Allogeneic hematopoietic stem cell transplant for familial hemophagocytic lymphohistiocytosis: a case report and literature review.

This study aims to discuss the clinical manifestations and treatment of Familial hemophagocytic lymphohistiocytosis (FHL) caused by a mutation in the UNC13D gene. A 6-year-old female child presented with unexplained febricity, splenomegaly, pancytopenia, hemophagocytic lymphohistiocytosis in bone marrow, decreased NK cell activity, soluble CD25 levels > 44000ng/ml. Genetic sequencing revealed a mutation in the UNC13D gene. Additionally, the patient experienced intermittent fever with seizures characterized by involuntary twitching of the left upper limb. Head magnetic resonance imaging (MRI) showed white matter lesions. According to the HLH-2004 diagnostic criteria revised by the International Society of Histiocytosis the patient was diagnosed with FHL. Despite receiving HLH-2004 treatment, the disease relapsed. However, after a salvage allogeneic Hematopoietic Stem Cell Transplant (HSCT), febricity, abnormal blood cells, and neurological symptoms significantly improved. Prompt performance of allogeneic HSCT is crucial upon diagnosis of FHL, especially when neurological involvement is present.

Bingjie L ，Linlin Z ，Futian M ，Fan X ，Huan D ，Wu X ，Zhou L ，Fuxu W ，Xuejun Z ，Ying W ... -  《Frontiers in Immunology》

Familial Hemophagocytic Lymphohistiocytosis secondary to UNC13D mutation: a report of two cases.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by some clinical signs (e.g., non-remitting fever, hepatosplenomegaly) and laboratory findings (e.g., cytopenia, increased ferritin level, hypofibrinogenemia, lipid disorders, coagulopathy, and multiple organ failure). Depending on the etiology, HLH is divided into familial (i.e., primary) and acquired (i.e., secondary) forms. Familial HLH (FHL), an autosomal recessive condition, is classified into five subtypes based on underlying genetic defects. The PRF1, STX11, UNC13D, HPLH1, and STXBP2 are the most well-known genes of this type which are related to granule-mediated cytotoxic T and Natural killer (NK) cells. The treatment is based on the HLH-2004 protocol. The current report presents two cases of HLH with presentations different from each other and previously reported cases. Case 1 was a 15-month-old boy with fever, skin rash, splenomegaly, and bicytopenia, raised triglyceride levels, AST (aspartate transaminase), and ALT (alanine aminotransferase), normal ferritin, and abundant hemophagocytic cell in bone marrow aspiration. He was diagnosed with HLH and received HLH protocol as treatment. The patient had a homozygous intronic mutation; NM_199242: c.2448-13G > A in UNC13D. The associated disease was Familial Hemophagocytic Lymphohistiocytosis 3 (FHL3). Case 2, a 37-day-old female presented with fever, a history of neonatal cholestasis, and huge hepatosplenomegaly. Her whole-exome sequencing report manifested that the patient had the same mutation as case 1. Unfortunately, both patients passed away. The sequencing of the entire UNC13D gene (coding and non-coding regions) is an applicable and valuable diagnostic procedure for the detection of deep intronic splicing variants and large inversions in patients with atypical manifestations of HLH (such as normal ferritin or triglyceride and cholesterol).

Sadeghi P ，Esslami GG ，Rokni-Zadeh H ，Changi-Ashtiani M ，Mohsenipour R ... -  《BMC Pediatrics》

Fatal sibling cases of familial hemophagocytic lymphohistiocytosis (FHL) with MUNC13-4 mutations: case reports.

Nakao T ，Shimizu T ，Fukushima T ，Saito M ，Okamoto M ，Sugiura M ，Yamamoto K ，Ueda I ，Imashuku S ，Kobayashi C ，Koike K ，Tsuchida M ，Sumazaki R ，Matsui A ... -  《-》

Clinical features, genetics, and outcome of pediatric patients with hemophagocytic lymphohistiocytosis in Korea: report of a nationwide survey from Korea Histiocytosis Working Party.

We analyzed a nationwide registry of pediatric patients with hemophagocytic lymphohistiocytosis (HLH) in Korea to assess the clinical and genetic features and treatment outcomes in pediatric HLH. The Korea Histiocytosis Working Party retrospectively analyzed data on 251 pediatric patients diagnosed with HLH between 1996 and 2011. In the study cohort, 25 cases were categorized with familial HLH, 64 with presumed secondary HLH, and 162 with unspecified HLH. Of 217 evaluable patients, 91 (42%) had concomitant Epstein-Barr virus infection. Of 238 evaluable patients, central nervous system (CNS) involvement, which was more frequent in the familial group, was evident in 81 cases (34%). Genetic tests revealed a predominant UNC13D mutation with a high incidence of two recurrent splicing mutations (c.118-308C>T and c.754-1G>C). The 5-yr overall survival rate was 68% (38% in the familial group and 81% in the presumed secondary group). The 5-yr overall survival rate among 32 patients who underwent allogeneic hematopoietic stem cell transplantation was 64%. In multivariate analysis, a younger age at diagnosis, severe transaminasemia, and a coagulation abnormality were independent prognostic factors for survival. Responses during initial treatments were also significant indicators of outcome. Our study showed the unique predominance of a UNC13D mutation and vulnerability to Epstein-Barr virus infection in Korean children with HLH and emphasizes the prognostic significance of age, liver dysfunction, and treatment responses in this disease. A multicenter prospective trial that builds on the present results is warranted to identify subgroups of patients with a poor prognosis and identify optimal treatments.

Koh KN ，Im HJ ，Chung NG ，Cho B ，Kang HJ ，Shin HY ，Lyu CJ ，Yoo KH ，Koo HH ，Kim HJ ，Baek HJ ，Kook H ，Yoon HS ，Lim YT ，Kim HS ，Ryu KH ，Seo JJ ，Korea Histiocytosis Working Party ... -  《-》

The occurrence and treatment of hemophagocytic lymphohistiocytosis caused by multiple factors: a case report and literature review.

Zhuo W ，Hao D ，Tong Y ，Wu W ，Bao S ，Huang K ，Ling Y ，Zhu H ，Sun Z ... -  《-》