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.DIAGNOSISNow 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.INHERITANCEAll 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.

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.PREGNANCY OPTIONSPREIMPLANTATION GENETIC DIAGNOSIS (PGD)PGD can be performed only on embryos in vitro (in a laboratory). That means this test is always performed in conjunction with an in vitro fertilization cycle.CHORIONIC VILLUS SAMPLING (CVS)Chorionic villus sampling (CVS) is a relatively new procedure used to diagnose certain birth defects in the first trimester of pregnancy. The test has been performed regularly since 1982, and many thousand have been performed around the world. CVS is a prenatal test that involves taking a tiny tissue sample from outside the sac where the fetus develops. This tissue contains the same genetic material as the fetus.


Skin (4 Stages)1. The earliest and most striking diagnostic features in IP occurs in the skin as progressive rashes. It has four stages which may overlap. The first stage is the erythematous (red) and vesicular (blister-like) stage which appears in infancy and is often present in the newborn. This consists of redness, blisters, and boils. It is the initial manifestation in 90% of patients.. It may last from a few weeks to a few months. The extremities and the scalp are most often affected, but the rash can be present on any body part. This rash may recur at times in the first few months of life, and rarely ever later. The rash may be confused with the skin rash seen in other infectious diseases including chicken pox, herpes, impetigo, or scabies. However, virus is never found in the blisters Each of these diseases is more common than IP and can be fatal in infants, so an infant may be treated for an infection before the diagnosis of IP is made. Knowledge of a family history of IP will aid in efficient diagnosis. As serious as it looks, the rash does not seem to be painful, although clothing may irritate the blisters. Secondary infection from common skin bacteria should be treated if it occurs.2. The second phase, which may overlap with the first, are blisters which develop a raised verrucous (wart-like) surface. The lesions look like pustules. There can be thick crusts or scabs with healing and areas of increased pigmentation (darkened skin). It may be present at birth (implying that the vesicular stage took place in the womb), but it usually evolves after the first stage in 70% of patients. The extremities are involved almost exclusively. This stage typically lasts months, but rarely as long as a year.3. The third phase is the hyperpigmented stage in which the skin is darkened in a swirled pattern often described as a “marble cake” appearance. In some patients, the adjacent areas ultimately thin and widen leaving streaky hypopigmentation. It may be present at birth in 5-10% of patients but usually appears between 6 and 12 months of life. This may or may not correspond to the areas that were involved in stages I and II. The heavy pigmentation tends to fade with age in most affected individuals.4. The fourth stage is the atrophic (scarred) stage. These scars often are present before the hyperpigmentation has faded and are seen in adolescents and adults as pale, hairless patches or streaks. These are most easily seen when they are on the calf or in the scalp. Once most patients reach adulthood (late teen and beyond), the skin changes may have faded and may not be visible to the casual observer.

TEETHMore than 80% of IP patients have abnormalities of their teeth, and these can be useful in making the diagnosis of IP. The primary (baby) teeth may be delayed. Both the baby and adult teeth may be affected. Some teeth may be missing altogether or when they do erupt, the teeth may be unusually shaped, typically peg-like or cone-shaped. The quality of the teeth and the enamel covering them is normal. Few individuals have serious dental problems, and most can be helped with cosmetic dentistry (orthodontics or prosthodontics) as necessary.Adult teeth can be affected even when baby teeth have been fairly normal. Unfortunately, issues with baby teeth do not predict the course of adult tooth development.

HAIRAbout 50% of women with IP have minor abnormalities of their hair, usually a loss or lack of hair (alopecia) on the crown of the head. The alopecia is probably caused by scarring from the rash, but this is not proven. As with other children, sparseness of hair as a child does not correlate with the quantity of hair as an adult. Hair color is normal, but the hair strands themselves may be coarse, wiry, and "lusterless". For the most part, individuals do not have substantial problems with their hair.

NAILSThe nails of the hands and feet may be involved. That involvement is usually mild and transient but can recur. The nails may be ridged, pitted, thickened, or completely disrupted. If these signs are present, they typically involve most or all the finger and toenails, not just one or two nails. Benign tumors have been described to grow under the nail bed and correspond with the blistering skin lesions seen in stage II. In extreme cases, these growths can be painful and may be associated with deformities of the finger bones.

BREASTDevelopmental abnormalities of the breast range from a missing breast, extra nipples, small or asymmetric size of breast development after puberty or abnormalities in nipple pigmentation. No consistent pattern has been observed.

