How to cite this article: Dishop MK, Bree AF, Hicks MJ. 2009. Pathologic changes of skin and hair in ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Am J Med Genet Part A 149A:1935–1941.
Pathologic changes of skin and hair in ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome†
Article first published online: 20 AUG 2009
Copyright © 2009 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Special Issue: Ankyloblepharon-Ectodermal Defects-Cleft Lip and/or Palate Syndrome and Ectodermal Dysplasias
Volume 149A, Issue 9, pages 1935–1941, September 2009
How to Cite
Dishop, M. K., Bree, A. F. and Hicks, M. J. (2009), Pathologic changes of skin and hair in ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Am. J. Med. Genet., 149A: 1935–1941. doi: 10.1002/ajmg.a.32826
- Issue published online: 20 AUG 2009
- Article first published online: 20 AUG 2009
- Manuscript Accepted: 13 FEB 2009
- Manuscript Received: 24 AUG 2008
- ectodermal dysplasia;
- electron microscopy
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. © 2009 Wiley-Liss, Inc.
The ectodermal dysplasias are a large group of rare disorders resulting from abnormal embryonic development of the ectoderm and abnormal interactions of the ectoderm with the mesoderm and endoderm [Freire-Maia, 1971; Solomon and Keuer, 1980; Pinheiro 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, teeth, and/or sweat glands. Dermatologic findings in these disorders may include adermatoglyphia, reticular pigmentation or hypopigmentation, 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 descriptions in a few individual patients and families. Skin biopsies and hair samples have been reported in very few of these patients.
Prior reports of light microscopic findings of AEC hairs have shown miniature hair bulbs. Previously reported scanning electron microscopy findings of hair samples documented abnormal shafts with longitudinal fluting and twisting as seen in pili torti, a scalloped 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, AEC-affected patients were invited to provide skin and hair samples 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 transmitted and polarized light. Additional hair shaft material from 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 provided 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), 11 children and adolescents (age 2–17 years), and 5 adults (18 years or older). Patient ethnicities included 16 Caucasian, 1 Hispanic, and 3 African-Americans. There were two sib sets (AEC 3, 10; AEC2, 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 patients showed scalp erosions and dermatitis clinically, no patients 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 hypopigmentation on the back, one patient with reticular hyperpigmentation 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 common findings were mild hyperkeratosis (47.3%; 9/19 patients), 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 (89.5%; 17/19) (Fig. 1). Skin appendages were noted in some cases, but were generally inconspicuous. Representative sections of skin in these 19 patients showed hair follicles in 6 cases (31.6%) and eccrine glands and/or ducts in 15 cases (78.9%). These structures were absent in 3 of 19 patients (15.8%).
|Histopathologic finding||Number, n = 19||Percentage (%)|
|Epidermal atrophy, mild||8||42|
|Irregularity and bridging of rete||6||32|
|Prominent superficial vascular plexus||11||58|
|Superficial perivascular lymphocytes, minimal/mild||17||89|
|Focal exocytosis of lymphocytes (interface dermatitis)||6||32|
|Variable basilar pigmentation||2||11|
|Dermal melanophages (pigment incontinence)||15||79|
|Rare dyskeratotic cell||1||5|
A variety of pathologic findings were identified by light microscopy and scanning electron microscopy in the hair samples (Table II). Most of the hair shafts were thin and atrophic-appearing; although, there was slight variation in width of the hair shafts, even in individual patients. One-third of patients had hair of two different colors (6/18); that is, some pigmented hair shafts and some with near-absent pigment. There was also variable pigmentation within individual hair shafts, including variable discontinuous medullation, areas of coarse clumped central pigment, pili annulati, and pigmented hairs with focal areas devoid of pigment (Fig. 2). All cases (100%, 18/18) showed irregularity of hair shaft structure, including pili torti, bent shafts, and at least focal grooved contours. Pili torti were noted by light and/or scanning electron microscopy in 4/18 cases (22.2%) (Fig. 3). Scanning electron microscopy showed more gradual non-periodic twists in an additional 7/18 cases (39%), 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 deep linear grooves (pili canaliculi). Although polarization of hair in most cases showed areas of light and dark mottling reflecting the irregular undulating surface, the alternating light and 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.
