Familial Haemophagocytic Lymphohistiocytosis

Familial Erythrophagocytic Lymphohistiocytosis, Primary Hemophagocytic Lymphohistiocytosis, FHL, FHLH

Familial haemophagocytic lymphohistiocytosis is a rare and life-threatening genetic condition where the immune system, instead of protecting the body, turns against it and attacks healthy organs.

Table of contents

• What is Familial Haemophagocytic Lymphohistiocytosis?
• Signs and Symptoms
• Causes and Inheritance
• How Common is It?
• Diagnosis
• Treatment and Management
• Outlook and Survival

What is Familial Haemophagocytic Lymphohistiocytosis?

Familial haemophagocytic lymphohistiocytosis (fHLH) is a severe genetic disorder that affects how the immune system works. The condition is defined by the presence of faulty genes that cause the immune system to become overactive.^[1] When someone has fHLH, certain white blood cells called T lymphocytes (a type of immune cell that normally fights infections) and macrophages (cells that engulf and destroy harmful substances) multiply excessively and begin attacking the body’s own organs instead of protecting them.^[1]

This overactivation leads to damage in several vital organs including the bone marrow, liver, spleen, and brain. The condition creates what doctors call a cytokine storm, where the immune system releases too many signaling proteins called cytokines, causing widespread inflammation throughout the body.^[3] These cells also destroy blood-producing cells in the bone marrow through a process called hemophagocytosis, which gives the condition its name.^[2]

• Bone marrow
• Liver
• Spleen
• Brain
• Lymph nodes
• Skin

Signs and Symptoms

Familial haemophagocytic lymphohistiocytosis usually presents as an acute and severe illness. The condition typically appears within the first months or years of life, though symptoms can sometimes develop later in childhood or even adulthood.^[1] The most common and consistent symptom is prolonged high fever that does not respond to antibiotics.^[1][4]

Common physical signs include an enlarged liver and spleen (hepatosplenomegaly). Many affected individuals also develop low blood cell counts called cytopenias, which means they have reduced numbers of different types of blood cells.^[1] This can lead to anemia (low red blood cells), which causes weakness and pale skin, and low platelets, which causes easy bruising and abnormal bleeding.^[2][4]

Additional symptoms may include rash and enlarged lymph nodes, though these are less common.^[1] Some people experience yellowing of the skin and eyes (jaundice) due to liver problems.^[3] Neurological symptoms can be particularly serious and may include irritability, seizures, abnormal muscle tone, impaired muscle coordination, delayed closure of skull bones in infants, neck stiffness, paralysis, blindness, and in severe cases, coma.^[2]

Laboratory tests typically show very high levels of ferritin (a protein that stores iron), elevated triglycerides (a type of fat in the blood), and low fibrinogen (a protein needed for blood clotting).^[1][6] In some cases, the condition can affect the heart, kidneys, and other organs. Affected individuals also have an increased risk of developing cancers of blood-forming cells such as leukemia and lymphoma.^[2]

Causes and Inheritance

Familial haemophagocytic lymphohistiocytosis is caused by genetic mutations that are present from birth. The condition is specifically defined by the presence of faulty variants in one of four genes: PRF1, STX11, STXBP2, or UNC13D.^[1] These genes provide instructions for making proteins that help the immune system destroy or deactivate lymphocytes that are no longer needed. By controlling the number of activated lymphocytes, these genes help regulate normal immune system function.^[2]

Approximately 40 to 60 percent of cases are caused by mutations in the PRF1 or UNC13D genes, while smaller numbers of cases result from mutations in the STX11 and STXBP2 genes.^[2] In some affected individuals, the genetic cause remains unknown. The gene mutations impair the body’s ability to regulate the immune system, resulting in the exaggerated immune response characteristic of this condition.^[2]

Familial HLH is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have mutations for the condition to develop.^[2] Parents of an individual with autosomal recessive fHLH each carry one copy of the mutated gene but typically do not show signs and symptoms of the condition. Each sibling of a child with familial HLH has a 25 percent chance of developing the disease, a 50 percent chance of carrying the defective gene without being affected, and a 25 percent chance of not being affected and not carrying the gene defect.^[6]

Although the genetic mutations are present from birth, symptoms usually develop when the immune system launches an exaggerated response to an infection. However, symptoms may also occur in the absence of infection.^[2]

How Common is It?

