Self-help Ichthyosis e.V.The self-help Ichthyosis e.V. is the only self-help group for this rare, genetic skin disease in Germany.
Federal Office for Self-Help Ichthyosis e.V.
c/o Kirstin Kiekbusch Strabe der Einheit 5d 15749 Mittenwalde OT Brusendorf
Phone 03 37 64 / 2 04 57 Fax 03 37 64 / 2 04 59 Mail [email protected]
Diagnostics and therapy of congenital ichthyoses
Revision status: 22.09.2020
from Prof. Dr. H. Traupe, Dr. Kira Submuth and Private lecturer Dr. V. Oji
University Skin Clinic Von-Esmarch-Str. 58 48149 Munster
Ichthyoses are disorders of keratinization that affect the entire or predominant surface of the skin and are based on weaving errors (mutations) in the genetic material (genes). A number of ichthyoses are already present at birth. Are therefore referred to as congenital. Other ichthyoses develop in the 1. Life year. Are called "vulgar" or also simple ichthyoses. They are called "vulgar" or simple ichthyosis. From the inherited ichthyoses one must distinguish such cornification disorders which are acquired, as e.g. B. the dry skin of old age or pathologically dry skin that develops in the context of nutritional deficiencies, z. B. can occur with a very one-sided, unbalanced vegetarian diet.
The genetic approach to ichthyosis has contributed a great deal to the understanding of this group of diseases. It is known today that there are certain predispositions (genes) whose products (proteins) are found exclusively in the skin. If such a gene has a mutation, the protein in question also has a defect or there is a deficiency of this protein. The resulting skin disease can of course then only manifest itself on the skin. A so-called non-syndromic ichthyosis develops, in which "only" the skin is affected. In addition, there are also genes that have roles in multiple organ systems. The proteins formed by these genes then occur not only in the skin, but z. B. also occur in bones, eyes, nerves and other ties. If a weaving error occurs in such a gene, then such a mutation leads to the fact that evenly not only the skin, but also other organs are affected. The result is then a so-called syndrome-ichthyosis, as it is present, for example, in the so-called Netherton syndrome or the Conradi-Hunermann-Happle syndrome. In this respect, we can distinguish two major groups, on the one hand the nonsyndromic congenital ichthyosis and on the other hand the syndromic congenital ichthyoses. Table 1 gives an overview. The somewhat cryptic abbreviations, such as ABCA12, etc., can be used to describe the disease., refer to the names of the causative genetic defects.
The non-syndromic congenital ichthyoses represent a group of disorders that include several individual ichthyoses. The most important of these diseases are discussed below.
Table 1 – Important congenital ichthyoses (selection) non-syndromic congenital ichthyoses
Harlequin babyAutosomal recessiveABCA12 Lamellar ichthyosisAutosomal dominantASPRV1 autosomal recessive congenital ichthyosis (ARCI)Autosomal recessive1. Transglutaminase-1 deficiency/TGM1 (ca. 30-50%) 2. Lipoxygenase mutations/ALOXE3 and ALOX12B 3. ABCA12 mutations 4. CERS3 5. CYP4F22 6. NIPAL4 7. PNPLA1 8. LIPN 9. SULT2B1 10. SDR9C7 Epidermolytic ichthyosisAutosomal-dominantKeratin-1- or. -10 defects Superficial epidermolytic ichthyosisAutosomal dominant Keratin 2e defect Confetti ichthyosisAutosomal dominantKeratin 10 defect Syndromal congenital ichthyosis
Sjogren-Larsson syndromeAutosomal recessiveDeficiencies fatty aldehyde dehydrogenase PIBIDS and Tay syndromeAutosomal recessiveDeficiencies DNA repair Netherton syndromeAutosomal recessiveLEKTI deficiency Conradi-Hunermann-Happle syndromeX-linked dominantCholesterol biosynthesis defect
2.1 Harlequin achthyosis
Harlequin ichthyosis is nowadays classified as a severe special form of autosomal recessive congenital ichthyosis. This is a very rare and at the same time extremely severe form of congenital ichthyosis, whereby patients are surrounded by an armor-like scaling at birth. Even today, a proportion of newborn children die shortly after birth. Often there are movement restrictions immediately after birth. These require additional movement therapy to prevent so-called flexion stiffening. Sometimes children with this clinical picture also have to be ventilated temporarily. When the critical phase in the first months of life is overcome, the further development is more favorable and the ichthyosis becomes milder and controllable. It clinically changes into a severe lamellar ichthyosis. However, the affected children have very large scales and a pronounced inflammation affecting the entire skin (so-called erythroderma).
Harlequin ichthyosis is inherited in an autosomal recessive manner. For parents with one affected child, the probability that further children will develop the disease is 25% per pregnancy. Causes a disorder in the so-called lamellar bodies/keratinosomes. In these structures, skin cells store mainly skin lipids, which are needed for the formation of the horny layer. The causative gene for harlequin ichthyosis involves so-called nonsense mutations in the ABCA12 gene. Remarkably, so-called missense mutations in the ABCA12 gene cause a much milder form of ARCI.
