7 Stigmata of the Atopic Constitution

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7 Stigmata of the Atopic Constitution

B. Przybilla, C. Bauer

Atopy is a constitutional state that can be defined as a genetically determined disposition to develop atopic eczema, allergic rhinoconjunctivitis, and/or allergic asthma. Up to now, no definite marker has been available that would enable one to decide with certainty whether atopy is present or absent in a given individual. This hampers not only the recognition of atopy in persons without manifest symptoms, but even the diagnostic classification of overt disease: it may not be possible to diagnose a condition as atopic when considering only its immediate symptoms. This holds true particularly for the diagnosis of atopic eczema. Thus, in order to establish the presence of an atopic disposition or of an atopic disease, it is necessary to look for features known to be characteristically related to atopy.

7.1 Features of Atopy

There are numerous features that are characteristic, yet mostly nonspecific indicators of atopy. With regard to the diagnosis of atopic eczema, the criteria established by Hanifin and Rajka [12], based on previous sugges- tions of these authors [11, 36], are those most often referred to. These and additional clues to atopy status can be obtained from the patient history, physical findings, or skin or laboratory tests (Table 7.1).

7.1.1 History

Anamnestic data on previous clinical findings may be reported by the patient, or information may be obtained from medical records. This makes a difference with regard to reliability. In particular, a history negative for atopic symptoms cannot be considered as

Table 7.1. Features of atopy Anamnestic Data

Atopic diseases (atopic eczema, allergic rhinoconjunctivitis, allergic asthma):

Personal history Family history

Eczema with the following characteristics:

Pruritus Early age of onset

Chronically relapsing course Seasonal variation

Influenced by environmental or emotional factors, or infections

Nonspecific hand dermatitis Food intolerance

Allergic (contact) urticaria Cutaneous infections Itch when sweating Light sensitivity Irritation from textiles

Wool intolerance

Intolerance of occlusive clothing Solvent intolerance

Physical Findings

Atopic eczema: manifestations and sequelae Full-blown typical atopic eczema (age-dependent) (Infantile) seborrheic atopic eczema

Patchy pityriasiform lichenoid eczema Nummular atopic eczema

Pityriasis alba

Widespread skin infection Atopic hand eczema

Dyshidrotic eczema (pompholyx) Pulpitis sicca

Nipple eczema Cheilitis

Perl`eche (angular cheilitis) Median fissuring of the lower lip Retroauricular intertrigo Infra-auricular fissuring Anterior neck folds Linear grooves Polished nails

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Table 7.1. (cont.) Pigmentary changes

Depigmentation Hyperpigmentation

Atopic respiratory disease: manifestations and sequelae Manifest allergic rhinitis, conjunctivitis or asthma (due to

common aeroallergens)

Facial mannerisms (“allergic salute”, nose or mouth wrin- kling)

Transverse nasal crease Mouth breathing Gingival hyperplasia Furrowed mouth syndrome Hypertrophy of the tonsils Granular pharyngitis

Facial deformities (e.g., longer face, flattened malar emi- nences, pinched nostrils, raised upper lip, overbite) Thoracic deformities (pectus carinatum/excavatum) Pulmonary emphysema

Associated conditions Ichthyosis vulgaris Keratosis pilaris Lingua geographica Juvenile plantar dermatosis Keratosis punctata Lichen striatus Cataract Keratoconus

Constitutional stigmata of atopy Dry skin

Hyperlinearity of the palms/soles Infraorbital fold

White dermographism Facial pallor

Orbital darkening Hertoghe’s sign Low hairline

Skin and Laboratory Test Findings

Immediate type (type I) skin test reactions to common allergens

Specific serum IgE antibodies to common allergens Elevated serum level of total IgE

Abnormal vascular reactions (e.g., delayed blanch to cholin- ergic stimulation, white reaction to nicotinic acid esters) Depressed cellular immunity

Shift toward a Th2 immune response

definitely diagnostic, whereas a positive history of clear-cut atopic disease, especially when obtained from medical records, provides valuable clues.

7.1.2

Physical Findings

Physical findings related to atopy fall into three catego- ries.

