What is Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)?
Incontinentia pigmenti (IP) or Bloch-Sulzberger syndrome, is a rare genetic skin condition. It has many other names such as Bloch–Siemens syndrome, Bloch–Sulzberger disease, melanoblastosis cutis, pigmented dermatosis Siemens-Bloch type, and nevus pigmentosus systematicus. This condition is caused by a mutation in a gene called IKBKG (also known as the NEMO or nuclear factor kappa essential modulator gene).
Incontinentia pigmenti affects the skin, central nervous system (which includes the brain and spinal cord), eyes, teeth, hair, and nails. The symptoms typically appear within the first few weeks after birth. It’s more commonly found in girls and is rarely seen in boys. Sadly, this condition can cause serious health problems in boys leading to early death. The symptoms vary among girls, owing to a biological process called lyonization that happens with many X-linked genetic disorders. One of the first symptoms that gets noticed is a skin rash which goes through four stages: forming blisters, growing wart-like bumps, becoming darker, and finally becoming lighter or scarred. Problems with the nervous system and the eyes can cause severe disabilities.
Doctors can diagnose Incontinentia pigmenti using physical examination and genetic testing. The treatment for IP requires a team approach. This includes skin specialists to deal with skin blisters and prevent skin infections, oral care specialists, eye doctors to prevent eye conditions like retinal detachment, nerve specialists to handle seizures and other nerve problems, and child growth experts to deal with potential delays in development.
Because this condition is rare, it can be challenging to diagnose and manage promptly. Nonetheless, guidelines have been set by the Incontinentia Pigmenti International Foundation and the National Foundation for Ectodermal Dysplasias to aid medical experts in monitoring and managing the condition.
What Causes Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)?
Incontinentia pigmenti is a condition that usually comes from the mother’s X chromosome. Babies with this condition often have a new mutation in the IKBKG gene, sometimes referred to as the IKK gamma or NEMO gene. This gene is located on an X chromosome. A mutation of this gene can disrupt the normal functions of the cell such as cell growth, inflammation and immunity.
Normally, a molecule known as NF-kB protects cells from dying; it is usually inactive within cells, but it can become activated and trigger an inflammation response if cells are under stress, or exposed to bacterial or viral infections. A mutation in the IKBKG gene can interfere with NF-kB’s function, making cells more likely to die when exposed to stress or infection.
Because incontinentia pigmenti is usually inherited via the X chromosome, it tends to be fatal in male embryos. However, there have been reported cases in males which could be explained by a few factors such as having cells that vary genetically, having a less severe mutation, or having Klinefelter syndrome (an extra X chromosome). Females inherit one X chromosome from each parent, and one of these usually gets switched off. However, this switching off is not seen in all cells. This means that women often have two kinds of cells. As a result, skin lesions (abnormal patches) develop along the so-called Blaschko’s lines. These lines are invisible but can be seen when a skin disorder is present.
Risk Factors and Frequency for Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)
Incontinentia pigmenti is a condition passed down through genes, with women carrying a 50% chance of passing on the problematic gene variant to their children. However, male babies carrying this defective gene are often miscarried. A review found that between 1993 and 2012, there were 1,393 reported cases of this condition.
- The number of cases in both men and women is increasing.
- The illness is quite rare, with an estimated 0.7 cases per million people globally.
- It mainly affects women, with 92 to 97% of living patients being female.
- About 28 new cases are reported worldwide each year.
Signs and Symptoms of Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)
Incontinentia pigmenti is a condition that primarily affects the skin, eyes, and central nervous system (CNS), mostly in women and occasionally in men. This condition has different signs that can be observed in the skin, hair, nails, teeth, CNS, eyes, and breast.
The signs on the skin are divided into four stages:
- Stage 1: Inflammatory Stage – This stage features blister-like lesions on a red base following Blaschko’s lines. They usually appear at birth or around eight weeks and last for 2 weeks to 4 months, mainly affecting the limbs and trunk.
- Stage 2: Verrucous Stage – This stage is characterized by wart-like papules and plaques noted in the linear distribution along Blaschko’s lines.
- Stage 3: Hyperpigmented Stage – This stage shows whorled grey hyperpigmented plaques (marble cake appearance). These tend to fade over time and are typically seen on the trunk, armpit, or groin. They usually disappear during adolescence.
- Stage 4: Hypopigmented Stage – During this stage, pale, hairless linear patches, and plaques devoid of sweat glands are commonly observed. They are most commonly seen on the back of the calves and arms.