2.2 Other autosomal recessive congenital ichthyoses (ARCI)
There are other forms of autosomal recessive congenital ichthyoses. These were formerly also called non-blistering ichthyosis congenita. Today it is known that there is both an autosomal dominant inherited lamellar ichthyosis – quite rare – and the somewhat more frequent autosomal recessive inherited forms of congenital ichthyosis (ARCI). Lamellar ichthyosis, which is inherited in an autosomal dominant manner, is characterized, among other things, by pronounced scaling on the soles of the feet. This is caused by mutations in the gene ASPRV1, which is involved in the degradation of filaggrin. If there is a mutation in ASPRV1, the key protein filaggrin, which is so important for the skin, is incompletely degraded and too little moisture is stored in the horny layer. This ichthyosis is very rare
Children with autosomal recessive congenital ichthyosis are often born as a so-called collodion baby, where the skin is surrounded by a membrane, but the membrane is shed from the skin within 2 weeks after birth. A part of the patients then takes a very good course (ca. 10%) and develops only a "minimal ichthyosis" or even heals completely. This form of ARCI is also called self-healing collodion baby or "self improving congenital ichthyosis" (SICI). In the other part of the patients, however, a very severe bladder disease can develop. Permanent lamellar ichthyosis or severe congenital ichthyosis from the group of syndromic ichthyoses develop. Newborns with a collodion baby/skin represent a medical emergency. Therefore, they are treated in a neonatal intensive care unit for the first 2-4 weeks of their lives. After that, however, the children can be discharged from the pediatric hospital. The parents take over the complex care.
At present, it is amed that there are at least 10 different genetically distinct forms of autosomal recessive congenital ichthyosis (ARCI). Through gene-panel diagnostics in specialized laboratories such as the Institute of Human Genetics at the University of Freiburg (headed by Prof. Fischer) can be found today approx. 90% of all ARCI cases can be clarified genetically. In 10% the cause remains unclear.
The most common form is due to a mutation in a gene called transglutaminase-1, located on the long arm of chromosome 14. This so-called transglutaminase deficiency is found in about 35% of all patients with ARCI. Another, rather rare form is caused by a gene located on the long arm of chromosome 2. This form of the disease is caused by a mutation in the ABCA12 gene, which forms a transport protein for fats. This defect is quite rare in German families. A third form involves mutations in two genes located in close proximity on the short arm of chromosome 17, called "lipoxygenase" genes, which have roles in epidermal lipid metabolism. Table 1 lists further genetic defects in ARCI. Many of the causative genes involved have an important role in the lipid metabolism of the skin in the formation of the lipid layers ("cornified lipid envelope") of the horny layer.
2.3 Histochemical testing of transglutaminase-1 on the skin
In the past, histochemical testing of transglutaminase-1 in the skin played a major role in diagnostics. Today, this procedure is performed almost exclusively for research purposes. Molecular diagnostics, in which several possible gene defects are tested simultaneously from one blood sample (gene panel diagnostics), has replaced histochemical TG-1 measurement in the skin. However, the test allows a biochemical understanding of the disease.
At our clinic, we have developed a special diagnostic procedure called histochemical transglutaminase detection, which uses a skin biopsy (skin sample) on a frozen section to determine whether or not a patient has a transglutaminase deficiency. For this purpose, a skin sample of a few mm in size is taken under local anesthesia. This biopsy is first frozen in nitrogen and then stored at minus 80° Celsius to allow biochemical analysis at a later stage. For this, tiny sections are made from the sample and placed on a slide, which is then overlaid with a "substrate" for transglutaminase. If the transglutaminase is present in the skin and also functional, one recognizes in the microscope (by immunofluorescence technique) a lighting up in the skin layers which contain the transglutaminase. Therefore, if the substrate does not appear in the microscope image, it means that the transglutaminase is missing or defective. The strongest activity of transglutaminase is found in a layer called the granular layer – stratum granulosum – which is located below the stratum corneum (Fig. 1).
We have now performed the transglutaminase assay in over 100 patients with ARCI and have been able to detect transglutaminase deficiency in approx. 35% find a deficiency of transglutaminase. The task of transglutaminase-1 is to build a special coat that surrounds the horn cells. One also speaks of the formation of a cornified cell envelope. This cornified cell envelope is built up in the granule layer. Replaces in the stratum corneum the original membrane of the skin cells. The cornified envelope stabilizes the horny cells. Allows better anchoring of lipids present in the stratum corneum with the corneocytes. A variety of proteins enter or are anchored in the cornified envelope, such as transglutaminase. B. also the keratins and proteins that are responsible for anchoring structures and are called corneodesmosomes.
Fig. 1 Histochemical detection of transglutaminase 1 deficiency. a) Normal skin with activity in the granular layer (stratum granulosum) b) Lack of transglutaminase activity
The clinical picture of congenital ichthyosis can vary from a comparatively mild infestation, sometimes coupled with a clear inflammation, to a severe infestation with large dark brown scales.