Familial haemophagocytic lymphohistiocytosis is a rare condition that occurs in approximately 1 in 50,000 individuals worldwide.^[2][3] These numbers appear to be increasing slightly, possibly due to improved detection and diagnosis of the disorder.^[3] The condition most commonly affects infants and young children, with approximately 70 percent of cases presenting before one year of age.^[6]

Diagnosis

Diagnosing familial haemophagocytic lymphohistiocytosis requires a combination of clinical findings and genetic testing. The diagnosis is established when a person with suggestive symptoms is found to have either two faulty copies of one of the four main genes (PRF1, STX11, STXBP2, or UNC13D) or, rarely, a specific type of variant in the STXBP2 gene.^[1]

Doctors use specific diagnostic criteria that were developed by medical research groups. These criteria include a combination of clinical signs and laboratory findings such as fever, enlarged liver and spleen, low blood cell counts, high ferritin levels, high triglyceride levels, low fibrinogen levels, and evidence of hemophagocytosis in bone marrow or other tissues.^[9]

Early genetic testing is crucial for identifying gene abnormalities, which is important for subsequent treatment decisions and understanding the prognosis.^[7] Familial HLH should be suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped.^[6]

Because symptoms of fHLH can be similar to severe infections or other conditions, careful evaluation by specialists is essential. Blood tests measure various markers of immune system activity and inflammation, and bone marrow examination may be performed to look for characteristic signs of the disease.^[2]

Treatment and Management

Treatment for familial haemophagocytic lymphohistiocytosis focuses on controlling the overactive immune response and ultimately providing a cure through stem cell transplantation. The standard approach involves using chemoimmunotherapy (medications that combine chemotherapy with immune-modulating drugs) to treat active disease, followed by allogeneic hematopoietic stem cell transplantation (HSCT), which is currently the only curative therapy.^[1]

Treatment regimens typically include medications containing etoposide, such as the HLH-94 and HLH-2004 protocols, followed by stem cell transplantation.^[1] In 2018, a targeted therapy called emapalumab, which blocks a specific immune protein called interferon-gamma, was approved for primary HLH and represents the first targeted therapy specifically for this condition.^[7]

Because of the severity of the disease, patients often require significant critical care support in intensive care units. This may include treatment for multi-organ dysfunction, management of infections, blood transfusions for low blood counts, and support for neurological complications.^[9]

The condition requires care from a team of specialists, including experts in blood disorders, immune system disorders, and stem cell transplantation. Early diagnosis and prompt initiation of treatment are essential for improving outcomes.^[7]

Outlook and Survival

Without treatment, familial haemophagocytic lymphohistiocytosis is usually fatal. The median survival in untreated infants who develop active disease is less than two months after the onset of symptoms.^[1] Progressive symptoms of fHLH, organ dysfunction, invasive infection, and bleeding account for the majority of deaths.^[1]

However, the outlook has improved significantly with modern treatment approaches. The use of newer chemoimmunotherapy protocols followed by allogeneic hematopoietic stem cell transplantation has substantially improved survival rates.^[1] If not detected and treated, primary HLH is usually fatal, typically within a few months. Even with treatment, the prognosis can be challenging unless a successful bone marrow transplant can be performed.^[3]

Early diagnosis through genetic testing, prompt initiation of appropriate therapy, and timely stem cell transplantation are all critical factors that influence the outcome. With successful treatment, including stem cell transplantation, many individuals can achieve long-term survival and go on to live full and meaningful lives.^[1]