Incontinentia Pigmenti Health Article

Definition

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.

Description

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. 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.

Genetic profile

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.

Demographics

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.