Keywords

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

1 Introduction

Filaggrin gene (FLG) mutations have a significant association with a number of common diseases such as atopic dermatitis (AD), asthma, and hand eczema [1, 2]. The primary effect of the FLG mutations is through the effects on the skin barrier leading to xerosis [3].

2 Atopic Dermatitis

Historically, AD was first described as an entity in the early 1930s. Nexmand, in his thesis from 1948 [4], noted an increase in the number of AD patients hospitalized in the Copenhagen Dermatology Departments during 1930–1946 (Fig. 29.1).

Fig. 29.1
figure 1

(a, b) Historical pictures from Nexmand’s thesis of severe AD in a child 2 years of age

Full size image

Later, population-based studies at the end of the twentieth century illustrated a significant increase in the prevalence of AD [5, 6].

Recently, the question was raised whether AD was associated with FLG mutations and as a specific variant of the disease. We analyzed this question in a retrospective cohort and found that the frequency of AD increased slightly more in those with the FLG mutations, arguing in favor of a disease modified by gene-environment interaction [7].

3 The Primary Clinical Effects of the Filaggrin Gene Mutation, Xerosis, and Early Onset of Atopic Dermatitis

In a prospective study on children born by mothers with asthma, we found that the FLG mutations were associated with a specific endotype of AD with a dominance of dermatitis on the cheeks and the dorsal part of the hands. Interestingly, this is the part of the skin that is mainly in prolonged contact with the climate (leading to aggravation of xerosis) and endures friction from clothes and bed linen [8]. These early signs of dermatitis may be the first step to a lifelong disease with AD, asthma, rhinitis, food allergy, and irritant allergic contact dermatitis (Fig. 29.2).

Fig. 29.2
figure 2

(a, b) A 51-year-old male patient who was a homozygous FLG mutation carrier with a lifelong history of AD. As long as he remembered, he had prominent skin folds on the palmar and dorsal parts of the hands and fingers independent of his AD. This symptom is a sign seen in many individuals with AD with the FLG mutation starting early in life and probably a sign of subclinical inflammation due to a defect skin barrier. The patients often tell us that they have been teased during childhood for having “elephant fingers”

Full size image

AD is today one of the most frequent childhood diseases, often continuing into adult life. AD, particularly combined with hand eczema in childhood, is also the most significant risk factor for hand eczema in adults [9]. Females are at particular risk due to both domestic and occupational irritant exposures, leading to onset of hand eczema in the early twenties that often persists as a chronic disease [10, 11]. Adult-onset hand eczema may provoke the first outbreak of AD in patients without AD in childhood [12, 13].

Even if AD is common and in some cases difficult to treat, the historical perspective tells a different story. The individuals with the FLG mutations represent a special subgroup that often requires more intensive treatment and closer follow-ups, particularly the homozygotic, which constitutes 0.3 % of the population [14], with the tendency to early-onset AD and more severe and prolonged problems.

AD in patients with FLG mutations still represents a major challenge to clinicians who treat patients with chronic widespread dermatitis and severe fissures, particularly on the hands and feet (Fig. 29.3).

Fig. 29.3
figure 3

(a, b) Severe fissured hands and feet on a 45-year-old male patient with generalized AD since early childhood and an FLG mutation

Full size image

4 Allergic Hand Eczema

Contact allergy is more common in individuals with both dermatitis and the FLG mutations compared to individuals without the mutation [15]. This has been known for nickel allergy for some years but seems to be a general trend [16, 17]. Probably because of the high histidine content in filaggrin and its degradation products, it is functioning as a specific skin barrier for nickel and probably other divalent metal ions [18, 19]. The FLG mutations not only increase the risk of contact allergy but also seem to modify the cause of the clinical disease. We recently reported a young female who developed severe vesicular bullous acute dermatitis on the hands, imitating rubber glove dermatitis. She had been contact sensitized to sorbitan sesquioleate and had applied a steroid ointment containing this emulsifier and had worn a pair of rubber gloves for housekeeping, at the same time. The point is that a weak contact allergen can simulate a reaction to a more potent allergen in individuals with FLG mutations [20].

Figure 29.4 depicts a patient with an FLG mutation and contact allergy to thiurams who has been exposed to rubber gloves. It is our clinical impression that the patients with allergic contact dermatitis and the FLG mutation more frequently have problems with long-lasting dermatitis and fissures.