Clinical Manifestations of Atopic Diseases. By definition, the presence of characteristic atopic eczema or allergic respiratory disease due to common inhalant allergens constitutes a definite diagnosis of atopy.

Besides full-blown atopic eczema, there are minor skin manifestations, such as nonspecific hand dermatitis, nipple eczema, cheilitis, or infra-auricular fissuring (Table 7.1). They have been referred to as indicators of atopic eczema. However, as they are manifestations of atopic eczema, they do not provide additional indepen- dent clues to the presence of atopy in a given individual.

Secondary to atopic disease, characteristic sequelae may occur (Table 7.1). These include, for example, reticulate pigmentation of the neck, pityriasis alba, and polished nails due to atopic eczema, or transverse nasal crease, facial deformity, and facial mannerism due to respiratory atopic disease.

Associated Conditions. Although not direct manifestations or sequelae of atopic diseases, a heterogeneous group of conditions has been found to be related to atopy (Table 7.1).

Stigmata of the Atopic Constitution. Only features that are not associated with morbidity, i.e., that are neither manifestations nor consequences of disease, should be regarded as true constitutional stigmata.

Furthermore, they should be observable without tech- nical devices. These features are listed in Table 7.1.

7.1.3

Skin and Laboratory Testing

Demonstration of positive immediate type skin test reactions or specific serum IgE antibodies to a common environmental allergen or of an elevated serum level of total IgE is frequently used to state atopy in a clinical setting. The diagnostic relevance of these parameters is discussed elsewhere in this volume.

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7.2 Constitutional Stigmata of Atopy

7.2.1 Dry Skin

Dry skin (xerosis, sebostasis) (Fig. 7.1) is a hallmark of the patient with atopic eczema. Clinically, it is characterized by a skin surface that is rough to the touch, noninflamed, and sometimes slightly scaly.

“Dry skin” has been regarded a misnomer, as the actual perception is “rough skin,” which would be a more appropriate designation [32]. Indeed, an in- creased roughness of dry skin in atopic eczema could

Fig. 7.1. Dry skin

be measured [55]. However, there is a long tradition of using the term “dry skin.” Also, “rough skin” may be mistaken for keratosis follicularis.

The occurrence of dry skin must be considered as influenced by exogenous factors, e.g., season of the year or skin care measures. Already short exposure to low air humidity increases skin roughness [7]. Also,

“localized” and “generalized” dry skin have been dis- tinguished [51].

Biopsies taken from dry, clinically noninflamed skin of patients with atopic eczema have been reported to exhibit the histological picture of mild eczema, sug- gesting that dry skin is a minor manifestation of the disease [10, 49, 51]. However, these results were not confirmed by others, who found histologically eczematous changes in less than 10 % of biopsies taken from the dry skin of atopic eczema patients [8, 9]. Thus, dry skin cannot be regarded simply as a subclinical variant of eczema, but minor disease manifestations may present as dry skin.

Another concept is that dry skin, if it is not eczema, may actually be autosomal dominant ichthyosis vulgaris, which was reported in up to 30 % of atopic eczema patients [49, 51]. The diagnosis of ichthyosis vulgaris was based in these studies merely on clinical findings (ichthyotic scaling, hyperlinearity of the palms) and light microscopical features, such as an absent or reduced granular layer [49, 51]. However, ultrastructural studies of dry skin in atopic eczema have dis- closed that concomitant ichthyosis vulgaris, proven by the presence of abnormal keratohyaline granules, occurs in only 4 % of patients [8, 9]. Thus dry skin is related to both atopic eczema and ichthyosis vulgaris [9]. “Ichthyosis vulgaris” should not be used to describe ichthyosiform scaling in atopic eczema patients.

The prevalence of dry skin has been assessed in numerous studies (Table 7.2). In patients with atopic eczema, dry skin was present in 48 %–100 %, whereas it was seen in only 8 %–40 % of controls. Dry skin is significantly linked to atopic eczema.

