Type I Neurofibromatosis Associated with Hypereosinophilic Syndrome: A Rare Case Report

Yu-Qing Hu, Xue Chen, Jian-Zhong Zhang?

Department of Dermatology, Peking University People’s Hospital, Beijing 100044, China.

Introduction

Hypereosinophilic syndrome(HES) encompasses a group of disorders characterized by marked peripheral blood eosinophilia, tissue eosinophilia, or both, resulting in organ damage attributable to the eosinophilia. Type I neurofibromatosis (NF-I) is an autosomal dominant genodermatosis with an increased risk of developing malignancies.1HES was also considered as paraneoplastic presentation and it is proved to arise in combination with hematological malignancies such as chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL),and non-Hodgkin lymphoma (NHL).2Here, we have reported a rare case of HES associated with NF-I that has not been reported so far, which may improve the knowledge of association between NF-1 and hematological malignancies.

Case report

A 44-year-old woman had a history of multiple brown patches and soft tumors since birth (Fig. 1). During the past 4 years, she had developed pruritic papules on her face, neck,trunk, and limbs. In the past 15 days, she had also developed a fever and slight pain in both axillary regions. She denied a history of either allergic diseases(such as allergic rhinitis and asthma) or contact with parasites. Her mother and sister had neurofibromatosis(Fig. 2).

Upon physical examination,multiple soft brown tumors and multiple café-au-lait patches were found over her trunk and extremities.Dermatitis was found on her lower extremities. Egg-sized lymph nodes were palpable in the axillary region with tenderness.

Laboratory tests showed the following results: white blood cell (WBC) count, 33.77×109/L; peripheral blood eosinophil count, 3.50×109/L (10.4%); C-reactive protein level, 19mg/L; serum total IgE level, ＞2,500IU/mL;and lactate dehydrogenase level,331U/L.The cytokeratin 19 and progastrin-releasing peptide levels were both normal. Antinuclear antibody was negative. B-Ultrasonography showed multiple enlarged lymph nodes in the axillary region, cervical region, hepatic hilar region, and pulmonary hilar region. Chest computed tomography revealed multiple enlarged hilar lymph nodes as well as nodular infiltration and ground-glass opacities in the left lower lung field. Histopathological examination of a skin lesion showed dermal infiltration of eosinophils and lymphocytes between collagen bundles and in perivascular areas(Fig.3).Immunohistochemistry of the lesion showed the following results:CD3(+),CD20(+),CD68(+),CD31(-), CD34 (+), Ki67 (10%+), MPO (-), and SMA (+)(Fig. 4). No tumor cells were found. Bone marrow aspiration showed hypereosinophilia (6.5% of nucleated cells)without dysplasia.No monoclonal tumor cells were found by flow cytometry. Reverse-transcriptase polymerase chain reaction of bone marrow revealed negativity for both theFIP1L1/PDGFRAfusion gene andBCR-ABLfusion gene.

The patient was diagnosed with HES associated with NF-I and treated with prednisone at 15mg/day and topical halometasone cream. Her lesions and pruritus improved rapidly, and her body temperature returned to normal.However,her WBC and eosinophil counts remained high and her dermatitis was not relieved after 1 week of treatment.Therefore,the dose of prednisone was increased to 20mg/day,and azathioprine at 100mg/day was added.Seven days later,her WBC count decreased to 28.60×109/L and her eosinophil count decreased to 2.07×109/L.Her dermatitis and pruritus were obviously alleviated.The size of the mass in her axillary region significantly decreased,and the pain was also relived.This patient was still under follow-up at the time of this writing.

Figure 1. Clinical images of the patient.(A)Multiple soft brown tumors and oval café-au-lait papules were seen over the trunk and extremities.(B)Dermatitis was present on the lower extremities. (C) Egg-sized lymphadenopathy was present in the right axillary region.

Figure 2. Pedigree of family with neurofibromatosis. The filled symbols represent affected individuals.

Discussion

We have herein reported a case of NF-I associated with HES. No other cases of HES associated with NF-I have been reported to date. Neurofibromatosis is a syndrome that is inherited in an autosomal-dominant manner and produces developmental changes in the nervous system,bones, and skin.1It can be divided into two types: NF- I and NF-II. In NF-I, which accounts for ＞85% of cases,patients have many neurofibromas,café-au-lait spots,and axillary freckles.The patient in this case had multiple caféau-lait macules that measured ＞15mm and neurofibromas. Her mother and sister also had neurofibromatosis.Thus,our patient satisfied the diagnostic criteria for NF-I as established at the Health Consensus Development Conference on Neurofibromatosis 1.

