Incontinentia Pigmenti (IP) is a genetic disease of the skin, hair, teeth and central nervous system. The condition was named because of the way the skin looks under the microscope. "Bloch-Sulzberger Syndrome" is another name commonly used for IP. Other names are: Bloch-Siemens Incontinentia Pigmenti, Melanoblastosis Cutis Linearis, and Pigmented Dermatosis, Siemens-Bloch Type.
Incontinentia Pigmenti (IP) is a rare genetic disorder. The cause has been traced to a defective gene on the X-chromosome called NEMO. The disease varies from very severe to mild and clinically inconsequential. The signs described in this brochure vary in severity from person to person, and there is variability even among affected individuals in the same family. The prevalence of IP is unknown. As is often the case with rare disorders, it is likely that IP often goes undiagnosed or misdiagnosed. A woman with IP has a 50% chance of passing on this gene to each of her daughters. For male fetuses, of the 50% who inherit the IP gene, the great majority will result in a spontaneous abortion (or miscarriage) as IP is nearly always lethal in a male fetus. But for extremely rare exceptions, any live born male will be unaffected. There is no known ethnic or racial predisposition and cases have been reported throughout the world. Treatment is symptomatic and supportive. There is currently no cure for IP. Genetic counseling for affected women, parents of affected children, and relatives at risk is recommended. However, with the discovery of the gene, NEMO, and the relationship of mutations and alterations within NEMO to IP, prenatal diagnosis is now possible.
Skin, Hair, Teeth, Nails, Eyes, Nervous System, Breast
All the genetic information that we need is inherited from our parents. The majority of the genes are present as two copies, one of which we have received from each parent. Genetic diseases can be inherited in a number of ways which are referred to as "Mendelian". Recessive diseases show up only when both copies of a pair of genes are abnormal. In dominant conditions, only one member of the pair needs to be abnormal for the disease to occur. A few diseases, of which IP is one, are caused by genes on the X-chromosome and are called "X-linked". This type of Mendelian inheritance is different because all females have two X-chromosomes, while males have only one X (and another, male-determining chromosome called the Y-chromosome). For most X-linked disorders, females are not affected since they have two X-chromosomes (one with the disease gene and one with a normal gene); the effect of the normal copy of the gene on one X overrides the effect of the abnormal copy on the other X. Males, however, do not have this second normal copy; they have only one X-chromosome, so they have no way to compensate for their only abnormal X-linked gene and thus they are affected with the disease. Some rare males can have two X chromosomes along with their Y--some males with IP have been found who have this chromosomal anomaly.
IP is a dominant X-linked condition. This means that females with only one copy of the abnormal gene will show the disease, even though they have a normal gene on their other X-chromosome. Males who inherit the abnormal gene (and, of course, do not have a balancing normal copy) do not survive, which demonstrates that the normal copy of the IP gene is extremely important. With the identification of the NEMO gene in IP, we now know that males lacking a function copy of this gene will not survive due to liver failure, typically in the first trimester of pregnancy.
A woman who is affected with IP has one normal X-chromosome, and one X-chromosome carrying the abnormal gene. At each pregnancy she will give half of her genetic information to each fetus. Thus, for any pregnancy there is a 50-50 chance that she will transmit the X-chromosome with the abnormal IP gene, regardless of the sex of the fetus. On average, half of her daughters will inherit the normal X-chromosome and be unaffected, and half will receive the abnormal X and have IP like their mother. Half of the sons will inherit the normal X-chromosome and be normal, and the other half will receive the abnormal X. Since males typically do not survive without a normal copy of the gene, these "affected" males will either miscarry or be stillborn. In summary, half the daughters of an affected IP female will have IP and half will not, but nearly all the live-born sons will be normal. This 50-50 chance for affected females is true for each pregnancy, regardless of whether previous pregnancies have been affected or not.
Now that the gene responsible for IP has been characterized, diagnosis can be supplemented with molecular testing. However, diagnosis of new patients is normally carried out using clinical criteria. If the classic rash is present in a newborn, the diagnosis is fairly straightforward, but it can be more difficult when the rash is mild, when not all the stages are present, or when an adult is seen and the lesions have faded. A skin biopsy that shows the presence of "loose" melanin (the brown-black skin pigment) in the dermis of the skin confirms the diagnosis, in the appropriate clinical setting. When there is little or no skin involvement, IP may be assumed to be the diagnosis in individuals "at risk" for the disease if they have other features such as tooth abnormalities, missing patches of hair, or overgrowth and scarring of the retinal blood vessels. Such an "at risk" individual would be a woman with two (or more) affected daughters, the daughter of an affected woman, or the sister of an affected woman who herself has had the miscarriage of more than one male fetus.
CAN MALES HAVE INCONTINENTIA PIGMENTI?
As stated above, males have only one X chromosome. If the IP gene on a male's only X chromosome is severely damaged, males cannot survive. A healthy version of the NEMO gene is apparently so critical to life that a nonfunctional version in males causes death before or shortly after birth. There are, however, several cases of males diagnosed with IP. These individuals typically manifest IP due to carrying an extra X chromosome (XXY) or to being mosaic for both XY and XX cells. These cases can be confirmed through testing for NEMO mutations. Some mutations in NEMO manifest in disorders in males that are different from IP. These males are often characterized as having ectodermal dysplasia and/or immune deficiencies. There is disagreement among researchers and clinicians as to whether these boys really have IP, or, do they have a similar disorder that closely resembles IP. One of the benefits of identifying the gene, is that these males can now be definitively diagnosed and it can be determined if they do indeed have IP. Early findings with the NEMO gene suggest that males with features of IP may have more subtle mutations that cause their symptoms. Several articles have been written and are available through the Foundation about males with IP. Further Studies are currently being conducted.