7.2.2

Hyperlinearity of the Palms or Soles

Hyperlinearity of the palms (Fig. 7.2) is a well-known feature of atopic eczema; hyperlinearity of the soles has attracted less attention. Palmar creases can be divided into three groups: major, minor, and secondary [42]:

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Table 7.2. Prevalence of dry

Study Patients with atopic skin

eczema

Controls^a P

Total (n) Dry skin (%) Total (n) Dry skin (%)

Svensson et al. 1985 [46] 47 98 47 34 < 0.001

Kang and Tian 1987 [15] 372 65 213 18 < 0.01

Diepgen et al. 1989 [4] 110 96 527 25 < 0.01

Werner Linde 1989 [54] 50 48 50 14 < 0.01

Kanwar et al. 1991 [16] 50 80 50 8 < 0.01

Przybilla et al. 1991 [34] 34 74 23 31 < 0.01

Diepgen and Fartasch 1992 [5] 428 91 628 26 23.2 – 33.8^b

Rudzki et al. 1994 [41] 481 85 150 11 < 0.001

Nagaraja et al. 1996 [31] 100 76 100 14 < 0.01

Böhme et al. 2000 [2] 157 100 99 40 < 0.05

Lee et al. 2000 [20] 130 68 198 18 < 0.001

aSee Table 7.9

bOdds ratio, 95 % confidence interval

the major and minor (primary) creases represent defined skin markings, the term “secondary crease”

describes any visible palmar line other than the primary ones. Systems for quantitative evaluation of palmar creases have been devised using either five or three grades of intensity [42, 47]. These refer particularly to the area of the palms that is traversed by secondary creases. Furthermore, the density and depth of creases can be evaluated. Imprints are the best method to visu- alize crease patterns. For clinical purposes, such a pro- cedure is too sophisticated, and usually the overall impression of “hyperlinearity” is considered.

The expression of palmar markings can be influenced by environmental factors (e.g., manual work as well as chemical and thermal factors) or age, and there may be differences between the right and left sides [13].

The relation of palmar hyperlinearity to autosomal dominant ichthyosis vulgaris has been a matter of dis- cussion. It has been suggested that hyperlinearity in patients with atopic eczema is indicative of concomitant ichthyosis vulgaris [28, 49 – 51]. This has been doubted for clinical reasons [14, 45]. By ultrastructural analysis, it could be shown that abnormal keratohyaline granules, proving autosomal dominant ichthyosis vulgaris, are demonstrable only in a minority (2/17) of atopic eczema patients with hyperlinearity of the palms [9]. Hyperlinearity thus is associated with both ichthyosis vulgaris and atopic eczema.

Studies on the prevalence of palmar and plantar hyperlinearity are summarized in Table 7.3. For the most part, this feature was significantly more frequent in patients than in controls.

Fig. 7.2. Palmar hyperlinearity

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Table 7.3. Prevalence of hyperlinearity of the palms or soles

Study Patients with atopic eczema Controls^a P

Total (n) Hyperlinearity (%) Total (n) Hyperlinearity (%)

Hirth et al. 1971 [13] Palm 17 65^b 300 31^b NG

Sole 17 65^b 300 29^b NG

Mevorah et al. 1985 [28] 61^c 33 247 22 NS

Kang and Tian 1987 [15] 372 49 213 9 < 0.01

Diepgen et al. 1989 [4] 110 49 527 6 < 0.01

Kanwar et al. 1991 [16] 50 54 50 20 < 0.05

Przybilla et al. 1991 [34] Palm 34 88 23 48 < 0.01

Sole 34 74 23 30 < 0.01

Diepgen and Fartasch 1992 [5] 428 50 628 8 9.8 – 13.9^d

Nagaraja et al. 1996 [31] 100 23 100 4 < 0.01

Böhme et al. 2000 [2] 157 4 99 0 NS

Lee et al. 2000 [20] 130 32 198 12 < 0.001

NG, not given; NS, not significant

aSee Table 7.9,^bIntensity grade III or IV,^cPatients with both atopic eczema and “frank ichthyosis” were excluded,

dOdds ratio, 95 % confidence interval

7.2.3

Infraorbital Fold

Infraorbital fold (Fig. 7.3) is included in most descrip- tions of atopic eczema. Morgan [30] was the first to report this sign. He referred to Dennie, who had considered a “definite wrinkle just beneath the margin of the lower lid of both eyes” to be pathognomonic for allergy, especially eczema, hay fever, and asthma.

