Pathologic changes of skin and hair in ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome.
ABSTRACT Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome is a rare disorder of hair, skin, nails, and dentition caused by mutations in the p63 gene. Pathologic changes of skin and hair in AEC syndrome have previously been described in isolated case reports. Biopsies of normal and lesional skin from 19 patients with AEC syndrome were examined by light microscopy. Hair samples from 18 patients were examined by light and scanning electron microscopy. Histopathologic changes identified within the skin biopsies from clinically unaffected skin include mild atrophy, focal orthokeratosis, and mild superficial perivascular lymphocytic dermatitis. Scattered melanophages in the superficial and deep dermis likely reflect post-inflammatory change. One patient with a unilateral eruption of monomorphic papulopustules on the chest and shoulder demonstrated an acneiform intraepidermal pustule. Examination of the hair shafts revealed atrophy and loss of melanin pigment in some of the patients. Structural abnormalities included pili torti, pili trianguli et canaliculi, and irregular indentation and shallow grooves. Skin and hair findings in AEC syndrome were found to be generally similar to those described in other ectodermal dysplasia syndromes and corroborates the few prior descriptions in AEC syndrome specifically.
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ABSTRACT: The ectodermal dysplasias are a large group of hereditary disorders characterized by alterations of structures of ectodermal origin. Although some syndromes can have specific features, many of them share common clinical characteristics. Two main groups of ectodermal dysplasias can be distinguished. One group is characterized by aplasia or hypoplasia of ectodermal tissues, which fail to develop and differentiate because of a lack of reciprocal signaling between ectoderm and mesoderm, the other has palmoplantar keratoderma as its most striking feature, with additional manifestations when other highly specialized epithelia are also involved. In recent decades, the genes responsible for at least 30 different types of ectodermal dysplasia have been identified, throwing light on the pathogenic mechanisms involved and their correlation with clinical findings.Actas Dermo-Sifiliográficas 07/2013; 104(6):451–470.
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ABSTRACT: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare monogenetic disorder that is characterized by severe abnormalities in ectoderm-derived tissues, such as skin and its appendages. A major cause of morbidity among affected infants is severe and chronic skin erosions. Currently, supportive care is the only available treatment option for AEC patients. Mutations in TP63, a gene that encodes key regulators of epidermal development, are the genetic cause of AEC. However, it is currently not clear how mutations in TP63 lead to the various defects seen in the patients' skin. In this review, we will discuss current knowledge of the AEC disease mechanism obtained by studying patient tissue and genetically engineered mouse models designed to mimic aspects of the disorder. We will then focus on new approaches to model AEC, including the use of patient cells and stem cell technology to replicate the disease in a human tissue culture model. The latter approach will advance our understanding of the disease and will allow for the development of new in vitro systems to identify drugs for the treatment of skin erosions in AEC patients. Further, the use of stem cell technology, in particular induced pluripotent stem cells (iPSC), will enable researchers to develop new therapeutic approaches to treat the disease using the patient's own cells (autologous keratinocyte transplantation) after correction of the disease-causing mutations. © 2014 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 10/2014; 164(10). · 2.30 Impact Factor
- European journal of dermatology: EJD 06/2014; · 1.95 Impact Factor
Pathologic Changes of Skin and Hair in
Lip/Palate (AEC) Syndrome
Megan K. Dishop,1* Alanna F. Bree,2and M. John Hicks1
1Department of Pathology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas
2Division of Dermatology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas
Received 24 August 2008; Accepted 13 February 2009
Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC)
syndrome is a rare disorder of hair, skin, nails, and dentition
caused by mutations in the p63 gene. Pathologic changes of skin
and hair in AEC syndrome have previously been described in
isolated case reports. Biopsies of normal and lesional skin from
19 patients with AEC syndrome were examined by light micros-
copy. Hair samplesfrom18patients were examined by light and
scanning electron microscopy. Histopathologic changes identi-
fied within the skin biopsies from clinically unaffected skin
include mild atrophy, focal orthokeratosis, and mild superficial
the superficial and deep dermis likely reflect post-inflammatory
change. One patient with a unilateral eruption ofmonomorphic
papulopustules on the chest and shoulder demonstrated an
acneiform intraepidermal pustule. Examination of the hair
shafts revealed atrophy and loss of melanin pigment in some of
the patients. Structural abnormalities included pili torti, pili
trianguli et canaliculi, and irregular indentation and shallow
grooves. Skin and hair findings in AEC syndrome were found to
be generally similar to those described in other ectodermal
in AEC syndrome specifically. ? 2009 Wiley-Liss, Inc.
ogy; electron microscopy
The ectodermal dysplasias are a large group of rare disorders
resulting from abnormal embryonic development of the ectoderm
and Freire-Maia, 1994; Priolo and Laguna, 2001; Itin et al., 2003;
Lamartine, 2003; Itin and Fistarol, 2004].
