Dermatologic findings of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome

Authors


  • How to cite this article: Julapalli MR, Scher RK, Sybert VP, Siegfried EC, Bree AF. 2009. Dermatologic findings of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Am J Med Genet Part A 149A:1900–1906.

Abstract

Hay–Wells syndrome, caused by mutations in the p63 gene, is an autosomal dominant ectodermal dysplasia with the main features of ankyloblepharon filiforme adnatum, ectodermal defects, and cleft lip/palate, from which the disorder's other name, AEC syndrome, is derived. The National Foundation for Ectodermal Dysplasias convened the International Research Symposium for AEC Syndrome on November 8–10, 2006, at Texas Children's Hospital/Baylor College of Medicine, Houston, TX with appropriate IRB approval. This multidisciplinary conference was the largest gathering of such patients to date and allowed us to further characterize dermatologic features of AEC syndrome, which included: sparse and wiry hair, nail changes, past or present scalp erosions, decreased sweat production, palmar/plantar changes, and unique pigmentary anomolies. Early recognition of the features of AEC syndrome and subsequent early diagnosis is important in minimizing invasive diagnostic studies, improving morbidity and mortality, and providing genetic counseling. Skin erosions, especially those of the scalp, were identified as the most challenging cutaneous aspect of this syndrome. Although the reasons for the skin erosions and poor healing are not known, mutations of p63 may lead to a diminished store of basal cells capable of replenishing the disrupted barrier. Therapeutic strategies currently under exploration include gene therapy, as well as epidermal stem cell therapy. Until then, gentle wound care and limiting further trauma seem to be the most prudent treatment modalities. © 2009 Wiley-Liss, Inc.

INTRODUCTION

Hay–Wells syndrome, inherited in an autosomal dominant pattern with variable expression, is part of a group of disorders that affects the embryonic development of ectodermal tissues, including skin, hair, nails, teeth, and sweat glands. Hay and Wells first described this condition in 1976 in seven affected patients from four families [Hay and Wells, 1976]. The main features they observed were ankyloblepharon filiforme adnatum, ectodermal defects, and cleft lip and/or palate, from which the disorder's other name, AEC syndrome, is derived.

The National Foundation for Ectodermal Dysplasias (www.nfed.org) convened the International Research Symposium for AEC Syndrome on November 8–10, 2006, at Texas Children's Hospital/Baylor College of Medicine, Houston, TX with appropriate IRB approval. This multidisciplinary conference was the largest gathering of AEC patients to date and allowed us to further characterize diagnostic dermatologic features of AEC syndrome.

METHODS

Eighteen patients, 9 males and 9 females, participated in our study. They ranged in age from 4 months to 30 years. We evaluated each patient by first taking a brief dermatologic history. Physical exam was divided into three parts: skin, hair, and nails. Fitzpatrick skin type, presence of erosions, scaling, palmar/plantar changes, hyperkeratosis, and pigmentary changes were all documented. We also described each patient's hair color, texture, and distribution as well as nail findings. Biopsies of normal and some abnormal skin, in addition to hair samples, were sent for microscopic examination. Dermatological findings from the 18 patients evaluated at the meeting are summarized in Table I.

Table I. Dermatological Findings of the 18 Symposium Participants
CharacteristicFinding
  • *

    Decreased sweat production 16/16 (100% excluding 2 infants who were too young to assess appropriately).

Hair
 Fair hair (compared to unaffected family members)16/18 (89%)
 Wiry hair18/18 (100%)
 Sparse or absent scalp hair16/18 (89%)
 Sparse or absent eyebrows18/18 (100%)
 Sparse or absent body hair7/18 (39%)
Nails
 Absent fingernails7/18 (39%)
 Absent toenails2/18 (11%)
 Dystrophic nails18/18 (100%)
 Hyperconvex nails17/18 (94%)
Skin
 Erythroderma at birth14/18 (78%)
 History of scalp erosions18/18 (100%)
 History of other erosions13/18 (72%)
 History of pigment changes10/18 (56%)
 Decreased sweat production16/16 (100%)* (2 infants unknown)
 Current scalp erosions10/18 (56%)
 Other current erosions10/18 (56%)
 Ichthyosiform scaling3/18 (17%)
 Palmar/plantar changes18/18 (100%)
 Hyperkeratosis7/18 (39%)
 Pigment changes18/18 (100%)

