The development of ichthyosis is now believed to result from genetic defects affecting the epidermal barrier along with a concomitant homeostatic repair response.
Among patients with two filaggrin mutations, about 30% do not have atopy; one filaggrin mutation is sufficient for predisposing patients to atopic eczema or allergic rhinitis.
Newborns with harlequin ichthyosis or who are born as a collodion baby are considered a “dermatological emergency” and should be transferred to a neonatal intensive care unit.
Patients with ARCI or keratinopathic ichthyosis often have significant vitamin D deficiency.
Long daily baths and mechanical keratolysis are essential for patients with severe ichthyosis.
Patients should be encouraged to contact and join a self-help organization.
Ichthyoses are genetically determined Mendelian disorders of cornification (MEDOC) that are characterized by universal scaling. Today we distinguish between non-syndromic and syndromic forms. Ichthyosis vulgaris is the most frequent type (prevalence 1:100) and is caused by autosomal semi-dominant filaggrin mutations. It is associated with a higher risk for the development of atopic diseases, such as atopic eczema and allergic rhinitis. Recessive X-linked ichthyosis (RXLI) occurs almost exclusively in boys; in Germany it has a prevalence of around 1:4,000. It is caused by steroid sulfatase deficiency and is often associated with further clinical problems, such as cryptorchidism (∼20%) or social communication deficits, such as attention deficit hyperactivity syndrome (40%) or autism (25%). Autosomal recessive congenital ichthyosis (ARCI) is genetically very heterogeneous and 8 different genes have been identified so far. The most frequent cause of ARCI is a transglutaminase 1 deficiency (prevalence 1:200, 000). Mutations in keratin genes are the cause of the keratinopathic ichthyoses, such as epidermolytic ichthyosis. They manifest at birth and often feature episodes of blistering. Most of these types are inherited as autosomal dominant traits, but autosomal recessive forms have also been described on occasion.
Ichthyoses belong to the large and clinically and genetically heterogeneous group of Mendelian disorders of cornification (MEDOC) . Ichthyoses are characterized by universal scaling, which usually involves the entire skin surface. In the patient's first year of life, congenital ichthyosis in particular may be life-threatening; the disease is often accompanied by severe skin inflammation and problems such as hypothermia and dehydration as a result of transepidermal water loss. In palmoplantar keratosis or palmoplantar keratoderma, unlike ichthyosis, the cornification disorder is not widespread, but almost exclusively affects the hands and feet. The previous distinction commonly made between ichthyoses and erythrokeratodermia is no longer used; rather, erythrokeratodermia is now considered a type of ichthyosis.
An important result of the consensus conference on ichthyosis was that we now distinguish between syndromic and non-syndromic forms of the disease. This distinction was first proposed by Traupe in 1989. The former division between “congenital onset” and “non-congenital manifestation” has fallen out of favor. Certain diseases such as X-linked recessive ichthyosis appear at birth in some patients and after several months in others. Instead, we distinguish between common and rare forms of ichthyosis. Common forms include ichthyosis vulgaris, with a prevalence of 1:100, as well as recessive X -linked ichthyosis. The latter has a prevalence of about 1:4,000. Based on European Union criteria, it is considered a rare disease. In non-syndromic ichthyosis, phenotypic expression of the underlying genetic defect is limited to the skin; in syndromic ichthyosis, the disorder is part of a larger syndrome as the genetic defect also affects other organs.
This review addresses only non-syndromic ichthyoses. It discusses recent findings on the biology of the diseases as well as surprising insights into their clinical variability.
The development of hyperkeratosis and ichthyosis as a clinical disease is now understood as a homeostatic repair response due to an abnormal epidermal barrier [1, 2]. Animal experiments in which the causal gene for ichthyosis is switched off have contributed to a better understanding of the disorder. The results of studies on mouse models, e.g., in regard to a transglutaminase deficiency, the lipoxygenase (ALOX12B) mutation, or the mutation in ABCA12 underlying harlequin ichthyosis (or for severe, lamellar ichthyosis), have shown that in all models, the animals are born with a severe clinical barrier defect. Most die within hours of birth. In nearly all mouse models of ichthyosis, the disease is lethal. The reason is a serious barrier defect, which leads to problems such as massively increased transepidermal water loss, against which mice (unlike humans) cannot compensated. Another difference between mouse models and human beings is that at birth mice do not have hyperkeratosis, but only inflammation of the skin and a deficient barrier. In humans, hyperkeratosis is believed to be part of a repair process. In the mouse models, hyperkeratosis has been observed in transplantation experiments. If a piece of skin is transplanted from a mouse with ichthyosis to an immunodeficient mouse, the transplant develops hyperkeratosis, which corresponds to ichthyosis in humans .