In addition to the skin:
- 38% of patients may experience mild, often unnoticeable, hair loss on the scalp. There might also be absence of eyebrows and eyelashes.
- 7 to 40% of patients may experience nail disruptions such as ridging, pitting, or nail dystrophy.
- Patients may also have dental abnormalities such as small teeth, missing teeth, delayed growth of permanent teeth, and cleft palate.
- About 30% of IP patients may suffer from central nervous system deficits and ocular manifestations, significantly reducing their quality of life. This could include seizures, paralysis, hearing loss, motor dysfunction, mental disability, and brain inflammation.
- Ophthalmologic abnormalities are present in 20 to 37% of patients. This includes retinal capillary nonperfusion (ischemia) and risk of retinal detachment. Other less common eye findings include strabismus, cataracts, optic atrophy, and small-sized eyes.
- Finally, abnormalities may be seen in breast tissue, which can range from missing breast tissue, underdeveloped breasts or nipples, to extra nipples.
Testing for Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)
Incontinentia pigmenti (IP) is a genetic condition usually diagnosed by pediatricians or dermatologists during infancy based on specific symptoms and medical criteria. To understand this a bit better, these experts look out for certain major and minor signs that suggest the condition.
The significant symptoms include a typical rash present at birth that involves redness and blisters, and an increased number of a specific type of blood cell called eosinophils. As the child grows, there’s also a pigmentation pattern that primarily affects the trunk and follows ‘Blaschko’s lines’—invisible lines that represent cellular development. This pigmentation tends to fade as the child moves towards adolescence. Another sign is the presence of linear, atrophic, hairless patches on the skin.
Less significant ‘supportive evidence’ include problems with the teeth, hair loss, wooly hair and abnormal nails, and potential damage to the retina, the layer at the back of your eyes that senses light.
At least one of these major signs is necessary to confirm a diagnosis of IP. The minor signs, while not enough on their own, help support the diagnosis. However, if none of these minor signs are present, the condition is classified as ‘uncertain’.
If a close female family member has evidence of IP, then the diagnosis would need to consider things like a history or evidence of a typical rash, changes in skin color or texture, anomalies with the teeth or hair, retinal disease, and a history of multiple miscarriage in men.
To further refine the diagnosis of IP, the criteria have been revised to include the four stages of skin lesions in IP as significant markers. The minor or supportive signs also now include dental and eye abnormalities, changes in the central nervous system (brain and spinal cord), hair loss, abnormal hair or nails, anomalies in the nipples or breasts, a history of multiple miscarriages in men, and specific findings on a skin biopsy.
If these features aren’t obviously present, your doctor may consider doing a genetic test to identify a specific mutation in a gene called IKBKG. A skin biopsy may also be done, where a small piece of skin is removed and examined under a microscope for certain features of IP.
In terms of evaluating the potential eye complications in IP, your doctor may recommend tests like a fundus photograph (a picture of the back of your eye), a fundus fluorescein angiogram (a procedure that uses a special dye to visualize blood flow in the back of the eye), and optical coherence tomography (OCT), which uses light waves to take cross-sectional pictures of your retina.
Imaging of the brain and spinal cord also plays a vital role in evaluating the potential impact of IP on the central nervous system.
Treatment Options for Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)
The treatment of incontinentia pigmenti involves looking after multiple organs, so a team approach is needed.
A skin specialist should manage the skin lesions. Sometimes, the early symptoms can be mistaken for other conditions like herpes, ebola, and chickenpox. It is crucial to keep all stages of skin lesions cool, dry, and protected from damage. Skin lesions can appear at the same time during the first year of life and may come back due to infection or sickness. Incontinentia pigmenti can also cause reduced sweating, leading to heat intolerance and possible dangerous overheating. This is why it’s important to find ways to cool down, like having cool baths, using ice packs, and staying in the shade.
There aren’t specific treatments for the skin lesions yet. The focus is on caring for wounds and treating any extra infections. An eye doctor should regularly check the patient’s retina. If any abnormal findings, a retina specialist should further examine. The aim is to prevent the retina from detaching or bleeding due to the growth of new blood vessels. Treatment can include laser treatment or sometimes surgery if there’s a retinal detachment or bleeding in the part of the eye that is filled with a clear, jelly-like substance.
