Two novel TP63 mutations associated with the ankyloblepharon, ectodermal defects, and cleft lip and palate syndrome: a skin fragility phenotype.
BACKGROUND
Ankyloblepharon, ectodermal defects, and cleft lip and palate (AEC) syndrome is a rare autosomal dominant disorder caused by mutations in the sterile alpha motif region of TP63, a homologue of the tumor suppressor TP53. Recent structure-function studies have identified complexities in the genotype-phenotype correlation of the p63 syndromes.


METHODS
We report 2 sporadic cases of AEC syndrome in infants. Both patients demonstrated skin erosions with prominent scalp involvement. Histologic studies demonstrated mild basal layer vacuolization and rare dyskeratotic keratinocytes, with evidence of both acantholysis and cytolysis at the blister edge. Immunohistochemistry using anti-p63 monoclonal antibody demonstrated basal epidermal nuclear staining in both healthy control and patient tissue samples. Ultrastructural studies showed focal disruption of anchoring fibrils near the blister edge of one patient and normal desmosomes, hemidesmosomes, and basement membrane zone in the nonblistered skin of the other patient. The DNA analysis of each patient revealed 2 novel missense mutations in the TP63 gene that resulted in L514S and R555P amino acid substitutions within the sterile alpha motif region of the p63 protein.


CONCLUSIONS
We report 2 novel TP63 mutations resulting in AEC syndrome. The R555P mutation is the most carboxy-terminal of all the reported AEC missense mutations of p63. The presence of skin fragility, manifested as erosive skin lesions in body areas in addition to the scalp, is postulated to be an important diagnostic feature of AEC syndrome.
Payne
Aimee S
AS
Department of Dermatology, University of Pennsylvania, 220 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104, USA. aimee.payne@uphs.upenn.edu
Yan
Albert C
AC
Ilyas
Erum
E
Li
Weijie
W
Seykora
John T
JT
Young
Terri L
TL
Pawel
Bruce R
BR
Honig
Paul J
PJ
Camacho
Jeanette
J
Imaizumi
Sonia
S
Heymann
Warren R
WR
Schnur
Rhonda E
RE
D000015:Abnormalities, Multiple / Q000235:genetics; D001120:Arginine; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D004268:DNA-Binding Proteins; D004476:Ectodermal Dysplasia / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D016147:Genes, Tumor Suppressor; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D011392:Proline; D012867:Skin / Q000473:pathology; D013577:Syndrome; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D001120:Arginine; D011392:Proline