Incontinentia pigmenti (IP) is an X-linked dominant disorder affecting primarily the skin, hair, teeth and nails (all components of the epidermis). This disease may have been initially described by Garrod in 1906. It was completely characterized by Bloch and Sulzberger in 1928. For this reason, incontinentia pigmenti has also been referred to as Bloch-Sulzberger syndrome.
Incontinentia pigmenti has been traditionally classified into two types: type I and type II. Much debate has occurred over whether or not type I, or sporadic, incontinentia pigmenti is actually the same disease as type II, or familial, male-lethal type, incontinentia pigmenti. The debate on this issue continues in the medical literature in early 2001. The growing consensus is that sporadic (type I) incontinentia pigmenti is not, in fact, the same disease as familial, male-lethal (type II) incontinentia pigmenti. Type II (familial, male-lethal) incontinentia pigmenti is considered to be the "classic" case of incontinentia pigmenti that matches the disease characterized by Bloch and Sulzberger in 1928.
The locus of the gene mutation responsible for incontinentia pigmenti type II has been mapped to the long end of the X chromosome at gene location Xq28. The affected gene is known as the NEMO gene.
A chromosome is a long chain of deoxyribonucleic acid (DNA ), a double-stranded molecule composed of individual units called nucleotides. The two strands that make up a single DNA molecule are held together by a matching (base pairing) of the nucleotides on one strand with the nucleotides on the other strand. Each set of a nucleotide on one strand paired with its nucleotide on the other strand is called a base pair.
A gene is a particular segment of a particular chromosome. Within the segment containing a particular gene there are two types of areas: introns and exons. Introns are sections of the particular chromosomal segment that do not actively participate in the functioning of the gene. Exons are those sections that do actively participate in gene function. A typical gene consists of several areas of exons divided by several areas of introns.
The NEMO gene was completely sequenced by the International Incontinentia Pigmenti Consortium in 2000. The NEMO gene consists of approximately 23,000 base pairs that compose 10 exons. The first exon of this gene, which is the exon that tells this gene to "turn on," has been found to have three variants; these are designated: 1a, 1b, and 1c.
The NEMO gene is known to partially overlap with the gene responsible for the production of glucose-6-phosphate dehydrogenase (G6PD). Mutations in the G6PD gene cause an under-production of red blood cells (anemia) that results in an insufficient amount of oxygen being delivered to the tissues and organs. Anemia resulting from mutations in the G6PD gene is observed with higher frequencies in Africans, Mediterraneans, and Asians.
The locus of the gene mutation responsible for type I incontinentia pigmenti has been mapped to band Xp11, on the short arm of the X chromosome. Individuals affected with this disorder show many of the signs of incontinentia pigmenti type II, but it is not an inherited condition. Type I incontinentia pigmenti is only exhibited as a sporadic and de novo trait. This means that when an affected individual has the symptoms of type I IP, that individual did not inherit this condition from his or her parents; rather the condition was caused by a mutation that occurred after conception.
Incontinentia pigmenti is observed with higher frequencies in Africans, Mediterraneans, and Asians than in other portions of the population. This was originally thought to be due to the greater ability to observe the skin-related symptoms in these individuals. But, with the additional evidence that the NEMO gene and the G6PD gene overlap and that anemia resulting from mutations in the G6PD gene also disproportionately affects these populations, this anecdotal explanation has to be discarded.
More than 95% of all patients diagnosed with IP are female. The occurrence in males is probably due to a spontaneous (de novo) mutation in the NEMO gene that is not as severe as the typical mutation leading to IP or the misdiagnosis of type I IP. Approximately 70% of all IP affected individuals have been found to have the same mutation in the NEMO gene. In these families, 100% lethality prior to birth is observed in males.
Signs and symptoms
Familial, male-lethal (type II) IP is characterized by progressive rashes of the skin. These have been classified into four stages: the red (erythematic) and blister-like (vesicular) stage; the wart-like (verrucous) stage; the darkened skin (hyperpigmented) stage; and the scarred (atrophic) stage.
The first, or erythematic vesicular, stage consists of patches of red skin containing blisters and/or boils. This condition usually appears in affected individuals at or near birth and is generally localized to the scalp, the arms, and the legs. This stage generally lasts from a few weeks to a few months and may recur within the first few months of life. It rarely recurs after the age of 6 months. This condition is often misdiagnosed as chicken pox, herpes, impetigo, or scabies. Each of these alternative diseases is potentially life-threatening in an infant, so most IP affected infants are treated for one of these diseases before the appropriate diagnosis of incontinentia pigmenti can be made.
The second, or verrucous, stage of IP is characterized by skin lesions that look like adolescent acne (pustules). Upon healing, these pustules generally leave darkened skin. This stage almost exclusively affects the arms and legs, but it may be observed elsewhere. The verrucous stage may occur at birth, which may indicate that the erythematic vesicular stage occurred prior to birth. But, more generally, the second stage of IP skin disorder is observed after the first stage has completed. The verrucous stage tends to persist for months. Rarely it may last for an entire year.
The third, or hyperpigmented, stage is characterized by "marbled skin," in which darkened areas of skin seem to make swirling patterns across the normal and less pigmented skin. This third stage generally occurs between six and 12 months of life. In 5-10% of affected individuals, this third stage is present at birth. These areas of hyperpigmentation tend to fade with age such that they are barely visible in adults affected with type II IP.
