Doris Weiss; Nikita Lakdawala, BS; Harleen Sidhu, MD; Robert Phelps, MD; Jason Emer, MD
All from Mount Sinai School of Medicine, Departments of Dermatology and Pathology, New York, New York.
Disclosure: The authors report no relevant conflicts of interest.
Message from the Section Editor
I would like to announce a new Special Section of JCAD entitled, “Diagnostic Dilemmas in Derm,” a section dedicated to highlighting clinically interesting, important, rare, or diagnostically challenging cases. This new section enables authors to emphasize noteworthy clinical scenarios, medical diagnoses, and/or novel treatments with clinical and pathological photographs and concise discussions. The nature of this section is to briefly provide essential information on challenging clinical entities in dermatology, while, at the same time, challenging the audience. Discussions will review the most up-to-date medical literature, debate diagnostic dilemmas, and/or propose novel therapeutic ideas. I am honored to present the first case and anticipate many excellent future presentations.
—Jason Emer, MD
Case Report
A 90-year-old Caucasian man with diabetes mellitus type 2 and congestive heart failure presented with a pruritic rash of two weeks’ duration unresponsive to initial treatment with topical clobetasol ointment and oral benadryl. Initially recognized on the lower extremities, the rash slowly became generalized by the time of presentation. The patient also reported fevers, joint pain, and malaise. Physical exam revealed generalized, confluent, erythematous, annular patches with central hypopigmentation and peripheral scale sparing the mucous membranes and palmoplantar surfaces (Figure 1). No joint swelling or tenderness was noted on examination. The patient’s past medical history was significant for a recent increase in dosage of hydralazine for worsening congestive heart failure. Initial laboratory investigation revealed marked leukocytosis with eosinophilia. A skin biopsy specimen was obtained from the edge of a large annular patch on the patient’s left lower extremity (Figure 2 and Figure 3).
Diagnosis
Hypereosinophilic syndrome (HES)
Microscopic Findings and Clinical Course
The skin biopsy specimen showed a nonspecific histopathological reaction pattern with significant eosinophilic infiltrate. Periodic acid-Schiff stain (PAS) was negative. Laboratory investigations revealed an elevated white blood cell count at 20.4×103/µL (normal 4.5–11.0×103/µL) with 61.0% eosinophils (normal 0–8%) on the differential. Three stool samples for ova and parasites were negative. After the exclusion of other possible underlying causes for hypereosinophilia, including helminthic and fungal infections as well as connective tissue disease, the diagnosis of HES was made. Serum biomarkers that aid in determining classification and management for HES, including tryptase, vitamin B12, and serum immunglobulins, were within the normal range. The patient was started on high-dose oral prednisone (1mg/kg daily) and systemic antihistamines (hydroxyzine 10mg three times daily), which successfully treated both his skin lesions and symptoms. Two months after the initial diagnosis, the patient has remained clinically asymptomatic. A six-month follow up was recommended and a potential need for bone marrow biopsy will be evaluated at that time.
Discussion
HES is a rare heterogeneous condition, originally characterized by the following: 1) blood eosinophilia of ?1500/µL for at least six months, 2) exclusion of alternative etiology for eosinophilia, and 3) evidence of associated organ involvement.[1,2] A diagnosis of exclusion, the presence of eosinophilia first prompts workup for potential causes including medications, allergy, parasitic infection, malignancy, and collagen-vascular disease. HES is a rare disease and the true incidence and prevalence are undefined. However, the Surveillance Epidemiology and End Results (SEER) database approximated its incidence to be between 0.018 and 0.036 per 100,000 persons/year and its prevalence at 0.36 to 6.3 per 100,000. The age of onset is most commonly between 20 and 50 years of age. It can occur, though very rarely, in childhood.[2,3,4]
The two main subtypes of HES are lymphocytic HES (L-HES) and myeloproliferative HES (M-HES).[2] More than 90 percent of all cases of HES occur in males. The myeloproliferative form occurs almost exclusively in males, whereas the lymphoproliferative form has an approximately equal incidence in males and females.[2,3] Patients with M-HES present with features, such as anemia, thrombocytopenia, and eosinophilic myocarditis, carrying a high rate of morbidity.[3] Serum tryptase and vitamin B12 can be elevated in this subtype. The pathogenesis involves one of several mutations, the most common being a fusion of protein fip1-like1 and platelet-derived growth factor receptor alpha (FIP1L1/PDGF-R?) resulting in intrinsic tyrosine kinase activity.[5,6] L-HES manifests predominantly with skin and soft tissue abnormalities.[7] It involves a clonal proliferation of T-lymphocytes secreting the eosinophilopoietic cytokine interleukin (IL)-5.8 L-HES typically follows a benign course relative to cases of M-HES, but may progress to lymphoma.
Clinically, more than 50 percent of patients with HES present with cutaneous lesions as the first manifestation, with erythematous pruritic papules and nodules, angioedema, and urticarial lesions being the most common.[9] Characteristic mucosal ulcers have been described in patients with M-HES.[7] End organ involvement may develop insidiously and is not correlated with the degree of blood eosinophilia.[10]
Treatment of HES is determined by classification with a goal of reducing symptoms by lowering the eosinophilia.2 Patients who are asymptomatic cutaneously should be treated at the first sign of organ involvement with corticosteroids being the first line of therapy. In patients with a FIP1L1/PDGF-R? mutation, imatinib has proven to be highly effective.[2,6] Alternative treatment options include interferon-?, hydroxyurea, cyclosporine, vincristine, and anti-IL-5 monoclonal antibody. Allogeneic stem cell transplant may be considered in patients who are unresponsive to pharmacological therapy.
References
1. Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). 1975;54(1):1–27.
2. Klion AD, Bochner BS, Gleich GJ, et al. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol. 2006;117:1292–1302.
3. Sheikh J, Weller PF. Clinical overview of hypereosinophilic syndromes. Immunol Allergy Clin North Am. 2007;27:333–355.
4. Crane MM, Chang CM, Kobayashi MG, Weller PF. Incidence of myeloproliferative hypereosinophilic syndrome in the United States and an estimate of all hypereosinophilic syndrome incidence. J Allergy Clin Immunol. 2010;126:179–181.
5. Klion AD, Noel P, Akin C, et al. Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness. Blood. 2003;101:4660–4666.
6. Griffin JH, Leung J, Bruner RJ, Caligiuri MA, Briesewitz R. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:7830–7835.
7. Leiferman KM, Gleich GJ, Peters MS. Dermatologic manifestations of hypereosinophilic syndromes: review. Immunol Allergy Clin North Am. 2007;27(3):415–441.
8. Roufosse F, Cogan E, Goldman M. Lymphocytic variant hypereosinophilic syndromes. Immunol Allergy Clin North Am. 2007;27:389–413.
9. Van den Hoogenband HM. Skin lesions as the first manifestation of the hypereosinophilic syndrome. Clin Exp Dermatol. 1982;7(3):267–271.
10. Bain BJ. Eosinophilia—idiopathic or not? N Engl J Med. 1999;341(15):1141–1143.