In conclusion, it is not possible to determine with certainty whether a person with ARCI has a transglutaminase deficiency on the basis of the external appearance of the skin alone. To answer this question, further investigations such as the histochemical detection described above or confirmation by gene panel DNA diagnostics are necessary.
2.4 New directions in the therapy of transglutaminase deficiency
At the present time, modern diagnostics essentially represent a gain in information about oneself and one's own disease. For the future we hope that new ways in treatment will be found. Specifically, in Munster, within the framework of the Network for Ichthyosis and Related Cornification Disorders (NIRK) and with financial support from both the German Federal Ministry of Education and Research and the Selbsthilfe Ichthyose e. V. From October 2003 to summer 2013, a project was carried out in which the normal functional human gene of transglutaminase is introduced into insect cells and then forms a functional human transglutaminase protein in these cells (so-called recombinant expression). In this way, it was possible to produce transglutaminase-1 (TG1) in sufficient quantities and to show a therapeutic effect experimentally in mice with TG1-deficient ichthyosis in very elaborate studies. For this, the University of Munster received a so-called "orphan drug designation" from the EU in 2013. However, the pharmaceutical industry has so far been reluctant to adopt and further develop the process because the production of TG1 in insect cells is very expensive. With the support of SI and the Italian self-help organizations UNITI and UFFI, we have recently been able to resume research work and have now found a humane manufacturing system for TG1. Encouraging effects are seen in cell culture. Experiments with mice carrying grafts of human ichthyosis skin on their backs are planned in Madrid in 2021. We hope to be able to convince the pharmaceutical industry to take over the project (clinical translation).
2.5 The blistering (bullous) ichthyosis
Another group of congenital ichthyoses may be associated with blistering. These are the bullous or. epidermolytic ichthyosis. Here, too, the clinical appearance can vary greatly. While at birth or in 1. Although there is often a massive inflammation of the skin in the sense of the already mentioned erythroderma during the first year of life, the inflammation may later decrease and spiky scales and a scaly thickening of the skin may dominate the clinical picture. Especially in these patients the taking of skin samples is very useful, since characteristic fine tie changes can be detected, namely the finding of a so-called epidermolytic hyperkeratosis.
Essentially, 3 different forms of bullous ichthyosis can be distinguished today, namely, on the one hand, epidermolytic ichthyosis – formerly called bullous ichthyosiform erythroderma, named after the French physician Brocq – and, on the other hand, a mostly milder form, superficial epidermolytic ichthyosis, formerly called ichthyosis bullosa Siemens, named after the German dermatologist Siemens. In the severe form, mutations have been found in certain proteins in the horny cells. These are the keratins, which the layman also knows from the hair. Keratins 1 and 10, among others, are produced in the skin. These can have mutations in the severe forms of bullous ichthyosis. In the milder forms (type Siemens), it was found for the first time in patients from Munster, among others, that mutations in a different keratin, called keratin 2e, are the cause.
A third form is called confetti ichthyosis or CRIE (congenital reticular ichthyosiform erythroderma). Blistering does not occur in this form. In the foreground is the massive reddening of the skin (erythroderma) and after the 3. The development of many small white patches in which the ichthyosis regresses in patches due to reverse mutations, which is why it is also called confetti ichthyosis. Causes are again very specific mutations in the gene keratin10. Occasionally keratin 1. Unfortunately, the "back-mutated" skin is also not as it should be. Unfortunately, the "backmutated" skin is also not as it should be.
2.6 Syndromic congenital ichthyoses
From the multitude of associated congenital ichthyoses, we would like to discuss 2 specific forms, namely Conradi-Hunermann-Happle syndrome and Netherton syndrome.
The Conradi-Hunermann-Happle syndrome only occurs in women, which is due to the fact that affected boys die already in early pregnancy. Affected girls show generalized inflammation of the skin (erythroderma) at birth, but this regresses within the first few months. Besides ichthyosis, other organ systems are also affected, especially the bones. Here, a so-called chondrodysplasia punctata occurs at an early stage, d. h. This leads to punctiform calcifications in the growth plates and thus also partly to asymmetries in the bone system, e.g., in the bone. B. a unilateral shortening of the leg length or problems with the hip, etc. In addition, according to our own investigations, many girls show a short stature, which is, however, relatively mild. In other words, the girls are about 20 cm shorter than their healthy siblings. Many girls have lens opacities (cataracts), which are often also unilateral or sectorial, d. h. affect only one section of the eye. Ichthyosis is typically linear, d. h. Stripes arranged. The rest of the physical. Mental development is normal. The remaining physical. Mental development is normal. The causative gene for this disease is located on the short arm of the X chromosome. Is called "Emopamil-binding protein" (EBP). In the skin, the emopamil-binding protein has important roles in the final steps of cholesterol formation. The disease must therefore be regarded as a cholesterol formation disorder. Cholesterol precursors can be detected in the blood, which accumulate due to the enzyme block.