RESULTS

Hair

Eighty-nine percent of participants had sparse or absent scalp hair, but all 18 had sparse or absent eyebrows and eyelashes. Scalp hair in all was coarse, wiry, and brittle; in some it had a spun-glass appearance (Fig. 1) and others had apparent scarring alopecia. The degree of alopecia was quite variable, and did not seem to correlate with patient age or the degree of prior scalp erosion. The two patients who did not have significant alopecia were 4 and 17 years old, with an age range of 4 months to 30 years for all participants; therefore, the hair loss did not appear to develop with age. The three African-American patients had dark hair (Fig. 2), but the rest of our participants, who were European-American, had fair-colored hair.

Figure 1.

This child displays hair with a spun-glass or uncombable hair phenotype.

Figure 2.

This African-American infant has dark but coarse, sparse hair.

Hair shafts from the 18 participants were evaluated in our series, and the microscopic findings are reported by Dishop et al. 2009.

Nails

Each affected individual had nail changes; some more extensive than others. All of the following abnormalities were seen: partial or total absence of the nail plates-most often the distal aspect, onycholysis, onychoschizia, onychauxis (pachyonychia or thickening of the nail plate), onychogryphosis, koilonychia, Beau's lines, atrophy with lichen planus-like appearance, pseudopterygium formation (Fig. 3), subungual hyperkeratosis, eczema-like periungual scaling, nail plate crumbling, frayed distal edge with resorption (Fig. 4), psoriasiform pitting, malalignment, increased transverse or longitudinal convexity, micro/anonychia, discoloration of the nail bed resembling the “oil drop” sign, and some bulbous appearing distal phalanges. We did not evaluate the nails for secondary onychomycosis, which may have contributed to changes seen in some of the subjects.

Figure 3.

The fingernails reveal loss of the cuticles and pseudoptyergium formation.

Figure 4.

These nail plates are noted to be frayed at the distal edge with resorption.

Skin

Scalp erosions are quite common, often extensive, and have been reported as a defining feature of AEC syndrome [Shwayder et al., 1986; Fosko et al., 1992; Cambiaghi et al., 1994; Rowan, 1996; Payne et al., 2005; Siegfried et al., 2005]. All 18 of the individuals we evaluated had a history of scalp erosions, and 13 of 18 participants had skin erosions at the time of our evaluation (Fig. 5). The youngest patient in our series without active skin erosions was 4 years old, with an age range of 4–10 years for the five subjects with absence of erosions at the time of our evaluation. Most individuals in our series reported experiencing intermittent skin erosions, with persistence into the teen years and even adulthood in our one adult patient. Erosions typically involved the scalp, head and neck, skin folds, palms, and/or soles and were often accompanied by crusting, granulation tissue, and secondary infection. Healing invariably resulted in scarring alopecia. Erosions, especially those on the shoulders, upper back and chest, often healed with residual scarring in a cribriform, reticulate, stellate, or punctate pattern. These changes were seen in a shawl distribution in several of the patients (Figs. 6 and 7). There was significant intrafamilial and interfamilial variability in the severity of the skin erosions.

Figure 5.

Erosion, hemorrhagic crusting and granulation tissue with secondary infection of the scalp are defining features of this syndrome.

Figure 6.

A close up of the cribriform and stellate scarring that is typically seen.

Figure 7.

A common finding with reticulated scarring in a shawl distribution.

