A Novel RAC2 Variant Presenting as Severe Combined Immunodeficiency.
A Novel RAC2 Variant Presenting as Severe Combined Immunodeficiency.
复制标题
一种表现为严重联合免疫缺陷的新型 RAC2 变体。
DOI：
10.1007/s10875-020-00915-2
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发表时间：
2021
影响因子：
9.1
通讯作者：
Andreae,DoertheAdriana
中科院分区：
文献类型：
--
作者：
Stern,Heather;Donkó,Agnes;Shapiro,Teresa;Hsu,AmyP;Leto,ThomasL;Holland,StevenM;Andreae,DoertheAdriana
An absence of both neutrophils and T cells is highly suspicious for reticular dysgenesis (RD), a type of SCID, caused by an adenylate kinase 2 (AK2) mutation. Recently, patients with this clinical presentation but normal AK2 have been reported and were found to have missense mutations in the RAC2 gene [1]. Recent reports on RAC2 mutations have widened our understanding of the clinical presentations that range from the newborn period into adulthood. Reported patients present with varying degrees of lymphopenia and neutrophil dysfunction. To date, there are 17 reported patients with RAC2 mutations. Two patients were diagnosed in infancy with dominant loss-of-function mutations [2, 3], two siblings with homozygous null mutations [4], and 13 patients with activating mutations [1, 5–8]. Unique to this cohort are 3 patients who presented as newborns with a severe phenotype of frequent infections and profound leukopenia. These patients were found to have severe bone marrow involvement caused by a dominant RAC2 activating mutation, p. G12R [1]. We report a novel RAC2 mutation, p. Q61R, presenting as a severe immunodeficiency in the newborn period. This is the 18th reported patient with a RAC2 mutation. A 2-day-old male infant presented with temperature instability and hyperbilirubinemia and subsequently underwent a sepsis work-up at which time agranulocytosis and severe lymphopenia without associated anemia or thrombocytopenia were noted. Infection was ruled out. Further work-up revealed severe leukopenia involving both neutrophils and lymphocytes; severe T, B, and NK cell lymphopenia undetectable IgM; and decreased proportion of naive CD4+ T cells (Table 1). An initial chest x-ray showed the absence of a thymus but no other pathology. Initial newborn screen for TRECS was indeterminate as was a repeat screen. Bone marrow biopsy revealed a virtually absent myeloid lineage with maturing erythroblasts and megakaryocytes. SCID was suspected, and a primary immunodeficiency gene sequencing panel was sent to Cincinnati Children’s Hospital. Reticular dysgenesis was considered as a possible diagnosis given agranulocytosis in addition to lymphopenia, but the patient did not have evidence of sensorineural hearing loss and ultimately did not have a defect in AK2. Along with several other variants of uncertain significance, the heterozygous RAC2 missense variant, c. 182 A> G, p. Q61R, was detected. Following parental testing, this variant was determined to be a de novo event. Patient received a reduced intensity conditioning regimen: busulfan based on pharmacokinetics× 2 (day− 8 and− 7), fludarabine 30 mg/m2/dose× 5 doses on days− 7 to− 3, rabbit thymoglobulin 3 mg/kg/day× 3 doses on days− 4 to− 2. The patient received a bone marrow stem cell transplant (4.0× 108 MNC/kg of bone marrow) from his 10/10 antigen-matched brother. The GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil.