Areas of scarred skin caused by the first two stages characterize the fourth, or atrophic, stage. These scars are often noticeable before the third stage has begun to fade. Adolescents and adults affected with type II IP will generally have pale, hairless patches or streaks, most visibly on the scalp or calves, that are associated with this fourth stage. In many adults affected with IP, the skin abnormalities may have faded to such a significant degree that they are no longer noticeable to the casual observer. Many type II IP affected individuals have a loss or lack of hair on the crown of the head (alopecia). This is suspected to be caused by the underlying skin atrophies of IP.
More than 80% of individuals affected with type II IP have abnormalities of the teeth which include missing teeth, late eruption of both the baby teeth and the adult teeth, unusually pegged or cone-shaped teeth, and deficiencies in the enamel. A smaller percentage (approximately 40%) of affected individuals have irregular formations of the finger and toe nails including missing nails, thickened nails, and ridged or pitted nails. In a small number of cases, the skin lesions associated with the first two stages of skin abnormalities may be present underneath a nail. In these cases, it is possible for this lesion to develop into a benign tumor that may cause abnormal bone development in the affected finger or toe.
Approximately 30% of all individuals affected with IP experience visual problems. Less than ten percent of type II IP affected individuals have vision problems related to an abnormal growth of blood vessels in the retina which may, if untreated, lead to a detachment of the retina possibly resulting in blindness. These symptoms generally are seen before the affected individual reaches the age of five. Other vision problems that have been observed in type II IP affected individuals include crossed eyes or "wall eyes" resulting from an improper alignment of the eyes (strabismus); partial or complete opaqueness in one or both lens (cataract); and, occasionally abnormally small eyes (microphthalmia). Because of these vision problems, some individuals affected with IP are blind at birth or will go blind if corrective treatment is not sought.
The incidence of breast development anomalies in type II IP affected girls is quite common. It is estimated to be more than ten times that of the general population. These anomalies range from the presence of an extra nipple to the complete absence of breasts.
Approximately 25% of all IP affected individuals have disorders of the central nervous system. These include mental retardation, slow motor development, epilepsy , an abnormally small brain (microcephaly) and increased muscle tone in both legs (spastic diplegia) or in all four limbs (spastic tetraplegia) similar to that seen in the classic case of cerebral palsy .
The genetic mutation responsible for type I incontinentia pigmenti has been fully mapped and sequenced; therefore, it is possible to perform a genetic test for the existence of this disease. However, most cases are still diagnosed on a clinical basis.
Clinical diagnosis of type I IP is based primarily on the skin abnormalities seen at birth. These skin problems may still be misdiagnosed as chicken pox or herpes. This misdiagnosis is easily corrected when the affected individual begins to develop the later stages of the skin anomalies. All suspected male infants should have a chromosome test performed to confirm diagnosis.
In older patients with scarred skin, a skin biopsy that shows "loose" melanin (the pigment that produces color in the skin) confirms a diagnosis of IP.
When the skin appears normal, a diagnosis of IP is indicated when an individual shows one or more of the physical symptoms characteristic of IP: teeth abnormalities, missing patches of hair (alopecia), and/or overgrowth and scarring of the retinal blood vessels; and, that individual is female, has two or more IP affected daughters, is the daughter or sister of an affected woman, or has experienced the miscarriage of two or more male fetuses.
The presence of seizures within the first weeks of life indicate central nervous system involvement in the IP affected individual and indicate an extremely high likelihood of subsequent developmental delay.
Treatment and management
Usually no treatment for the skin conditions associated with IP is necessary other than the control of secondary infection that may occur.
In a female newborn where IP is suspected, an eye exam to look for retinal abnormalities, or any of the other possible eye disorders associated with IP, should be conducted within the first few days after birth. Older affected individuals should have regular eye exams to ensure that retinal abnormalities do not develop. Laser treatments and freezing treatments (cryopexie) are often required to prevent retinal detachment.
Dental treatment is often necessary to repair damaged enamel or for cosmetic reasons in the cases of missing teeth or abnormally shaped teeth.
In cases where there is involvement of the central nervous system, the necessary treatments are on a symptomatic basis. These may include early and continuing intervention programs for developmental delays, anticonvulsants to control seizures, muscle relaxants to control spasticity, and/or surgery to release the permanent muscle, tendon, and ligament tightening (contracture) at the joints that is characteristic of longer term spasticity.
Incontinentia pigmenti is generally fatal in males prior to birth. Females, and the few surviving males, who are affected with IP can expect a normal lifespan if treatment is undertaken to repair or manage any of the associated symptoms.
"Gene discovery should help diagnose incontinentia pigmenti." Baylor College of Medicine Press Release (May 24, 2000).
Smahl, A., et al. "Genomic rearrangement in NEMO impairs NF-kB activation and is a cause of incontinentia pigmenti." Nature (May 25, 2000): 466-72.
National Incontinentia Pigmenti Foundation. 30 East 72nd St., New York, NY 10021. (212) 452-1231. Fax: (212) 452-1406. <http://imgen.bcm.tmc.edu/NIPF>.
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
McKusick, Victor A. "#308300 Incontinentia Pigmenti; IP." [September 16, 1998]. OMIM—Online Mendelian Inheritance in Man.<http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?308300>.
"Nutrition: Incontinentia Pigmenti." [June 16, 1998]. Vanderbilt Medical Center Pediatric Digital Interactive Library.<http://www.mc.vanderbilt.edu/peds/pidl/nutrit/incont.htm>.
Paul A. Johnson