Division of General Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University Southern California, 4650 West Sunset Boulevard, Los Angeles, CA 90027, USA.
Clin Immunol. 2012 Nov;145(2):102-7. doi: 10.1016/j.clim.2012.07.016. Epub 2012 Aug 7.
Familial hepatic veno-occlusive disease with immunodeficiency (VODI, OMIM: 235550), a rare form of severe combined immune deficiency, was first described in Australian Lebanese patients as being associated with homozygous mutations in SP110, a gene encoding a PML nuclear body-associated protein. We present the first case of confirmed VODI in the United States, and identify the first novel missense mutation in SP110. The 3-year-old daughter of Hispanic parents without known consanguinity presented at age 5 months with fever, hepatomegaly, and pancytopenia. Her brother died at age 3 months from hepatic failure of undetermined etiology. Initial T- and B-cell counts were low, but eventually normalized. Serum IgG and IgM levels were low for age. Lymphoproliferation to mitogens and allogenic B-cells was normal, but absent to tetanus and candida antigens. Serum antibody levels against pneumococcal, Hib and tetanus antigens were low. Liver biopsies at ages 5 and 9 months were consistent with hepatic veno-occlusive disease or hVOD (also known as sinusoidal obstruction syndrome or SOS) and broncho-alveolar lavage detected Pneumocystis jiroveci. The patient recovered from her acute disease and has been clinically stable on immunoglobulin replacement therapy and trimethoprim-sulfamethoxazole prophylaxis. T-Cell receptor excision circle (TREC) analysis suggests that VODI will not be detected by newborn screening for severe combined immunodeficiency that relies on this assay. DNA was obtained from the patient, 4 siblings, and both parents, and SP110 was sequenced. The first missense mutation, a homozygous deletion/insertion variation in exon 2 (NM_080424.2 (SP110):c.78_79delinsAT) was detected in the patient. This novel mutation segregated in the heterozygous state in other living unaffected family members. The mechanism by which this SP110 mutation associates with VODI is consistent with the normal length mutated SP110 protein being subject to enhanced proteosome degradation resulting in marked reductions in SP110 protein.
家族性肝静脉闭塞病伴免疫缺陷（VODI，OMIM：235550），一种罕见的严重联合免疫缺陷形式，最初在澳大利亚黎巴嫩患者中被描述为与 SP110 纯合突变相关，SP110 是一种编码 PML 核体相关蛋白的基因。我们报告了美国首例确诊的 VODI 病例，并鉴定了 SP110 中的第一个新的错义突变。这例 3 岁的西班牙裔女孩，父母无近亲结婚，在 5 月龄时出现发热、肝肿大和全血细胞减少。她的哥哥在 3 月龄时死于病因不明的肝衰竭。初始 T 细胞和 B 细胞计数较低，但最终恢复正常。血清 IgG 和 IgM 水平低于年龄。对有丝分裂原和同种异体 B 细胞的淋巴增殖正常，但对破伤风和念珠菌抗原无反应。血清抗肺炎球菌、Hib 和破伤风抗原抗体水平较低。5 月龄和 9 月龄时的肝脏活检符合肝静脉闭塞病或 hVOD（也称为窦状隙阻塞综合征或 SOS），支气管肺泡灌洗液中发现卡氏肺孢子虫。该患者从急性疾病中恢复，在免疫球蛋白替代治疗和复方磺胺甲噁唑预防的基础上临床稳定。T 细胞受体切除环（TREC）分析表明，严重联合免疫缺陷的新生儿筛查不会检测到 VODI，该筛查依赖于该检测。从患者、4 个兄弟姐妹和父母获得 DNA，并对 SP110 进行测序。在患者中发现了第一个错义突变，即外显子 2 中的纯合缺失/插入变异（NM_080424.2（SP110）：c.78_79delinsAT）。该新突变在其他存活的未受影响的家族成员中呈杂合状态。该 SP110 突变与 VODI 相关的机制与正常长度的突变 SP110 蛋白易受增强的蛋白酶体降解一致，导致 SP110 蛋白明显减少。
