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Systemic Inflammation Gone Awry: PASH Syndrome and Temporomandibular Joint Ankylosis

Left lower extremity with large ulcerations with hyperpigmented and indurated margins.

Left lower extremity with large ulcerations with hyperpigmented and indurated margins.

The development of new symptoms in a patient with hidradenitis suppurativa led to the recognition of a systemic autoinflammatory condition. A long battle with hidradenitis suppurativa and acne became even more difficult for a 24-year-old man who developed increasing pain and malodorous drainage from the chronic subcutaneous nodules on his axillae, groin, and buttocks, as well as new rapidly progressive ulcers on his legs. He had first been diagnosed with hidradenitis suppurativa at age 13 years. His skin lesions had been managed with hygiene, wound care, and topical and oral antibiotics. Despite this, lesions on his buttocks became especially severe, prompting excisional surgery with skin grafting and diverting loop ileostomy at age 21 years. Perioperative testing had revealed a fistula between a buttocks lesion and his rectum, which was managed conservatively. Computed tomography did not reveal radiographic features of inflammatory bowel disease. He had no personal or family history of inflammatory bowel disease. His recent medical care had been limited because of his incarceration until a few months previously.

In addition to his worsening skin lesions, he also reported a history of progressive trismus. He had sustained facial trauma in a physical altercation 8 years ago but had normal jaw function until 2 years ago, when he developed progressive difficulty and pain with opening his mouth. He now was unable to open his mouth more than 1 to 2 inches, causing him difficulty with eating and speaking.

Assessment

On admission, he had a temperature of 36.3°C, a blood pressure of 129/73 mm Hg, a heart rate of 86 beats/min, a respiratory rate of 14 breaths/min, and an oxygen saturation of 100% on room air. He appeared uncomfortable but not acutely ill. He had numerous tender nodules involving the axillae, face, medial thighs, and buttocks with extensive scarring, induration, and open sinus tracts draining purulent fluid. He also had bilateral lower-extremity large ulcerations with hyperpigmented and indurated margins in addition to hemorrhagic pustules and papules with early ulcer formation. He had substantial tenderness over his bilateral temporomandibular joints and was unable to open his mouth to more than a maximal inter-incisor opening of 4 mm.

Laboratory analysis demonstrated elevated inflammatory markers (erythrocyte sedimentation rate 88 mm, C-reactive protein 4.0 mg/dL). He was treated with intravenous fluids, analgesics, and wound care. On the basis of a suspected bacterial superinfection of his hidradenitis suppurative lesions, broad-spectrum intravenous antibiotics with vancomycin and cefepime were administered. On the basis of the appearance of his lower-extremity ulcers, pyoderma gangrenosum was suspected, and punch biopsies were sent for analysis. To further evaluate his trismus, computed tomography of his maxillofacial bones was performed.

Diagnosis

Hidradenitis suppurativa is a chronic relapsing condition associated with follicular occlusion. It most commonly affects regions of skin containing a high density of folliculopilosebaceous units, such as the axilla, groin, and buttock. Presentation consists of recurrent, painful, inflamed odorous pustules and nodules, resulting in fibrous scars. Our patient’s pain improved with initial management. Skin biopsies of his leg ulcers revealed a superficial neutrophilic and granulomatous infiltrate with pustular exudate, consistent with pyoderma gangrenosum with bacterial superinfection. Pyoderma gangrenosum characteristically evolves rapidly from an initial pustule or papule into a quickly expanding and painful ulcer with neutrophil-predominant infiltrates. It has been associated with several diseases, including inflammatory bowel disease, inflammatory arthritis, and hematologic malignancy. Less commonly, as in our patient, pyoderma gangrenosum is associated with acne and suppurative hidradenitis, a constellation of findings collectively described as pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) syndrome.

Pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome is a recently described autoinflammatory disorder similar to but distinct from the previously recognized pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome. Pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome is an autosomal dominant hereditary disease caused by mutations in the PSTPIP1 gene on chromosome 15. Proline-serine-threonine phosphatase interacting protein 1 encodes a protein that appears to be involved in inflammasome formation and interleukin-1 β activation through interaction with pyrin (mutations in which underlie familial Mediterranean fever). Targeted therapy of pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome with the interleukin-1 receptor antagonist anakinra has been reported. In contrast to pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome, the molecular pathogenesis of pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome remains unknown. On the basis of its clinical features and their similarity to other syndromes, pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome is suspected to be caused by dysregulation of inflammatory pathways. Pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome does not follow a strict Mendelian inheritance, and targeted exonic sequencing of proline-serine-threonine phosphatase interacting protein 1, MEFV, NLRP3, and TNFRSF1A did not identify candidate mutations.

In regard to our patient’s diagnostic evaluation for trismus, maxillofacial computed tomography revealed diffuse nodular thickening of the skin and subcutaneous soft tissues of the face related to hidradenitis suppurative with associated severe degenerative changes and ankylosis of the bilateral temporomandibular joints. Temporomandibular joint ankylosis is characterized by fusion of the mandible with the fossa by bony or fibrotic tissue. It can be caused by many factors, including trauma, infection, inflammation, arthritis, and congenital malformations. The cause of our patient’s temporomandibular joint ankylosis is unclear, with possible contributions from prior trauma and infected hidradenitis suppurative lesions. Of note, another case report described a patient who would otherwise exhibit features of pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome but who also developed inflammatory arthritis involving the axial spine (seronegative spondyloarthritis). The term “pyoderma gangrenosum, acne conglobata, suppurative hidradenitis, and seronegative spondyloarthritis syndrome” was proposed to describe this association.

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-Jeffrey J. Wargo, MD, Brian T. Emmer, MD, PhD

This article originally appeared in the April 2016 issue of The American Journal of Medicine.

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