At birth, the patient demonstrated ankyloblepharon, erosive scalp dermatitis, hyponychia, hypoplastic nipples, webbed penis, and cleft palate without cleft lip. Superficial swabs of skin erosions at birth revealed Candida albicans. The erosive scalp dermatitis has continued to persist despite aggressive topical therapy with petrolatum gauze, silicone-based dressings, and topical antibiotics where needed, with most recent cultures demonstrating Candida parapsilosis and Pseudomonas aeruginosa. DNA analysis of buccal swabs revealed a G to C mutation in exon 14 of TP63, predicting an R555P mutation in the carboxyl terminus of the SAM region of p63 (numbered according to GenBank accession number AF075430). Hay and Wells first described the syndrome of ankyloblepharon, ectodermal defects, and clefting of the lip and palate (AEC) in a series of seven patients from 4 affected families. The trait is transmitted in an autosomal dominant fashion, although many sporadic cases have been described. In addition to the classic triad of congenital anomalies, affected individuals may demonstrate varying degrees of alopecia, onychodystrophy, hypohidrosis, hypodontia, maxilllary hypoplasia, alveolar synechiae, syndactyly, auricular deformities, and supernumerary nipples.
Germline mutations in TP63, a homologue of the tumor suppressor TP53, are responsible for AEC syndrome. Mutations in TP63 have also been identified in a subset of patients with EEC (ectrodactyly, ectodermal defects, and cleft lip/palate) syndrome, as well as limb-mammary syndrome, split-hand/split-foot malformation, ADULT (acro-dermato-ungual-lacrimal-tooth) syndrome, and Rapp-Hodgkin ectodermal dysplasia, an AEC-like syndrome with distinctive facies. In addition to the distinguishing feature of ankyloblepharon, AEC may be differentiated from EEC by the common occurrence of an erosive scalp dermatitis that is often colonized with mixed flora and may necessitate early topical and systemic antibiotic therapy.
Structure function analysis has revealed a genotype-phenotype correlation within the p63 syndromes. p63, like p53, contains a transactivation domain, a DNA binding domain, and an oligomerization domain, in addition to a unique carboxyl terminal sterile alpha motif (SAM). AEC mutations cluster in the SAM region of p63 and are thought to disrupt protein-protein interactions, while EEC mutations occur in the DNA binding domains of the protein and are expected to affect transcriptional activity of the protein. However, the same genetic mutation has been reported in both EEC syndrome and isolated split-hand/split-foot malformation, suggesting that the penetrance of these disorders is incomplete. Genetic analysis of this patient revealed a novel L514S mutation in the SAM region of p63. Two different mutations at this same site (L514K, L514V) have previously been reported in AEC syndrome. Given the complexities of genotype-phenotype correlation, accurate diagnosis of the p63 syndromes relies not only on DNA testing, but also the presence of the typical constellation of findings associated with each syndrome.
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