Epidemiology and cause
The most common type of ichthyosis is ichthyosis vulgaris. Data from Northern England have reported a prevalence of 1:100 . The cause of disease is filaggrin mutations, which are inherited as an autosomal semi-dominant trait. About two-thirds of patients have two filaggrin mutations with relatively serious disease; one-third of those with the disease have only one filaggrin mutation and a milder course . The null mutations in the filaggrin gene lead to a marked reduction of natural moisturizing factors (NMF), which play an important role in hydration of the stratum corneum. Physiological studies have shown that in people with two filaggrin mutations, skin moisture levels are moderately (up to one-third) lower, while at the same time there is a moderate increase in transepidermal water loss .
Histology and ultrastructure
Patients with ichthyosis vulgaris have orthohyperkeratosis with a diminished or absent granular layer. In terms of ultrastructure, the filaggrin deficiency leads to a characteristic keratohyalin defect, with abnormally small and crumbly granules.
The typical clinical presentation consists of a fine, usually light gray scale. The joint flexures are not involved, and scaling usually does not occur until two to six months after birth (Figure 1a). There is spontaneous improvement during the summer. Many patients say that they do not sweat normally . The furrows on the hands are typically deeper (hyperlinearity) (Figure 1b).
Some 50% of patients with ichthyosis vulgaris develop atopic dermatitis, and another 20% develop other atopic manifestations such as allergic rhinitis and bronchial asthma.
Recessive X-linked ichthyosis
Epidemiology and cause
Recessive X-linked ichthyosis (XRI) nearly always manifests in boys. The prevalence of disease is about 1:4,000. The disease is caused by mutations in the gene for steroid sulfatase (STS); in about 90% of patients, there is a deletion affecting the STS gene. This deletion can extend to adjacent genes, which may lead to more complex disease associations such as XRI occurring in Kallmann syndrome, the recessive form of X-linked ichthyosis chondrodysplasia punctata, or the common cryptorchidism (ca. 20%), with attention-deficit hyperactivity syndrome (ADHS) (40%), or with autism (25%) . The high rate of ADHS may also be a direct result of steroid sulfatase deficiency.
Histology and ultrastructure
Histology reveals orthohyperkeratosis and a well-maintained, sometimes thicker granular layer. Ultrastructurally, there are persistent corneodesmosomes (retention hyperkeratosis).
The clinical appearance consists of firmly attached, rhomboid scales covering the whole body. The elbows and the backs of the knees are usually spared. The palms of the hands and the soles of the feet are unaffected. About 70% of patients have a light brown scale (Figure 2b), and in 30% the scale is light gray (Figure 2a). Mothers of boys with the disease frequently report complications during birth, including weakness of labour or the need for a Cesarean section.
Autosomal recessive congenital ichthyosis (ARCI)
This term includes all non-syndromic autosomal recessive congenital forms of ichthyosis without a tendency toward blistering; it includes harlequin ichthyosis as well as lamellar ichthyosis and congenital ichthyosiform erythroderma . This group of diseases is caused by diverse genetic defects (Table 1) . There are genotype-phenotype relationships in terms of certain mutations, e.g., in the transglutaminase 1 gene, which may cause bathing suit ichthyosis, while other mutations in the same gene at another site may also be associated with inflammatory forms of ARCI (congenital ichthyosiform erythroderma). Certain ABCA12 mutations as well may cause lamellar ichthyosis, while in CERS3 patients, both phenotypes have been described. The LIPN mutation causes a clinical appearance that is not yet present at birth; nevertheless, it is classified as ARCI by the group that first reported this entity.