A visit to a pediatric neurologist is also necessary to manage seizures and get images of the brain. It’s recommended to have MRI scans early to establish baseline results and repeat these if seizures or other issues occur. Seizures are the most common brain-related problem in incontinentia pigmenti. EEG testing may be needed if seizures are present. Regular monitoring is necessary to spot any motor skill deficits or developmental delays.
Genetic counselors and specialists can aid in genetic testing. Around 25 to 35% of cases are passed down through families, while the rest happen randomly. A thorough examination of patients and their at-risk relatives can help identify inheritance patterns. If there are no physical signs, genetic testing for a mutation in the IKBKG gene can be done if incontinentia pigmenti is suspected.
Regular check-ups with the pediatrician are needed to monitor developmental progress. Children struggling with school activities may need to undergo testing for mental health disorders. Other complications to look out for include damage to the smallest blood vessels in the body and high blood pressure within the lungs without any heart disease.
Women with incontinentia pigmenti can still become pregnant, but there is a higher risk of miscarriage if the baby is male. Therefore, women considering pregnancy should have prenatal testing and advice. Men with this condition have a specific type of genetic mutation that makes passing the condition onto their daughters highly unlikely.
What else can Incontinentia Pigmenti (Bloch-Sulzberger Syndrome) be?
When trying to identify incontinentia pigmenti, doctors will look at skin symptoms and consider various conditions that might cause a similar appearance during different stages of the disorder. These conditions include:
- Stage 1 (vesicular)
- Congenital herpes simplex, which can cause grouped bleeding blisters, often on the scalp or at sites of injury from scalp electrodes. These can appear at birth or in the first few weeks of a baby’s life.
- Bullous impetigo
- Epidermolysis bullosa
- Congenital ichthyosiform erythroderma
- Stage 2 (verrucous): linear epidermal nevus and lichen striatus
- Stage 3 (hyperpigmented): linear and whorled nevoid hypermelanosis
- Stage 4 (atrophic/hypopigmented): hypomelanosis of Ito, Goltz syndrome (focal dermal hypoplasia)
Further, doctors would also evaluate the retina to distinguish incontinentia pigmenti from other disorders that could cause similar changes. Other conditions to consider are:
- ROP
- FEVR (familial exudative vitreoretinopathy)
- Norrie disease
Remember, incontinentia pigmenti is a significant cause of leukocoria (white pupil).
What to expect with Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)
The outlook for patients can vary and largely depends on how much the skin and various organs are affected. Skin changes do not typically lead to serious health problems. However, the seriousness of abnormalities in the eyes and central nervous system, which includes the brain and spine, can cause the most health complications and are the main cause of death. Additionally, patients who experience seizures and have structural abnormalities in their central nervous system are at the highest risk for developmental delay and impairment. On the other hand, if the patient doesn’t have severe eye or neurological issues, they generally have a good prognosis and can expect to live a normal lifespan.
Possible Complications When Diagnosed with Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)
In a newborn’s case, it’s important to lower the chance of their blisters getting infected, besides dealing with skin lesions in a standard way. Keeping a watchful eye for any signs of the whole body getting affected is sensible at this stage. Retinal detachment can potentially occur, especially in children below seven years old, so frequent eye checks are needed. While a head injury might increase the chances of retinal detachment, there are no specific guidelines at the moment to discourage participation in contact sports.
A recommended timetable for eye checks is:
- Every month until the baby is four months old
- Every three months from 4 months to 1 year old
- Every six months from age 1 to 3 years old
- Once a year after that
Regular exams of the baby’s nervous system functions also required, and regular dental check-ups are suitable as well.
Preventing Incontinentia Pigmenti (Bloch-Sulzberger Syndrome)
Support and advocacy groups can be very beneficial for patients and their families as they can help them find important services. These groups can provide professional and social resources, so it’s really crucial to connect with experts early on for advice and diagnosis. Diagnosing rare conditions can be tough and often requires testing of the genes and collaboration from various medical specialists.
This might however, be a bit difficult to navigate for families who aren’t very familiar with medical terms or don’t have enough means. This is where skin doctors (dermatologists) and children’s doctors (pediatricians) can play a huge role. They often are the first people patients and families see for medical help, and can guide them to the right support networks.
Patients and their families can get more information about Incontinentia Pigmenti (IP), a rare disease, by checking out the websites of these organizations:
- Incontinentia Pigmenti International Foundation
- National Organization for Rare Diseases
These sources can provide valuable knowledge and assistance for anyone dealing with IP.
