Incontinentia Pigmenti
Incontinentia Pigmenti, also known as IP or Bloch-Sulzberger syndrome, is an extremely rare genetic disease that is mostly found in females. The worldwide incidence of PI is estimated to be about 1.2 patients in 100,000 people.
In about 80% of cases, Incontinentia Pigmenti develops as a result of a spontaneous mutation. In other cases, IP is passed on in an X-linked dominant hereditary pattern. This means that one parent, most likely the mother, passes on a mutated X-chromosome, which will be enough for the child to develop the disease. Since the affected gene carries out crucial functions in our body, male fetuses usually don’t survive gestation and die during the third or fourth month of pregnancy. This explains the female to male ratio of about 37 : 1. The few boys that do survive until after birth, may have developed somatic mutations, which means that the mutation is present in only a few cells of the body and not all of them. Another way that allows boys to survive IP is when they also suffer from Klinefelter syndrome. In that case boys carry 2 X and 1 Y chromosomes (XXY).
For girls and boys with Klinefelter syndrome, PI syndromes vary widely. The reason for that is a process called X-chromosome inactivation. Because girls have 2 X-chromosomes and healthy boys have only one X-chromosome, one of the two chromosomes in girls must get inactivated. This process is usually random which means that roughly half of a girl’s body cells have the active chromosome from her mother and the other half from her father. The same happens in boys with Klinefelter syndrome. In IP the process of X-chromosome inactivation is usually not random but skewed. This is because cells with an active X-chromosome that carries the mutated gene is very susceptible to cell death, called apoptosis. Therefore, most body cells in girls with IP carry the wild-type version of the gene in question. And yet, symptoms of IP may be severe.
What are those symptoms and how dangerous are they?
Symptoms may vary significantly between patients and not every patient develops all known symptoms. However, what every IP patient does develop are alterations to the skin. This is also the determining diagnostic factor. Skin alterations go through 4 stages:
Stage I is called vesicular stage and is characterized by vesicles, pustules and papules that are likely a result of an inflammatory process. These lesions can be mostly found on extremities but may also present on head and neck. Most patients are born with stage I skin alterations or develop them within the first two weeks of life. After about 4 months, they disappear on their own.
Stage II is called verrucous stage and is characterized by crusty plaques and warty papules. They are most commonly found on extremities and trunk but can also be seen on the head and neck. Usually, stage II skin alterations develop between 2 and 6 weeks of age and disappear by 6 months.
Stage III is called hyperpigmentation stage and is characterized by hyperpigmented lesions mostly found on extremities and trunk but can also be seen in skin folds, on head and neck. These skin alterations usually develop a few months after birth and often disappear during adolescence. Stage III is the characteristic stage of IP and the name Incontinentia Pigmenti stems from the skin cells’ incontinence of the pigment melanin which is responsible for the hyperpigmentation observed.
Stage IV is called hypopigmentation stage and is characterized by skin lesions that lack pigmentation. They develop during adolescence and usually persist into adulthood or may even be permanent.
As you may have noticed, the four stages of skin alterations happen chronologically. However, not every patient experiences all four stages and some stages can also occur simultaneously.
The skin alterations in IP are not dangerous and usually resolve by themselves. However, they are not the only symptom observed in IP. As a multisystemic disease, Incontinentia Pigmenti affects multiple organs. Less severe symptoms include hair loss, missing teeth and other dental problems, nail abnormalities, and alterations to the skeleton.
More severe symptoms affect the eyes and the central nervous system. The most feared alterations in eyes affect the retina. For example, detachment and avascular retina. Other common eye symptoms include strabismus and cataract. These eye alterations occur in up to 80% of patients, severely impact the quality of life and can even lead to blindness.
Incontinentia Pigmenti gets dangerous when the central nervous system is affected. This is the case in about 30% of patients. Neurological manifestations vary and include seizures, psychomotor retardation, intellectual impairment, hemiplegia, epilepsy, cerebellar ataxia, microcephaly, encephalitis and neonatal and childhood stroke.
So, what’s happening in people with IP to explain all these symptoms?
The affected gene in IP is called IKBKG gene, which is located on the long arm of the X-chromosome. The most common mutation that accounts for about 80% of all IP cases is a deletion of exons 4-10. Check out my video on Duchenne muscular dystrophy to learn more about exons.
The IKBKG gene codes for a protein called NEMO and NEMO is part of a larger protein complex called IKK complex. The IKK complex is a crucial element in an intracellular signaling cascade called NF-κB. In healthy cells, the IKK complex inhibits the function of another complex called IκB which in turn inhibits NF-κB when functional. Therefore, IKK indirectly activates NF-κB because it blocks the inhibiting function of IκB. It’s a little bit like math where minuses equal a plus. NF-κB can now execute its function, move into the nucleus and activate the expression of many genes. Those genes are involved in many different processes including inflammation and cell death.
The IP mutation in the IKBKG gene leaves the NEMO protein without any function. This also renders the IKK complex non-functional and now IκB can efficiently block NF-κB. This is catastrophic for the cell because now all those genes that would usually get expressed because of NF-κB are no longer getting expressed. As a result the cells die and we see an increase in inflammatory responses such as stage I and II skin lesions.
What does this mean with regard to a prognosis and treatment for patients with IP?
Luckily, life expectancy in patients with IP is normal unless there are severe neurological symptoms during the neonatal stage. The characteristic skin lesions usually resolve by themselves and don’t need special treatments. Topical corticosteroids can be applied to reduce discomfort. Regular check-ups with an eye specialist starting immediately after birth are highly recommended and treatments for neurological symptoms are available as well, including anti-seizure medicine for example.
Fertility in women is not affected, however, they experience a higher rate of miscarriage due to the low viability of male fetuses.
Literature used
https://www.orpha.net/data/patho/GB/uk-incontinentia-pigmenti.pdf
https://www.ncbi.nlm.nih.gov/books/NBK1472/pdf/Bookshelf_NBK1472.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938351/
https://cdn.mdedge.com/files/s3fs-public/Document/September-2017/079050355.pdf
