Alanna F. Bree

Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS)

The first international colloquium on basal cell nevus syndrome (BCNS) was held at Saint Louis University School of Medicine and supported by the Basal Cell Carcinoma Nevus Syndrome (BCCNS) Life Support Network (www.gorlinsyndrome.org). The foremost goal of the conference was to review and revise the prior diagnostic criteria and define the surveillance recommendations for affected pediatric and adult patients to allow for early intervention. The invited consensus group participants included geneticists, dermatologists, orthopedists, neurologists, and dental/oral medicine specialists, who treat patients with BCNS or related disorders. This group also included individuals who have a research interest in BCNS and who additionally serve on the medical advisory board of the BCCNS Life Support Network. Expert opinion was based on the collective clinical and research experience of the consensus group participants after presentation and review of the previously published literature regarding diagnosis and treatment of BCNS. A consensus was achieved and agreed upon by open roundtable discussion of the group participants. The consensus statement outlines the proposed diagnostic and management protocols that will hopefully limit morbidity and mortality for affected individuals until more specific and targeted therapies are widely available.

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

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 disorders 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 Childrens 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 anomolies. 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.

Pathologic changes of skin and hair in ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome†

Ankyloblepharon‐Ectodermal defects‐Cleft lip/palate (AEC) syndrome is a rare disorder of hair, skin, nails, and dentition caused by mutations in the p63 gene. Pathologic changes of skin and hair in AEC syndrome have previously been described in isolated case reports. Biopsies of normal and lesional skin from 19 patients with AEC syndrome were examined by light microscopy. Hair samples from 18 patients were examined by light and scanning electron microscopy. Histopathologic changes identified within the skin biopsies from clinically unaffected skin include mild atrophy, focal orthokeratosis, and mild superficial perivascular lymphocytic dermatitis. Scattered melanophages in the superficial and deep dermis likely reflect post‐inflammatory change. One patient with a unilateral eruption of monomorphic papulopustules on the chest and shoulder demonstrated an acneiform intraepidermal pustule. Examination of the hair shafts revealed atrophy and loss of melanin pigment in some of the patients. Structural abnormalities included pili torti, pili trianguli et canaliculi, and irregular indentation and shallow grooves. Skin and hair findings in AEC syndrome were found to be generally similar to those described in other ectodermal dysplasia syndromes and corroborates the few prior descriptions in AEC syndrome specifically.

International Research Symposium on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) syndrome.

Ankyloblepharon‐ectodermal defects‐cleft lip/palate (AEC) syndrome (Hay–Wells syndrome, MIM #106220) is a rare autosomal dominant ectodermal dysplasia syndrome. It is due to mutations in the TP63 gene, known to be a regulatory gene with many downstream gene targets. TP63 is important in the differentiation and proliferation of the epidermis, as well as many other processes including limb and facial development. It is also known that mutations in TP63 lead to skin erosions. These erosions, especially on the scalp, are defining features of AEC syndrome and cause significant morbidity and mortality in these patients. It was this fact that led to the 2003 AEC Skin Erosion Workshop. That conference laid the groundwork for the International Research Symposium for AEC Syndrome held at Texas Childrens Hospital in 2006. The conference brought together the largest cohort of individuals with AEC syndrome, along with a multitude of physicians and scientists. The overarching goals were to define the clinical and pathologic findings for improved diagnostic criteria, to obtain tissue samples for further study and to define future research directions. The symposium was successful in accomplishing these aims as detailed in this conference report. Following our report, we also present 11 manuscripts within this special section that outline the collective clinical, pathologic, and mutational data from 18 individuals enrolled in the concurrent Baylor College of Medicine IRB‐approved protocol: Characterization of AEC syndrome. These collaborative findings will hopefully provide a stepping‐stone to future translational projects of TP63 and TP63‐related syndromes.

Facial clefting and oroauditory pathway manifestations in ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome.

Ankyloblepharon–ectodermal defects‐cleft lip/palate (AEC) Syndrome is a rare disorder characterized by ectodermal dysplasia, along with other malformations such as cleft lip and palate, and various secondary issues such as chronic sinusitis, otitis media, and conductive hearing loss (CHL). The International Research Symposium for AEC Syndrome convened at Baylor College of Medicine in Houston, Texas. Patients with a suspected diagnosis of AEC syndrome attended, and members of the dental, dermatology, plastic surgery, otolaryngology, and audiology services examined each patient. Eighteen patients with a diagnosis of AEC were evaluated. Mean age was 7.5 years (range: 4 months–30 years). Fourteen of the 15 subjects tested (93.33%) demonstrated CHL, with seven showing moderate to severe hearing deficits (41–90 dB). Nine of 13 respondents reported hoareness or voice problems; 8 were noted to display this on examination. Fourteen of 16 subjects reported speech was below average for age; 8 were in speech therapy. All 18 subjects reported a history of otitis externa or otitis media. Eleven of the subjects (61.11%) required myringotomy and pressure equalizing (PE) tubes. All patients demonstrated cleft palate defects. Of these, 16 (94.11%) presented with clefting of the soft palate, and 10 (58.82%) showed hard palate defects. Three subjects (16.67%) were noted to have submucous clefts. Our experience leads us to propose that while the oroauditory problems in those with AEC syndrome is likely multifactorial, many issues may stem from palatal clefting. Despite this, some abnormalities persist following surgical cleft closure, which indicates other complicating factors are also involved.