Accordingly, this feature is known also as Dennie-Mor- gan infraorbital fold, Morgan’s fold, or Dennie’s fold.

There may be single or double folds. Usually, the wrinkle is present on both eyelids, but occasionally a unilateral manifestation is seen [29, 48]. The original definition [30] has been modified by some who read the sign as being present only if there is a definite dou-

Fig. 7.3. Infraorbital fold

ble fold [26] or if one or more creases, outlining skin folds and starting at the inner canthus, extend laterally at least beyond an imaginary perpendicular line through the pupil [29]. When creases are considered, the physiologic sulcus palpebralis inferior must not be mistaken for the stigma.

It has been claimed that infraorbital folds are related to eyelid eczema: Uehara found this feature in 83 % of atopic eczema patients with, but in only 7 % of patients without lower eyelid dermatitis [48]. Furthermore, he saw infraorbital folds in 8 of 11 nonatopic patients with allergic contact dermatitis of the lower eyelids [48]. On the other hand, infraorbital folds are not infrequent in subjects without eczema [44, 46, 57], indicating that not all folds are due to inflammation. We found infraorbital folds in patients with atopic eczema as frequently as in subjects with respiratory atopic diseases without a history of eczema [34].

Infraorbital folds were significantly more frequent among atopic eczema patients than controls in the majority of studies; however, in a substantial number of studies this was not the case (Table 7.4). These differences may be related not only to the definition of “infraorbital fold,” but also to ethnic variations or to inclusion criteria for patients and controls. Infraorbital folds were less prevalent in Japanese patients [48]; Kang and Tian [15] did not find “meaningful infraorbital folds” in Chi- nese individuals. On the other hand, a prominent infraorbital crease was found in 49 % of normal black children, compared with 25 % of white children [57], but a rather high prevalence of infraorbital folds (31 % or

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Table 7.4. Prevalence of infra- orbital fold

Study Patients with atopic

eczema

Controls^a P

Total (n) Infraorbital fold ( %)

Meenan 1980 [26] 100 9 100 2 NG

Meenan 1981 [27] 148 12 168 1 NG

Uehara 1981 [48] 300 25 300 2 NG

Svensson et al. 1985 [46] 47 60 47 38 < 0.05

Mevorah et al. 1988 [29] 105 51 113 51 NS

Diepgen et al. 1989 [4] 110 57 527 17 < 0.01

Kanwar et al. 1991 [16] 50 82 50 54 < 0.01

Przybilla et al. 1991 [34] 34 82 23 13 < 0.01

Rudzki et al. 1994 [41] 481 78 150 49 < 0.001

Nagaraja et al. 1996 [31] 100 63 100 27 < 0.01

Williams and Pembroke 1996 [57] 15 27 145 34 NS

Singh and Kanwar 1997 [44] 20 20 480 36 NS

Böhme et al. 2000 [2] 157 3 99 2 NS

Lee et al. 2000 [20] 130 52 198 14 < 0.001

NG, not given;

NS, not significant

aSee Table 7.9

bOdds ratio, 95 % confidence interval

51 %) in control subjects was also found in two studies evidently conducted with Caucasian subjects [29, 46].

The wide variation of prevalence of infraorbital folds among patients and controls in different studies might also be explained by their association with “pure”

respiratory atopic disease, i.e., their presence in atopic patients without eczema [34]. The presence or absence of respiratory atopic disease among patients or controls (Table 7.9) was not always considered.

7.2.4

White Dermographism

White dermographism (Fig. 7.4) is a “classic” finding in patients with atopic eczema. According to Korting [18], it was first described by Marey in 1858. Whereas firm stroking of normal skin with a blunt instrument leads to a partially or fully developed triple response of Lewis (red, more or less urticarial “line” with reflex erythema) in the majority of the population [58], white dermographism (white line) develops instead in some individuals. This white reaction replaces the initially mechanically provoked red line about 15 – 60 s after stroking [3, 58]. White dermographism in atopic eczema patients has a longer time to start and a shorter duration than red dermographism in controls [59].

Usually dermographism is elicited with an instrument that is readily available, such as a paper clip or a tongue depressor. For quantitative studies, various instru- ments have been devised [6, 38, 43, 59].

