Harlekin ichthyosis (Harliquin)

  

This is the most severe keratinization disorder. The children are encased at birth by a thick keratotic armor. Thick yellowish plates are present which may crack forming deep fissures. Movements of the arms and legs is impaired. Those children who have an extreme manifestation often die within the first weeks despite intensive care. However, there are also many cases who take a much milder course and from a clinical perspective there are cases of transition between very severe collodion baby and Harlekin ichthyosis. In such cases the drug acitretin - in Germany the brand name is Neotigason® - can be extremely helpful as it is possible to achieve within short time the detachment of the much thickened horny layer. In later life those cases surviving the critical period as a neonate the skin condition corresponds to that of very severe and at the same time very inflammatory (erythrodermic) types of lamellar ichthyosis. In this type the scales remain large. Later the children have difficulties to gain weight and look "undernourished".

  

Bullous congenital ichthyosiform erythroderma of Brocq

  

This is an uncommon autosomal dominant keratinization disorder affecting the entire skin and featuring at birth erythema scaling and blister formation. At birth one usually notices a complete reddening of the skin with a detachment of the upper layers of the skin. This may look rather horrible and more dangerous than it really is. The detachment of the skin is rather superficial and usually resolves within a few days. Actually there is a true blister formation of the skin. However, as the blisters form at a very high level the roof of the blister is easily lost so that one does not see always intact blisters. The sensitivity of the skin and the proneness for blister formation is quite variable. Some affected children have blisters for a couple of days after birth only while in others the proneness for blister formation remains for many years. Critical periods can be in the summer when the weather is hot. With increasing age fewer blister occur, while instead the keratinization becomes more prominent. The appearance is different from that in most type of lamellar ichthyosis as the scales are not "lamellar" or platelike but rather keratotic spines are present.

At the histological level the blister formation is caused by a characteristic alteration. Therefore usually a definite diagnosis can be established by a skin biopsy and histologic and ultrastructural examination of this specimen. The molecular causes are known today. The disease is due to mutations in the genes for keratin1 and keratin10. As discussed above these keratins are needed for the formation of fibril-like structures/filaments or tonofilaments. These filaments have an important function for the stability of the cells. If a wrong keratin is incorporated into such a fibril this fibril will not function properly and the cells loose stability when a mechanical friction occurs: the result is a blister. Why the prominent keratosis/keratinization disorder results is not really clear. However, one has to keep in mind that the tonofilaments insert into structures called desmosomes and these desmosomes in the end also form part of the cornified envelope. In this sense bullous congenital ichthyosiform erythroderma is also a disease of the cornified envelope.

Comèl-Netherton syndrome

	Fig. 1

  

In the US and English literature this disease is today Netherton syndrome called only although it was first described under the name of "ichthyosis linearis circumflexa" by an Italian namely Dr. Comèl. This is a rare autosomal recessive keratinization disorder featuring congenital ichthyosis, a marked inflammation of the skin at birth/the red neonate and peculiar hair anomalies. At birth the skin is usually universally red. Later on the skin condition may improve markedly and round or gyrate scale formation can develop and often circinate, annular patches are bordered by distinctive, double-edged scales. These patches are erythematous and can move on the skin meaning that they appear in some places in particular on the trunk and after some time disappear to reappear somewhere else. When looking at the hair under the microscope typical invaginations can be found of the hair shaft resembling that of the nodes of a bamboo. Therefore these invaginations are often called in German bamboo hair, the medical term would be "trichorrhexis invaginata". At the places of these invaginations the hair shaft can break easily. A further feature many doctors are not aware of is that the hair can be pulled out rather easily it does not adhere to the scalp as firmly as normal hair does.

Quite a few children suffer from more severe types of the Netherton syndrome featuring at birth a marked erythema of the skin which remains present in later life. In these children the type of ichthyosis can be rather difficult to distinguish from those of other types of autosomal recessive congenital ichthyosis and even from other inflammatory skin disease such as Ommen syndrome, seborrhoic dermatitis or atopic dermatitis. Children with the more severe type of Netherton syndrome frequently have problems with the immune system in particular a proneness to infections, fever, malnutricion and growth retardation.

If one consider to treat children with Netherton syndrome with acitretin at all it should be kept in mind that the dosage has to be very low because otherwise irritations and a worsening of the skin condition can result.

The molecular cause of Netherton syndrome are mutations in the gene SPINK5 which encodes a protein that is called LEKTI. LEKTI is a protease inhibitor and inhibits enzymes having a trypsin or chymotrypsin-like activity in the skin.

  

Figure 1: Neonate suffering from Netherton syndrome. The entire skin is inflamed and red ("Erythroderma"). The inflamed skin is very permeable for water resulting in increased transepidermal water loss. This means that neonates have a high risk of dehydration in the first weeks of life and need intensive care in the pediatric unit.

  

 

Figure 2: LEKTI deficiency in a child suffering from Netherton syndrome are a) positive staining of the skin for LEKTI in normal skin in the stratum granulosum, b) lack of LEKTI in the skin of a patient with Netherton syndrome.