Idiopathic histiocytoid Sweet syndrome: a case report with clinical and histopathological considerations.

BACKGROUND: Histiocytoid Sweet syndrome is characterized by a predominant neutrophilic dermal infiltrate. Usual clinical differential diagnosis includes erythema multiforme, drug eruption, and erythema nodosum. Histiocytoid Sweet syndrome is considered an uncommon histopathological variant of the disease. METHODS: We evaluated clinical, histopathological, and immunohistochemical findings of a case categorized as idiopathic histiocytoid Sweet syndrome in which clinical-epidemiological data raised the possibilities of Sweet syndrome, leprosy, and drug reaction. RESULTS: Positive reaction to myeloperoxidase (MPO) in histiocytoid cells of the dermal infiltrate, response to oral corticosteroids, clinical and laboratory investigation, and absence of cutaneous lesions or clinical complaints within 1 year of follow-up are consistent with the diagnosis of idiopathic histiocytoid Sweet syndrome. CD68 (PG-M1) and CD15 positive cells were also present among dermal cells. CONCLUSIONS: Epidemiological data are relevant while considering a clinical differential diagnosis of Sweet syndrome that can be further expanded, from a histopathological point of view, when dealing with the histiocytoid variant since neutrophils, macrophages, and immature myelomonocytic cells with histiocytoid morphology are present. The significance of the MPO positive mononuclear dermal cells are not completely established.

ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis.

Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6spin mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated a pivotal role for several kinases such as SYK, RIPK1, and TAK1 in promoting inflammatory disease in Ptpn6spin mice. In order to identify new kinases involved in SHP-1-mediated inflammation, we took a genetic approach and discovered apoptosis signal-regulating kinases 1 and 2 (ASK1 and ASK2) as novel kinases regulating Ptpn6-mediated footpad inflammation. Double deletion of ASK1 and ASK2 abrogated cutaneous inflammatory disease in Ptpn6spin mice. This double deletion further rescued the splenomegaly and lymphomegaly caused by excessive neutrophil infiltration in Ptpn6spin mice. Mechanistically, ASK regulates Ptpn6spin-mediated disease by controlling proinflammatory signaling in the neutrophils. Collectively, the present study identifies SHP-1 and ASK signaling crosstalk as a critical regulator of IL-1α-driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.

Inflammatory cells, cytokines and matrix metalloproteinases in amicrobial pustulosis of the folds and other neutrophilic dermatoses.

Amicrobial pustulosis of the folds (APF) is a rare cutaneous disease characterized by relapsing sterile pustules frequently associated with autoimmune disorders. Although APF pathophysiology is still undefined, scattered reports suggest involvement of neutrophils. The aim of the present study is to evaluate the role of the skin inflammatory infiltrate, selected multifunctional cytokines and effectors of tissue damage in APF and other neutrophilic dermatoses. We studied, by immunohistochemical methods, inflammatory cell markers (CD3, CD163, myeloperoxidase), cytokines (TNF-alpha, IL-8, IL-17), metalloproteinases (MMP-2, MMP-9) and vascular-endothelial-growth-factor (VEGF) in lesional skin from six patients with APF, 11 with pyoderma gangrenosum (PG), 7 with Sweet's syndrome, and in 20 normal skin samples. Immunoreactivities of CD3, CD163, myeloperoxidase, TNF-alpha, IL-8, IL-17, MMP-2, MMP-9 and VEGF were significantly higher in APF, PG and Sweet's syndrome than in controls (p=0.0001). IL-8 was more expressed in PG than in APF (P=0.002) and Sweet's syndrome (p=0.001). In APF, MMP-9 reactivity was higher than in Sweet's syndrome (p=0.035), but less intense than in PG (p=0.020). Our study supports the role of proinflammatory cytokines/chemokines and MMPs as important effectors for the tissue damage in APF similarly to classic neutrophilic dermatoses.

Utility of myeloperoxidase stain in the differential diagnosis of leukemia cutis vs. hystiocitoid Sweet syndrome.

Leukemia cutis is defined as a skin infiltration by leukemic cells. The diagnosis of myeloid leukemia cutis (MLC) can represent a challenge, especially in those cases without symptoms of systemic disease. The clinical appearance, histopathological analysis and immunohistochemical profile can be indistinguishable from those observed in cases of hystiocitoid Sweet syndrome (HSS). We present a case of MLC in which the cutaneous affectation was the first sign of the systemic leukemia. In this setting, the myeloperoxidase stain was the clue to rule out the possibility of HSS. We discuss the role and the utility of the myeloperoxidase stain in the differentiation of these two entities.

Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum.

OBJECTIVE: Mevalonic aciduria as a result of mevalonate kinase deficiency is an inborn error of cholesterol biosynthesis characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises, usually manifesting in early infancy, accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash. The febrile crises are similar to those observed in hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). Pathogenic mutations in the mevalonate kinase gene in both disorders have demonstrated a common genetic basis. Our aim was to describe the clinical picture of adolescent patients with mevalonate kinase deficiency and to expand the clinical and biochemical spectrum of mevalonate kinase deficiency, particularly with regard to HIDS. METHODS: We report the clinical history and biochemical findings of 3 patients with mevalonic aciduria. RESULTS: In 2 siblings with mevalonic aciduria, a 15-year-old girl and a 14-year-old boy, the phenotype shifted with age. Ataxia has become the predominant clinical manifestation, whereas the febrile attacks occur less frequently but as yet have not disappeared. Both of them show marked elevations of immunoglobulin D (IgD). Psychomotor development is retarded but not regressive. Short stature developed in both patients. Additional findings include the development of retinal dystrophy and cataracts in both of them. The third patient is a 6-year-old boy who presented at the age of 5 years with cerebellar ataxia and retinal dystrophy. He is different from all known patients with mevalonic aciduria because of the mild neurologic involvement and because he has never developed febrile crises. In addition, levels of IgD were repeatedly normal. CONCLUSION: The clinical and biochemical spectrum of patients with mevalonic aciduria is heterogeneous. Manifestations of the disease seem to be age dependent, as evident from this first report of adolescent patients. In patients who survive infancy, short stature, ataxia caused by cerebellar atrophy, and ocular involvement with retinal dystrophy become predominant findings. Recurrent febrile crises seem to diminish with increasing age and may not even be an obligatory finding. Elevation of IgD is most likely a secondary phenomenon that seems to be linked to recurrent febrile crises.