Table 1. Gene defects in autosomal recessive congenital ichthyosis (ARCI)
Bathing suit ichthyosis (BSI)
Formation of the cornified envelope
Congenital ichthyosiform erythroderma
Epidermal lipoxygenase/hepoxilin metabolism
Epidermal lipid barrier
Epidemiology and cause
Recent data show that the prevalence of ARCI in the German population is 1.7:100,000. The data on the prevalence of ARCI in Spain are similar (1.6 : 100,000) . In regard to the transglutaminase 1 deficiency, the most common cause of ARCI, there is a prevalence of 1:200,000 in Germany.
Histology and ultrastructure
The histological appearance of ARCI varies. Given the variety of genetic defects, this is not surprising. Typical features include orthohyperkeratosis, a well-developed, thicker granular layer, and usually epidermal thickening as a sign of epidermal hyperproliferation as well as lymphohistiocytic infiltrates in the dermis as an expression of the accompanying inflammation. Electron microscopy shows genetic defects which are correlated with the typical findings such as the presence of cholesterol clefts in the horny layer in transglutaminase 1 deficiency or balloon-like lamellar bodies in harlequin ichthyosis as a result of an ABCA12 nonsense mutation. Vesicular structures in the lamellar bodies are commonly found in mutations in the lipoxygenase genes or in the NIPAL4 gene. In Germany, a transglutaminase 1 deficiency is found in about 30% of all patients with ARCI; the second most common cause are mutations in the lipoxygenase genes ALOXE3 and ALOX12B, which are found in about 10% of all patients . NIPAL4 mutations and CYP4F22 mutations are also more common, while mutations in the gene for ABCA12 or PNPLA1 or CERS3 are very rare.
With the exception of harlequin ichthyosis, ARCI generally manifests at birth as “collodion baby.” Cyp4F22 patients are rarely born as collodion babies. In harlequin ichthyosis, the babies are born with armor-like skin (Figure 3a), which can considerably impair movement and often limits the ability to breathe and eat or drink. Ectropion and eclabium are also major problems as is the tendency toward infection of the skin and other organs (e.g., lungs). Even today, about 50% of babies born with harlequin ichthyosis die of the disease. In children who survive the critical phase of disease, the thickening of the stratum corneum resolves somewhat, and large, lamellar scales develop; symptoms are accompanied by marked skin inflammation (erythroderma) (Figure 3b).
The more common clinical presentation of ARCI at birth is collodion baby (Figure 4). The term describes a transient condition in newborns. At birth, children born with the disease are encased in a shiny membrane, which cracks within a few days and then usually peels within the first four weeks of life. Afterward, there may be complete healing, which is temporary. In most instances, collodion baby is followed by the development of classic severe congenital ichthyosis. Clinical presentations include lamellar scaling with dark brown keratosis; this is usually accompanied by underlying inflammation (clinical appearance of lamellar ichthyosis) (Figure 5a, b). Other presentations include a fine, light gray scaling, often with accompanying inflammation (congenital ichthyosiform erythroderma). Typically, the large joint flexures are involved; many patients also have keratotic lichenification, i.e., keratotic coarsening of the skin relief. This is also seen in other types of ichthyosis such as Sjögren-Larsson syndrome.
Immediate management problems in harlequin ichthyosis and collodion baby at birth
The infants have a very abnormal epidermal barrier, which leads to transepidermal water loss and thus problems such as hypothermia and hypernatremic dehydration. They should thus be placed in an incubator with high humidity (70–80%) and their weight continually monitored in order to detect any water loss. Occasionally, infusions and the use of a gastric tube are needed. To treat ectropion, a special eye ointment (e.g., dexpanthenol-based Corneregel®) is advisable. During the first year of life, topical treatment should consist of bland ointments.
In about 10% of collodion babies, there is either long-term clinical healing or the disease transitions into very mild forms of ARCI. The previously used term “self-healing collodion baby” has been replaced by self-improving congenital ichthyosis (SICI). Ichthyosis types with self-healing or marked spontaneous improvement have been reported in patients with transglutaminase 1 deficiency and in those with ALOX12B and ALOXE3 mutations .
Another special clinical type is bathing suit ichthyosis (BSI). These are also collodion babies, but then there is long-term healing on the extremities (Figure 6). The cause of BSI are temperature-sensitive mutations in transglutaminase 1.
The technical term “keratinopathic” was agreed on at a consensus conference as an umbrella term for all types of ichthyosis whose mutations are due to one of the keratin genes (Table 2). The cause is usually autosomal dominant inheritance, although autosomal recessive inheritance can occasionally occur.
