Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of the immune system primarily affecting young infants and children, although it can develop for the first time at any age. According to a large, population-based study published in Sweden, it was estimated to occur in 1.2 cases per million children, which corresponds to 1 in 50,000 births. However, this number must be considered minimal, as there are probably many patients today who are not diagnosed. For the autosomal-recessive forms of HLH (FHL), there is believed to be an equal number of males and females diagnosed with this disease. In addition, there are two known X-linked forms of FHL, affecting only males.
HLH involves over-production and activation of normal infection-fighting cells called histiocytes and T cells. In contrast, often NK (natural killer) cell function is decreased. Decreased NK function is related to the consequence of genetic mutations which cause HLH. HLH is often referred to as either the “primary” form which is hereditary, or the “secondary” form associated with infections, viruses, autoimmune diseases, and malignancies (or cancers).
In the primary form, also known as familial hemophagocytic lymphohistiocytosis (FHL or FHLH), defective genes are inherited from either both parents (autosomal recessive) or from the mother alone. Since 1999, five genes have been identified which correspond with five subtypes of autosomal recessive HLH. The genes are PRF1 (perforin), MUNC13-4, STX11 (Syntaxin), STXBP2, and RAB27A. PRF1 encodes the protein (or toxin) normally involved in “killing” or eliminating abnormal immune cells. The proteins encoded by the other four genes facilitate the delivery of perforin to the cells which are to be killed.
While great progress has been made through research in recent years to define these genes, there remains a considerable proportion of FHL patients with as yet unknown underlying gene defects.
Onset of disease occurs under the age of 1 year in an estimated 70% of cases. FHL is suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. Each full sibling of a child with FHL has a 25% chance of developing the disease, a 50% chance of carrying the defective gene (which is very rarely associated with any risk of disease), and a 25% chance of not being affected and not carrying the gene defect.
So-called “secondary HLH” is often diagnosed in older patients, and there is no family history of this disease. It may be associated with vaccinations, viral infections such as Epstein-Barr, cytomegalovirus (CMV), or herpes virus, and other underlying diseases, principally autoimmune disorders and cancers, as mentioned previously.
It is difficult to know whether a patient has primary or secondary HLH on the basis of symptoms, which may be very similar. Therefore, genetic testing is usually recommended in order to make the proper diagnosis, regardless of age.
The first description of HLH was published in 1952, but it has only been in recent years that it has received more widespread attention. In 1985, physicians from around the world who were interested in studying the histiocytic disorders gathered in Philadelphia and formed the Histiocyte Society. Funds raised by the Histiocytosis Association, as well as national subgroups, have financed research that has led to significant breakthroughs in the diagnosis and treatment of HLH during the past 15 years. As awareness and understanding of this disease have increased worldwide, the diagnosis and survival rates have improved significantly. However, HLH remains a rapidly progressive disease requiring effective immunosuppressive and anti-inflammatory therapy.
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