Fig. 7.4. White dermographism

The elicitation of white dermographism depends on a number of factors. It has been said to occur more easily on the lower than on the upper half of the body [3], and on the arms, legs, and neck rather than on the abdo- men and trunk [33, 38]. Its occurrence may also be restricted to some localized skin sites [18]. Even slight stroking can elicit white dermographism [56]. The reaction to a stimulus that is too strong may be a red line with a white halo instead [38]. White dermographism has been found to occur with greater ease in individuals up to 30 years of age than in older ones [6].

However, during infancy the ability to develop white dermographism is reduced and was found to increase with age [1]. In patients with atopic eczema, the occurrence of white dermographism on skin appearing clinically normal was related to disease severity [40, 60].

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The pathophysiologic aspects of abnormal vascular reactivity of patients with atopic eczema are reviewed elsewhere in this volume. Here, only the relation of white dermographism to eczema itself will be briefly considered. For more than 70 years, it has been known that white dermographism can be elicited almost regu- larly in the diseased skin of patients with atopic eczema [40]. However, it can also be elicited in lesions of other chronic inflammatory dermatoses [38, 56]. In atopic eczema patients, white dermographism was found on lichenified skin in 86 %, on dry and rough skin in 76 %, and on normal appearing skin in only 1 % [52]. As histo- logic examination of biopsies taken from dry and rough skin revealed eczematous changes, it was concluded that white dermographism is a secondary phenomenon related to inflammation. Nonetheless, since white dermographism is more frequent in atopic eczema than in other types of eczema [15, 52], the atopic state may pre- dispose one to this form of reaction. Furthermore, the observation of white dermographism on the normal skin of individuals without atopic eczema (Table 7.5) argues against the concept that white dermographism is only secondary to inflammatory skin changes. It is assumed that white dermographism can have different causes, inflammation and the atopic state concurring in the lesional skin of patients with atopic eczema.

Table 7.5. Prevalence of white dermographism^a

eczema

Controls^b P Test site

Total

(n) White dermo- graphism (%)

Total

(n) White dermo- graphism (%)

Rajka 1960 [35] 100 81 40 10 NG Diseased skin (atopic eczema

patients)

Uehara and Ofuji 1977 [52] 100 86 20 18 NG Lichenified skin

76 Dry and rough skin

1 0 Normal skin

Svensson et al. 1985 [46] 47 100 47 100 Normal skin of the foreleg

Kang and Tian 1987 [15] 230 60 32 34 < 0.05 Lesioned skin

Mevorah et al. 1988 [29] 103 42 111 14 < 0.005 Uninvolved skin (usually on

the forehead)

Kanwar et al. 1991 [16] 50 12 50 2 NS Eczematous as well as unin-

volved skin of the back

Przybilla et al. 1991 [34] 34 38 23 4 < 0.01 Clinically normal skin

(usually on the upper back)

Böhme et al. 2000 [2] 116 3 0 Lesional

141 0 99 1 NS Nonlesional

NG, not given; NS, not significant

aStudies indicating the condition of the test site and not using a test apparatus,^bSee Table 7.9

The reported prevalence of white dermographism in both atopic eczema patients or controls was 0 %–

100 % (Table 7.5). These large differences are probably due to varying test modalities. Nevertheless, in the majority of studies a significant association between atopic eczema and white dermographism was found.

7.2.5 Facial Pallor

Facial pallor is generally regarded as a characteristic feature of atopic eczema. Just like white dermographism, this diffuse paleness is attributable to an abnormal vascular reactivity with a tendency toward vaso- constriction of small blood vessels. Beyond the clinical impression, facial pallor can be recognized more dis- tinctly by comparing a skin area rendered anemic by pressure of a glass spatula to the natural skin color.

Maximum pallor is characterized by the finding of no difference in response to this maneuver. Patchy pale areas on the face may also occur due to rubbing in patients with white dermographism, and flushing or erythema can alternate with pallor [11, 36]. Facial pallor (erythema) was found to be more frequent in youn- ger than in older patients [15, 46], but in children only 2 years old it was virtually absent [2].