Clinical manifestations are variable, but they are generally
unified by the presence of abnormalities of the skin, nails, hair,
may include adermatoglyphia, reticular pigmentation or hypopig-
mentation, atopic dermatitis, scaling, telangiectasias, atrophy, and
palmoplantar hyperkeratosis. Alopecia and hypotrichosis are
components of many ectodermal dysplasias, often associated with
brittle or uncombable hair [AEC, 2008].
Due to the rarity of AEC syndrome, descriptions of the skin and
hair abnormalities have been limited to predominantly clinical
and hair samples have been reported in very few of these patients.
Prior reports of light microscopic findings of AEC hairs have
microscopy findings of hair samples documented abnormal shafts
appearance, as well as longitudinal, sigmoid-shaped, or transverse
greenstick fractures (trichoclasis) [Hay and Wells, 1976; Greene
et al., 1987; Rowan, 1996]. Systematic study of the pathologic
changes of skin and hair has not previously been possible due to
the rarity of this condition.
An international conference on AEC syndrome was convened at
Texas Children’s Hospital (Baylor College of Medicine, Houston,
TX, USA) in November 2006. During this research conference,
Megan K. Dishop, M.D., Assistant Professor, Department of Pathology,
6621 Fannin; MC 1-2261, Houston, TX 77030.
Published online 20 August 2009 in Wiley InterScience
How to Cite this Article:
Dishop MK, Bree AF, Hicks MJ. 2009.
Pathologic changes of skin and hair in
lip/palate (AEC) syndrome.
Am J Med Genet Part A 149A:1935–1941.
? 2009 Wiley-Liss, Inc.
for pathology studies. Twenty-one participants and relatives were
consented for this component of the study. Four-mm punch
biopsies of skin were obtained from normal-appearing skin in
most cases, and in a few cases from regions with pigmentary,
hyperkeratotic, or inflammatory lesions. The skin biopsies were
fixed in 10% neutral buffered formalin. After standard processing,
a representative hematoxylin & eosin (H&E)-stained section
of each biopsy was examined and the histopathologic changes
tabulated. Leveled sections or horizontal sections of dermis were
not performed. Scalp hair samples were also obtained from each
patient with consent. Several hair strands from each sample were
mounted on glass slides and examined by light microscopy using
each sample was also examined by scanning electron microscopy
(EM) using standard methods. The study was conducted after
institutional research board (IRB) approval and with informed
consent from participants. Funding for this conference was pro-
vided by the National Foundation for Ectodermal Dysplasias.
Skin punch biopsies and scalp hair shaft samples were obtained
from 20 participants, including 17 patients with samples of both
skin and hair, 2 patients with skin biopsy only, and 1 patient with
hair samples only. One patient had skin biopsies performed at two
sites, yielding a total of 20 punch biopsies and 18 hair samples.
Patient demographics included 8 male and 12 female patients with
an age range of 4 months to 59 years. The patients providing
skin and/or hair samples included 4 infants (age <24 months),
or older). Patient ethnicities included 16 Caucasian, 1 Hispanic,
12, 14) and 4 parent–child pairs.
Skin biopsies were obtained from the arm (9), thigh (4), leg (1),
back (4), shoulder (1), and an unspecified site (1). While some
were biopsied at this site. Pathologic findings identified by light
microscopy of the skin biopsies are summarized in Table I. Three
biopsies were obtained at sites of clinically apparent abnormality
including one patient with atrophy, telangiectasia, and hypopig-
mentation on the back, one patient with reticular hyperpigmenta-
tion and hypopigmentation on the back, and one patient with a
pustule on the shoulder. The remaining 17 biopsies were obtained
from ‘‘normal’’ skin without clinically apparent lesions. The most
mild papillomatosis (15.8%; 3/19), epidermal atrophy (42.1%;
8/19), variable basilar pigmentation and/or pigment incontinence
(78.9%; 15/19), and prominence of the superficial perivascular
plexus with a minimal to mild perivascular lymphocyte infiltrates
glands and/or ducts in 15 cases (78.9%). These structures were
absent in 3 of 19 patients (15.8%).
