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

Texas Children's Hospital, Department of Pediatric Dermatology, Baylor College of Medicine, 6621 Fannin Street, Houston, TX 77030, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 09/2009; 149A(9):1900-6. DOI: 10.1002/ajmg.a.32797
Source: PubMed


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 anomalies. 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.

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    • "One of these, AEC syndrome (or Hay-Wells syndrome; OMIM 106260), is caused by missense or frame-shift mutations mostly affecting the carboxy-terminal portion of the p63 alpha protein, and differs from the other conditions in the occurrence of ankyloblepharon, the absence of ectrodactyly and in the severity of the skin phenotype (17,18). Skin involvement includes congenital erythroderma, skin fragility and severe skin erosions most prominently on the scalp that appear at or soon after birth and can last several years (17,19). Erosions typically involve the scalp, head and neck, skin folds, palms and/or soles and are often accompanied by crusting, granulation tissue and secondary infection. "
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    ABSTRACT: Ankyloblepharon, ectodermal defects, cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder caused by mutations in the p63 gene, essential for embryonic development of stratified epithelia. The most severe cutaneous manifestation of this disorder is the long-lasting skin fragility associated with severe skin erosions after birth. Using a knock-in mouse model for AEC syndrome we found that skin fragility was associated with microscopic blistering between the basal and suprabasal compartments of the epidermis and reduced desmosomal contacts. Expression of desmosomal cadherins and desmoplakin was strongly reduced in AEC mutant keratinocytes and in newborn epidermis. A similar impairment in desmosome gene expression was observed in human keratinocytes isolated from AEC patients, in p63-depleted keratinocytes and in p63 null embryonic skin, indicating that p63 mutations causative of AEC syndrome have a dominant-negative effect on the wild-type p63 protein. Among the desmosomal components, desmocollin 3, desmoplakin and desmoglein 1 were the most significantly reduced by mutant p63 both at the RNA and protein levels. Chromatin immunoprecipitation experiments and transactivation assays revealed that p63 controls these genes at the transcriptional level. Consistent with reduced desmosome function, AEC mutant and p63-deficient keratinocytes had an impaired ability to withstand mechanical stress, which was alleviated by EGFR inhibitors known to stabilize desmosomes. Our study reveals that p63 is a crucial regulator of a subset of desmosomal genes and that this function is impaired in AEC syndrome. Reduced mechanical strength resulting from p63 mutations can be alleviated pharmacologically by increasing desmosome adhesion with possible therapeutic implications.
    Human Molecular Genetics 10/2012; 22(3). DOI:10.1093/hmg/dds464 · 6.39 Impact Factor
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    • "AEC syndrome differs from other conditions resulting from p63 mutations , in the severity of the skin phenotype , the occurrence of ankyloblepharon and the absence of ectrodactyly ( Dishop et al , 2009 ; McGrath et al , 2001 ) . Dermatological features include mild atrophy , often associated with congenital erythroderma , wide - spread skin erosions at or soon after birth and ectodermal dysplasia ( Dishop et al , 2009 ; Fete et al , 2009 ; Julapalli et al , 2009 ) . "
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    ABSTRACT: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, which is characterized by cleft palate and severe defects of the skin, is an autosomal dominant disorder caused by mutations in the gene encoding transcription factor p63. Here, we report the generation of a knock-in mouse model for AEC syndrome (p63+/L514F) that recapitulates the human disorder. The AEC mutation exerts a selective dominant-negative function on wild-type p63 by affecting progenitor cell expansion during ectodermal development leading to a defective epidermal stem cell compartment. These phenotypes are associated with impairment of fibroblast growth factor (FGF) signalling resulting from reduced expression of Fgfr2 and Fgfr3, direct p63 target genes. In parallel, a defective stem cell compartment is observed in humans affected by AEC syndrome and in Fgfr2b−/− mice. Restoring Fgfr2b expression in p63+/L514F epithelial cells by treatment with FGF7 reactivates downstream mitogen-activated protein kinase signalling and cell proliferation. These findings establish a functional link between FGF signalling and p63 in the expansion of epithelial progenitor cells and provide mechanistic insights into the pathogenesis of AEC syndrome. See accompanying article
    EMBO Molecular Medicine 03/2012; 4(3):192-205. DOI:10.1002/emmm.201100199 · 8.67 Impact Factor
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    • "Notably, our patient did not have a history of erosive scalp dermatitis, a characteristic feature of the Hay Wells syndrome, but his mother had an erosive dermatitis with a marked alopecia[13]. "
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    ABSTRACT: Several clinical entities combine ectodermal dysplasia (ED) and cleft lip and/or palate (CL/P). These disorders have been recognized with a narrow phenotypic spectrum and very similar clinical features. We report a case with a clinical diagnosis of Hay Wells syndrome (ankyloblepharon, ED and CL/P), who is a descendent of a mother with Bowen Armstrong syndrome (ED, CL/P, mental retardation). Due to the clinical similarities, we suggest that Hay Wells syndrome and Bowen Armstrong syndrome may be the same clinical entity with variable manifestations. This case highlights the difficulties in trying to classify the ED syndromes on clinical features.
    03/2011; 21(1):121-5.
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