Fig. 29.4
figure 4

A 48-year-old female’s thumb of the right hand, with allergic contact dermatitis to thiurams from rubber gloves. She was heterozygous to a common FLG mutation. Note the vesicular inflammation with secondary fissures

Full size image

Figure 29.5 depicts a 66-year-old female who is heterozygotic for FLG mutation; she has had xerotic skin and slight ichthyosis on her lower legs all her life, but she never had AD or hand eczema in childhood. At 40 years of age, she developed acute vesicular hand eczema due to contact allergy to thiuram and exposure to rubber gloves. The vesicular component of the hand eczema disappeared gradually, and then the dermatitis transformed into lichenified, slightly hyperkeratotic hand eczema located on both the dorsal and the volar part of the hands. Her ichthyosis on the lower legs at the same time changed into a lichenified chronic dermatitis. Most dermatologists, including us, would until a few years ago have called such a case “adult-onset AD,” but these types of cases [12] are probably not uncommon in individuals with an inborn defect of the skin barrier who, because of environmental skin exposures to allergens and irritants, develop chronic skin inflammation that leads to degeneration of an already weak skin barrier [21].

Fig. 29.5
figure 5

(a, b) A 66-year-old female patient heterozygous for an FLG mutation. She has never had AD. She developed lasting skin changes similar to AD after an acute episode of allergic contact dermatitis due to thiurams. Such a patient should not be classified as having AD but as sequela from allergic contact dermatitis in a patient with the FLG mutation. This may have significant medicolegal consequences

Full size image

The progress in the understanding of disease mechanisms will improve treatment and classification of such cases.

5 Protein Contact Dermatitis

Protein contact dermatitis is an inflammatory skin disease that can be a result of the protein exposure acting either as an allergen or as an irritant. An increased risk of type I sensitization to food items has been described in individuals with the FLG mutations, specifically for peanuts [22] and more generally in a large population-based study [23].

We have recently described a heterozygous carrier of an FLG mutation who most likely developed primary occupational type I skin allergy to salmon [24]. She later developed asthma and anaphylaxis when she was working in a room where salmon were handled. Protein contact dermatitis is a difficult condition to classify. In the future, further subclassifications by genomic studies might be possible in those cases that have a skin barrier defect and thereby are exposed to the protein through the skin.

6 Irritant Contact Dermatitis

Irritant contact dermatitis (ICD) depends on the interplay between the quality of the skin barrier and the magnitude of the irritant exposure. Irritant exposure qualifying for occupational ICD is today defined as 2 h of wet work or 2 h of glove use daily [25]. The definition probably only holds true for a fraction of individuals. In individuals with a defect in the skin barrier, the trauma required to make an irritant skin exposure is much less, and in another group of individuals, much larger. Individuals with FLG mutations have a risk of developing dorsal hand eczema within the first few months of life simply from exposure to air and friction from clothes [8]. We have recently shown that individuals with the FLG mutations, AD, and hand eczema in childhood to a large extent avoid wet work and occupational irritant exposure in adulthood [26]. These types of jobs account for 40 % of all available jobs. This observation is in agreement with the fact that individuals with AD are underrepresented among hairdresser trainees/apprentices [27]. Early-onset occupational ICD has been a repeated observation, particularly in young females with childhood AD and with or without childhood hand eczema [10, 11].

Notwithstanding this observation, it is clear from the epidemiological studies that a large group of individuals with the FLG mutations and only dry skin in childhood and teenage years, but without AD and hand eczema, will enter into wet work jobs. In a recent study based on selected occupational ICD, it was clearly shown that FLG mutations were individual risk factors for this disease independent of AD and childhood eczema [28]. In this context, it needs to be remembered that in large population studies the FLG mutation only acts as a risk factor for hand eczema in conjunction with AD and individuals with only the FLG mutation and no AD have a risk for hand eczema in the same magnitude as the population in general [29]. So this is an area still open to further research to understand and identify the group at particular risk. First of all, the FLG mutation gives more severe and persistent disease, and painful skin fissures are a typical symptom [29, 30] (Fig. 29.6).

Fig. 29.6
figure 6

A moderate case of a steatotic ICD based on professional oil contact in a patient with the FLG mutation. The case is notable because of the multiple knifelike cut fissures following the fine lines in the palms. The patients have many expressions for the vulnerability of their hands. One patient expressed to us “when the winter comes with its dry air, my hands sing like crystal and then they crack”

Full size image

Conclusion

The discovery of the association between xerosis, AD, and the FLG mutations [1, 3] has been an eye opener for the clinical dermatologists who work with eczema disease. In our clinic, we have used this knowledge for the last 5 years. Even though information about whether a patient has a mutation may not result in immediate help for the patient, it is a major step in their understanding of the disease and of their whole family history.

It is our impression that this information and understanding lead to more focus on the rationale for using emollients and anti-inflammatory topical drugs. It also leads to less speculation on all other reasons for the background of their illness. The understanding of the FLG mutation for the skin barrier has opened up a completely new area for understanding the eczema mechanism and prognosis and, further, for development of specific topical and systemic treatments.