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Q1. Hemophagocytic lymphohistiocytosis (HLH) is a syndrome describing patients with severe systemic hyperinflammation. Which of the following statements are WRONG? (1) Characteristic features include unremitting fever, cytopenias, hepatosplenomegaly, and elevation of typical HLH biomarkers. (2) Patients can develop rash, hepatitis, coagulopathy and liver failure. (3) Central nervous system involvement is rarely in patients with HLH. (4) The first genetic cause of familial HLH to be discovered was MYCN, which encodes perforin. (5) HLH can also develop in patients during infections without a known (or as-yet-identified) genetic predisposition.

  • (A) 1+2
  • (B) 1+3+5
  • (C) 1+4
  • (D) 3+4
  • (E) 2+4+5
點此顯示正解

(D) 3+4

詳解

The correct answer is (D) 3+4 — statements 3 and 4 are WRONG.

Analysis of Each Statement:

Statement 1 (TRUE): Characteristic features include unremitting fever, cytopenias, hepatosplenomegaly, and elevation of typical HLH biomarkers. This accurately describes the HLH-2004 diagnostic criteria, which require 5 of 8 findings including fever ≥38.3°C, splenomegaly, bicytopenia, and elevated biomarkers such as ferritin, triglycerides, and soluble CD25126.

Statement 2 (TRUE): Patients can develop rash, hepatitis, coagulopathy, and liver failure. These are well-recognized manifestations of HLH. The syndrome can cause hepatitis, coagulopathy, liver failure, and multiorgan failure6. Hypofibrinogenemia (coagulopathy) is one of the HLH-2004 diagnostic criteria2.

Statement 3 (FALSE): Central nervous system involvement is NOT rare in HLH — it is actually common. CNS involvement occurs in approximately 50% of primary HLH patients[^9]. In one pediatric cohort, 50% of primary HLH patients had CNS involvement compared to 25.3% of secondary HLH patients[^9]. CNS manifestations include cranial nerve injury (81.8%), seizures (77.3%), ataxia (63.6%), encephalopathy (59.1%), and limb paralysis (40.9%)[^10]. CNS involvement is associated with worse prognosis, with 3-year overall survival of 53.8% in patients with CNS involvement versus 94.4% without[^9].

Statement 4 (FALSE): The first genetic cause of familial HLH was PRF1 (not MYCN), which encodes perforin. In 1999, Stepp et al. reported that gene defects in PRF1 were the underlying cause of familial HLH[7][8]. MYCN is an oncogene associated with neuroblastoma and is completely unrelated to HLH. The four genes causing familial HLH are PRF1, UNC13D, STX11, and STXBP2, which encode proteins essential for lymphocyte cytotoxicity[^7].

Statement 5 (TRUE): HLH can develop during infections without a known genetic predisposition. This describes secondary HLH, which can occur in patients during infections (especially EBV) or malignancies without an identified genetic defect6. Secondary HLH is distinct from familial HLH and can be triggered by various infectious, malignant, or rheumatologic conditions16.

詳解 · 中文翻譯

正確答案是 (D) 3+4 — 敘述 3 和 4 是錯誤的。

每個敘述的分析：

敘述 1（真實）： 特徵特徵包括持續發熱、細胞減少症、肝脾腫大和典型 HLH 生物標誌物的升高。這準確描述了 HLH-2004 診斷標準，要求 8 個發現中的 5 個，包括發熱 ≥38.3°C、脾腫大、兩系減少症和升高的生物標誌物，如鐵蛋白、三酸甘油酯和可溶性 CD25126。

敘述 2（真實）： 患者可能發展出皮疹、肝炎、凝血病和肝衰竭。這些是 HLH 的公認表現。該綜合症可導致肝炎、凝血病、肝衰竭和多器官功能衰竭6。低纖維蛋白血症（凝血病）是 HLH-2004 診斷標準之一2。

敘述 3（假）： 中樞神經系統受累不是罕見的 — 實際上是常見的。中樞神經系統受累發生於約 50% 的原發性 HLH 患者[^9]。在一項兒科隊列中，50% 的原發性 HLH 患者有中樞神經系統受累，而 25.3% 的繼發性 HLH 患者[9]。中樞神經系統表現包括顱神經損傷（81.8%）、癲癇發作（77.3%）、共濟失調（63.6%）、腦病（59.1%）和四肢麻痺（40.9%）[10]。中樞神經系統受累與較差的預後相關，在有中樞神經系統受累的患者中 3 年總體生存為 53.8%，而無中樞神經系統受累為 94.4%[^9]。

敘述 4（假）： 家族性 HLH 的第一個遺傳原因是 PRF1（不是 MYCN），其編碼 perforin。在 1999 年，Stepp 等人報告 PRF1 中的基因缺陷是家族性 HLH 的基礎原因[7][8]。MYCN 是與神經母細胞瘤相關的原癌基因，與 HLH 完全無關。導致家族性 HLH 的四個基因是 PRF1、UNC13D、STX11 和 STXBP2，其編碼對淋巴細胞細胞毒性至關重要的蛋白質[^7]。

敘述 5（真實）： HLH 可在無已知遺傳易感性的感染期間發展。這描述了繼發性 HLH，可在患者無已識別遺傳缺陷的感染（特別是 EBV）或惡性腫瘤期間發生6。繼發性 HLH 不同於家族性 HLH，可由各種傳染性、惡性或風濕學條件觸發16。

參考文獻 (AMA)

  1. Henter JI. Hemophagocytic Lymphohistiocytosis. The New England Journal of Medicine. 2025;392(6):584-598. doi:10.1056/NEJMra2314005. PMID:39908433. ↩↩↩↩

  2. Jordan MB, Allen CE, Greenberg J, et al. Challenges in the Diagnosis of Hemophagocytic Lymphohistiocytosis: Recommendations From the North American Consortium for Histiocytosis (NACHO). Pediatric Blood & Cancer. 2019;66(11):e27929. doi:10.1002/pbc.27929. PMID:31339233. ↩↩↩↩

  3. Canna SW, Marsh RA. Pediatric Hemophagocytic Lymphohistiocytosis. Blood. 2020;135(16):1332-1343. doi:10.1182/blood.2019000936. PMID:32107531. ↩

  4. Zhao C, Zhang Q, Zhang R, et al. Genetic and Clinical Characteristics of Primary Hemophagocytic Lymphohistiocytosis in Children. Annals of Hematology. 2024;103(1):17-28. doi:10.1007/s00277-023-05499-6. PMID:37851074. ↩

  5. You Y, Wu W, Li B. Familial Hemophagocytic Phohistiocytosis Induced by PRF1 Mutation With Neurologic Manifestations as the Initial Clinical Presentations: A Case Report. Medicine. 2023;102(26):e34198. doi:10.1097/MD.0000000000034198. PMID:37390248. ↩

  6. Jordan MB. Hemophagocytic Lymphohistiocytosis: A Disorder of T Cell Activation, Immune Regulation, and Distinctive Immunopathology. Immunological Reviews. 2024;322(1):339-350. doi:10.1111/imr.13298. PMID:38100247. ↩↩↩↩↩↩↩↩

Slide annotations

Familial hemophagocytic lymphohistiocytosis (fHLH), defined as the presence of biallelic pathogenic variants in one of four genes (PRF1, STX11, STXBP2, or UNC13D)

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