Table 2. Gene defects in keratinopathic ichthyoses
*Formerly known as “Brocq.” **Formerly known as “ichthyosis bullosa Siemens.”
In terms of histology, most types of keratinopathic ichthyosis exhibit epidermolytic hyperkeratosis. The ultrastructure is characterized by collapsed keratin aggregates (tonofilaments). These often aggregate around the cell nucleus; they have lost their connection to the desmosomes. The keratinocytes therefore no longer are connected to each other which promotes an intraepidermal blistering. The clinical appearance may thus include blistering. In mutations involving the keratin genes 1 and 10, the problem develops in the suprabasal layers of the epidermis (for example in the model disease of epidermolytic ichthyosis). In a mutation in the keratin 2 gene, with expression at the level of the granular layer, the corresponding findings are found at higher levels of the epidermis. Clinically, this leads to superficial epidermolytic ichthyosis.
Clinical presentation of epidermolytic ichthyosis (mutation KRT1 or KRT10)
At birth, the presentation usually consists of congenital ichthyosiform erythroderma, sometimes with marked blistering. In newborns, differential diagnosis often includes epidermolysis bullosa. In the first months of life, the blistering resolves and hyperkeratosis develops. Often, there is keratotic lichenification (Figure 7), and sometimes there are very prominent spiny scales, especially in regions where the body temperature is somewhat elevated, such as the flexures and axillae. In mutations in KRT1, the palms as well as the soles of the feet are often affected, which can significantly impair walking.
The treatment of patients with KRT1 mutations if often very difficult, and the use of systemic retinoids such as acitretin may worsen disease. Patients with a keratin 10 mutation generally respond well to moderate dosages of systemic retinoids (0.5 mg/kg of body weight).
At birth, the clinical appearance resembles that of epidermolytic ichthyosis. Yet, over the course of disease, it is milder and more localized. That is, the keratosis is limited to the region around the navel, on the hands and feet (dorsal aspect), or the arm and axillary region, while there is healing on much of the upper body.
Congenital reticular ichthyosiform erythroderma (CRIE, “ichthyosis with confetti”)
At birth, the clinical appearance consists of severe congenital ichthyosiform erythroderma, which also dominates the clinical appearance in the first years of life. Patients also have keratotic lichenification. At the age of 3–10 years, multiple white islands form which can later grow to 2 cm in size. In terms of molecular genetics, there may be localized spontaneous healing (i.e., natural gene therapy) due to recombination processes. Many patients with CRIE are severely ill and fail to thrive. Often there are bone remodeling processes, for instance, affecting the ankle joints.
Treatment of non-syndromic ichthyosis
Generally speaking, only non-specific measures are available to alleviate symptoms. Only for transglutaminase 1-deficient ichthyosis is there a causal topical enzyme replacement therapy on the horizon. The goal of most treatment measures is to reduce scaling, for example by elevating the moisture level of the skin. Urea-based ointments (up to 10%) and lactic acid-based ointments (also up to 10%) as well as glycerin-based ointments are available. Substances such as macrogol 400 can decrease scaling; this may be incorporated into ointments in concentrations of up to 20%. In Germany, ointments with higher water content are preferred for the treatment of ichthyosis. In terms of galenical composition, these correspond to a cream. In other countries, such as Great Britain, petrolatum-like ointments are used. For patients with ichthyosis vulgaris and X-linked recessive ichthyosis, twice daily application of cream with a urea-based or glycerin-based ointment (e.g., Dexeryl®) is sufficient. Patients with ARCI or keratinopathic ichthyosis generally also need to bathe at least once a day. After soaking the skin, the patient or the parents of the patient can use a sponge or microfiber cloth to rub the skin and thus promote desquamation as well as remove any remaining ointment. Afterward, the ointment may be carefully applied. For problem areas, vitamin A acid ointments may also be used, for instance on the knees and elbow joints. Patients with marked inflammation (e.g., congenital ichthyosiform erythroderma) often cannot tolerate ointments containing urea or lactic acid. Other substances, such as glycerin, dexpanthenol, or macrogol should be used. Systemic retinoids, such as acitretin, are frequently administered to patients over age 16 (who have stopped growing). In women, the possibility of birth defects should be recalled. In patients with harlequin ichthyosis, the use of retinoids is warranted, even in newborns. In Germany, there is a reluctance to use long-term retinoid therapy in children, while in Great Britain there is much less concern with doing so.
