What is Familial Haemophagocytic lymphohistiocytosis Syndrome?

Familial Hemophagocytic Lymphohistiocytosis : Risks and Complications

Familial Hemophagocytic Lymphohistiocytosis Syndrome (fHLH) is a rare, often life-threatening immune disorder caused by genetic mutations that impair immune regulation, leading to severe inflammation and tissue damage. HLH, the broader term, may be inherited or acquired, with secondary HLH—triggered by infections or cancer—being more common. Ongoing research aims to better understand and prevent this serious condition.

What are the types of haemophagocytic lymphohistiocytosis syndrome?

Hemophagocytic Lymphohistiocytosis Syndrome can be of two types:

1. Familial or Primary (fHLH) : When a genetic predisposition is involved, Familial Hemophagocytic Lymphohistiocytosis Syndrome occurs. It is rare and mostly appears within the first few years of life. Adults rarely develop symptoms of fHLH.
2. Secondary (HLH) : If underlying medical conditions, such as infections and cancer, are the reasons for developing symptoms of HLH syndrome, it is secondary HLH.

According to research, approximately 75% of patients are diagnosed with secondary HLH, and only 25% are patients with the primary (fHLH). It is equal to 1 in every 50,000 people globally.

What are the symptoms of familial hemophagocytic lymphohistiocytosis syndrome?

Some common symptoms of familial hemophagocytic lymphohistiocytosis syndrome (fHLH) and hemophagocytic lymphohistiocytosis (HLH) are as follows:

1. Rashes in different parts of the body, including the scalp, trunk, face and upper chest.
2. Prolonged, high fever that does not respond to antibiotics.
3. Enlarged lymph nodes indicate a hyperactive immune response.
4. Enlarged spleen and liver are known as hepatosplenomegaly.

Including these, other symptoms of Hemophagocytic Lymphohistiocytosis Syndrome (HLH) include neurological disorders, dizziness, digestive issues, anaemia, jaundice, irritability and headaches.

What is the cause of fHLH?

Familial Hemophagocytic Lymphohistiocytosis (fHLH) is a part of HLH and is caused by genetic predispositions. Mutations in genes such as PRF1 (perforin), UNC13D, STX11, STXBP2, and RAB27A disrupt the function of cytotoxic T-cells and natural killer (NK) cells. Specifically, these mutations impair the pathway these cells use to kill infected or abnormal cells (perforin-mediated cytotoxicity). This failure to kill target cells and terminate an immune response leads to uncontrolled activation of immune cells and a massive, damaging release of inflammatory cytokines.

What is the cause of HLH?

HLH can sometimes be acquired. The following are some of the causes of Hemophagocytic Lymphohistiocytosis Syndrome (HLH):

1. Viral, bacterial and fungal infections
2. Strong immune triggers
3. Cancer
4. Epstein-Barr Virus
5. Autoinflammatory disease
6. Juvenile idiopathic arthritis or rheumatological diseases
7. Autoimmune conditions
8. Disorders in metabolism

What are the complications of fHLH and HLH?

The following are some common complications of fHLH and HLH:

1. Organ Damage : When there is inflammation and a hyperactive immune response, overproduction of cytokines and immune cells occurs. These cells infiltrate and damage organs such as the liver, spleen, bone marrow and brain.
2. Abnormalities in Blood : Since fHLH interrupts the normal functions of the immune system, it often causes damage to the blood cells of the bone marrow. As a consequence, conditions such as hypofibrinogenemia and pancytopenia occur.
3. Cancer Risk : Both fHLH and HLH can cause widespread inflammation in the body, which might damage various body parts. This can trigger risks of blood cancers such as leukaemia and lymphoma.

How is Familial Hemophagocytic Lymphohistiocytosis Syndrome Diagnosed?

Based on the patient's symptoms, the medical professionals conduct a series of tests to diagnose FHLH:

1. Physical examination
2. Genetic tests (prenatal genetic testing)
3. Blood tests
4. Bone marrow biopsy
5. Liver function tests

What is the Best Treatment for HLH?

Initial therapy almost always involves high-dose corticosteroids (e.g., Dexamethasone) to rapidly control the systemic inflammation. The following are some of the best treatment methods for HLH:

1. Allogeneic Haematopoietic Stem Cell Transplant (alloSCT) : Allogeneic haematopoietic stem cell transplant (alloSCT) helps to treat the primary form of HLH. The same can be applied to patients with secondary HLH as well. In this treatment method, medical professionals replace damaged stem cells with healthy blood-forming stem cells acquired from a donor.
2. Etoposide : The first-line treatment for HLH, both familial and severe secondary, is immunochemotherapy based on the HLH-94 protocol (or its successor, HLH-2004). This includes etoposide, a chemotherapy drug that suppresses the hyperactive and proliferating immune system by killing rapidly dividing cells, including the activated T-cells and macrophages driving the disease. Dexamethasone (a potent steroid) is used concurrently to suppress inflammation.

Except for these treatment processes, doctors use certain medications such as antivirals and antibiotics to reduce the hyperactivity of the immune system. Additionally, blood transfusion and chemotherapy are some of the most effective treatment methods for HLH.

As a genetic disorder, familial HLH cannot be prevented by lifestyle changes. The cornerstone of management is early diagnosis and preparation for curative treatment with hematopoietic stem cell transplant (HSCT). For all forms of HLH, prompt identification and treatment of infections are crucial, as they can trigger severe flares.

Furthermore, early diagnosis and relevant treatment plans, such as stem cell transplants, effectively cure familial haemophagocytic lymphohistiocytosis syndrome. It is the only way to prevent the recurrence of fHLH and HLH. However, if the condition is left untreated, it can turn fatal.