Incontinentia pigmenti is a hereditary form of skin pigmentation disorder, which is often combined with malformations of teeth, hair, nails and eyes. The symptoms of the disease are characterized by pronounced stages – first, an erythematous rash appears on the skin in the form of spots and lines, then hyperkeratosis develops in its place, followed by spots and subsequent hypopigmentation with atrophy of the skin. Diagnosis is based on the data of the patient’s current status, histological examination of skin samples in the affected area, study of hereditary history and molecular genetic analyses. There is no specific treatment for this pathology at the moment, symptomatic and supportive measures of various kinds are used.
incontinentia pigmenti (Bloch-Sulzberger syndrome, neurocutaneous melanoblastosis) is a genetic disease characterized by a violation of melanin metabolism in the skin and a number of concomitant malformations. For the first time this disease was described in 1926 by the Swiss dermatologist B. Bloch, then a more detailed study of this pathology was conducted by the American pediatrician M. Sulzberger in 1929 and, independently of previous researchers, the German physician G. Siemens. That is why in the literature you can find another name for this disease – Bloch-Siemens syndrome. It was found out that the pathology is inherited concatenated with the X chromosome, while the mutant allele is dominant. For this reason, the incontinentia pigmenti is many times more common in girls – the sexual distribution is approximately 6:210, since the presence of this mutation in male embryos is almost always fatal and leads to spontaneous termination of pregnancy. The development of the disease in boys may be due to genetic mosaicism, the presence of concomitant Klinefelter syndrome or rare point “soft” mutations. The total occurrence of incontinentia pigmenti is approximately 1 case per 75,000 newborns.
With incontinentia pigmenti, the IKBKG gene, which is located on the X chromosome, is damaged. The product of its expression is a multifunctional complex protein – a regulatory subunit of NEMO-inhibitory kinase involved in the signaling system of an important transcription factor (NF-kappa-B). This factor and its corresponding signaling pathway regulate a huge number of different processes in the human body – it participates in the processes of adaptation to stress, immune response, some forms of inflammatory reactions, cell adhesion processes, and also inhibits the processes of apoptosis. The most common cause of Bloch-Sulzberger syndrome is large translocations and deletions of the IKBKG gene, as a result of which the expression and isolation of protein from this gene completely stops.
Since women have two X chromosomes, in the presence of a second normal allele of the IKBKG gene, such a mutation is not life-threatening, but causes the development of Bloch-Sulzberger syndrome. It is a well-known fact that only one X chromosome is always active in the somatic cells of the female body, while the second one is condensed into sexual chromatin. A significant variability in the severity of the symptoms of the disease is due to the distribution of cells where the chromosome with the mutant form of the IKBKG gene is active. As a consequence, the regulatory subunit of NEMO-inhibitory kinase is not formed in the above cells, which leads to characteristic malformations that form the clinical picture of Bloch-Sulzberger syndrome. Skin symptoms are associated with a violation of the permeability of melanocyte membranes (as a result of which almost all the pigment leaves the cells unhindered) and autoimmune reactions.
Unlike women, men normally have only one X chromosome, so if there is a nonsense mutation in the IKBKG gene, the release of an important protein does not occur in absolutely all cells of the body. This causes massive apoptosis of hepatocytes even at the stage of intrauterine development – normally this process is delayed by the NF-kappa-B system. The development of disorders similar to Bloch-Sulzberger syndrome in boys is possible in the presence of concomitant Klinefelter syndrome (karyotype XXY) or genetic mosaicism, when only a part of the cells in the body has a defect of the IKBKG gene. In recent years, point mutations of this gene have been identified, which do not lead to a complete stop of transcription, but change the structure of the final protein. However, most often boys with such defects do not have incontinentia pigmenti, but other genetic diseases – ectodermal dysplasia, immunodeficiency, skeletal malformations.
One of the most pronounced and common manifestations of incontinentia pigmenti is dermatosis, which is detected at birth or (less often) occurs during the first days of a newborn’s life. In the development of skin changes in this pathology, a characteristic stage is observed, which is also an important diagnostic sign. Localization of such changes is on the lateral surfaces of the limbs, trunk, neck, along the Charcot lines or projections of the main nerve trunks. In most cases, there are four main stages of the skin symptoms of incontinentia pigmenti:
- Stage 1 – inflammatory or vesiculobullous. It begins at the birth of the patient or during 2-3 weeks of life and lasts until the age of 3-8 months. At this stage of the disease, vesicles, erythematous rash occur, blisters and pustules may develop. Taking into account the age of patients with this disease, there is a certain risk of infectious complications in the affected areas of the skin.
