How to cite this article: Bree AF. 2009. Clinical lessons learned from the International Research Symposium on ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Am J Med Genet Part A 149A:1894–1899.
Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) or Hay–Wells syndrome is a rare genetic disease due to mutations in the p63 gene. Due to the rarity of this disorder and the paucity of information known, the 2006 International Research Symposium was convened. Prior to this conference, it was obvious that a standardized, collaborative approach was vital for progress in terms of clinical investigation and translational research. By sharing knowledge, establishing a dataset of clinical information and obtaining tissues for further investigation, we were able to develop a broader understanding of this orphan disease. Our collective findings are detailed in the 11 manuscripts within this special section, which includes an outline of the conference proceedings [Fete et al., 2009] and the clinical, pathologic, and mutational findings of the 18 AEC-affected participants in the study.
Eighteen patients with AEC syndrome from 13 different families were enrolled in this study. There were two sibling sets from two separate families, and four subjects from another family. There were nine males and nine females, and they ranged in age from 4 months to 30 years. All were examined by subspecialists in the areas of audiology, dentistry, dermatology, genetics, growth/nutrition/gastroenterology, otorhinolaryngology, ophthalmology, plastic surgery, and psychiatry. Clinical history and physical examination findings with photographs were documented prospectively. Seventeen of the 18 subjects also donated skin and blood samples for pathologic and mutational analysis, respectively. Family members of certain subjects who were not enrolled in the full study also donated skin and blood samples for investigation. Information from the evaluations was entered into a dataset for analysis, and tissue samples have been archived for future investigation.
Figure 1 tabulates the 18 subjects' clinical photographs coupled with the identified mutations to provide individual genotype–phenotype correlates. Photographs were contributed by Sutton et al. 2009 and mutational analysis results were provided by Rinne et al. 2009.
While genotype–phenotype correlations in AEC syndrome could not be made from our study, there were many notable findings that were recognized by examination of such a large cohort of affected individuals at the same time and place that may not have otherwise been recognized in this rare disease. The first is that while affected individuals share many characteristics, there is significant variability in the expression and severity of these findings among patients, and even among members of the same family despite identical mutations. This highlights the fact that there are other undefined epigenetic factors that affect how a mutated gene product manifests itself in any one individual.
As well, there were other interesting clinical findings that came to light. Dental findings of note included a higher incidence of maxillary hypoplasia and missing permanent maxillary incisors and canines than seen in other ectodermal dysplasia syndromes. The number of individuals with dental prosthesis to replace missing teeth was also lower than expected when compared to other ectodermal dysplasia syndromes [Farrington and Lausten, 2009]. All subjects demonstrated some form of a cleft palate defect [Cole et al., 2009]. Regarding cutaneous changes, 100% of enrolled participants had sparse and wiry hair, nail changes, history of scalp erosions, decreased sweat production, palmar/plantar changes, and unique pigmentary anomolies [Julapalli et al., 2009]. Anthropometric measurements identified previously unreported findings that were determined to be statistically significant including short philtrum length, small ears, and decreased inner and outer canthal distance. Limb abnormalities, most commonly syndactyly, were found in 17 of 18 subjects [Sutton et al., 2009]. This finding was significantly higher than anticipated, as this sign is often used to help distinguish AEC from another p63-related disorder, ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome. Short stature and linear growth abnormalities were found to be significant, with decreased weight improving with age due to increased body fat [Motil and Fete, 2009]. The psychological impact of AEC syndrome had not previously been studied. Various instruments were utilized, and it was found that AEC-affected individuals and families had similar quality of life parameters as individuals with other chronic, non-life threatening, pediatric conditions. Interestingly, there was also a fair number within the cohort who responded with strikingly positive responses regarding stress and impact on functioning [Lane et al., 2009].
There were also new discoveries regarding the pathology and underlying mutations associated with AEC syndrome. Prior to this study, there had not been a systematic review of microscopic skin and hair changes in this condition. The most common histopathologic changes demonstrated in skin biopsy samples from apparently unaffected skin were mild hyperkeratosis, epidermal atrophy, basilar pigmentation, and/or pigment incontinence, and a prominent superficial vascular plexus with mild perivascular lymphocytic infiltrate. All patients had irregularities of the hair shaft including irregular shallow grooves and indentation, along with variable pigmentation [Dishop et al., 2009]. The mutational analysis of our subjects supported prior reports, with the majority of mutations in our subjects occurring as missense mutations within the coding region of the sterile alpha motif (SAM) domain. Six of these were noted to be novel mutations not previously reported. This is also the first report of missense mutations occurring in the transactivation inhibitory (TI) domain, with all mutations in the TI domain identified as novel mutations not previously published [Rinne et al., 2009].
While a sample size of 18 may seem small, it is the largest number of individuals with this condition ever convened. When coupled with talented clinicians and knowledgeable scientists, this provided a rich environment for learning. It was a unique opportunity for studying a very rare disease, and hopefully our collaborative investigation and resultant knowledge will have a translational impact on future therapies available to these individuals [Beaudry et al., 2009; Koster et al., 2009].
This work would not have been possible without the contribution by many individuals. I am deeply indebted to the National Foundation for Ectodermal Dysplasias, especially Mary Fete, for their vision and support; my mentors, Dr. Elaine Siegfried and Dr. Virginia Sybert, who laid the groundwork for this symposium and inspired my desire to learn more; and to all of the dedicated and enthusiastic physicians and researchers who were committed to following this project to publication. Most importantly, I am forever grateful to the individuals and the families who participated in this study. Without their willingness to take part with the hopes of making the future brighter for others, none of this could have been achieved.