A biochemically closely related clinical picture is the so-called CHILD syndrome. Bone changes also occur with this disease, z. B. leg shortening, and to relatively circumscribed cornification disorders on the skin. The causative gene here is called NSDHL. The corresponding gene was elucidated by the partners from Marburg within the framework of the NIRK ichthyosis network funded by the German government.
2.7 Netherton syndrome
Children with Netherton's syndrome have very inflamed skin (erythroderma) at birth. In some children, the disease takes a mild course, and the skin inflammations regress significantly in the first months of life. A so-called ichthyosis linearis circumflexa then develops, which affects only parts of the body and shows arching skin changes. In many patients, however, the entire skin remains affected, although even then the inflammation of the skin improves somewhat with age.
This disease also affects the hair, which is brittle, especially easy to pull out, and has characteristic abnormalities (trichorrhexis invaginata/bamboo hair).
Associated with Netherton syndrome is often a tendency to allergies, such as z. B. Asthma. Hay fever. asthma and hay fever. In the severe forms of the disease, there is failure to thrive, often associated with growth retardation and enteropathy (malabsorption of food in the gastrointestinal tract). Many children are at risk for skin infections, z. B. by the germ Staphylococcus aureaus. Some also have severe immunodeficiencies, from which they can also die (e.g. B. Pseudomonas sepsis). The first year of life is especially critical.
The skin barrier is significantly disturbed in children with Netherton syndrome, and there is a marked increase in water loss through the skin. Especially with newborns, critical situations (dehydration) can occur here. Many children must therefore be treated as newborns in an intensive care unit.
Netherton syndrome is inherited in an autosomal recessive manner. The disease is caused by a deficiency of the serine protease inhibitor LEKTI, which is caused by mutations in the SPINK5 gene. Serine proteases include a number of enzymes such as z. B. Plasmin and trypsin as well as other trypsin-like enzymes in the skin such as the so-called stratum corneum chymotrypsin enzyme (kallikrein). Serine proteases can thus cleave other proteins. It is now known that they can also cleave anchoring structures between the skin cells, the so-called corneodesmosomes, and it is suspected that uninhibited activity of these enzymes in children with Netherton syndrome in their skin leads to a dissolution of the cohesion of the horny cells in the horny layer, so that the horny layer as a whole also becomes very thin. Indeed, children with Netherton syndrome have a microscopically thin horny layer, and their scales are usually comparatively fine.
To really understand the cause of this disease, one must think a little around the corner. There is a lack of an inhibitor in the skin (LEKTI). This leads to a balance disturbance. Certain other enzymes then work too violently. For the diagnosis of this clinical picture, the following are available in Munster. Also available in many other university hospitals in Germany good options for. Thus, on skin samples, it is possible to directly detect the deficiency of the inhibitor LEKTI in the skin (Fig. 2).
Fig. 2 LEKTI deficiency in Netherton syndrome. a) Normal skin with evidence of LEKTI in the stratum granulosum. b) Absence of LEKTI in a patient (from Traupe 2005)
Functionally, the enzyme kallikrein 5 cannot be inhibited in Netherton syndrome. There are approaches to use new inhibitors of kallikrein 5 as ointments for therapy. There are encouraging results in dogs. An Australian biotec company is currently trying to raise the money for a human clinical trial on the capital market. Another company focuses on a slightly different kallikrein. We are hopeful that clinical trials in affected patients will occur in the foreseeable future.
3.1 Treatment with ointments
The mainstay of any therapy for ichthyoses continues to be treatment with ointments. The overwhelming advantage of ointments is that they are easy to apply and most ointments have no side effects, so that even a lifelong application or. an application over very many years can be advocated without reservation. Many less severe forms of congenital ichthyosis can be treated quite well with ointments, but on the other hand many patients have found that ointment therapy alone is not sufficient. The time required for the care of the own body of patients with congenital ichthyosis is usually considerable. In no way comparable to the time spent on personal hygiene by "normal citizens". It should also be borne in mind that textiles worn must be washed more frequently and intensively, and that objects such as washing machines understandably wear out more quickly. In dermatologist German, ointment therapy is also referred to as local, d. h. topical or "topical" therapy designated.
At the beginning we would like to mention what should be avoided, what is at least problematic. This includes the use of salicylic acid. Salicylic acid is very effective in concentrations of 5 – 10%, but there are a number of considerations why a maximum of 25% of the body surface should be treated with an ointment containing salicylic acid. On the one hand, these are the acute toxicity, d. h. the toxicity, and on the other hand the presumed chronic toxicity. Regarding acute toxicity, there are case reports of infants who developed dizziness, ringing in the ears and shortness of breath, among other symptoms, or even died after multiple treatments with salicyl-containing ointments on the entire body. The latter is of course the extreme exception. One problem is that in many children with ichthyosis the skin is very massively inflamed and thus naturally much more permeable to both salicylic acid and other substances than normal skin (increased transepidermal water loss – see for example the section on this in Netherton's syndrome). Therefore, it is not possible to start from the situation encountered with normal skin.