- Stage 2 – hypertrophic or verrucose. It is characterized by the development of hyperkeratosis in the form of plaques, warty and lichenoid growths on the affected areas of the body. Their distribution is usually symmetrical and linear, along Charcot lines or projections of nerve trunks. The duration of this stage of the incontinentia pigmenti is several months (up to the age of one year), in some patients it may be absent.
- Stage 3 is pigmented. At this stage of the disease, patients with hyperpigmentation foci of various shapes and sizes of dark brown color appear on the affected areas of the skin. In almost half of patients with pathology, such foci appear on unchanged areas of the body and are not associated with rashes characteristic of previous stages. The duration of hyperpigmentation is several years, usually before puberty.
- Stage 4 is atrophic. It is characterized by the loss of pigment on the lesions with the development of signs of skin atrophy. In some patients with Bloch-Sulzberger syndrome, such manifestations may be very poorly expressed, in some cases, the symptoms of the disease completely disappear after puberty.
In addition to skin manifestations, disease can lead to the development of focal alopecia, nail dystrophy. Almost 80% of patients have anomalies of the dentition – curvature, absence of teeth. In half of the cases of the disease, visual disturbances are detected – cataracts, strabismus, optic nerve atrophy and some other disorders. Mental development in incontinentia pigmenti usually does not suffer, but some delay is possible. In rare cases, oligophrenia is noted. All manifestations of the disease tend to weaken after the end of adolescence.
Diagnosis and treatment
To determine the incontinentia pigmenti, many diagnostic methods and techniques are used – dermatological examination, study of hereditary history, histological examination of the affected areas of the skin, molecular genetic analyses. Examination reveals various (depending on the age of patients and the stage of the disease) skin changes of an erythematous, vesicular or hyperkeratic nature, in older patients, focal hyper- or hypopigmentation of the skin may be determined. In addition to these manifestations, with incontinentia pigmenti, nail dystrophy, alopecia, anomalies of the structure of teeth are possible.
A hereditary history can reveal the familial, dominant and X-linked nature of the inheritance of pathology. In some cases, the patient’s mother has a history of several cases of spontaneous termination of pregnancy – this is due to the intrauterine death of the male fetus. The results of histological examination of skin tissues in incontinentia pigmenti depend on the stage of the disease – at the first stage, spongiosis is detected, the development of epidermal blisters filled with eosinophils and fibrin masses. At the second stage of pathology, signs of intraepithelial keratinization, acanthosis and hyperkeratosis are revealed, edema with neutrophilic and eosinophilic infiltration is noted in the dermis. At the third stage of the Bloch-Sulzberger syndrome, inflammatory changes in the dermis (edema, infiltration) disappear, but there is a significant accumulation of pigment in the upper layers of the skin. The fourth stage is characterized by the disappearance of pigment, the development of fibrous tissue and the partial disappearance of skin appendages.
Molecular genetic diagnosis of incontinentia pigmenti is performed by a geneticist and can be performed by several basic techniques. Direct automatic sequencing of the sequence of the IKBKG gene makes it possible to detect almost any changes in its structure. Translocations and deletions of significant sections of the gene, often acting as the cause of incontinentia pigmenti, can be detected using the FISH analysis technique. This disease can also be confirmed by examining the inactivation of X chromosomes in the cells of the affected tissues.
There is currently no specific treatment for incontinentia pigmenti, skin lesions at the inflammatory stage of the disease are treated with antiseptic agents and solutions to prevent infectious complications. In addition, local administration of glucocorticoid steroids is recommended to reduce inflammation, but such treatment should be carried out with caution, given the high permeability of the skin in young children. Other manifestations of the Bloch-Sulzberger syndrome (malformations of teeth, eyes) are treated if there are indications.
Prognosis and prevention
The prognosis of incontinentia pigmenti is most often favorable, since since the onset of puberty, the manifestations of the disease weaken significantly. The prognosis may worsen changes in internal organs, nervous system, eyes, violations of which are occasionally observed in this pathology. In addition, in some cases of incontinentia pigmenti, primary immunodeficiency may occur, which also significantly worsens the prospects of the disease. Prevention of pathology is reduced only to prenatal diagnosis and medical and genetic counseling of parents with burdened heredity in the expectant mother.