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Neutrophilic dermatoses, pseudoxanthoma elasticum, and infantile hemangioma

GENETIC ABNORMALITIES IN THE PATHOGENESIS OF SWEET SYNDROME AND PYODERMA

GANGRENOSUM

Sweet syndrome and pyoderma gangrenosum are neutrophilic dermatoses, rare

disorders whose pathogenesis is poorly understood. Despite apparent

associations with inflammatory bowel disease, rheumatoid arthritis, and

hematologic malignancies, at least half of cases are idiopathic.

Infiltration of skin with polymorphonuclear leukocytes is present in both

conditions. A similar disease in mice produces skin with a moth-eaten

appearance; it is characterized by neutrophilic infiltration of the skin,

peripheral blood, lungs, and spleen. Caused by failure of apoptosis, the

disorder has been linked to a genetic defect in the protein tyrosine

phosphatases nonreceptor type 6 (PTPN6) gene.

Noting similarities in the neutrophilic infiltrates in affected mice and

humans with neutrophilic dermatoses, investigators{super 1} studied 23

patients (pyoderma gangrenosum, 14; and Sweet syndrome, 9 -- one with a

familial autoinflammatory disorder). Only the one patient with familial

Sweet syndrome had a heterozygous mutation of PTPN6. Roughly half of the

remaining patients had abnormalities in the gene, but the full-length

coding sequence was present in all others. The authors note that these

disorders might be polygenic.

Bottom line: This is intriguing work, but the heterogeneity of these

diseases, the variability of their associations, and the inconsistency of

patients' response to therapy dissuade me from thinking that a single

genetic defect or polygenic abnormality explains their pathogenesis. In

addition, many patients have single episodes of neutrophilic disease, which

further argues against a genetic defect.

-- P. Callen, MD FAILURE OF ANAKINRA IN A PATIENT WITH INFLAMMATORY

BOWEL DISEASE AND PYODERMA GANGRENOSUM

Patients with pyoderma gangrenosum frequently have inflammatory bowel

disease. The autoinflammatory syndrome PAPA (pyogenic arthritis, pyoderma

gangrenosum, and acne) is an autosomal dominant disease caused by mutations

in the threonine phosphatase-interacting protein 1 (PSTPIP1) gene on

chromosome 15. PSTPIP1 mutations lead to elevated levels of interleukin

(IL)-1{beta} and have been successfully treated with the recombinant human

IL-1 receptor antagonist anakinra. Patients with Crohn disease and aseptic

abscesses have also been found to have microsatellite genetic abnormalities

of the PSTPIP1 promoter region.

Investigators{super 2} studied genetic abnormalities in a patient with

recurrent peristomal pyoderma gangrenosum and Crohn disease treated

empirically with anakinra daily for 8 weeks. They found no genetic

abnormalities in PSTPIP1, and the disease did not respond to therapy.

Bottom Line: This observation is important because the authors used genetic

analysis to attempt to link therapeutic response to a specific genetic

defect. More such studies might help to identify patients likely to respond

to targeted therapies.

-- P. Callen, MD ARE ORAL PHOSPHATE BINDERS EFFECTIVE FOR

PSEUDOXANTHOMA ELASTICUM?