|Number, n = 18 patients||Percentage (%)|
|Amount of pigment|
|Bicolored (pale and pigmented)||6||33|
|Pale/sparse to absent pigment||2||11|
|Light uniform pigment||3||17|
|Dark uniform pigment||7||39|
|Pattern of pigment distribution|
|Discontinuous medulla/aggregated pigment||17||94|
|Pili torti (regular periodic torsion)||4||22|
|Gradual twisting only||7||39|
|Pili canaliculi (deep grooves)||12||67|
|Shallow linear grooves only||6||33|
Due to the rarity of AEC syndrome, pathologic changes of skin in this syndrome are inadequately described and limited to individual case reports or small series. In one such report, skin biopsies from a parent and child with AEC syndrome showed mild to moderate papillomatosis with basal layer hyperpigmentation and epidermal digitate budding (reticulate acropigmentation, Kitamura-like), with a lesser degree in the mother relative to her 2-year-old and very 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 and appendages on the scalp may predispose to fragility, inflammation and infection [Cliff and Holden, 1997]. Reports of follicular and eccrine structures in AEC patients have been variable, with an initial description indicating “almost complete absence of epidermal 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 from random skin sites (arm, thigh, leg, back) with a discrete lesion 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 abnormalities, which are reflected in the random biopsies by variable basilar pigmentation and scattered melanophages in the superficial dermis. Given that most of these biopsies also showed minimal to mild perivascular lymphocytes and rare exocytosis of lymphocytes, the melanin incontinence may be a post-inflammatory phenomenon. 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 patients. Hypopigmentation of terminal hairs is a common finding in reports of both AEC syndrome and Rapp–Hodgkin syndrome, which are now considered to represent varying clinical manifestations 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 et al., 1993; Sahin et al., 2004; Park et al., 2005; Steele et al., 2005], as well as other ectodermal dysplasia syndromes [Micali et al., 1990; Trüeb 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 surfaces have also been noted in hypohidrotic ectodermal dysplasia and ectrodactyly ectodermal dysplasia-clefting (EEC) syndrome [Hicks et al., 2001; Park et al., 2005]. Scanning electron microscopy of hair shafts in AEC syndrome has also shown defective cuticles.
In the current cases, light microscopy and scanning electron microscopy of hair from AEC patients showed a number of changes 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 twists with a few of these showing several tight twists (pili torti). The 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 showed variable pigmentation, with many showing pallor and near absent pigment. Several patients had bicolored hair with some hairs showing retained pigment and some pale hairs nearly devoid of pigment. One case showed an area of pili annulati composed of alternating bands of depigmentation and aggregated dark pigment. Others showed less conspicuous aggregation or clumping of central pigment. However, no pathognomonic hair shaft alterations were identified.
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 (ADULT), Rapp–Hodgkin (RHS), and limb-mammary syndrome (LMS). p63 mutations have also been described in two non-syndromic conditions: split-hand/split-foot malformation (SHFM) and non-syndromic cleft lip [Brunner et al., 2002a,b; van Bokhoven 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 involved in developmental regulation, and it is thought that the p63 SAM domain determines interaction of TP63 protein with other proteins involved in transcriptional regulation and skin appendage development [McGrath et al., 2001; Barbieri and Pietenpol, 2006; Mikkola, 2007]. Immunohistochemistry using antibodies to p63 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 other structural skin proteins in AEC patients have shown a normal staining pattern with keratins 10 and 14, but aberrant nuclear and cytoplasmic expression of anti-filaggrin, which is normally expressed only in the cytoplasm [McGrath et al., 2001]. No increase in apoptosis has been observed by TUNEL staining. TP63 protein is likely essential not only for embryologic commitment of immature ectoderm to specific epidermal lineages, but also for the maintenance of the epidermal stem cell population necessary for epithelial morphogenesis and renewal [Morasso and Radoja, 2005]. Precisely how the interactions of the abnormal TP63 protein and other regulatory proteins in the skin translate into the clinical phenotypes of skin fragility, pigmentation, and hyperkeratosis remains unknown; 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 et canaliculi are thought to result from focal asymmetry of hair bulbs with lateral loss of hair matrix, resulting in a linear groove along the hair shaft. The inner root sheath is of uniform thickness, conforming to the contour of the triangular or grooved hair shaft, while the outer root sheath fills in the focal defect of the hair shaft, resulting in 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].
While there were no pathognomonic findings of the skin and hair identified in our study, there were several interesting changes noted as characteristic and consistent among subjects. The histopathologic changes in the skin may be due to the underlying mutation but may also be secondary to inflammation related to the disrupted gene product and its effects. The structural and pigmentary changes of the hair may be due to similar phenomena. Regardless of the cause, these pathologic features of the skin and hair are noteworthy as they are described in the largest cohort of patients affected by AEC 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 who participated and to the National Foundation for Ectodermal Dysplasias for support of this symposium.
- AEC. 2008. Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC syndrome, Hay-Wells syndrome). Online Mendelian Inheritance in Man (OMIM #106260). http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=106260. Last accessed April 13, 2008.