Congenital erythroderma was present in 78% of our patients. This, along with the extensive erosions also common at birth, often led to the initial misdiagnosis of epidermolysis bullosa (EB). The most severe erosions seen in neonates with AEC syndrome involve the scalp. Erosions at other sites tend to be more superficial than the blisters and erosions of EB [Shwayder et al., 1986; Vanderhooft et al., 1993; Siegfried et al., 2005; Yoo et al., 2007]. Disorders of cornification are also occasionally misdiagnosed in some neonates with AEC, who may have shiny, collodion-like skin, desquamation, and ichthyosiform scaling [Shwayder et al., 1986; Vanderhooft et al., 1993; Siegfried et al., 2005].

Palmar and plantar changes were universal in our group of patients, all of whom had effaced dermatoglyphics. Other findings included hyperkeratosis, punctate keratoderma, hyperlinearity, atrophy, erosions, and redness (Fig. 8). Scaling and thickening were also commonly appreciated. Hyperkeratosis was also seen on the knees and elbows in some patients.

Figure 8.

Diminished dermatoglyphics and typical erosive palmar changes.

Dyspigmentation, both hyperpigmentation and hypopigmentation, were noted in all of the individuals with AEC. The hyperpigmentation was predominantly in intertriginous areas and often had a reticulate pattern with progression noted with age (Figs. 9–12). Our young African-American subjects were noted to have significant hypopigmentation of the scalp, forehead, nasoalar and malar cheeks with significant periocular sparing that gave a masked appearance. These changes were noted to gradually improve with age, as documented in photographs, in the three individuals of African descent in this group (Figs. 13 and 14). The cause of these collective pigment changes is unknown. Post-inflammatory pigmentary alteration is unlikely to be the single culprit as the loss or gain of pigmentation often develops in previously “normal” skin.

Figure 9.

Poikilodermatous hyperpigmentation on the lateral flank.

Figure 10.

Progressive reticulated hyperpigmentation on the chest of an affected adult.

Figure 11.

Reticulated hyperpigmentation was common in intertriginous areas.

Figure 12.

Hyperpigmentation that was progressive on the face and neck.

Figure 13.

Hypopigmentation resembling a masked appearance typical on the face of affected African American infants.

Figure 14.

Spontaneous improvement of the hypopigmentation is noted with increasing age.

Every participant had impaired sweat production either by report or on examination. Ten of the eighteen patients underwent sweat testing with use of starch iodide paper, and all but one demonstrated diminished or absent palmar sweating.

Other skin findings of uncertain significance in our patients included acneiform papulopustules in a unilateral pattern on the chest and upper extremities in two patients, aged 8 and 17 years of age (Fig. 15), xerosis in nearly all participants, and acanthosis nigricans-like changes in three adolescents who were not overweight.

Figure 15.

Unusual papulopustules with a unilateral distribution on the chest and shoulder seen in two participants.

DISCUSSION

Among the many skin changes associated with AEC/Hay–Wells syndrome, the most challenging are the erosions, especially those of the scalp. These can be extensive, life-threatening, slow or seemingly impossible to heal and a source of significant discomfort and disability. No successful approach to therapy has been defined, and no currently available treatment modalities have been shown to significantly alter the course or speed healing. The following are general comments that can be made regarding skin care based on previous case reports in the literature and the conference participants' experience.

The primary goal is to prevent skin breakdown. Vigorous cleaning of the newborn to remove vernix should be eschewed. If erosions develop, gentle cleansing and application of a bland emollient from single use containers is a safe and reasonable approach. Non-adherent dressings may help address the disrupted barrier; but in some anecdotal cases, the scalp erosions seem to heal better in a dry, rather than a moist, wound environment. Therefore, the benefit of emollients and dressings is not clear and response may be idiosyncratic.

