Stevens-Johnson syndrome; Toxic epidermal necrolysis – HLA-B gene.

Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS / TEN) is an intense skin reaction most often triggered by certain medications. Although Stevens-Johnson syndrome and toxic epidermal necrolysis were thought to be separate conditions, they are now considered part of the same disease. Stevens-Johnson syndrome represents the less severe end of the disease spectrum, while toxic epidermal necrolysis represents the most severe end.

Frequently, both SJS and TEN begin with fever and flu-like symptoms. A few days later, blisters develop on the skin, forming painful erosions that resemble a severe hot water burn. Usually, skin lesions begin on the face and chest before spreading to other parts of the body. In the most affected individuals, it also damages the mucous membranes, including the oral mucosa, mouth and respiratory tract, which can cause problems with swallowing and breathing. The formation of painful blisters can also affect the urinary tract and genitals. SJS / TEN often affects the eyes as well, causing irritation and redness of the conjunctiva and cornea. Because the skin normally acts as a protective barrier, large damages can lead to a dangerous loss of fluids and allow infections to develop. Serious complications may include pneumonia, sepsis, shock, multi-organ failure and death.

About 10% of people with Stevens-Johnson syndrome die from the disease, while the condition is fatal in up to 50% of those with toxic epidermal necrolysis. Among those who survive, the long-term effects of SJS / TEN may include changes in skin pigmentation, xerosis, hyperhidrosis, alopecia, and abnormal growth or loss of finger and toe nails. Other long-term problems may include deterioration of taste, difficulty urinating and genital abnormalities. A small percentage of affected individuals develop chronic dryness or inflammation of the eyes, which can lead to photophobia and vision impairment.

Several genetic changes have been identified that increase the risk of SJS / TEN in response to triggers such as medications. Most of these changes occur in genes that are involved in the normal function of the immune system. The genetic variations most strongly associated with SJS / TEN occur in the HLA-B gene (major histocompatibility complex, class I, B), located on the short arm of chromosome 6 (6p21.33). This gene encodes a protein that plays an important role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body´s own proteins from the proteins produced by invaders (such as viruses and bacteria). Each HLA gene has different normal variations, allowing each person´s immune system to react to a wide range of foreign proteins.

Several variations of the HLA-B gene have been studied as risk factors for Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS / TEN). For example, the HLA-B*1502 variation increases the risk of SJS / TEN in people taking certain medications used to treat seizures, especially carbamazepine. This version of the gene is more frequent among people of ethnicity or ancestry of Southeast Asia. Another version of the HLA-B*5801 gene increases the risk of SJS / TEN in people treated with allopurinol. This association has been confirmed in Southeast Asians and people of non-Asian descent, although HLA-B*5801 occurs less frequently in non-Asian populations.

It is likely that variations of the HLA-B gene associated with SJS / TEN cause the immune system to react abnormally to some medications. In a process that is not well understood, the trigger drug causes cytotoxic T cells and natural killer cells (NK) to release granulisin. This substance destroys cells in the skin and mucous membranes, including the lining of the mouth and respiratory tract. The death of these cells causes blisters and peeling that can have fatal effects. Most people who have variations in the HLA-B gene that are associated with an increased risk of SJS / TEN never develop the disease, even if they are exposed to drugs that can trigger it. It is believed that additional genetic and non-genetic factors, many of which are unknown, probably play a role in whether a particular individual develops SJS / TEN.

Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS / TEN) is not a hereditary disease. Nevertheless, genetic changes that increase the risk of developing SJS / TEN can be transmitted from one generation to the next. 

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Stevens-Johnson syndrome; Toxic epidermal necrolysis, by means of the complete PCR amplification of the exons of the HLA-B gene, respectively, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).