While even today in dermatology salicylic acid is routinely and justifiably applied externally for the disease psoriasis, the situation is different for patients with ichthyosis, since here not only 20-25% of the body surface is affected by inflamed skin, but it is often the case that the entire skin is inflamed and thus very high amounts of salicylic acid are absorbed.
Even with less pronounced inflammation, the Large area application of salicylic acid problematic. If one ames that a patient needs 30 g of ointment per day and that a 10% salicylic acid ointment thus contains 3 g of salicylic acid, then with a resorption of approx. 20% or more of at least half a gram to one gram of salicylic acid per day can be ingested. The resulting strain on the body is comparable to a continuous load of 1 – 2 aspirin tablets per day. With such exposure, it must be amed that in the long run there will be considerable side effects, z. B. on the kidney, comes. In our opinion, salicylic acid should therefore only be used in ichthyosis patients for the treatment of smaller areas such as the skin. B. palms and soles of the feet suitable and definitely contraindicated for newborns.
Conclusion: We do not recommend the use of salicylic acid in congenital ichthyosis.
What to do with the newborn?
In the newborn and infant, the skin is not fully mature and therefore, ins-pecially when inflamed, is susceptible to a number of substances, z. B. also for urea, much more permeable than for older children and adults. Moreover, the newborn's body surface area in relation to its weight is 2.4 times greater than the body surface area of an adult.
For newborns, we therefore recommend first of all the use of pure care ointments/brand ointments (z. B. Linolafett®, Bepanthen®, Neribas® ointment). Patients have told us that they have had good experiences with the combination of linolenic fat and the vitamin E preparation Optovit® with their newborn children. In principle it is so that just in the ointment therapy also once different bases can and should be tested out, in order to find out individually, with which one gets along best.
Urea treatment is problematic in neonates if the entire body is to be treated. Here, too, there have been isolated reports of poisoning symptoms, although the intoxications were milder than in the case of salicylic acid poisoning. According to the medical guideline, which SI was also involved in drafting, urea treatment should only be started after the 1. Begin at the age of.
What is standard for small children and adults?
Saline ointments, containing up to 10% saline, urea-containing ointments, also containing up to 10% urea, and lactic acid-containing ointment, also containing up to 10% active ingredient, have been tried and tested for a long time. Many patients know from their own experience the good effect of a bath in the Mediterranean Sea. Of a subsequent stay in the sun. Bathing in salt water in the North Sea can also be helpful, just as a stay already at the North Sea for reasons of the high salt content of the air often helps. These effects were also known earlier, and therefore the salt treatment has a long tradition. However, to make salt baths that are effective, at least a 3% salt concentration is needed, d. h. that with 150 liters volume of bath water per bath tub 4,5 kg salt must be added to the bath. This is not feasible for the vast majority of patients, if only for technical reasons. May also lead to corrosion effects on tubing. However, for circumscribed periods of time, z. B. in the context of a stay in a rehabilitation clinic, a so-called Balneo-photo-therapy, which involves bathing and subsequent treatment with UV light. This balneo-photo-therapy is offered in many rehabilitation clinics. In Munster, we do not perform balneo-photo therapy on patients with ichthyosis.
We have had rather bad experiences with the dissolving of common salt in ointment in the formulation of ointments in the outpatient therapy. A number of patients have reported that they were not satisfied with these and felt that the salt crystallized out and rubbed uncomfortably on the skin.
On the other hand, I have heard from other sufferers that their experiences were much better. Obviously it depends on how the pharmacist dissolves the salt and then incorporates it into the ointment. A good trick seems to be to first add salt in a small volume of water, z. B. 20 – 40 ml, dissolve the salt, then warm the ointment slightly and work the dissolved water into the slightly warmed ointment. In particular, the basic base called Unguentum Cordes®, which is popular in Munster, is easier to work with and also easier to apply once it has been warmed up. For the spreadability of the Unguentum Cordes ointment, the water content of this ointment is also important, we usually add a 20% water content. It makes sense that the Unguentum Cordes ointment is then stored in the refrigerator, but the amount to be applied daily is taken out shortly before application and warmed, for example, on the heater or in the hand.
It can thus be stated that saline ointments can feel quite pleasant on the skin and often also have the effect of "visually" smoothing the skin, i.e. making it appear less flaky. The scale-dissolving ("keratolytic") effect, however, is less than with urea- and lactic acid-containing preparations.
