Acta Dermato-Venereologica 99-1CompleteContent | Page 28

105 SHORT COMMUNICATION Novel Compound Heterozygous Mutations in RAG1 in a Patient with Cutaneous Lymphoproliferative Disease Cong-cong XU # , Zhi-ming CHEN # , Jing-shu XIONG, Lu GAN, Ying ZHANG, Hao CHEN* and Jian-fang SUN Department of Pathology, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing 210042, China. *E-mail: [email protected] #These authors contributed equally to this work. Accepted Sep 18, 2018; Epub ahead of print Sep 18, 2018 Severe combined immunodeficiency (SCID) is cha- racterized by absent or non-functional T and B cells. A series of different genetic variants are known to cause SCID. Mutations in recombinase activating genes 1 and 2 (RAG1 and RAG2) are the most common mutations of T-B-NK+ SCID (1). During the development of T and B cells, these genes are responsible for the rearrangements of the variable, diversity and joining segments of T- and B-cell receptors (2). The first case of SCID caused by mutation in RAG1 was reported in 1996 by Schwarz et al. (3). Mutations at RAG1 located within human 11p13 chromosome result in many kinds of primary immuno- deficiency diseases, including SCID, Omenn syndrome (OS) and selective immunoglobulin A deficiency (SIgAD) (4). We described here a patient who was diagnosed with SCID with cutaneous lymphoproliferative diseases caused by novel mutations in RAG1. CASE REPORT A 5-year-old boy was referred to our clinic with a 3-year history of asymptomatic infiltrated erythematous plaques on his trunk and limbs. He was otherwise healthy, except for frequent upper respiratory tract infections. His parents are not close relatives. Phy- sical examination revealed multiple, asymptomatic, dull-coloured and irregular-shaped infiltrated erythematous plaques with a dry surface located on the trunk and limbs, and ulcerating erythemas or plaques with scab on his extremities (Fig. 1). Other physical examination was notable for mild hepatomegaly. Blood counts demonstrated lymphopaenia (1,008 cells/mm 3 ). IgA level (0.06 g/l) was decreased significantly. A significant reduction in T and B lymphocytes was revealed by flow cyto- metry analysis (Table I). Routine laboratory tests, such as ANA, anti-dsDNA antibody, ENA and T-SPOT tests, were all normal. Epstein–Barr virus DNA was not detected in plasma. Bone mar- row biopsy investigation was normal. A biopsy from the plantar skin showed hyperkeratosis and focal infiltration of lymphocytes with minimal atypia in the upper and middle dermis (Fig. S1 1 ). Table I. Lymphocyte subsets of the patient Items Patient Normal range CD3+, % CD3+CD4+, % CD3–CD19+, % CD3–CD56+, % 25 16 4 60 55–82 27–57 10–29 10–40 These cells were stained positively by CD4, CD5, CD20, CD56, CD68, CD79a, TIA-1 and GrB, but were negative for CD8, CD30 and CD31. The fraction of Ki-67 positive cells was 40%. The pathological diagnosis was lymphoproliferative disease (LPD). To investigate the genetic mutations in RAG1, we amplified DNA extracted from whole blood of the patient and family members who provided informed consent. Direct sequencing of the RAG1 amplification product identified novel compound heterozygous mutations in RAG1. Five heterozygous mutations were found at the cDNA positions of 813(c.813T>A), 870(c.870G>A), 2219(c.2219C>T), 2583(c.2583A>G) and 6440(c.6440G>A) in the patient. The patient’s father has 3 heterozygous mutations at cDNA positions, including 813(c.813T>A), 870(c.870G>A) and 6440(c.6440G>A) located in the RAG1. Sequence analysis also showed that the RAG1 of the patient’s mother was hete- rozygous for 2219(c.2219C>T) mutation and homozygous for 2583(c.2583A>G) and 6440(c.6440G>A) mutations. The RAG1 of the patient’s uterine sister was homozygous for 2583(c.2583A>G) and 6440(c.6440G>A) mutations (Fig. S2 1 ). The patient was treated with a combination of prednisone and methotrexate and is preparing for hematopoietic stem cell transplant. DISCUSSION Primary immunodeficiency disease (PID) is a group of clinical syndromes characterized by the deficiency of immune organs, immune cells or immune reactive mole- cules caused by gene mutations. According to the update https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-3042 1 Fig. 1. Clinical pictures of the patient with severe combined immunodeficiency. (a, b) Dull-coloured, irregular-shaped infiltrated erythematous plaques located on the patient’s limbs. (c) Ulcers with scab on the patient’s feet. This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3042 Acta Derm Venereol 2019; 99: 105–106