How is HLH diagnosed?
It is sometimes difficult to establish the diagnosis of HLH, and the combination of the clinical picture and certain laboratory test criteria is required. A test that has been found very useful in substantiating a clinical diagnosis of HLH is absent or low NK (natural killer)-cell function. This is found in 90% of patients with FHL, as well as in many cases of secondary disease. Results of NK-cell function testing are generally reliable if the blood sample is properly shipped and tested in less than 24 hours. NK function cannot be determined prenatally, and it may not be reliably studied until a child is several weeks old. Notably, this test does not discriminate between familial and secondary disease.
Detection of perforin by staining of lymphocytes and analysis by flow cytometry is a highly reliable method for predicting the likelihood of the PRF1 gene mutation as the cause of FHL in a given patient. This test can also be used with reasonable predictive potential to screen parents and siblings to determine whether they might be carriers of PRF1 mutations. This test is not available prenatally.
Another test recently described analyzes the expression of a molecule on the surface of NK-cells (CD107) by flow cytometry that marks NK-cell degranulation. Reduced expression can predict mutations in the UNC13D gene. This test also requires specially prepared blood samples and cannot be used prenatally.
Genetic testing is recommended in cases of suspected FHL and confirms the diagnosis. Usually a blood sample is used. Even in the event of death, salvaged tissue can be tested. Once the genetic defect of a patient is known, the parents and siblings can be easily tested to determine if they are carriers for this specific defect. In such cases, prenatal diagnosis is possible as well.
How is HLH treated?
Without treatment, FHL is usually rapidly fatal with a median survival of about 2 months. The current treatment protocol, HLH 2004, provides recommendations for HLH therapy with a combination of immunosuppressive drugs and chemotherapy. The protocol has been accepted internationally and is used in many countries worldwide. In order to prevent early death or severe persisting organ damage, therapy must be initiated in a timely manner. In FHL cases, only temporary remission will be achieved. For a definite cure, the patient must undergo BMT.
With the former HLH-94 protocol and the now active HLH-2004 protocol, high remission rates and cure rates with BMT have been reported.
Secondary HLH sometimes resolves spontaneously or after treatment of the underlying disease. In some cases, modified immunochemotherapy can be applied, while in others, full immunochemotherapy is required.
How can a genetic counselor help?
Genetic counselors are members of the health care team who work closely with referring physicians and other health care professionals to provide accurate, relevant, and consistent information to families at risk of inherited diseases, including HLH and other immunodeficiency disorders. Genetic counselors are trained to identify families at risk, provide information to families about a specific disorder, analyze inheritance patterns and risk of recurrence in a family, and discuss available options for testing. For disorders in which genetic testing is available, the genetic counselor helps families evaluate the potential risks and benefits of genetic testing, arranges for appropriate testing and collection of samples, and interprets and communicates the results of genetic testing to families in a meaningfuland compassionate manner. Genetic counselors also provide supportive counseling throughout this process and can assist with referrals to other health care providers and support services. Genetic counselors do not make decisions for their patients; rather they provide the information that each family needs to make decisions that are consistent with their own values and beliefs.
Where do I get more information?
The study center of the international HLH-2004 protocol is located in
It is recommended that genetic testing be coordinated through and requested by referring physicians or genetic counselors. There are several institutions that provide information and perform genetic testing.
For more information, please contact the following persons:
North America
Northern Europe
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