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Table 7.6. Prevalence of facial pallor

eczema

Controls^a P

Total Facial pallor Total Facial pallor

(n) ( %) (n) ( %)

Svensson et al. 1985 [46]^b 47 64 47 32 < 0.001

Kang and Tian 1987 [15] 372 22 213 4 < 0.01

Kanwar et al. 1991 [16]^b 50 14 50 0 < 0.05

Przybilla et al. 1991 [34] 34 85 23 13 < 0.01

Diepgen and Fartasch 1992 [5]^b 428 39 628 11 4.5 – 6.3^c

Nagaraja et al. 1996 [31] 100 26 100 6 < 0.01

Böhme et al. 2000 [2] 157 1 99 0 NS

Lee et al. 2000 [20]^b 130 41 198 5 < 0.001

aSee Table 7.9

bFacial pallor/erythema considered

cOdds ratio, 95 % confidence interval

Nearly all studies assessing the prevalence of facial pallor found it to be significantly more frequent in patients with atopic eczema than in controls (Table 7.6).

7.2.6

Orbital Darkening

Orbital darkening (Fig. 7.5) is regarded as a feature of both atopic eczema [11, 12, 37, 39] and allergic nasal disease [22 – 25]. Also known as allergic shiners, this sign is characterized by a brownish to grayish or bluish discoloration of the orbital region, particularly in its lower half. Sometimes there is also slight edema. Alto- gether, this gives the patient a tired look [21]. Orbital darkening was reported to be correlated with young age [46].

Orbital darkening in patients with atopic eczema may be interpreted as secondary hyperpigmentation following chronic inflammation. Thus, it could be caused by eyelid eczema. Another mechanism has been

Fig. 7.5. Orbital darkening

suggested for orbital darkening associated with peren- nial rhinitis. Persistent edema of the mucous mem- branes of the nasal cavities and perhaps also spasm of the musculus tarsalis would impede venous blood flow from the orbital region, thus causing edema and discoloration [22, 23]. Both mechanisms can explain the occurrence of orbital darkening, and in either case it would be a sequela of disease. However, it is a common clinical observation that orbital darkening may also be seen in atopic patients who have never had eczema of the eyelids or manifest respiratory disease. In the majority of studies, orbital darkening was found to be significantly more prevalent in atopic eczema patients than in controls (Table 7.7).

7.2.7

Hertoghe’s Sign

Thinning or complete absence of the eyebrows in their lateral aspects (Fig. 7.6) was first described by Hertog-

Fig. 7.6. Hertoghe’s sign

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Table 7.7. Prevalence of

orbital darkening Study Patients with atopic

eczema

Controls^a P

Total

(n) Orbital darkening (%)

Total

(n) Orbital darkening (%)

Svensson et al. 1985 [46] 47 47 47 32 NS

Kang and Tian 1987 [15] 372 55 213 7 < 0.01

Kanwar et al. 1991 [16] 50 32 50 8 < 0.01

Przybilla et al. 1991 [34] 34 85 23 26 < 0.01

Rudzki et al. 1994 [41] 481 53 150 7 < 0.001

Nagaraja et al. 1996 [31] 100 12 100 2 < 0.05

Böhme et al. 2000 [2] 157 0 99 9 NS

Lee et al. 2000 [20] 130 39 130 9 < 0.001

aSee Table 7.9

Table 7.8. Prevalence of

Hertoghe’s sign Study Patients with atopic

eczema

Controls^a P

Total Hertoghe’s sign Total Hertoghe’s sign

(n) ( %) (n) ( %)

Diepgen et al. 1989 [4] 110 39 527 1 < 0.01

Przybilla et al. 1991 [34] 34 68 23 44 < 0.01

Nagaraja et al. 1996 [31] 100 0 100 0 NS

Lee et al. 2000 [20] 130 20 198 0 < 0.001

aSee Table 7.9

bOdds ratio, 95 % confidence interval

he at the turn of the nineteenth to the twentieth century as a feature related to hypothyroidism [18]. Its occurrence in patients with atopic eczema was attributed to different causes: It has been interpreted as secondary to rubbing of the skin [53], but others have suggested that it is related to disturbances of the autonomic nervous system [18]. Indeed, rubbing or scratching of the eyebrow region may mechanically cause loss of the brows, but there are individuals who exhibit typical Hertog- he’s sign without any manifest or previous eczema or other inflammatory skin disease of the face. It has been proposed to term rarefied eyebrows secondary to mechanical injury “pseudo“ Hertoghe’s sign in order to delineate them from “true” Hertoghe’s sign [18].