About vitamin A acid
An additive that is quite effective is vitamin A acid. The use of vitamin A acid in concentrations of 0.03% – 0.1% was first introduced in 1962 by Prof. Swanbeck. Stuttgen introduced. He could prove that the topical application of vitamin A acid can be quite effective, however, vitamin A acid is very often also irritating to the skin. For patients with very inflammatory courses, d. h., if the skin is very red, vitamin A acid is therefore not suitable. As a commercial preparation there are z. B. the preparation VAS-Carbamid-Widmer®. We use this preparation on problem areas, z. B. if you have a thick scaling in the neck area or also on the forehead and want to dissolve it. One can also decide not to treat every day with the ointment containing vitamin A acid, but z. B. only every second or every third day. In this way, skin irritation can be avoided in most cases. On the other days, one can then apply a urea-containing cream or a nourishing ointment.
Treatment with urea is based on Prof. Swanbeck, a dermatologist from Sweden, and was first used by him in 1968. Today, urea treatment is a very proven standard therapy, although it must be said that urea can also be irritating to skin lesions, especially if more than 5% is used. Many children mention that urea preparations "burn" on the skin and are not pleasant to them. Patients with very inflammatory forms of ichthyosis, in which the skin is more reddened, also tolerate urea poorly. Glycerin-containing ointments such as Dexeryl® cream are suitable here. Urea "hydrates" the epidermis as it binds water. The skin is "watered", so to speak. It also inhibits cell division. Can dissolve proteins ("keratolytic effect"). The effect of urea can be further increased by adding z. B. Lactic acid or also common salt combined with it. A formulation commonly used in Munster is as follows:
Urea pura 20.0 Aqua dest. 40.0 Ung. Cordes to 200,0
The water content of 20% specified in this ointment can also be increased to 40%, which improves the spreadability somewhat.
About lactic acid
Treatment with lactic acid was introduced into the treatment of ichthyosis by van Scott and Yu in 1974 and is very popular in the USA. Lactic acid can also be very irritating. Exhibits a number of other "galenic" problems. Unfortunately, the production of ointments containing lactic acid is not trivial. Lactic acid, as already mentioned, can also be combined with urea, in which case we advise not to exceed a 10% urea concentration and not to combine it with more than 5% lactic acid. Many ready-to-use products also contain both active ingredients, as lactic acid also acts as a preservative in ointments.
For the treatment with lactic acid as well as with urea it has to be considered that also here the ointment base plays an important role. In general, with a few exceptions, ointments are lipid bases from which urea has a greater depth effect when applied to the skin. Creams, on the other hand, contain more water and are therefore easier to apply, but the depth effect of the preparations mixed in is not quite as great. The latter can also be said about the so-called lotions containing urea.
To ointments containing vitamin D
Vitamin D-containing ointments containing, among others, the substances calcipotriol and calcitriol, such as those used for the treatment of the skin. B. The substances present in Psorcutan® or Curatoderm® are used for patients with psoriasis and also for children with psoriasis. However, it should be noted that these preparations are not suitable for treatment of the entire body, as they are not approved for this purpose and full-body treatment may lead to calcification of the skin. B. can occur in the kidney. Ointments containing vitamin D can therefore only be used on small areas, a maximum of one third of the body surface, in patients with congenital ichthyosis. The effect of these ointments is possibly also partly dependent on the form of ichthyosis.
About polyethylene glycol (macrogol)
We were informed about this form of treatment in 2003-2009 by the research group of Prof. Kuster in Bad Salzschlirf, who had very positive experiences with patients who had received undiluted polyethylene glycol batch 400 for severe head infestations. Polyethylene glycol has a keratolytic effect due to the protein-denaturing properties of this substance. However, undiluted polyethylene glycol is very liquid. In my opinion, not suitable for the body as an ointment base. On the head, on the other hand, a liquid. Thus easily applicable base quite desirable. Chemically, polyethylene glycol is a "polymer" of ethylene oxide, which is added to many cosmetic products. The designation "400" refers to the molecular weight. Polyethylene glycol is non-toxic to the skin and does not irritate. However, colleagues from pediatrics have criticized that macrogol can also be absorbed into the blood and can have a "hyperosmolar" effect – i.e. can make the blood "thicker. In clinical practice, however, we have not had any negative experiences so far.
In recent years, we have used a 20% addition of polyethylene glycol of batch (molecular weight) 400 in many patients and z. B. can be mixed together with 20% water in the ointment base Unguentum Cordes which we use routinely. In our experience, the effect of such an ointment containing polyethylene glycol is quite equivalent to treatment with a 5% urea additive. However, the ointment containing polyethylene glycol has the decisive advantage that it does not "burn" on the skin. A formulation often used in Munster looks as follows:
Polyethylene glycol Charge 400 40.0 Aqua dest 40.0 Ung. Cordes to 200.0g
It should be noted, however, that this cream after the 12. B It is considered to be non-toxic and better tolerated on the skin than urea, and is only reimbursable by the statutory health insurance funds with an additional urea content of 5%. Glycerin is also hydrating. Is applied in ointments with about 15%. It is considered non-toxic and is better tolerated on the skin than urea. A finished product is Dexeryl® cream.