A variety of pathologic findings were identified by light micros-
copy and scanning electron microscopy in the hair samples
although, there was slight variation in width of the hair shafts,
even in individual patients. One-third of patients had hair of two
with near-absent pigment. There was also variable pigmentation
within individual hair shafts, including variable discontinuous
cases (100%, 18/18) showed irregularity of hair shaft structure,
including pili torti, bent shafts, and at least focal grooved contours.
4/18 cases (22.2%) (Fig. 3). Scanning electron microscopy showed
yielding a total of 61.1% of cases with twisting of the hair shaft.
Many hairs were flattened to ovoid and some were angulated to
reniform (pili trianguli). All cases had at least irregular shallow
grooves and irregular indentation, and 12 cases (66.7%) had
distinct deeplinear grooves (pilicanaliculi).Althoughpolarization
of hair in most cases showed areas of light and dark mottling
dark bands of trichothiodystrophy were not demonstrated. Non-
specific cuticular weathering, partial hair fracture (trichoclasis),
and trichorrhexis nodosa were seen occasionally. No cases showed
trichorrhexis invaginata, trichoschisis, or monilothrix.
Due to the rarity of AEC syndrome, pathologic changes of skin in
parent and child with AEC syndrome showed mild to moderate
papillomatosis with basal layer hyperpigmentation and epidermal
digitate budding (reticulate acropigmentation, Kitamura-like),
TABLE I. Summary of Skin Histopathologic Changes in AEC
Epidermal atrophy, mild
Irregularity and bridging of rete
Prominent superficial vascular
Focal exocytosis of lymphocytes
Variable basilar pigmentation
Rare dyskeratotic cell
1936AMERICAN JOURNAL OF MEDICAL GENETICS PART A
similar to that seen in our patients [Drut et al., 2002]. The erosive
scalp dermatitis characteristic of AEC syndrome leads to scarring
alopecia and corresponds microscopically to perifollicular and
intrafollicular neutrophil infiltrates, focal follicle destruction with
lymphoplasmacytic infiltrates, ‘‘naked’’ hair shafts, fibrous follicle
tracts, and reduced terminal hair density [Park et al., 2005]. In this
syndrome, it has been suggested that immaturity of the epidermis
FIG. 1. Histopathology of skin in AEC syndrome. Low power demonstrates variable epidermal architecture, with some biopsies showing atrophy and
with short ‘‘digitate’’ rete in many cases. The majority of biopsies showed minimal to mild lymphocyte infiltrates associated with a prominent
noted in this African-American child.
DISHOP ET AL.
and appendages on the scalp may predispose to fragility, inflam-
and eccrine structures in AEC patients have been variable, with an
initial description indicating ‘‘almost complete absence of epider-
mal appendages’’ and later reports indicating normal-appearing
eccrine structures [Hay and Wells, 1976; Fosko et al., 1992].
In our patients, the skin biopsies were obtained predominantly
biopsied in only one case (acneiform pustule, AEC19). The scalp
dermatitis and palmoplantar keratotic lesions were not biopsied.
Many of our patients had irregular reticulate pigmentation abnor-
malities, which are reflected in the random biopsies by variable
dermis. Given that most of these biopsies also showed minimal to
the melanin incontinence may be a post-inflammatory phenome-
non. Eccrine glands and hair follicles were present in a minority of
the skin biopsy sections, suggesting paucity of these structures
overall; although, systematic quantitation was not performed. In
those cases with skin appendages, no morphologic abnormalities
of the hair follicles, eccrine ducts or glands were identified.
Little is known about the hair pigmentation and structure in AEC
in reports of both AEC syndrome and Rapp–Hodgkin syndrome,
which are now considered to represent varying clinical manifes-
tations of the same condition [Hay and Wells, 1976; Greene
et al., 1987; Fosko et al., 1992; Zenteno et al., 1999; Park et al.,
2005]. Pili torti and pili canaliculi have been reported in AEC and
Rapp–Hodgkin syndrome (RHS) patients [Silengo et al., 1982;
Salinas and Montes, 1988; Walpole and Goldblatt, 1991; Camacho
well as other ectodermal dysplasia syndromes [Micali et al., 1990;
Tr€ ueb et al., 1994, 1995; Hicks et al., 2001]. In one review of AEC
syndrome, 4 of 12 patients reportedly had pili torti et canaliculi
[Fosko et al., 1992]. Longitudinal grooves and flattening of hair
and ectrodactyly ectodermal dysplasia-clefting (EEC) syndrome
of hair shafts in AEC syndrome has also shown defective cuticles.
