Hemophagocytic Lymphohistiocytosis, Familial, 2

Alternative Names

  • FHL2
  • HPLH2
  • HLH2

Associated Genes

Perforin 1
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WHO-ICD-10 version:2010

Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism

OMIM Number

603553

Mode of Inheritance

Autosomal recessive

Gene Map Locus

10q22.1

Description

Familial hemophagocytic lymphohistiocytosis-2 (FHL2) is an autosomal recessive disorder of immune dysregulation with onset in infancy or early childhood. It is characterized clinically by fever, edema, hepatosplenomegaly, and liver dysfunction. Neurologic impairment, seizures, and ataxia are frequent. Laboratory studies show pancytopenia, coagulation abnormalities, hypofibrinogenemia, and hypertriglyceridemia. There is increased production of cytokines, such as gamma-interferon and TNF-alpha, by hyperactivation and proliferation of T cells and macrophages. Activity of cytotoxic T cells and NK cells is reduced, consistent with a defect in cellular cytotoxicity. Bone marrow, lymph nodes, spleen, and liver show features of hemophagocytosis. Chemotherapy and/or immunosuppressant therapy may result in symptomatic remission, but the disorder is fatal without bone marrow transplantation. [From OMIM]

Epidemiology in the Arab World

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Other Reports

Oman

Al-Lamki et al. (2003) conducted a nationwide study on all patients diagnosed with HLH in Oman during the 5-year period 1997-2001. They reported the clinical presentations and outcomes of 13 children diagnosed with FHL and the study group (mean age at presentation was 60 days SD 130 days) consisted of five boys and eight girls. Consanguinity was present in 11 patients, and positive family history was present in seven of them (two had unexplained neonatal deaths among their siblings). All children had persistent fever, pallor and splenomegaly, 11 had enlarged liver, and four had diffuse cervical, axillary and inguinal lymph nodes enlargement (one child had stridor due to an enlarged cervical node). Clinical bleeding (skin and mucous membrane) was the initial presentation of two patients, while seven others had it during their course of illness, and it was the terminal event in six patients. Five out of nine, who had laboratory evidence of CNS disease at presentation, had neurological signs. All patients had hypoalbuminemia, hyperferritinemia, hypertriglyceridemia, and signs of bone marrow hemophagocytosis, while lymph node and cerebrospinal fluid hemophagocytosis was present in some patients. Low fibrinogen was detected in 10 patients. Eight patients had high transaminase levels, and 10 had pancytopenia (three had bicytopenia). TORCH and EBV serology studies were negative in all patients. A total of eleven patients died during the course of the illness; nine of them before starting treatment. In none of the patients could an infectious cause be identified. Ten children were referred late in the disease course, and the concern about starting chemotherapy before exclusion of an acute viral infection resulted in delayed treatment in some patients. Two children were started early on the HLH-94-therapy followed by successful BMT in one child. In the successfully transplanted child, the response to intrathecal hydrocortisone appeared to be better than standard therapy with intrathecal methotrexate. The other received a haplo-identical transplant and developed secondary rejection of her father's stem cells, but her condition improved and was in remission. Finally, a novel missense mutation in the perforin gene was identified in 2 patients and their family members, causing a transition of proline to threonine at codon 89. Since the novel perforin mutation has been reported in only 2 patients from Oman, and since similar polymorphism in the sequencing data of the members of their families has been identified, a founder effect is possible in this population. Al-Lamki et al. (2003) concluded that early diagnosis and treatment of this disease is important with considering intrathecal corticosteroids in patients with refractory CNS disease.

Saudi Arabia

Elyamany et al., (2016) conducted a study between January 2005 and December 2014 in Saudi Arabia to analyze the data of hemophagocytic lymphohistiocytosis patients.  Mutations in the PRF1 gene were identified in two patients.  Both patients received the HLH-2004 treatment protocol.  One of these patients was born to consanguineous parents and had a positive family history of the condition.  He was alive at the age of 4-months at the time of reporting.  The other patient died as a result of relapsed disease at the age of 3-months.

In a retrospective study, Awan et al. 2013 analysed case histories of ten patients with hemophagocytic lymphohistiocytosis (HLH) seen at Pediatric Hematology/Oncology in Tawam Hospital, UAE between 2006 and 2012. All patients had prolonged fever, splenomegaly, and cytopenia, and 50% of patients displayed central nervous system-related symptoms. A Saudi patient (male, 8 months) was identified with mutation in PRF1  gene, which is associated with hemophagocytic lymphohistiocytosis, familial, 2.

 

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