Hemophagocytic Lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder usually affecting infants and young children, but it can occur at any age. While the exact cause of HLH is unknown, it is felt to be caused by a disorder of immune system regulation, which leads to the activation of infection fighting cells called histiocytes and lymphocytes. Their normal function is to travel throughout the body and destroy foreign material and fight infections. Patients with HLH have too many of these activated histiocytes and they begin to accumulate in normal tissue and cause inflammation and damage to a variety of organs. Common sites of involvement include the bone marrow, lymph nodes, liver, spleen and brain.

There are two main types of HLH: the familial form and the secondary form. The familial form of HLH (FHL) is genetic, and families who have more than one child with HLH will be diagnosed with this form. In these families, there will be a 25 percent risk that each subsequent sibling will develop FHL usually within the first two years of life.

The secondary form of HLH develops secondary to abnormal activation of the immune system, which can occur after certain infections or after the use of drugs which suppress the immune system. It is very difficult to tell these two forms apart without a previously affected sibling. However, early age of onset is suggestive of the familial form and onset in older children is more common in the secondary form and there may be an association with a recently detected infection. It is important to note though, that children with FHL may also have the disease triggered by an infection.

Most children with HLH will develop fevers, enlargement of the liver, spleen and sometimes lymph nodes. They will have low blood counts (anemia and low white blood cell and platelet counts). Some may also develop bleeding and seizures. The first step in the treatment of the disease is to get it controlled and into remission. This is usually accomplished with chemotherapy and immunosuppressive medications. In the primary form of HLH disease control is temporary and the disease will eventually return if treatment is discontinued. In secondary HLH, if the underlying cause of the disease can be treated the HLH may be cured, however, even in some of those children remission may only be temporary.

The only know cure for HLH is blood or marrow transplantation. For this procedure high doses of chemotherapy are given to destroy the patients bone marrow, which is where the abnormal immune system cells come from. Ideally, the transplant should be performed when the disease is in complete remission (no signs of any active disease). Blood or  marrow transplant is most successful when a normal sibling who has the same tissue (or HLA) type is used for the donor. Unfortunately, only about 10-15 percent of children with HLH will have a sibling donor available. However, the University of Minnesota has been a leader in research that has led to the successful use of bone marrow from unrelated donors, peripheral blood stem cells, or umbilical cord blood, for the source of normal bone marrow and immune system cells. Because of this, a donor can be identified for the majority of children with HLH.

Severe Combined Immune Deficiency (SCID)
SCID (Severe Combined Immunodeficiency) is a primary immune deficiency represented by a severe defect in the T- and B-lymphocyte systems. Infants with SCID usually experience one or more serious, even life-threatening, infections such as pneumonia, meningitis or bloodstream infections within the first few months of life.

The exact of cause of SCID is unknown, but research indicates it may be caused by absent or poorly functioning T-lymphocytes, an absent or poorly functioning thymus gland, or defective bone marrow stem cells from which the mature T-or B-lymphocytes develop. For many forms of SCID, specific genetic defects have been identified which lead to the source abnormalities in the developing immune system.

Infants with SCID commonly fail to thrive and experience an excessive number of infections and complications. Normal childhood infections and viruses (chicken pox, measles, cold sore virus, etc.) may be fatal to an infant with SCID. The term "bubble baby" has been used to describe the children because of the sterile environment used to decrease the risk of infections. SCID is usually fatal within one year after birth.

The first successful bone marrow transplant for treatment of SCID was done at the University of Minnesota in 1968. In the decades that followed, blood or marrow transplantation has become accepted as the treatment of choice for SCID and a number of other prematurely lethal primary immunodeficiencies. BMT is the only treatment currently in use that has been shown to cure these immunodeficiencies.

In the current era patients with SCID can expect a 90 percent cure rate with BMT. Unfortunately, for the majority of patients with primary immunodeficiencies, more than 90 percent, lack suitable histocompatible sibling donors. For this reason alternative sources of stem cells are being investigated to treat these patients. Bone marrow from closely matched relatives, closely matched unrelated individuals, and parents (with T depletion), peripheral blood stem cells, or cord blood from siblings or unrelated newborns have all been used successfully in selected cases.

Wiscott-Aldrich Syndrome
Wiscott-Aldrich syndrome (WAS) is a primary immune deficiency which is inherited in a X-linked fashion so it only affects males. The disease is characterized by recurrent infections due to defects in T-lymphocyte and B-lymphocyte function of the immune system. Affected boys also have a low number of blood platelet counts, which can cause bleeding problems, and many frequently have an eczema type of skin rash.

The immune system defects in WAS lead to a significantly increased susceptibility to infections. In boys with WAS, due to the abnormality in the B-lymphocyte function, infections with certain types of bacteria cannot be responded to in the same way the immune system would normally, and they may develop frequent and recurrent ear infections, pneumonia, or even meningitis. Defects in the T-lymphocyte function can lead to infections with “opportunistic organisms” such as fungus or yeast, pneumocystis carinii type of pneumonia, or one of the herpes viruses. Any of these infections can be life-threatening.

The other major problem for boys with WAS results from the low platelet counts. These counts generally run low enough that there is risk of bleeding into skin, mucous membranes, or internal organs either spontaneously or after only minor trauma. The platelets in WAS are smaller in size than normal and this sometimes can help to confirm the diagnosis.

WAS is frequently diagnosed at birth due to bleeding or bruising and low platelet counts. The eczema may by present, or may be seen as “cradle cap” or severe diaper rash in infants. In older infants and children, the low platelet counts can often be confused with other disorders that cause this in children, and careful examination of the platelet size, skin findings, and infection history must be performed. When WAS is suspected, a complete evaluation of the child’s immune system must also be undertaken with tests for both B-lymphocyte and T-lymphocyte function. The gene which causes WAS has been identified and confirmation of the diagnosis can now be performed by a genetic test for the WAS gene, called WASP.

Blood or marrow transplantation is the only treatment available which is curative for boys with WAS. It provides correction of the lymphocyte defects (the immune deficiency) as well as the low platelet counts. Unfortunately, only about 15 percent of boys with WAS will have a suitably matched family donor. Over the past decade however, the University of Minnesota has been a leader in the development of transplant methods using closely-matched unrelated donors for patients with WAS and this has become an accepted treatment with excellent overall success.