Ankyloblepharon-Ectodermal Defects-Cleft Lip/palate

A number sign (#) is used with this entry because of evidence that the AEC syndrome (ankyloblepharon-ectodermal defects-cleft lip/palate) is caused by heterozygous mutation in the TP63 gene (603273) on chromosome 3q27.

Allelic disorders with overlapping features include EEC3 (604292), limb-mammary syndrome (LMS; 603543), ADULT syndrome (103285), Rapp-Hodgkin syndrome (RHS; 129400), and SHFM4 (605289).

Clinical Features

Hay and Wells (1976) described 7 individuals from 4 families with an uncommon disorder characterized by congenital ectodermal dysplasia with coarse, wiry, sparse hair; dystrophic nails; slight hypohidrosis; scalp infections; ankyloblepharon filiforme adnatum; hypodontia; maxillary hypoplasia; and cleft lip/palate. Speigel and Colton (1985) reported an affected mother and son who both had cleft lip and palate. The eyelashes were rudimentary, and in the son there was fusion of the right upper and lower eyelids at birth. Greene et al. (1987) described 2 isolated cases. Weiss et al. (1992) described an isolated case. They reported 2 other patients with ankyloblepharon filiforme adnatum who had chromosomal abnormalities and 1 patient who had the abnormality as an isolated finding. Seres-Santamaria et al. (1993) reported a family in which 2 sibs showed cleft palate, ankyloblepharon, and ectodermal defects and, in addition, had congenital adhesions between the upper and lower jaws (alveolar synechiae). Neither parent had any features of the syndrome, suggesting this is either a recessive form of Hay-Wells syndrome with additional features or should be viewed as a separate entity. It is possible, of course, that the family reported by Seres-Santamaria et al. (1993) represented an instance of germinal mosaicism for the dominant mutation in one of the normal parents.

Bertola et al. (2000) described a 5-year-old Brazilian boy with ectodermal dysplasia, ankyloblepharon, and bilateral choanal atresia but without cleft palate. The authors noted that choanal atresia was present in 1 of the patients reported by Hay and Wells (1976). The patient's nonconsanguineous parents had no ectodermal abnormality, and there was no family history of the disorder.

Fete et al. (2009) provided a conference report from the 2006 International Research Symposium on AEC Syndrome. They noted that features present in 100% of 12 AEC patients presented in a workshop included scalp/skin erosions, ankyloblepharon, dental abnormalities, recurrent otitis media, and nail abnormalities; in addition, 92% had cleft palate, and 83% had cleft lip. Nails were not characteristically 'hyperconvex' as previously described, but were more often thin, distorted, or absent. The most dramatic ophthalmologic abnormality was blepharitis. Scalp erosions were a major source of morbidity for affected infants, and tetracyclines, especially doxycycline, were recommended for dual antimicrobial and matrix metalloproteinase activity. Fete et al. (2009) noted that many children with AEC have nutritional issues, with a majority suffering failure to thrive that was out of proportion compared to other children with isolated cleft lip/palate; the reasons for this were not clear.

Cole et al. (2009) evaluated 18 patients with a diagnosis of AEC, who all had a history of otitis externa or otitis media; 14 of 15 subjects tested had conductive hearing loss, and 8 had hoarseness or voice problems. The authors suggested that many oroauditory problems in AEC are likely related to palatal clefting, as well as associated disorders such as feeding difficulty, recurrent middle ear infection, and speech disarticulation. Cole et al. (2009) noted that persistent feeding difficulties following cleft closure indicated that additional factors might be involved, and suggested that increased tissue vulnerability associated with absent epidermal appendages might also play a role.

Sutton et al. (2009) examined 17 AEC patients from 13 unrelated families and found that short stature and poor weight gain with preservation of head circumference were present in nearly all patients. Additional features included trismus in 35% and hypospadias in 85% of males. In contrast to previous reports of syndactyly limited to the soft tissue, 8 (47%) of 17 patients had bilateral complete 2-3 toe syndactyly, and 3 cases (18%) had 3-4 toe syndactyly that was noted to extend to the fifth toe in some cases. In 4 (24%) of 17 cases there was webbing and/or syndactyly of the hands involving the third and fourth digits. Other limb anomalies included hammertoe deformities in 8 (47%) of the 17 patients. Sutton et al. (2009) concluded that limb involvement in AEC is more significant than previously thought; they also noted that these patients confirmed the extreme clinical variability in AEC.

Dishop et al. (2009) used light microscopy to examine biopsies of normal and lesional skin from 19 AEC patients; in addition, hair samples from 18 patients were examined by light and scanning electron microscopy. Histopathologic changes identified within the skin biopsies from clinically unaffected skin included mild atrophy, focal orthokeratosis, and mild superficial perivascular lymphocytic dermatitis. Scattered melanophages in the superficial and deep dermis were believed to reflect postinflammatory changes. Examination of hair shafts revealed atrophy and loss of melanin pigment in some patients; structural abnormalities included pili torti, pili triangli et caniculi, and irregular indentation and shallow grooves. No pathognomonic findings of skin or hair were identified.

Molecular Genetics

Some phenotypic overlap can be recognized with Hay-Wells syndrome and other ectodermal dysplasia syndromes, including ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC; 604292). Celli et al. (1999) demonstrated that heterozygous mutations in the TP63 gene are the major cause of EEC syndrome. McGrath et al. (2001) analyzed the TP63 gene in AEC syndrome patients and identified missense mutations in 8 families. All mutations gave rise to amino acid substitutions in the sterile alpha motif (SAM) domain, and were predicted to affect protein-protein interactions. In contrast, the vast majority of the mutations found in EEC syndrome are amino acid substitutions in the DNA-binding domain. The authors suggested that a distinct genotype-phenotype correlation can be recognized for EEC and AEC syndromes.

In 2 sibs and their mother who had been diagnosed with Rapp-Hodgkin syndrome (RHS; 129400), Dianzani et al. (2003) identified a 1-bp deletion in the TP63 gene (603273.0017). The mother had a slight ankyloblepharon on the right eye at birth which was surgically treated; Dianzani et al. (2003) suggested that AEC and RHS are the same clinical entity.

In a patient with AEC previously described by Bertola et al. (2000), Bertola et al. (2004) identified an ile510-to-thr mutation in the TP63 gene (603273.0018). They identified the same mutation in a patient with RHS and concluded that AEC and RHS represent variable expression of a single genetic disorder.

In an 11-year-old boy who displayed an overlapping phenotype with features of both AEC and RHS, Prontera et al. (2008) identified heterozygosity for an 11-bp duplication in the TP63 gene (603273.0027). The authors stated that their findings confirmed the hypothesis that AEC and RHS are variable expressions of a single genetic disorder, and suggested that intermediate phenotypes are possible.

Animal Model

Koster et al. (2009) generated mice with downregulated delta-N-p63-alpha, the predominantly expressed TP63 isoform in postnatal skin. The mutant mouse epidermis developed severe skin erosions resembling those of AEC patients and similarly characterized by suprabasal epidermal proliferation, delayed terminal differentiation, and basement membrane abnormalities. The authors suggested that by failing to provide structural stability to the epidermis, these defects likely contribute to the observed skin fragility.