Figure 3. Histopathology of the biopsy sample (hematoxylin and eosin, ×400). (A) Infiltration of eosinophils and lymphocytes was present around small vessels in the dermis.The black arrows indicate eosinophils.(B)Infiltration of eosinophils and lymphocytes around small vessels.

Figure 4. Immunohistochemistry of the skin lesion (400×). (A) CD3(+). (B) CD20(+). (C) CD68(+). (D) CD34(+). (E) SMA(+). (F) Ki67(10%+).

HES consists of a group of disorders characterized by abnormal accumulation of eosinophils in the blood or peripheral tissue.2A diagnosis of HES has three initial requirements: (1) persistent eosinophilia of ＞1,500cells/mm3for ＞6 months(or death before 6 months associated with signs and symptoms of hypereosinophilic disease);(2)no evidence of secondary causes of eosinophilia such as allergic diseases,parasite infection,or malignancy;and(3)organ damage secondary to eosinophilia, including damage to the skin, heart, lungs, gastrointestinal tract,or nervous system. HES is divided into three subtypes3:myeloproliferative HES,lymphocytic HES,and idiopathic HES. In myeloproliferative HES, eosinophil clonality and interstitial deletion on the 4q12 chromosome result in fusion of the FIP1qL1 and PDGFRa genes. The fusion protein and elevated tryptase level with myeloid precursors can promote the proliferation of hematopoietic cells,which may contribute to leukemia.Lymphocytic HES has been found to be associated with circulating T-cell clones of the CD4+ phenotype with Th2 cytokines. These Th2 cytokines may stimulate the proliferation of eosinophils in both the peripheral blood and bone marrow, which may contribute to T-cell lymphoma.Finally,idiopathic HES is diagnosed in patients who cannot be easily classified as having either myeloproliferative or lymphocytic HES.The early stage of myeloproliferative and lymphocytic HES may be diagnosed as idiopathic HES because of negative results regarding fusion genes and monoclonal tumor cells.In the present case, the laboratory tests and skin biopsy showed an elevated eosinophil count in the peripheral blood, skin lesions, and bone marrow for more than 6 months. The patient also had symptoms of other organ damage secondary to eosinophilia,including the skin,liver,and lungs.She had no other evidence of secondary causes such as allergic disease or parasite infection.Hematological malignancies,especially eosinophilic leukemia and lymphoma, were suspected because of her elevated peripheral eosinophil count and multiple enlarged lymph nodes.However, her lymph node tenderness and enlargement improved significantly after systemic glucocorticoid treatment, and no tumor cells were found in the skin biopsy.Thus,the lymph node enlargement was considered to have been caused by systemic involvement of HES.Additionally,she was negative for FIP1qL1/PDGFRa fusion genes and had a normal phenotype of CD4+T-cell clones.Therefore,the diagnosis of idiopathic HES was eventually established.

NF-I is a common neurocutaneous disorder caused by mutation of the NF-I gene.4Its protein product, neurofibromin, is a negative regulator of cell proliferation and differentiation and functions as a tumor suppressor.Walker et al.5analyzed 448 individuals with NF-I for a total of 5,705 years of follow-up.They concluded that the overall risk of cancer was 2.7 times higher in this cohort of patients with NF-I than in the general population,including individuals with hematological malignancy.The increased risk of hematological malignancy in patients with NF-I is enigmatic because it is one of the few malignancies associated with NF-I that does not primarily involve cells derived from the neural crest.The association might be elucidated by further study of chromosomal abnormalities, such as loss of heterozygosity of the NF-I allele in the bone marrow. However, the explicit association is still unknown. Chusid et al.3described a continuum in hypereosinophilic diseases with hematological malignancies, such as eosinophilic leukemia, existing as myeloproliferative disorders at one pole of the spectrum. Song and Park6reported a patient with eosinophilic leukemia associated with neurofibromatosis,confirming the association between NF-I and HES. These findings suggest that mutation of the NF-I gene may contribute to the proliferation of hematopoietic cells such as eosinophils, leading to eosinophilic leukemia or HES.Regrettably,the patient in the present case refused further examination of mutation of the NF-I gene and chromosome. HES has also been considered as a paraneoplastic presentation7; therefore, this patient still needs further follow-up in case a hematological malignancy develops in the future. However, the causative relationship between these two disorders remains unclear,and the possibility of coincidence cannot be excluded. Further studies on mechanism are needed.