However, in the individual patient with atopic eczema, it will be difficult or impossible to differentiate in this way. Assessed only in a few studies, Hertoghe’s sign was found mostly to be significantly associated with atopic eczema (Table 7.8).

7.2.8 Low Hairline

A low hairline (Fig. 7.7) in the frontal and temporal region has been mentioned only rarely as a stigma of patients with atopic eczema [17, 18, 39]. The term “fur

hat-like hairline” describes this feature in plain words [19]. Often, the low hairline is most prominent in the temporal region, where there may be, between the scalp and the margin of the eyebrows, not only a reduced distance, but even a direct connection by some terminal hairs. Rarefied lateral eyebrows, that is Her- toghe’s sign, do not preclude this feature. We found a low hairline, defined as a distance of e 3 cm between scalp and margin of the eyebrows, in 88 % of 34 atopic eczema patients and in 52 % of 23 controls (p < 0.01, definition of controls in Table 7.9) [34].

Fig. 7.7. Low hairline

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Table 7.9. Studies^aon the prevalence of constitutional atopy stigmata in atopic eczema patients: selection criteria for controls

Study Selection criteria for controls

Rajka 1960 [35] Patients with asthma bronchiale and/or atopic rhinitis Hirth et al. 1971 [13] Persons without skin disease

Uehara and Ofuji 1977 [52] Patients with contact dermatitis

Meenan 1980, 1981 [26, 27] Children suffering from warts and with no history of atopy Uehara 1981 [48] Persons with no personal or family history of atopy

Mevorah et al. 1985 [28] Patients with dermatoses other than ichthyosis or atopic eczema and without a past history of atopic eczema or a known family history of ichthyosis or scaling

Svensson et al. 1985 [46] Patients without a present eczematous dermatitis or previous medical care for such a disease Kang and Tian 1987 [15] Assessment of white dermographism: Patients with chronic eczema without atopy

Assessment of other stigmata: Dermatological patients without atopy

Mevorah et al. 1988 [29] Individuals without a personal or family (close relatives) history of eczema, asthma, or allergic rhinitis

Diepgen et al. 1989 [4] Persons without present or previous flexural eczema

Werner Linde 1989 [54] Persons from the venereal disease outpatient clinics without atopy Kanwar et al. 1991 [16] Patients with neither personal nor family history of any atopic disorder

Przybilla et al. 1991 [34] Individuals without a personal or family history of atopic eczema, allergic rhinitis, or asthma and with no prick test reaction to common aeroallergens (grass pollen, cat epithelia, house dust mite).

Diepgen and Fartasch 1992 [5] Individuals without eczema or respiratory allergy (n = 510) Patients with respiratory allergy without eczema (n = 118) Rudzki et al. 1994 [41] Individuals without any skin changes or atopic diseases

Nagaraja et al. 1996 [31] Patients with dermatoses other than eczema, exclusion of those with either a personal or a family history of atopy

Williams et al. 1996 [57] Absence of active atopic eczema Singh et al. 1997 [44] Absence of active atopic eczema Böhme et al. 2000 [2] No history of eczema

Lee et al. 2000 [20] Volunteers with no personal or family history of atopic disease

aFor results, see Tables 7.2 – 7.8

7.3 Constitutional Stigmata as Markers of Atopy

The stigmata reviewed here are nonspecific with regard to atopic eczema, as they can be found also in other conditions (e.g., hyperlinearity of the palms or dry skin in autosomal dominant ichthyosis vulgaris) or in controls. However, although in different studies the prevalence rates found for certain stigmata varied con- siderably, there was overall a significant association between these features and atopic eczema.

Some features (dry skin, infraorbital fold, white dermographism, orbital darkening, Hertoghe’s sign) have been said to be direct manifestations or sequelae of atopic eczema itself. These then would not fulfill the criteria proposed for “true” constitutional stigmata.

