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Familial Hemophagocytic Lymphohistiocytosis
Sunday, 31 August 2003
Sunday, 28 November 2004
FHL, FHLH

What

Familial Hemophagocytic Lymphohistiocytosis (FHL or FHLH) is an immune disorder characterized by uncontrolled activation of T cells, macrophages and NK (natural killer) cells, leading to a subsequent overproduction of inflammatory proteins (called cytokines). It is usually triggered by a viral infection and in most cases, the first signs include high fever, edema (swelling) and hepatosplenomegaly (enlarged liver and spleen).  The name may sound intimidating, but the word "familial" means that this form of the disease is inherited and passed on within families. It is used to differentiate between the two major forms of Hemophagocytic Lymphohistiocytosis - the primary form, FHL, and an acquired form, which develops secondary to abnormal activity of the immune system usually after the use of immunosuppressive therapy or infections.

"Hemophagocytic" means that the immune cells that normally destroy bacteria and viruses by engulfing them ("phago-"means to eat) are abnormally activated in the blood . "Lymphohistiocytosis" describes the fact that patients with active FHL have too many lymphocytes and histiocytes, both of which are white blood cells that help to fight infection and can cause inflammation (swelling, redness, heat, pain, and loss of function). When abnormally activated, these cells may also accumulate and damage a variety of organs such as the bone marrow, lymph nodes, liver, spleen, skin, membranes surrounding the brain, spinal cord or the brain.

Who

 

FHL is an autosomal recessive disease affecting about 1/50,000 births. It was originally thought to occur primarily in children under the age of 2, but we now understand that the disease may present itself in utero or in the first four decades of life.  Both males and females have roughly the same incidence of disease.  Patients from many different ethnicities can have FHL, but since FHL is an autosomal recessive disease, an increased incidence has been reported in ethnic groups where consanguinity is part of the cultural tradition. 

Signs and Symptoms

FHL may present itself in a variety of ways, mimicking a number of other diseases and thus making it difficult to diagnose. However, it commonly presents with early symptoms that include intermittent or constant fever more than 7 days, paleness, and hepatosplenomegaly (enlargement of the liver and spleen). In addition, neurological complications may be the dominant presentation of FHL, including irritability, a bulging fontanel (the soft spot between the bones in an infant's skull), neck stiffness, changes in muscle tone (either increased or decreased), convulsions and other nervous system abnormalities.  Laboratory studies show decreased cell counts - most commonly a decrease in platelets (thrombocytopenia)  and/or in red blood cells (anemia). Platelets help the blood clot, and red blood cells transport oxygen from the lungs to the organs.  Since other organ systems can be involved, affected patients may also have abnormal liver and hematologic labs as well.

Possible Causes

Studies have shown that FHL is "genetically heterogeneous", or that it may be caused by several different gene mutations.  There have been at least three different identified genes which, when mutated, cause 50-80% of FHL cases.  A gene located on chromosome 10 codes for perforin, a protein that is required not only for the lysis, or breakdown, of abnormal cells but also for the down-regulation of cellular immune activation. Thus, without perforin, there is abnormally increased immune activation and defective cytotoxic, or cellular killing, activity. The activated macrophages secrete large amounts of cytokines, or cellular signals, possibly causing the characteristic symptoms in FHL patients.  A second gene mutation was identified in a gene for a protein called MUNC 13-4.  This protein is involved in secretion of products from cells into the environment, and the mutation disrupts this release, leading to cellular dysfunction and dysregulation.  A third gene mutation has been identified in a gene that encodes a protein called syntaxin 11.  This protein is also involved in the release of the cellular contents into the environment.  Very often, then, patients first develop a viral infection (like Epstein Barr Virus or other herpes-type viruses) that stresses their body and triggers the HLH symptoms.  The disease is sometimes associated with other immunodeficiency syndromes, including Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type II, and X linked Lymphoproliferative Syndrome.

Diagnosis

:    It is often difficult to diagnose FHL, as its clinical presentation may be similar to a number of other diseases and the expected hallmark, hemophagocytosis, is commonly not found on the initial bone marrow examination.  The Histiocyte Society's HLH-2004 guidelines state that in order to diagnose the disease, patients must have either a genetic mutation known to cause the disease, or must have at least 5 of 8 following features:

  1. persistent fever without clear cause
  2. enlarged spleen
  3. cytopenia in 2 out of 3 cell lines (neutrophils, red blood cells, and/or platelets)
  4. elevated triglycerides or low fibrinogen
  5. hemophagocytosis noted in either the spinal fluid, bone marrow, spleen, or lymph nodes but without evidence of cancer
  6. low or absent activity of the natural killer cells
  7. elevated ferritin (a marker of inflammatory activity)
  8. elevated levels of soluble CD25 (also a marker of inflammatory cell activity)

It may also be useful to do head or abdominal CT scans to rule out other possible infectious or malignant causes that can also present with symptoms associated with FHL. 

It is extremely difficult to distinguish between a primary (familial) and secondary (acquired) form of HLH in each patient. However, onset at an early age is more suggestive of a familial form. Prenatal diagnosis of FHL can be achieved through genetic testing if the family's mutation has already been identified.

Treatment

The first aim of treatment is to induce remission of the disease.  Many of the medicines used in treatment of the disease include those used in organ transplantation to suppress the immune system or those that can kill the overactive T cells.  Control of the disease, if achieved, is temporary in the primary inherited form (FHL); the disease always returns sooner or later if treatment is discontinued.  The acquired form of the disease may ultimately resolve with treatment of the inciting stimulus and with management of the overactive immune system.  Standardized protocols are in place for treatment of FHL, including the "HLH-94" and "HLH-2004" protocols.

If a patient's disease can be well-controlled with medications, the patient would then benefit from bone marrow transplantation, which would be the definitive cure for the primary form of the disease.  Bone marrow transplantation does require that the patient is relatively healthy and not infected, and that a suitable donor can be identified; this process can be lengthy in time.  Immediately following transplantation, because of their extreme immune suppression, patients are still very susceptible to infections and to symptoms similar to the FHL symptoms, including fevers, anemias, and nervous system damage. 

Prognosis

Overall, the survival rate for children with FHL has improved during the last decade.  However, because it can be difficult to diagnose, children may already have severe and irreversible brain damage or invasive fungal infections by the time of diagnosis.  The prognosis for long-term survival largely depends upon the success of an appropriate bone marrow transplant.  Prior to the incident of chemotherapies used currently, 50% of patients died within the first month after diagnosis, and only 5% survived to a year after diagnosis.  However, with appropriate treatment and subsequent bone marrow transplantation, 50-70% of patients will be alive 5 years after diagnosis and have a near-normal long term prognosis. 

Connect with other parents

In the spirit of community and support, Madisons Foundation offers the unique service of connecting parents of children with rare diseases. If you would like to be connected to other parents of children with this disease, please fill out this brief form.

Weblinks

Histiocytosis Association of America

http://www.histio.org/

A well written, detailed website for parents, good links under "Online Library"- especially the personal websites, and informative medical articles.

E-medicine

http://author.emedicine.com/PED/topic745.htm

Comprehensive article on Lymphocytosis

Google Search for Familial Hemophagocytic Lymphohistiocytosis

References and Sources

Flipovich, AH (2006). "Hemophagocytic lymphohistiocytosis and related disorders,"  Curr Opin Allergy Clin Immuno 6:410-415. 

http://www.histio.org/

author.emedicine.com/PED/topic745.htm