Aggressive CD8+ epidermotropic cutaneous T-cell lymphoma associated with homozygous mutation in SAMHD1 CASE SERIES Aggressive CD81 epidermotropic cutaneous T-cell lymphoma associated with homozygous mutation in SAMHD1 Miesha Merati, DO, a Douglas J. Buethe, MD, b Kevin D. Cooper, MD, b Kord S. Honda, MD, b Heng Wang, MD, c,d and Meg R. Gerstenblith, MD b Richmond Heights, Cleveland, and Middlefield, Ohio From of Me Me Ne Ra Fund Confl Corre De Me Key words: cutaneous T-cell lymphoma; SAM domain and HD domainecontaining protein 1. Abbreviations used: AGS: Aicardi-Goutieres syndrome CTCL: cutaneous T-cell lymphoma SAMHD1: SAM domain and HD domain- containing protein 1 SAMS: stroke, aneurysm, moyamoya, and stenosis SLE: systemic lupus erythematosus INTRODUCTION Mutations in the SAMHD1 (SAM domain and HD domainecontaining protein 1) gene are impli- cated in SAMS (stroke, aneurysm, moyamoya, and stenosis) association,1,2 also described as Aicardi- Goutieres syndrome type 5 (AGS-5). 3 We present a patient with homozygous germline mutations in SAMHD1 who subsequently had a CD81 aggressive epidermotropic cutaneous T-cell lymphoma (CTCL). CASE REPORT A 29-year-old Amish woman with intellectual disability and arthritis caused by the homozygous mutation c.1411-2A [ G in the SAMHD1 gene (identified by Xin et al1), presented with fever, cervical lymphadenopathy, and a diffuse rash. The rash began 8 weeks before presentation and consisted of reddish-brown scaly plaques on the chest, abdomen, and back, which were treated with topical steroids by her primary physician. She then became acutely ill and was admitted to the medical intensive care unit of our institution for circulatory shock and hypoxemic respiratory failure. On examination by the dermatology service, the patient had diffuse, red-brown, circinate, coalescing, scaly plaques involving the trunk, proximal extrem- ities, and face (Fig 1, A). A 3-cm 3 3-cm red-purple, exophytic tumor was noted on the right posterior thigh (Fig 1, B). Joint examination found deformities of the bilateral hands without active synovitis. Laboratory evaluation was notable for normocytic University Hospitals Richmond Medical Center a ; Department Dermatology, Case Western Reserve University School of dicine, UH Seidman Cancer Center, University Hospitals Case dical Center, Clevelandb; DDC Clinic, Center for Special eds Children, Middlefield c ; and Department of Pediatrics, inbow Babies and Children’s Hospital, Cleveland. d ing sources: None. icts of interest: None declared. spondence to: Meg R. Gerstenblith, MD, Department of rmatology, Case Western Reserve University School of dicine, UH Seidman Cancer Center, University Hospitals anemia, thrombocytopenia, elevated erythrocyte sedimentation rate, elevated C-reactive protein, positive antinuclear antibodies with 1:10,240 titer, positive antiedouble-stranded DNA antibodies, and positive antichromatin antibodies. Blood, lower respiratory, and urine cultures were negative. Computed tomography of the neck, chest, abdomen, and pelvis showed bilateral pulmonary infiltrates and cervical, axillary, retroperitoneal, and gastro- hepatic lymphadenopathy. Skin biopsy from the abdomen showed significant exocytosis of lymphocytes with mildly enlarged hyperchromatic nuclei without significant cyto- plasm. Some lymphocytes were surrounded by clear halos. There was also a moderate superficial and mid-dermal interstitial and periadnexal lymphocytic infiltrate (Fig 2). Flow cytometry from affected skin found a population of atypical T cells (32% of all events) that were CD21, CD31, CD4�, CD71, CD81, CD25dim, CD26dim, CD56dim, CD30�, HLA-DR�, CD45RO�, and CD45RA�. The cells were T-cell Case Medical Center, Cleveland, OH 44106. E-mail: Meg.Gersten blith@uhhospitals.org. JAAD Case Reports 2015;1:227-9. 2352-5126 � 2015 by the American Academy of Dermatology, Inc. Published by Elsevier, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc- nd/4.0/). http://dx.doi.org/10.1016/j.jdcr.2015.05.003 227 Delta:1_given name Delta:1_surname Delta:1_given name Delta:1_surname Delta:1_given name Delta:1_surname mailto:Meg.Gerstenblith@uhhospitals.org mailto:Meg.Gerstenblith@uhhospitals.org http://creativecommons.org/licenses/by-nc-nd/4.�0/ http://creativecommons.org/licenses/by-nc-nd/4.�0/ http://dx.doi.org/10.1016/j.jdcr.2015.05.003 Fig 1. Aggressive CD81 epidermotropic CTCL. Cutaneous findings on initial presentation from the abdomen (A) and right posterior thigh (B). Fig 2. Aggressive CD8 1 epidermotropic CTCL. Histopa- thology from lesional skin shows significant exocytosis of normal-size atypical lymphocytes. The lymphocytes stain with antibodies against CD3 and CD45RB, without significant CD4 or CD8 staining. (Hematoxylin-eosin stain; original magnification: 340.) JAAD CASE REPORTS JULY 2015 228 Merati et al receptor (TCR)-a/b positive and did not react with any antibodies used in the TCR-Vb analysis, consis- tent with an abnormal clonal T-cell population. Peripheral blood flow cytometry found no evidence of a peripheral lymphoproliferative disorder. TCR-g chain gene rearrangement from affected skin was negative. Based on these results, an aggressive CD81 epidermotropic CTCL was diagnosed. Lymph node biopsy was declined, as it would not change management, and because of severe thrombocyto- penia, it represented an unnecessary risk to the patient. The patient’s family declined treatment with systemic chemotherapy, and she subsequently died