Daily baths help many patients with congenital ichthyosis considerably and are sometimes done as a cleansing bath, sometimes with the addition of table salt, bath oil or baking soda. In the baths, the skin is softened, and then you can manually brush the skin with various tools to perform a mechanical removal of scales in the bath. At the same time, the baths serve to remove ointment residues, scales and bacteria from the skin. If you want to add a bath oil additive, then it is recommended to use a spreading oil bath like z. B. the commercial preparation Balmandolol®. This oil can also be applied pure to the skin – for example after bathing. In the case of an oil bath, it is important that the oil film is not "rubbed off" the skin during drying. It may therefore be worth considering a daily cleansing bath with mechanical scale removal first, and only then applying an oil. Foam baths are counterproductive, as they lead to a violation of the lipid skin film. However, many sufferers avoid oil baths because it is easy to slip on a film of oil in the bathtub, and when drying off the oil film is removed from the skin and ends up in the towel.
Due to ignorance, many dermatologists advise patients with keratinization disorders not to take a daily bath because they believe that this would exacerbate the problem of dry skin. However, this is not the case, it is sufficient to stay away from bubble baths and too much shower gels. Daily contact with water is not a problem for the skin, if it is lubricated accordingly.
Baking soda or. Sodium bicarbonate as a bath additive
Many members of the self-help group have reported to us almost "euphorically" that they add baking soda, resp. Add sodium bicarbonate (about 6g per liter, so that the water feels greasy), and that this has a strong scale-dissolving effect, although in some cases also somewhat stressing the skin. In the AWMF guideline, this form of treatment is now recommended, but the prescription of sodium bicarbonate at the expense of the GKV can cause problems.
About the steam sauna
In self-help, the idea was also born to favorably influence the skin appearance in ichthyosis with the help of a steam sauna. However, the installation of a steam sauna in one's own home is not exactly cheap, and one should first try out whether this method really helps and is pleasant for one. Conceptually, steam sauna treatment leads to high humidity and can thus "hydrate" both the stratum corneum and the underlying layers of the epidermis, thus mimicking the active principle of urea.
3.2 Internal treatment with retinoids
The internal or systemic therapy with Retinoids (d. h. The use of oil baths (with derivatives of vitamin A acid) for patients with ichthyosis was started in Switzerland and Germany in about 1977. There are therefore some patients who have had personal experience with this therapy for more than 40 years.
For the treatment with vitamin A acid preparations, the preparation Neotigason® (active ingredient acitretin) is mainly used in Germany. It has a number of effects that are mediated directly through the cell nucleus. A large number of genes are influenced by this preparation, but no specific correction of a genetic disorder takes place. In this respect, therapy with Neotigason or with another retinoid is always a symptomatic or symptom-suppressing treatment, similar to the treatment with ointments. Retinoids were originally developed to treat patients with psoriasis or acne. It was only then that it was found that patients with ichthyosis also benefit well from it. However, the aim of retinoid therapy should not be to make ointment treatment superfluous, but to supplement it in a meaningful way.
Before initiating therapy, retinoids require laboratory and a series of radiographic examinations to rule out growth disturbance. During therapy, if necessary. further X-ray controls are necessary, especially in the case of complaints of the skeletal system. The usual dosage recommended for neotigasone is generally 0.5 mg/kg body weight, but individual dose adjustment is required. In the course of a long-term therapy – designed for longer than 1 year – one should always strive to carry out an ointment treatment at the same time in order to keep the total dose (cumulative effects) of the retinoids low. It should be remembered that even with long-term therapy, laboratory controls should be performed at least every 3 months. Here the liver values as well as the fat values must be checked. Checking the blood count. In some patients, the preparation can lead to an increase in cholesterol and triglycerides.
There are a number of subjectively unpleasant side effects under treatment with retinoids, but most of them are tolerable and manageable. These include, among other things, that the lips may become dry (labial inflammation). Both the nasal mucosa and the eye mucosa may become noticeably dry. These side effects can be controlled by appropriate countermeasures such as z. B. the use of lipsticks, nasal oil and eye drops are usually well controlled and are partly also dose-dependent.
Some patients also develop headaches while taking the drug, which may be a reflection of increased intracranial prere after retinoid use. In the vast majority of cases, the headache subsides by itself after a while of taking the medication. However, if they are very severe, the patient may be forced to stop taking the medicine. Also some antibiotics (z. B. the so-called tetracyclines) can cause increased intracranial prere. Therefore, they should not be combined with a retinoid if possible.
Occasionally, Neotigasone may cause "muscle soreness", which usually resolves after dose reduction or spontaneously. Regressive hair loss is also observed after prolonged treatment – in our experience especially frequently in women. However, it is usually not really bad. From time to time, the skin on the hands and feet can be seen to peel off more and more.
Much more seriously, mood swings (depression) can very occasionally occur with retinoids, but in our experience these are more likely to occur with the related drug isotretinoin, and we have not personally seen them in patients with ichthyosis or psoriasis with respect to neotigasone.
