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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