Dermatologic Findings of Ankyloblepharon-
Ectodermal Defects-Cleft Lip/Palate (AEC) Syndrome
Meena R. Julapalli,1Richard K. Scher,2Virginia P. Sybert,3Elaine C. Siegfried,4and Alanna F. Bree1*
1Texas Children’s Hospital, Department of Pediatric Dermatology, Baylor College of Medicine, Houston, Texas
2University of North Carolina, Department of Dermatology, Chapel Hill, North Carolina
3University of Washington, Division of Medical Genetics and Dermatology, Seattle, Washington
4Saint Louis University, Department of Pediatrics and Dermatology, St. Louis, Missouri
Received 24 August 2008; Accepted 26 January 2009
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
TX with appropriate IRB approval. This multidisciplinary con-
ference 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 sub-
sequent 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.
Key words: ectodermal dysplasia; congenital ectodermal defect;
skin; hair; nails; skin care; wound healing; p63; TP63 protein
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 appro-
priate 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.
Eighteenpatients,9males and9females,participated inour 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, hyper-
keratosis, and pigmentary changes were all documented. We also
as nail findings. Biopsies of normal and some abnormal skin, in
addition to hair samples, were sent for microscopic examination.
Grant sponsor: National Foundation for Ectodermal Dysplasias (NFED).
Alanna F. Bree, M.D., Assistant Professor of Dermatology and Pediatrics,
Baylor College of Medicine, 6621 Fannin Street CC 620.16, Houston, TX
77030. E-mail: firstname.lastname@example.org
Published online 13 August 2009 in Wiley InterScience
How to Cite this Article:
Julapalli MR, Scher RK, Sybert VP, Siegfried
EC, Bree AF. 2009. Dermatologic findings of
lip/palate (AEC) syndrome.
Am J Med Genet Part A 149A:1900–1906.
? 2009 Wiley-Liss, Inc.
Dermatological findings from the 18 patients evaluated at the
meeting are summarized in Table I.
Eighty-nine percent of participants had sparse or absent scalp hair,
all was coarse, wiry, and brittle; in some it had a spun-glass
appearance(Fig.1)andothers hadapparentscarring alopecia. The
degree of alopecia wasquite variable, anddidnot 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;
participants, who were European-American, had fair-colored hair.
and the microscopic findings are reported by Dishop et al. .
Each affected individual had nail changes; some more extensive
thanothers. Allof thefollowingabnormalities wereseen:partialor
total absence of the nail plates-most often the distal aspect,
ing of the nail plate), onychogryphosis, koilonychia, Beau’s lines,
atrophy with lichen planus-like appearance, pseudopterygium
formation (Fig. 3), subungual hyperkeratosis, eczema-like periun-
(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
seen in some of the subjects.
TABLE I. Dermatological Findings of the 18 Symposium Participants
Fair hair (compared to
unaffected family members)
Sparse or absent scalp hair
Sparse or absent eyebrows
Sparse or absent body hair
Erythroderma at birth
History of scalp erosions
History of other erosions
History of pigment changes
Decreased sweat production
(2 infants unknown)
Current scalp erosions
Other current erosions
*Decreased sweat production 16/16 (100% excluding 2 infants who were too young to assess
FIG. 1. Thischilddisplayshairwithaspun-glassoruncombablehair
FIG. 2. ThisAfrican-Americaninfanthasdarkbutcoarse,sparsehair.
JULAPALLI ET AL.
Scalp erosions are quite common, often extensive, and have been
reported as a defining feature of AEC syndrome [Shwayder et al.,
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
absence of erosions at the time of our evaluation. Most individuals
patient. Erosions typically involved the scalp, head and neck, skin
granulation tissue, and secondary infection. Healing invariably
resulted in scarring alopecia. Erosions, especially those on the
in a cribriform, reticulate, stellate, or punctate pattern. These
changes were seen in a shawl distribution in several of the patients
variability in the severity of the skin erosions.
Congenital erythroderma was present in 78% of our patients.
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 [Shwayderet al., 1986; Vanderhooft
et al., 1993; Siegfried et al., 2005; Yoo et al., 2007]. Disorders of
cornification are also occasionally misdiagnosed in some neonates
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,
FIG. 3. The fingernails reveal loss of the cuticles and
FIG. 4. Thesenailplatesarenotedtobefrayedatthedistaledgewith
FIG. 5. Erosion, hemorrhagic crusting and granulation tissue with
secondary infection of the scalp are defining features of this
FIG. 6. A close up of the cribriform and stellate scarring that is
1902AMERICAN JOURNAL OF MEDICAL GENETICS PART A
also commonly appreciated. Hyperkeratosis was also seen on the
knees and elbows in some patients.
tion, were noted in all of the individuals with AEC. The hyperpig-
a reticulate pattern with progression noted with age (Figs. 9–12).
Our young African-American subjects were noted to have signifi-
cant 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
gain of pigmentation often develops in previously ‘‘normal’’ skin.
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.
FIG. 7. A common finding with reticulated scarring in a shawl
FIG. 8. Diminished dermatoglyphics and typical erosive palmar
FIG. 9. Poikilodermatous hyperpigmentation on the lateral flank.
FIG. 10. Progressive reticulated hyperpigmentation on the chest of
an affected adult.
JULAPALLI ET AL.
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
FIG. 11. Reticulated hyperpigmentation was common in
FIG. 12. Hyperpigmentation that was progressive on the face and
FIG. 13. Hypopigmentation resembling a masked appearance
typical on the face of affected African American infants.
FIG. 14. Spontaneous improvement of the hypopigmentation is
noted with increasing age.
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Among the many skin changes associated with AEC/Hay–Wells
impossible to heal and a source of significant discomfort and
disability. No successful approach to therapy has been defined,
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
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
healing of these erosions, and previous reports have identified
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 etal.,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
of the patients in our study were treated with multiple antibiotics,
bothtopical andoral,forlongcoursesthroughouttheir 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 inflammationandincreasedmatrix metalloproteniases
areknowntooccurinlong-standingwounds.Intermittent use ofa
has therefore been suggested for non-healing erosions [Hofman
metalloproteinases of the wound environment, but its use must be
with AEC syndrome.
What is clear regarding therapy, both from reports in the
literature and from the experience in this group, is that aggressive
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
Although the reasons for the skin erosions and poor healing are
not fully known,it seems that animpaired barrier, chronic inflam-
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
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
AEC syndrome shares many features with other types of
ectodermal dysplasia syndromes, as well as disorders presenting
inherited blistering disorders and ichthyoses; however, we believe
the dermatologic findings of the patients participating in our
hair, nail changes that were sometimes congenital, past and/or
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/
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
this diagnosis if other diagnostic cutaneous findings are present,
series had noted limb changes [see Sutton et al., 2009]. Early
recognition of these features and subsequent early diagnosis is
FIG. 15. Unusualpapulopustuleswithaunilateraldistributiononthe
chest and shoulder seen in two participants.
JULAPALLI ET AL.
important in minimizing invasive diagnostic studies, improving
morbidity and mortality, and providing genetic counseling.
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
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