Familial hemophagocytic lymphohistiocytosis

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Familial hemophagocytic lymphohistiocytosis is a disorder in which the immune system produces too many activated immune cells (lymphocytes) called T cells, natural killer cells, B cells, and macrophages (histiocytes). Excessive amounts of immune system proteins called cytokines are also produced. This overactivation of the immune system causes fever and damages the liver and spleen, resulting in enlargement of these organs.

Familial hemophagocytic lymphohistiocytosis also destroys blood-producing cells in the bone marrow, a process called hemophagocytosis. As a result, affected individuals have low numbers of red blood cells (anemia) and a reduction in the number of platelets, which are involved in clotting. A reduction in platelets may cause easy bruising and abnormal bleeding.

The brain may also be affected in familial hemophagocytic lymphohistiocytosis. As a result, affected individuals may experience irritability, delayed closure of the bones of the skull in infants, neck stiffness, abnormal muscle tone, impaired muscle coordination, paralysis, blindness, seizures, and coma. In addition to neurological problems, familial hemophagocytic lymphohistiocytosis can cause abnormalities of the heart, kidneys, and other organs and tissues. Affected individuals also have an increased risk of developing cancers of blood-forming cells (leukemia and lymphoma).

Signs and symptoms of familial hemophagocytic lymphohistiocytosis usually become apparent during infancy, although occasionally they appear later in life. They usually occur when the immune system launches an exaggerated response to an infection, but may also occur in the absence of infection. Without treatment, most people with familial hemophagocytic lymphohistiocytosis survive only a few months.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Familial hemophagocytic lymphohistiocytosis may be caused by mutations in any of several genes. These genes provide instructions for making proteins that help destroy or deactivate lymphocytes that are no longer needed. By controlling the number of activated lymphocytes, these genes help regulate immune system function.

Approximately 40 to 60 percent of cases of familial hemophagocytic lymphohistiocytosis are caused by mutations in the PRF1 or UNC13D genes. Smaller numbers of cases are caused by mutations in other known genes. In some affected individuals, the genetic cause of the disorder is unknown.

The gene mutations that cause familial hemophagocytic lymphohistiocytosis impair the body's ability to regulate the immune system. These changes result in the exaggerated immune response characteristic of this condition.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Familial hemophagocytic lymphohistiocytosis occurs in approximately 1 in 50,000 individuals worldwide.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormality of serum cytokine level · Very frequent (99-80%)

Abnormality of the cytokine levels in the blood, i.e., an abnormality of any of the non-antibody proteins made by inflammatory leukocytes and some non-leukocytic cells that affect the behavior of other cells.

Abnormality of tumor necrosis factor secretion · Very frequent (99-80%)

An abnormality in the production or cellular release of tumor necrosis factor.

Anemia · Very frequent (99-80%)

A reduction in erythrocytes volume or hemoglobin concentration.

Elevated circulating hepatic transaminase concentration · Very frequent (99-80%)

Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.

Fever · Very frequent (99-80%)

Body temperature elevated above the normal range.

Hemophagocytosis · Very frequent (99-80%)

Phagocytosis by macrophages of erythrocytes, leukocytes, platelets, and their precursors in bone marrow and other tissues.

Hypoalbuminemia · Very frequent (99-80%)

The concentration of albumin in the blood circulation is below the lower limit of normal.

Immune dysregulation · Very frequent (99-80%)

Altered immune function characterized by lymphoid proliferation, immune activation, and excessive autoreactivity often leading to autoimmune/inflammatory complications.

Increased circulating ferritin concentration · Very frequent (99-80%)

Increased concentration of ferritin in the blood circulation.

Increased serum interferon-gamma level · Very frequent (99-80%)

An elevation in the concentration of interferon gamma measured in the blood circulation.

Thrombocytopenia · Very frequent (99-80%)

A reduction in the number of circulating thrombocytes.

Abnormality of multiple cell lineages in the bone marrow · Very frequent (99-80%)

Abnormal natural killer cell physiology · Frequent (79-30%)

Abnormal response of natural killer (NK) cells to stimuli.

Abnormal renal physiology · Frequent (79-30%)

An abnormal functionality of the kidney.

Other findings in the same source

From: Orphanet

Additional reported features include Abnormal skin morphology (Frequent (79-30%)); Abnormality of the coagulation cascade (Frequent (79-30%)); Abnormality of the respiratory system (Frequent (79-30%)); CSF pleocytosis (Frequent (79-30%)); Decreased liver function (Frequent (79-30%)); Decreased total neutrophil count (Frequent (79-30%)); Ecchymosis (Frequent (79-30%)); Erythroderma (Frequent (79-30%)); Hepatomegaly (Frequent (79-30%)); Hypertriglyceridemia (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Familial hemophagocytic lymphohistiocytosis is Allergy and Immunology, with a allergist / clinical immunologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the history suggest an allergy, an immune problem or another explanation?
• How would any proposed allergy or immune test change care?
• Is an individual emergency plan needed, and who should understand it?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.