Self-help and information for patients and doctors
Membership in a patient organization can be very helpful for patients and their families. One such organization in Germany is Selbsthilfe Ichthyosis e.V. (http://www.ichthyose.de). This gives patients the chance to discuss everyday problems (e.g., scalp care) with others as well as the chance to benefit from their experience. This patient organization is also active on a European level (European Network of Ichthyoses) and is also represented in other umbrella organizations such as Alliance for Chronic Diseases (Allianz für chronische seltene Erkrankungen, ACHSE) and the Federal Working Group on Self-Help (Bundesarbeitsgemeinschaft Selbsthilfe, BAG). Another resource for general information on the disease is the German Network for Ichthyoses (NIRK [www.netzwerk-ichthyose.de]). In regard to molecular diagnosis, a helpful Website has been set up by the Institute of Human Genetics at the University of Freiburg (http://www.uniklinik-freiburg.de/humangenetik/).
Fragen zur Zertifizierung durch die DDA
Welche Aussage zur Pathophysio-logie der kongenitalen Ichthyose ist zutreffend?
Die Störung bei Ichthyosis vulgaris befindet sich im Stratum spinosum.
Die Ichthyose spiegelt im weitesten Sinne die Reaktion des Körpers auf einen epidermalen Barrieredefekt wider.
Mit Ichthyosis assoziierte Gendefekte zeigen an der Haut ein sehr spezifisches klinisches Bild.
Die Verdickung der Hornhaut zeigt, dass bei Ichthyose eine gute epider-male Barrierefunktion besteht.
Die häufigste Ursache der lamellären Ichthyose ist in den Keratin-Genen zu suchen.
Ein ansonsten gesundes männliches Neugeborenes zeigte nach einer Woche eine generalisierte weiße Hautschuppung. Welche Aussage trif f t zu?
Das Vorliegen einer seltenen konge-nitalen Ichthyose ist ausgeschlossen.
Zur Behandlung des Neugeborenen eignen sich Cremes ab 5% Harnstoff.
Das Vorliegen einer X-chromosomal rezessiven Ichthyose ist möglich.
Häufiges Baden des Kindes sollte vermieden werden.
Ichthyosis vulgaris manifestiert sich meistens bereits bei Geburt.
Die bislang als „bullöse Ichthyose“ bezeichneten Formen der Ichthyose werden nach der neuen Nomenklatur als keratinopathische Ichthyose (KPI) bezeichnet. Welche Aussage zu den KPI trifft zu?
Bei epidermolytischer Ichthyose (EI) zeigt sich eine epidermolytische Hyperkeratose entsprechend der Expression von Keratin-1 oder -10 im Stratum basale.
Epidermolytische Ichthyose auf-grund von Keratin-1-Mutationen ist mit Palmoplantarkeratose assoziiert.
Alle Formen der KPI zeigen eine epidermolytische Hyperkeratose.
Die Ichthyose Curth-Macklin ist durch Keratin-9-Mutationen verursacht.
Alle KPI werden als autosomal dominante Erkrankungen vererbt.
Die Gruppe der autosomal rezes-siven kongenitalen Ichthyosen (ARCI) ist klinisch und genetisch heterogen. Welche Erkrankung gehört in diesem Sinne nicht zu den autosomal rezessi-ven kongenitalen Ichthyosen (ARCI)?
kongenitale ichthyosiforme Erythrodermie
Die Diagnose der Ichthyosen basiert neben der molekularen Diagnostik auf Klinik und Morphologie. Welche Aussage zur Diagnostik trifft nicht zu?
Die Ichthyosis vulgaris lässt sich sehr gut elektronenmikroskopisch bestätigen.
Zur molekularen Diagnostik eignet sich eine EDTA-Blutprobe der/des Betroffenen.
Bei vielen kongenitalen Ichthyosen eignen sich ultrastrukturelle Marker zur diagnostischen Eingrenzung.
Eine epidermolytische Hyperkera-tose lässt sich nur in der elektro-nenmikroskopischen Untersuchung erkennen.