NERVOUS SYSTEM Although most individuals are neurologically normal, severe neurologic complications can occur as a consequence of IP. Abnormalities of the nervous system can include Seizures (epilepsy”) occurring in infancy are an indication that the nervous system has not been spared. Paralysis, developmental and mental retardation, and small head size in infancy are an indication that the nervous system has not been spared. Careful studies of the frequencies of these symptoms in individuals with confirmed IP are underway. Currently, it is unknown how common neurological problems are in IP. The discovery of NEMO mutations in IP has allowed more patients to be identified, leading to the appreciation that IP is more common than previously recognized.

While this is not enough information upon which to base strong conclusions, it does suggest that the vast majority of individuals with IP will be neurologically normal. There is increasing evidence that, if problems are going to arise, they will within the first year of life. Seizures or other complications should be treated as in any other infant, but these problems do not need special or unusual managements.EYESThe majority of IP patients have normal vision. Some problems, like near- and far-sightedness, are common in IP individuals, but these are probably no more frequent than in the general population without IP. The classical eye finding in IP is an abnormality in the growth of blood vessels in the inside of the eye (the retina). Growth of abnormal blood vessels, and the associated scarring can cause loss of vision but may be treated if recognized early enough.For this reason, babies diagnosed with IP should have an eye examination immediately after birth and be followed by an ophthalmologist closely during the first few years of life. Careful examination by a pediatric ophthalmologist or retinal disease specialist should be done 3-4 times in the first year, then every 6 months until age 4 years, then annually. Please go to Eye Examination for a detailed explanation of how to examine the eyes of an IP patient.Rare eye abnormalities have included small eye (microphthalmos), cataract, and degeneration of the optic nerve (optic atrophy). Permanent visual deficiency or total blindness may occur.

EYE EXAMINATION OF CHILDREN AFFECTED WITH IPIn a female newborn in whom the diagnosis of IP is confirmed or strongly suspected, a dilated fundus exam as soon after birth as the neonatologist thinks it is safe is indicated. Sometimes, if there are any suspected retinal abnormalities, an examination under anesthesia may be required. The ophthalmologist should look at the optic nerve head, the macula (in the center of the retina), and the far peripheral retina where the typical pathologic events tend to occur. This should be done before the baby leaves the hospital. In a small fraction of infants with IP, abnormal blood vessels grow in the peripheral margins of the retina, similar to the abnormalities that occur in Retinopathy of Prematurity.Severe retinal disease is often associated with brain dysfunction and is a marker to pursue x-ray scanning studies of the head. With respect to the eyes themselves, some babies with IP, and even some older patients, might benefit from laser treatment or freezing therapy (cryopexy) in an effort to prevent retinal detachment or vitreous hemorrhage from the consequences of the typical retinal neovascularization that occurs in this disorder.

Ophthalmologists with IP expertiseMorton F. Goldberg, M.D. Director and William Holland Wilmer Professor of OphthalmologyThe Wilmer Ophthalmological Institute Johns Hopkins University 

School of MedicineTel: 410 955-6846 Fax: 410 955-0675Email: mgoldbrg@jhmi.eduRichard A. Lewis, M.D., M.S.Professor, Departments of Ophthalmology, Medicine, Pediatrics, and Molecular and Human Genetics Cullen Eye Institute, Baylor College of MedicineTel: 713-798-3030 Fax: 713-798-3042Email: rlewis@bcm.tmc.eduDrs. Lewis and Goldberg would like to offer their services to any patients who might benefit from ophthalmic consultation and/or treatment under their direction. They are also willing to consult with medical professionals about this topic. Drs. Lewis and Goldberg are both members of the Scientific Advisory Council of the Incontinenta Pigmenti International Foundation.FOR MORE INFORMATION AND SUPPORT VISIT ... www.ipif.orgthe OFFICIAL WEBSITE for IPIF.Disclaimer: The Incontinentia Pigmenti International Foundation” (IPIF) does not engage in the practice of medicine. It is not a medical authority nor does it claim to have medical knowledge. This site is an educational service of the “The Incontinentia Pigmenti International Foundation” and is not meant to provide diagnostic or treatment advice. Information contained or suggested on this Web site does not constitute medical advice. For all information related to care, medication or treatment, the IPIF recommends consulting a physician to determine if information presented is applicable. Please review these additional cautions about medical information provided.

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