We observe that neotigasone is absorbed (reabsorbed) very differently by patients, so that the dose necessary to achieve a satisfactory effect varies greatly from individual to individual.
A major problem in the therapy with neotigasone is the Pregnancy because the preparation is absolutely Harmful to fertility and that one must not become pregnant under this therapy. Since the drug can also accumulate in fatty tie, women must continue to take Neotigasone for 3 years after discontinuation (!) refrain from pregnancy. This leads to a particular reluctance to use neotigasone in women and female teenagers. However, the retinoid isotretinoin is an alternative preparation in this case.
Acicutan (Neotigason®) and the skeleton
If the preparation Neotigason® is given for many years (5 and more years), controls of the spinal column are necessary in order to prevent so-called hyperostoses, d. h. calcifications z. B. in the area of the ligamentous apparatus of the spinal column as well as on bones to be excluded. However, the disease value of hyperostoses is not entirely clear, since many elderly people develop such hyperostoses even without neotigasone treatment. In the worst case, the mobility can be reduced. B. are restricted in the back. In my personal experience, many older ichthyosis patients develop such problems during long-term therapy. However, these problems can occur in older people just as well without retinoid therapy. As long as there is no clear symptomatology, the discontinuation of retinoid therapy when hyperostoses are detected is not mandatory.
The initially very good success of neotigasone therapy cannot be maintained in the same way in the long term in many patients. Nevertheless, retinoid therapy can be an enormous relief for everyday life.
To summarize: after careful consideration, we consider the administration of neotigasone to be reasonable and still justifiable, even over long periods such as 10 or 20 years. The use must be carefully considered in each individual case. Being monitored in the long term.
Neotigason® and children
Neotigason® (active ingredient Acicutan) is also approved for use in children and adolescents. Here, however, one must be aware that side effects on the maturation of the growth plates of the bones are not really predictable and may even occur unnoticed at first. In the literature there are only a few reports on this subject, which also concern patients who have been treated with relatively high doses. Personally, a patient whom we treated in Munster as an adolescent for several years with a medium dose of Neotigason® reported to me that he had an asymmetric outgrowth of the legs and a leg length difference of 2.5 cm. Wears special footwear for this reason. We suspect that this is ultimately an undesirable side effect of the neotigasone therapy carried out at the time. We have therefore become quite cautious about the use of neotigasone in adolescents and children, but we are also aware that neotigasone therapy can be a blessing for adolescents, especially in the case of the many problems that occur during puberty. We consider the administration of neotigasone in harlequin ichthyosis to be justifiable and reasonable and otherwise recommend not starting acitretin until after 16. to start the treatment at the age of. In neighboring European countries such as France or the UK, the view is usually more "relaxed". It should be noted that the dosage of the drug plays a decisive role with regard to the possible side effects and nowadays we choose lower and more cautious dosages.
For psoriasis and neurodermatitis, the so-called biologics have been celebrating great therapeutic successes for some years now. In ichthyosis we often see an accompanying inflammatory component similar to psoriasis or neurodermatitis. We have already used biologics in these cases; and there is the prospect of a clinical trial for inflammatory ichthyosis, which could take place in centers in Berlin, Rostock and Munster. We have observed in individual cases of ichthyosis sometimes very good effects with one or the other biologic and are therefore glad that there is new research activity in this field. We have to answer the question which biologic can be used for which form of ichthyosis, and the safety of the treatment is closely monitored. For psoriasis z. B. some sufferers have a subcutaneous injection at home every 1-3 months. Have the general blood values checked every 3 months. B. some patients have a subcutaneous injection at home every 1-3 months. Have general blood values checked every 3 months. Affected patients receive a subcutaneous injection at home every 1-3 months. Have the general blood values checked every 3 months.
We thank our patients for their cooperation and feedback. In particular, the exchange of experiences with the self-help Ichthyosis e.V. is always important for us. The scientific work of Prof. Heiko Traupe on the topic of ichthyoses were funded by the German Federal Ministry of Education and Research (BMBF) within the funding priority of the BMBF Network for Rare Diseases GFGM01143901 from 2003 to 2013, here the funding of the Network for Ichthyoses and Related Cornification Disorders, by the German Research Foundation (DFG TR228/6-2) and by the Selbsthilfe Ichthyose e.V. I am especially grateful to SI and UFFI for the current funding of research on enzyme cream in transglutaminase-1 deficiency related ARCI (lamellar ichthyosis) which will continue after my retirement from the Munster clinic.
You are also welcome to send me (Heiko Traupe) an e-mail with a personal question. Please keep in mind that I am now retired and often visit the skin clinic only once a week. My co-author, Dr. Vinzenz Oji is currently working with Dr. Kira Submuth once a week the ichthyosis consultation at the Munster clinic by. Is otherwise established as a dermatologist with his own practice in Munster. A further clinical contact person in Munster is Dr. Kira Submuth at the disposal. Among other things, her scientific work focuses on the histological pattern diagnostics of ichthyosis.