Der Transglutaminase-1-Mangel lässt sich durch Enzymmessung einer Hautprobe bestimmen.
Die lamelläre Ichthyose (LI) und kongenitale ichthyosiforme Erythro-dermie (CIE) werden als ein Krank-heitsspektrum aufgefasst. Welche Aussage hierzu trifft nicht zu? a) Die Erkrankungen können durch be-stimmte Mutationen im ABCA12-Gen
verursacht sein, welches ansonsten aber auch mit der Harlekin- Ichthyose assoziiert ist.
Im Hautbefund zeigt die lamelläre Ichthyose eine dunklere und grobe Schuppung.
Die verminderte Fähigkeit zu schwitzen ist klinisch von geringer Relevanz.
Für die Behandlung eignen sich re-gelmäßige Bäder mit Backpulver als Badezusatz (1–2 Hände pro Badewanne).
Im Spektrum des Transglutamina-se-1Mangels ergeben sich sehr unterschiedliche Krankheitsverläufe.
Eine Mutter stellt erstmalig ihren 4-jährigen Sohn mit einer hellgrauen mittel-lamellären Ichthyose vor, die im Sommer nahezu abheilt. Auf Nachfra-ge gibt sie an, dass ihr Vater ebenfalls eine Ichthyose gehabt hätte. Der Junge zeigt unauffällige Handinnenflächen. Welche Aussage ist nicht zutreffend?
Es könnte ein X-chromosomal rezessiver Erbgang vorliegen.
Das Vorliegen eines Netherton-Syndroms ist denkbar.
Das Vorliegen einer ausgeprägten Ichthyosis vulgaris ist unwahrscheinlich.
Die Diagnose lässt sich mittels Steroidsulfatase-Messung verifizieren.
Weitere Symptome wie ein ADHS könnten vorliegen.
Bei der Ichthyosis vulgaris (IV) handelt es sich um die häufigste Form der Ichthyosen. Welche Aussage trifft nicht zu?
Zirka 50–60% der Betroffenen leiden gleichzeitig an einer Erkrankung aus dem atopischen Formenkreis.
Die Erkrankung ist mit einer Reduktion des natural moisturizing factor assoziiert.
Ausgesparte Ellen- und Kniebeugen erlauben die Abgrenzung zur X-chro-mosomal rezessiven Ichthyose.
Charakteristisch ist die palmoplantare Hyperlinearität.
Die Vererbung erfolgt semidominant.
Ein Neugeborenes zeigte bei sta-bilen Vitalparametern eine ausgepräg-te Erythrodermie, dann entwickelt es pergamentpapierartige Haut mit mildem Ektropium und Eklabium. Wie schätzen Sie den Befund ein?
Zu befürchten ist, dass es sich bei der Erkrankung um eine Harlekin-Ichthyose handelt.
Der Temperatur- und Flüssigkeits-haushalt sollte engmaschig kontrol-liert werden.
Das Kind zeigt das typische Bild einer lamellären Ichthyose.
Das Kind wird zeitlebens an einer schweren Verhornungsstörung leiden.
Auf eine Hautprobe kann verzichtet werden, da das Ergebnis keine Relevanz hat.
Eltern einer 6-jährigen Tochter mit lamellärer Ichthyose erkundigen sich vor der Einschulung beim Arzt. Welcher Hinweis ist am wenigsten hilfreich?
Teilnahme am Schulsport kann Probleme bereiten.
Ichthyose…, da kann man nicht viel machen!
Vorsicht wegen verminderter Schwitzfähigkeit und Gefahr der Hyperthermie (Meidung des Fens-terplatzes im Sommer, klimatisierter Raum wäre sinnvoll)!
Nützlich ist der Kontakt zur Ichthyosis-Selbsthilfe-Organisation.
Der Vitamin-D-Spiegel sollte kontrolliert werden.
Liebe Leserinnen und Leser,
der Einsendeschluss an die DDA für diese Ausgabe ist der 19. Februar 2014. Die richtige Lösung zum Thema, Andrologische Basisdiagnostik“ in Heft 9 (September 2013) ist: 1c, 2c, 3b, 4e, 5d, 6a, 7e, 8b, 9d, 10c.
Bitte verwenden Sie für Ihre Einsendung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg.akademie-dda.de ein.