An interpretation of some features as secondary to disease is correct apparently in certain, but evidently not in all cases, as stigmata are present also in controls without eczema. Further, secondary changes are not necessarily just phenocopies; they may represent provoked manifestations under conditions of a given lia-

bility. This is exemplified by white dermographism, which is more frequent in the lichenified skin of atopic than of nonatopic eczema [52].

Constitutional stigmata have been discussed mainly in relation to atopic eczema. The question arises as to their prevalence in respiratory atopic disease. White dermographism was reported to occur in 10 % of patients with asthma and/or atopic rhinitis compared to 81 % with the lesioned skin of atopic eczema [35]. A significant correlation between the absence of orbital darkening and allergic rhinitis or asthma has been reported [46], which contrasts with other opinions [22 – 25, 39]. Furthermore, the same authors [46] found an association between asthma and the absence of an intraorbital fold.

We evaluated the prevalence of constitutional stigmata discussed here in patients with allergic rhinoconjunctivitis and/or asthma without any present or previous atopic eczema [34]: with the exception of Hertog- he’s sign, dry skin, and white dermographism, all other features were significantly more frequent in patients with respiratory atopic disease than in controls; except

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for dry skin, individuals with atopic eczema or respiratory atopic disease did not differ significantly with regard to any of the other stigmata investigated [34].

This suggests that most of these stigmata are related to the atopic state and not only to atopic eczema. There- fore, patients with atopic respiratory disease should be omitted from control groups in studies on the prevalence of stigmata in atopic eczema, which was not always done (Table 7.9).

There are as yet no definite test methods to establish the presence of an atopic state in the absence of manifest atopic disease. In this respect, the assessment of constitutional stigmata of atopy may be helpful.

Identification of presumably atopic, but not yet diseased, individuals (“silent atopy”) will, for example, allow their counseling at the start of an occupational career or their exclusion from control groups in studies on atopic conditions. Markers of atopy also can

Table 7.10. Assessment of constitutional stigmata of atopy

Stigma Parameter Grading^a

Dry skin Clinical impression obtained by evaluation of the entire skin surface

Absent Mild Moderate Prominent

Hyperlinearity of palms or soles

Clinical impression Absent Mild Moderate Prominent

Infraorbital fold Fold starting at the inner corner of the eye and running laterally

Absent Mild: underlining at most half of the medial palpebral fissure

Moderate: underlining at most whole palpebral fissure

Prominent: running beyond the palpebral fissure

White dermographism

Testing on clinically normal skin (prefera- bly on the upper back) with a blunt instrument

Red dermographism

Red dermographism with a white halo

White dermographism

Facial pallor Clinical impression Absent Mild Moderate Prominent

Orbital darkening Clinical impression Absent Mild Moderate Prominent

Hertoghe’s sign Lateral thinning/absence of the eyebrows extending medially

Absent Mild: thinning/

absence extending not beyond the lateral corner of the palpebral fissure

Moderate:

thinning/absence involving the eyebrow above the lateral quarter of the palpebral fissure

Prominent: thinning/

absence extending to the eyebrow above the medial three quarters of the palpebral fissure

Low hairline Lowest distance between scalp hairs and the margin of the eyebrows

Absent:

> 3.0 cm

Mild: 1.6 cm – 3.0 cm

Moderate: up to 1.5 cm

Prominent: direct transition from scalp hair to eyebrows

aExternal influences (e.g., the use of emollients on dry skin, the effect of eyebrow plucking on Hertoghe’s sign) have to be considered

corroborate the clinical diagnosis of manifest atopic disease. The use of atopic stigmata for such purposes is hampered by their nonspecificity. Practically, only in the presence of several clear-cut features should atopy be presumed.

Further studies are needed to determine the value of assessing constitutional atopy stigmata more precisely.

Their expression should be evaluated with regard to possibly modifying parameters (e.g., disease activity, environment, age, ethnic background) and the devel- opmental mechanisms leading to their expression. It would be important to define stigmata clearly with reproducible criteria also considering their grades of expression. A proposal for a classification is given in Table 7.10.

Acknowledgements. The authors wish to thank Mr. P.

Bilek, photographer, for skillful photography.

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