Familial hemophagocytic lymphohistiocytosis (FHL) is a condition that is usually diagnosed in infants. In a minority of cases, the condition manifests later in childhood or adulthood [1].

FHL is also referred to as primary hemophagocytic lymphohistiocytosis and is a genetic disease inherited in an autosomal recessive pattern. It has been reported more frequently in children of consanguineous parents. Most cases of FHL results from mutations in the PRF1 (perforin 1) and UNC13D (unc-13 homolog D) genes [2]. It is a contrast compared to secondary hemophagocytic lymphohistiocytosis, which is often triggered by an inflammatory process such as an infection, malignancy, or by a low immunity. Manifestations result from the abnormal function of macrophages and T lymphocytes [3]. The condition may prove fatal if untreated.

Because FHL affects numerous organ systems, there is a wide range of possible presenting manifestations. The typical clinical characteristics of FHL are a prolonged fever that is accompanied by hepatomegaly, elevated liver enzymes, cytopenias, and less commonly, a rash and lymphadenopathy. About half of patients have abnormal cerebrospinal fluid (CSF) findings [4]. Neurological signs have also been described and can include increased or decreased tone, seizures, ataxia, cranial nerve palsies, and signs of raised intracranial pressure. Patients may also exhibit a reduced level of consciousness, neck stiffness, and loss of vision. Another defining feature of the disease is the phagocytosis of several lines of blood cells in the bone marrow by overactive histocytes.

In older individuals, the course of the illness may be acute, or gradual and recurrent, with some episodes resolving spontaneously. It is not uncommon for FHL to be misdiagnosed as an infection, as it can manifest with non-specific symptoms. Moreover, FHL has been reported to sometimes occur together with infections such as those caused by the herpes virus or Leishmania parasites [5].

The diagnosis of familial hemophagocytic lymphohistiocytosis is based on the clinical picture and genetic testing to detect mutations [6]. Family history is important as patients may have siblings with the same disease, or siblings who died of an obscure illness or infection. Furthermore, if there is parental consanguinity, the diagnosis of FHL is even more likely. Clinical criteria as stipulated by the Histocyte Society must be met [7]. According to the criteria, at least five of a given list of possible signs and symptoms should be present, namely prolonged fever lasting over 7 days, cytopenia of multiple blood lineages observed through peripheral smear, low hemoglobin, platelets or neutrophils, raised triglyceride levels, splenomegaly, fibrinogen less than 1.5 g/L, and hemophagocytosis.

Further investigations that can be carried out include:

• CSF analysis: This may show an increased number of inflammatory cells as well as high protein content.
• Bone marrow analysis: Rules out leukemia, which is one of the main differential diagnoses.
• Blood tests: Elevated plasma ferritin and D-dimers support the diagnosis of FHL.
• Magnetic resonance imaging (MRI): There are certain features on MRI that, if observed, are suggestive of FHL. These include inflammatory lesions in the brain, demyelination, intracranial hemorrhage, generalized atrophy, and brain edema [8].
• Computed tomography (CT) and ultrasonography: These imaging techniques may detect ascites, pleural effusions, and other changes that can take place in FHL.

The disease typically presents within the first year of life, however, cases of late presentations are being reported more frequently [9]. Some literature suggests that the presence of fever, splenomegaly, and thrombocytopenia is enough to suspect FHL if leukemia has been eliminated as a possible alternative diagnosis [10].

Treatment of HLH aims to suppress the overactive immune response and address any underlying causes. Initial treatment often involves immunosuppressive therapy, such as corticosteroids and chemotherapy drugs like etoposide. In some cases, immunotherapy with drugs like anakinra or tocilizumab may be used. For patients with familial HLH or those who do not respond to initial treatment, hematopoietic stem cell transplantation (HSCT) may be considered as a curative option.

The prognosis for HLH varies depending on the underlying cause, the patient's response to treatment, and the timeliness of diagnosis. Without treatment, HLH can be rapidly fatal. However, with appropriate therapy, many patients can achieve remission. Familial HLH often requires more aggressive treatment and may have a poorer prognosis without stem cell transplantation. Early diagnosis and intervention are crucial for improving outcomes.

HLH can be classified into primary (familial) and secondary forms. Primary HLH is caused by genetic mutations that affect the immune system's ability to regulate itself. Secondary HLH can be triggered by infections (such as Epstein-Barr virus), malignancies (like lymphomas), or autoimmune diseases (such as systemic lupus erythematosus). In some cases, the exact trigger remains unknown.

HLH is a rare condition, with an estimated incidence of 1 in 50,000 to 1 in 100,000 children per year. It is less common in adults, but awareness is increasing. Familial HLH typically presents in infancy or early childhood, while secondary HLH can occur at any age. The condition affects both males and females and occurs worldwide, with no specific ethnic predilection.

The pathophysiology of HLH involves a dysregulated immune response. Normally, the immune system activates to fight infections and then calms down. In HLH, this regulation fails, leading to persistent activation of immune cells called macrophages and T-lymphocytes. These cells release inflammatory substances called cytokines, causing widespread inflammation and damage to organs and tissues.

Currently, there are no specific measures to prevent HLH, especially in cases of familial HLH due to genetic mutations. However, early recognition and treatment of infections, malignancies, or autoimmune diseases that could trigger secondary HLH may help reduce the risk. Genetic counseling may be beneficial for families with a history of familial HLH.

Hemophagocytic Lymphohistiocytosis is a rare but serious condition characterized by an overactive immune response. It can be inherited or acquired and presents with a range of symptoms that can mimic other diseases. Early diagnosis and treatment are crucial for improving outcomes. Treatment involves immunosuppressive therapy and, in some cases, stem cell transplantation. Understanding the underlying cause is essential for managing the condition effectively.

If you or a loved one is experiencing symptoms such as persistent fever, fatigue, or unexplained enlargement of the liver or spleen, it is important to seek medical evaluation. HLH is a complex condition that requires specialized care. Treatment is available and can be effective, especially when started early. If you have a family history of HLH, consider discussing genetic testing and counseling with your healthcare provider.

1. Zhang K, Jordan MB, Marsh RA, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118(22):5794-5798.
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3. Feldmann J, Le Deist F, Ouachee-Chardin M, et al. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol. 2002;117(4):965-972.
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10. Sieni E, Cetica V, Santoro A, et al. Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis type 3. J Med Genet. 2011;48(5):343-352.