In the current cases, light microscopy and scanning electron
in common with uncombable hair syndrome (pili trianguli et
canaliculi) [Hicks et al., 2001]. In contrast to the round or ovoid
shape of normal hair on cross-sections, the hair from patients with
AEC syndrome frequently showed flattening with angulation,
triangular shape, deep grooves (canaliculi) resulting in a reniform
shape or undulating contours, shallow grooves, and irregular
surface indentations. Most cases showed at least occasional partial
surface irregularity, flattening, and twists in the hair shaft were
accentuated by examination under polarized light.
In addition to these structural abnormalities, the hair shafts
showing retained pigment and some pale hairs nearly devoid of
pigment. One case showed an area of pili annulati composed of
pigment. However, no pathognomonic hair shaft alterations were
Role of p63 in AEC syndrome. Five syndromes are caused
by mutations in the p63 gene: AEC, ectrodactyly-ectodermal
dysplasia-clefting (EEC), Acro-dermato-ungual-lacrimal-tooth
(LMS). p63 mutations have also been described in two non-
syndromic conditions: split-hand/split-foot malformation (SHFM)
and Brunner, 2002; Rinne et al., 2007]. AEC syndrome typically
results from heterozygous missense mutations in the sterile alpha
motif (SAM) domain [McGrath et al., 2001]. The SAM domain
contains protein–protein interaction modules of over 40 proteins
SAM domain determines interaction of TP63 protein with other
development [McGrath et al., 2001; Barbieri and Pietenpol, 2006;
Mikkola, 2007]. Immunohistochemistry using antibodies to p63
TABLE II. Summary of Scalp Hair Pigment and Structure in AEC
Syndrome, by Light Microscopy and Scanning Electron Microscopy
Amount of pigment
Bicolored (pale and pigmented)
Pale/sparse to absent pigment
Light uniform pigment
Dark uniform pigment
Pattern of pigment distribution
(regular periodic torsion)
Gradual twisting only
Pili canaliculi (deep grooves)
Shallow linear grooves only
1938AMERICAN JOURNAL OF MEDICAL GENETICS PART A
has been used to study expression in skin biopsies from AEC
patients [McGrath et al., 2001; Drut et al., 2002]. In these cases,
p63 shows abnormally increased expression in the basal layer and
also in the suprabasilar keratinocyte nuclei. Studies of keratins and
staining pattern with keratins 10 and 14, but aberrant nuclear
and cytoplasmic expression of anti-filaggrin, which is normally
ectoderm to specific epidermal lineages, but also for the mainte-
how the interactions of the abnormal TP63 protein and other
of skin fragility, pigmentation, and hyperkeratosis remains un-
known; although, p63 regulation of involucrin and loricrin in the
skin may play a role [Barbieri and Pietenpol, 2006].
The role of p63 in producing the abnormally sparse and wiry
hair in AEC syndrome is also unclear. In general, pili trianguli
hair shaft. The inner root sheath is of uniform thickness, conform-
ingto the contour of the triangular or grooved hairshaft, whilethe
round hair follicles on cross-section. These morphologic changes
are the converse of the normal relationship of the inner and outer
root sheaths by which the inner root sheath compensates for
irregularities in the hair surface and the outer root sheath is a fixed
cylindrical structure. The variability in the outer root sheath in pili
trianguli et canaliculi has been suggested to reflect a defect in the
keratinization process [Hicks, 2001].
as characteristic and consistent among subjects. The histopatho-
may also be secondary to inflammation related to the disrupted
of the hair may be due to similar phenomena. Regardless of the
syndrome to date.
The authors wish to thank Mr. Jim Barrish and Mr. Ralph
Nichols for their technical expertise in performing the scanning
electron microscopy for this study. Thank you also to the patients
FIG. 2. Hair shaft pigment and structure: Light microscopy. The hair shafts were generally thin with variable pigment and non-specific structural
abnormalities. Some patients showed bicolored hair (A, AEC15 4?). Pigment alterations included alternating dark and light bands of pili annulati
(B, AEC13 4?) andfocal segments devoid of pigment. Structural defects included surface grooves, gentle non-periodic twisting ofthe hair shafts,
andother irregularbendingofthehairshaft(C,AEC1010?).Polarizedlightaccentuates theirregularitiesinthe hairshaftstructure,includingpili
torti (upper right) and variable light and dark mottling (lower left) (D, AEC4 10?).
DISHOP ET AL.
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