Secondary colonization and infection may play a role in the non-healing of these erosions, and previous reports have identified Staphylococcus aureus, other gram-positive bacteria, gram-negative bacteria, and yeast within scalp erosions of AEC patients [Fosko et al., 1992; Vanderhooft et al., 1993; Cambiaghi et al., 1994; Mancini and Paller, 1997; Pruszkowski et al., 2000; Payne et al., 2005; Siegfried et al., 2005]. Daily bathing or soaks, utilizing water, dilute bleach, dilute Dakin solution (0.25% sodium hypochlorite), or chlorohexadine, can aid in gentle debridement and may limit pathogenic organisms [Siegfried et al., 2005; Yoo et al., 2007]. Many of the patients in our study were treated with multiple antibiotics, both topical and oral, for long courses throughout their lives, often with only temporary or minimal improvement of their lesions. Therefore, antibiotics are likely of limited benefit in this setting unless there are signs of active infection.

Chronic inflammation and increased matrix metalloproteniases are known to occur in long-standing wounds. Intermittent use of a low-potency topical corticosteroid to reduce chronic inflammation has therefore been suggested for non-healing erosions [Hofman et al., 2007; Shwayder et al., 1986]. Use of low dose doxycycline may also be a useful alternative in reducing the inflammation and matrix metalloproteinases of the wound environment, but its use must be balanced with its potential side effects [Siegfried et al., 2005]. While both of these treatments have theoretical benefit for therapy, neither has been found to be effective in the treatment of erosions associated with AEC syndrome.

What is clear regarding therapy, both from reports in the literature and from the experience in this group, is that aggressive wound care, debridement and split or full thickness skin grafting in areas of erosion are not beneficial and can lead to worsening [Vanderhooft et al., 1993; Siegfried et al., 2005]. Therefore, these therapies are discouraged and should be avoided. Thus, gentle wound care and limiting further trauma seem to be the most prudent treatment modalities that can be recommended at this time.

Although the reasons for the skin erosions and poor healing are not fully known, it seems that an impaired barrier, chronic inflammation and secondary infection are potential factors. Furthermore, the role of p63 in the formation and maintenance of the basal cells and in the differentiation of the epidermis may be critical contributors. It is possible that the mutant alleles lead to a gene product that yields a diminished store of basal stem cells capable of replenishing the disrupted barrier. This may be most pronounced on the scalp because of the particular role that TP63 might play in establishing and replenishing hair. Future therapeutic strategies that are currently under exploration include gene therapy, as well as the use of epidermal stem cells for repair, replacement, or regeneration of affected skin [Siegfried et al., 2005]. Pathogenic mechanisms underlying these erosions, as well as therapies to address them, are clearly topics which warrant further investigation.

AEC syndrome shares many features with other types of ectodermal dysplasia syndromes, as well as disorders presenting with congenital erythroderma and collodian phenotype such as the inherited blistering disorders and ichthyoses; however, we believe the dermatologic findings of the patients participating in our symposium allowed identification of several characteristic features. While we found phenotypic variations even among family members with the same genetic defect, all of our patients had sparse and wiry hair, nail changes that were sometimes congenital, past and/or present scalp erosions, decreased sweat production, palmar/plantar changes and unique pigmentary alteration. In the setting of ankyloblepharon and cleft lip/palate, these ectodermal defects are diagnostic of AEC syndrome.

Any newborn with erythroderma and the presence of a cleft lip/palate, which may not be easily identified as some have submucous clefts [see Cole et al., 2009], should raise the possibility of AEC syndrome, as ankyloblepharon is not always present at the time of evaluation and its absence should not deter consideration of this diagnosis. As well, the presence of limb anomalies does not exclude this diagnosis if other diagnostic cutaneous findings are present, especially skin and scalp erosions, as many of the patients within our series had noted limb changes [see Sutton et al., 2009]. Early recognition of these features and subsequent early diagnosis is important in minimizing invasive diagnostic studies, improving morbidity and mortality, and providing genetic counseling.

Acknowledgements

We would like to thank Dr. Moise Levy, Dr. Denise Metry and Dr. Vivian Lombillo for assistance in skin examinations and recording of data; Derek Ruths for dataset guidance; Mary Fete at the National Foundation of Ectodermal Dysplasias who organized this symposium; and our patients and their families for their assistance and cooperation. This work was supported in part by financial funding through the National Foundation for Ectodermal Dysplasias (NFED).

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