Paediatric Immunology Department, Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, London, United Kingdom.
Immunology Unit, Marqués De Valdecilla University Hospital, Santander, Spain.
Front Immunol. 2023 Jun 12;14:1186575. doi: 10.3389/fimmu.2023.1186575. eCollection 2023.
Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is associated with biallelic variants in , comprising a multisystemic disease characterized by steroid resistant nephrotic syndrome, primary adrenal insufficiency, neurological problems, skin abnormalities and immunodeficiency in described cases. Signal transducer and activator of transcription 1 (STAT1) plays an important role in orchestrating an appropriate immune response through JAK-STAT pathway. Biallelic loss of function (LOF) variants lead to STAT1 deficiency with a severe phenotype of immunodeficiency with increased frequency of infections and poor outcome if untreated.
We report novel homozygous SGPL and variants in a newborn of Gambian ethnicity with clinical features of SPLIS and severe combined immunodeficiency. The patient presented early in life with nephrotic syndrome, severe respiratory infection requiring ventilation, ichthyosis, and hearing loss, with T-cell lymphopenia. The combination of these two conditions led to severe combined immunodeficiency with inability to clear respiratory tract infections of viral, fungal, and bacterial nature, as well as severe nephrotic syndrome. The child sadly died at 6 weeks of age despite targeted treatments.
We report the finding of two novel, homozygous variants in and in a patient with a severe clinical phenotype and fatal outcome early in life. This case highlights the importance of completing the primary immunodeficiency genetic panel in full to avoid missing a second diagnosis in other patients presenting with similar severe clinical phenotype early in life. For SPLIS no curative treatment is available and more research is needed to investigate different treatment modalities. Hematopoietic stem cell transplantation (HSCT) shows promising results in patients with autosomal recessive STAT1 deficiency. For this patient's family, identification of the dual diagnosis has important implications for future family planning. In addition, future siblings with the familial variant can be offered curative treatment with HSCT.
鞘氨醇磷酸酶缺乏症（SPLIS）与 中的双等位基因变异有关，包括一种多系统疾病，其特征为类固醇耐药性肾病综合征、原发性肾上腺功能不全、神经问题、皮肤异常和免疫缺陷。信号转导和转录激活因子 1（STAT1）通过 JAK-STAT 途径在协调适当的免疫反应中发挥重要作用。双等位基因 的功能丧失（LOF）变异导致 STAT1 缺乏，表现为严重的免疫缺陷表型，感染频率增加，如果未经治疗则预后不良。
我们报道了一名冈比亚血统新生儿的新型 SGPL1 和 纯合变异，其具有 SPLIS 和严重联合免疫缺陷的临床特征。该患者在生命早期即出现肾病综合征、需要通气的严重呼吸道感染、鱼鳞病和听力损失，伴有 T 细胞淋巴细胞减少。这两种情况的结合导致严重联合免疫缺陷，无法清除病毒、真菌和细菌性质的呼吸道感染，以及严重的肾病综合征。尽管进行了靶向治疗，但该患儿在 6 周大时不幸死亡。
我们报告了一名具有严重临床表型和早期致命结局的患者中 和 的两个新型纯合变异。该病例强调了在生命早期出现类似严重临床表型的其他患者中，完成原发性免疫缺陷基因谱的重要性，以避免漏诊第二种诊断。对于 SPLIS，目前尚无治愈方法，需要更多研究来探讨不同的治疗方法。造血干细胞移植（HSCT）在常染色体隐性 STAT1 缺陷患者中显示出良好的效果。对于该患者的家庭，双重诊断的确定对未来的家庭规划具有重要意义。此外，携带家族性 变异的未来兄弟姐妹可以通过 HSCT 获得治愈性治疗。