under hospice care. DISCUSSION SAMS association was first described in the Old Order Amish in 2011. The clinical phenotype is highly heterogeneous, ranging from normal cogni- tive development to severe intellectual impairment and early death from recurrent strokes.1 It is likely that AGS-5 and SAMS association might be the same entity,3 although most patients from the Amish cohort, particularly the mildly affected patients, do not fit the clinical spectrum of AGS-5.2 The clinical features of AGS-5 include progressive encephalopa- thy, basal ganglia calcification, white matter changes, and cerebrospinal fluid abnormalities of lymphocy- tosis and elevated interferon alfa levels.4-6 The SAMHD1 protein degrades the intracellular pool of deoxynucleoside triphosphates, maintaining genomic stability and the innate immune system.7 SAMHD1 is upregulated in response to viral infections and is a restriction factor for HIV-1 infection.8 Absence of SAMHD1 causes an imbalance in DNA precursors, which acts as a danger signal to the innate immune system, triggering a type I interferon immune response.7 Activation of the innate immune system plays a central role in SAMS association/AGS-5 and may lead to autoimmunity. Many of the symptoms of SAMS association overlap with autoimmune conditions such as vasculitis, systemic lupus erythematosus (SLE), rheumatoid arthritis, and mixed connective tissue disease, and AGS is associated with systemic autoimmunity and SLE.1,6 Our patient met 4 of 11 American College of Rheumatology classification criteria required for the diagnosis of SLE (arthritis, thrombocytopenia, positive antinuclear antibodies and antiedouble-stranded DNA antibodies). Genomic instability caused by SAMHD1 muta- tions may lead to increased mutagenesis and cancer development. SAMHD1 somatic mutations have been identified in 11% of refractory cases of chronic lymphocytic leukemia and in lung adenocarcinoma; JAAD CASE REPORTS VOLUME 1, NUMBER 4 Merati et al 229 glioblastoma; and breast, pancreatic, and colorectal cancers. Recently, Clifford et al8 and de Silva et al9 found decreased SAMHD1 expression in 8 patients with Sezary syndrome and 1 with advanced-stage mycosis fungoides. Aggressive CD81 epidermotropic CTCL is a rare subtype associated with a poor prognosis. Median expected lifespan from diagnosis is 22.5 to 33 months, with an 18% chance of 5-year survival. Tumor markers CD2� and CD71 appear to predict a more aggressive clinical course.10 Our patient’s CTCL was CD21 and CD71. Although CD81 CTCL is often clonal,10 our patient did not have TCR-g gene rearrangement. Potential explanations include insufficient representation of the clone, genetic instability leading to deletion of portions of the TCR-g gene, or other unknown factors. The absence of prior reports of CTCL in patients with homozygous mutations of SAMHD1 could relate to the rarity of AGS-5 or SAMS association and the reduced lifespan caused by recurrent cerebrovascular accidents seen in these patients. Along with de Silva et al,9 our case provides further evidence for a possible link between SAMHD1 deficiency and CTCL. Additional studies to further characterize the role of SAMHD1 in the pathogenesis of CTCL are indicated. Author Contributions: Drs Gerstenblith and Merati, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Drs Merati, Buethe, Cooper, Honda, Wang, Gerstenblith Acquisition, analysis, and interpretation of data: Drs Merati, Buethe, Cooper, Honda, Wang, Gerstenblith Drafting of the manuscript: Drs Merati, Buethe, Cooper, Honda, Wang, Gerstenblith Critical revision of the manuscript for important intellectual content: Drs Merati, Buethe, Cooper, Honda, Wang, Gerstenblith REFERENCES 1. Xin B, Jones S, Puffenberger EG, et al. Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke. Proc Natl Acad Sci. 2011;108(13):5372-5377. 2. Xin B, Li W, Bright A, Hinze C, Wang H. Reply to du Moulin, et al. Cerebral vasculopathy is a common hallmark in individuals with SAMHD1 mutations. Proc Natl Acad Sci. 2011;108(26): E233. 3. Rice GI, Bond J, Asipu A, et al. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009;41(7): 829-832. 4. Thiele H, du Moulin M, Barczyk K, et al. Cerebral Arterial Stenoses and Stroke: Novel Features of Aicardi-Gouti�eres Syndrome Caused by the Arg164X Mutation in SAMHD1 Are Associated with Altered Cytokine Expression. Hum Mutat. 2010;31(11):E1836-E1850. 5. Ramesh V, Bernardi B, Garone C, et al. Intracerebral large artery disease in Aicardi-Gouti�eres syndrome implicates SAMHD1 in vascular homeostasis. Dev Med Child Neurol. 2010;52(8): 725-732. 6. Ramantani G, Kohlhase J, Hertzberg C, et al. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Gouti�eres syndrome. Arthritis Rheum. 2010;62: 1469-1477. 7. Kretschmer S, Wolf C, K€onig N, et al. SAMHD1 prevents autoimmunity by maintaining genome stability. Ann Rheum Dis. 2015;74(3):e17. 8. Clifford R, Louis T, Robbe P, et al. SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage. Blood. 2014;123(7):1021-1031. 9. de Silva S, Wang F, Hake TS, Porcu P, Wong HK, Wu L. Downregulation of SAMHD1 expression correlates with promoter DNA methylation in S�ezary syndrome patients. J Invest Dermatol. 2014;134(2):562-565. 10. Berti E, Tomasini D, Vermeer MH, Meijer CJ, Alessi E, Willemze R. Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphomas: a distinct clinicopathological entity with an aggressive clinical behavior. 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