- 2006. P63 and epithelial biology. Exp Cell Res 312: 695–706. , .
- 2002a. P63 gene mutations and human developmental syndromes. Am J Med Genet 112: 284–290. , , .
- 2002b. The P63 gene in EEC and other syndromes. J Med Genet 39: 377–381. , , .
- 1993. Rapp-Hodgkin syndrome with pili canaliculi. Pediatr Dermatol 10: 54–57. , , , , .
- 1997. What syndrome is this? Rapp-Hodgkin syndrome. Pediatr Dermatol 14: 149–650. , .
- 2002. Bilateral nephroblastoma in familial Hay-Wells syndrome associated with familial reticulate pigmentation of the skin. Am J Med Genet 110: 164–169. , , .
- 1992. Ectodermal dysplasias associated with clefting: Significance of scalp dermatitis. J Am Acad Dermatol 27: 249–256. , , .
- 1971. Ectodermal dysplasias. Hum Hered 21: 309–312. .
- 1987. Variable expression in ankyloblepharon-ectodermal defects-dleftliip and palate syndrome. Am J Med Genet 27: 207–212. , , .
- 1976. The syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate: An autosomal dominant condition. Br J Dermatol 94: 287–289. , .
- 2001. Uncombable hair (cheveux incoiffables, pili trianguli et canaliculi) syndrome: Brief review and role of scanning electron microscopy in diagnosis. Ultrastructural Pathol 25: 99–103. , , , .
- 2004. Ectodermal dysplasias. Am J Med Genet Part C 131C: 45–51. , .
- Genodermatoses. Chapter 7. In: Schachner LA, Hansen RC, editors. Pediatric dermatology. 3rd edition. Philadelphia: Mosby. 2003. pp 263–269. , , , , , , , , , , , , .
- 2003. Towards a new classification of ectodermal dysplasias. Clin Exp Dermatol 28: 351–355. .
- 2001. Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of P63. Hum Mol Genet 10: 221–229. , , , , , , , , , , , , , , , , , , .
- 1990. Structural hair abnormalities in ectodermal dysplasia. Pediatr Dermatol 7: 26–32. , , , .
- 2007. p63 in skin appendage development. Cell Cycle 6: 285–290. .
- 2005. Dlx genes, p63, and ectodermal dysplasias. Birth Defects Res C Embryo Today 75: 163–171. , .
- 2005. Rapp-Hodgkin syndrome: A review of the aspects of hair and hair color. J Am Acad Dermatol 53: 729–735. , , , .
- 1994. Ectodermal dysplasias: A clinical classification and a causal review. Am J Med Genet 53: 153–162. , .
- 2001. Ectodermal dysplasias: A new clinical genetic classification. J Med Genet 38: 579–585. , .
- 2007. P63-associated disorders. Cell Cycle 6: 262–268. , , .
- 1996. Scalp dermatitis, ectodermal dysplasia and cleft lip and palate: Rapp-Hodgkin or AEC syndrome. Australas J Dermatol 37: 102–103. .
- 2004. Ectodermal dysplasia showing clinical overlap between AEC, Rapp-Hodgkin and CHAND syndromes. Clin Exp Dermatol 29: 486–488. , , , , .
- 1988. Rapp-Hodgkin syndorme: Observations on ten cases and characteristic hair changes (pili canaliculi). Birth Defects Orig Artic Ser 24: 149–168. , .
- 1982. Distinctive hair changes (pili torti) in Rapp-Hodgkin ectodermal dysplasia syndrome. Clin Genet 21: 297–300. , , , , , , .
- 1980. The ectodermal dysplasias. Arch Dermatol 116: 1295–1299. , .
- 2005. Spectrum of phenotypic manifestations from a single point mutation of the p63 gene, including new cutaneous and immunologic findings. Pediatr Dermatol 22: 415–419. , , , .
- 1994. Pili torti et canaliculi in ectodermal dysplasia. Hautarzt 45: 372–377. , , , .
- 1995. Scalp dermatitis, distinctive hair abnormalities and atopic disease in the ectrodactyly-ectodermal dysplasia-clefting syndrome. Br J Dermatol 132: 621–625. , , , , , .
- 1997. Scarring folliculitis in the ectrodactyly-ectodermal dysplasia-clefting syndrome. Dermatology 194: 191–194. , , , , .
- 2002. Splitting p63. Am J Hum Genet 71: 1–13. , .
- 1991. Rapp-Hodgkin hypohidrotic ectodermal dysplasia syndrome. Clin Genet 39: 114–120. , .
- 1999. Evidence that AEC syndrome and Bowen-Armstrong syndrome are variable expressions of the same disease. Pediatr Dermatol 16: 103–107. , , .