicine Patient 1 Patient 2 Figure 1. Genogram of patients 1 and 2. gastrointestinal, or arthritic disease. The findings bowel disease or connective tissue disease. Of from the physical examination in March 1996 interest, the patient’s mother had a history of a revealed a 4ϫ4.5-cm ulcer with violaceous border nonhealing ulcer in an abdominal scar. On exami- and surrounding erythema on the left medial nation, a 3ϫ2-cm ulcer with a violaceous border shin (Figure 2). Biopsy results of the ulcer demon- was observed on the left lower abdominal quadrant. strated epidermal ulceration with an inflammatory Results of polymerase chain reaction demonstrated infiltrate of neutrophils and mononuclear cells. the presence of Chlamydia pneumoniae in the serum. Cultures of the biopsy specimen demonstrated mod- Despite treatment with rifampin, trimethoprim- erate growth of coagulase-positive Staphylococcus. sulfamethoxazole, amoxicillin, isoniazid, and Cultures tested negative for acid-fast bacilli and aggressive local wound care with alternating fungus. Results from the hepatitis profile and ANA topical antibiotics (bacitracin, mupirocin, and were normal. Also, complete blood cell count, metronidazole), the patient’s ulcer persists. complement, and immunoglobulin levels were Patient 4—In 1989, the then 65-year-old within normal limits. During the next 3 years, the mother of patient 3 presented to our clinic com- patient improved minimally with therapies includ- plaining of a nonhealing ulcer with an undermin- ing doxycycline, cephalosporin, erythromycin, ing and purplish rolled border at a previous surgical systemic steroids, topical antibiotics, and multiple site. Four months previously, the patient under- split-thickness skin grafts. went an elective abdominal panniculectomy, and Patient 3—A 56-year-old white woman pre- the surgical site never completely healed. Therapy sented in August 1997 with a 10-month history of with oral tetracycline and local wound care with an ulcer involving the left lower abdominal quad- neomycin and mupirocin were unsuccessful. The rant. The patient denied any trauma to the site but patient’s medical history was significant for dia- reported that tape stripping dressings induced adja- betes mellitus, cholecystectomy, and large cell lym- cent papules to break down and become persistent phoma of the stomach. The patient’s lymphoma ulcers. Her medical history was significant for a left was believed to be in remission, after undergoing a total knee replacement, complicated by an infec- partial gastrectomy and completing 4 courses of tion that required removal of the prosthesis. The chemotherapy 13 months before the panniculec- patient denied any medical history of inflammatory tomy. The patient denied a history of connective 428 CUTIS® Dermatology in General Medicine Figure 2. Chronic nonhealing ulcers of patient 1 (top) and patient 2 (bottom). tissue or inflammatory bowel disease. Results of the aggressive use of immunosuppressive agents and physical examination revealed 2 deep ulcerated various antibiotic regimens. areas with rolled violaceous borders and a serofi- Pyoderma gangrenosum was described first in brinous base. Subcutaneous erythematous nodules 19308 yet remains a poorly understood disease. It measuring 1 to 2 cm in diameter surrounded the appears to be a multifactorial process, with the ulcers. Results of cultures of the nonhealing wound common finding of immune surveillance abnor- were negative for bacteria, acid-fast bacilli, and malities. Both humoral and cell-mediated defects fungus. Results of a biopsy of the ulcer completed have been reported in association with pyoderma at another institution indicated an inflammatory gangrenosum. Congenital humoral defects include infiltrate with mononuclear cells and neutrophils hypogammaglobulinemia, hyper–immunoglobulin but no evidence of large cell lymphoma. After sur- E syndrome, and autoantibody production against gical excision and oral colchicine therapy, the the skin and gastrointestinal tract.1 In addition, ulcers finally healed 3 months later. cell-mediated abnormalities described are defective neutrophil function,9,10 impaired lymphocyte activ- Comment ity,11 cutaneous anergy,12 and congenital deficiency Each of the patients described above was affected of leukocyte-adherence glycoproteins.1 Recently, a by a chronic ulcerative process clinically and/or chronic infection with C pneumoniae has been pro- histologically compatible with pyoderma gangreno- posed as a possible etiologic factor in the patho- sum. Laboratory data failed to demonstrate other genesis of some patients with previously idiopathic etiologies of cutaneous ulceration or underlying pyoderma gangrenosum.13,14 systemic disease. In all 4 cases, the patients exhib- Familial clusters of pyoderma gangrenosum–like ited the typical clinical features of pyoderma lesions suggest a possible genetic role in disease devel- gangrenosum—a chronic nonhealing ulcer with opment in some patients. Yet to be elucidated, inher- violaceous rolled border. Three of the 4 cases ited and acquired immune surveillance abnormalities, exhibited pathergy. All 4 patients had an unremit- in combination with persistent infection, may lead to ting