Craniofacial and Anthropometric Phenotype in Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome (Hay-Wells Syndrome) in a Cohort of 17 Patients

Ankyloblepharon–ectodermal dysplasia–cleft lip/palate (AEC) syndrome and Rapp–Hodgkin syndrome are well‐characterized clinical entities caused by mutations in the TP63 gene. While AEC and Rapp–Hodgkin had been thought to be clinically distinct entities, the elucidation of their molecular etiology confirmed that they are a clinical continuum as opposed to distinct disorders. We have evaluated 17 patients with AEC syndrome using a systematic clinical approach. In our study, we have identified new features and others that were thought to occur only rarely. These include short stature and poor weight gain with preservation of head circumference in nearly all subjects, trismus in 35% and hypospadias in 78% of males. In addition, we describe the frequency of phenotypic features and demonstrate the extreme clinical variability in the largest cohort of AEC individuals reported in the literature thus far.

Prevalence of atopic disorders and immunodeficiency in patients with ectodermal dysplasia syndromes

BACKGROUND Ectodermal dysplasia (ED) syndromes are a diverse group of disorders that affect multiple ectodermally derived tissues. Small studies and case reports suggest an increase in atopy and primary immunodeficiencies (PIDs) among patients with ED syndromes. OBJECTIVE To determine the prevalence of clinical symptoms suggestive of atopy or immunodeficiency among a large cohort of children with ED syndromes. METHODS A 9-page questionnaire was mailed to families who were members of the National Foundation for Ectodermal Dysplasias. The surveys were completed by parents of children younger than 18 years with a diagnosis of an ED syndrome or carrier state. Portions of the questionnaire were adapted from previously validated questionnaires developed by the International Study of Asthma and Allergies in Childhood (ISAAC). RESULTS We received 347 completed questionnaires (41%). When compared with the 13- to 14-year-old children surveyed by ISAAC, we found both all-aged and age-matched children with ED syndromes, respectively, had significantly higher rates of asthma (32.2% and 37.2% vs 16.4%), rhinitis symptoms (76.1% and 78.3% vs 38.9%), and eczema (58.9% and 48.9% vs 8.2%). The prevalence of physician-diagnosed food allergies (20.7%) and PIDs (6.1%) in these ED patients also exceeded known rates in the general pediatric population. CONCLUSION This large-scale, retrospective study demonstrates a greater reported prevalence of symptoms suggestive of atopic disorders and PIDs among children with ED syndromes than the general pediatric population. A combination of genetic and environmental factors in ED syndromes may contribute to breaches of skin and mucosal barriers, permitting enhanced transmission and sensitization to irritants, allergens, and pathogens.

Quality of life and depression assessment in nevoid basal cell carcinoma syndrome

Background  Nevoid basal cell carcinoma syndrome (NBCCS) is a rare genetic disease which causes a variety of dermatological lesions, especially basal cell carcinomas (BCCs), often on the face, neck, and head.

Features of basal cell carcinomas in basal cell nevus syndrome.

Basal cell nevus syndrome (BCNS) is an autosomal dominant genodermatosis that is characterized by early onset basal cell carcinomas (BCCs) that define the disease and often lead to diagnosis of the underlying syndrome. The objective of this study was to investigate the anatomic location, subtypes, and impact of BCCs on a group of 61 individuals affected with BCNS attending a research colloquium. Fifty individuals had at least one prior BCC with 22 participants having over 100 lesions. The median age of syndrome diagnosis was 11 years and median age of first BCC was 16 years. Males had more lesions on the upper back, upper extremities, and M‐zone of the face, while females had more lesions on the scalp, back, and lower extremities. Pigmented BCCs were concentrated on the neck, upper trunk, and extremities. Subjects with >100 lesions showed wider anatomic distribution. The number of BCCs did not correlate with any of the other major features of the syndrome. Eighty percent of affected individuals reported great concern related to BCCs, citing the limitations and morbidity of available treatments. Vigilant surveillance, which was found to be inconsistent for participants in this study, is warranted. Future work should include development of a consensus guideline on skin examinations and strategies to optimize therapy of BCCs in this syndrome.

Psychosocial functioning and quality of life in children and families affected by AEC syndrome

Ankyloblepharon‐ectodermal defects‐cleft lip/palate (AEC) syndrome, also known as Hay–Wells syndrome, is a rare genetic condition that results in abnormalities of the skin, hair, nails, and teeth and requires frequent self‐management and medical care. We sought to describe the psychological adjustment and quality of life in children and adolescents with AEC syndrome, as well as the impact of the childs illness on their families. The sample included 18 children and adolescents with AEC syndrome and their parents who attended the International Research Symposium on AEC syndrome. Parents completed standardized self‐report questionnaires about child and family functioning and participated in a semi‐structured interview about the childs cognitive and social functioning and the impact of AEC syndrome on the child and family. Children completed standardized self‐report questionnaires of psychosocial functioning and quality of life. Overall, results reflected a range of functioning across children and families, with some families reporting few ill effects of the condition and others describing reduced quality of life and negative impact on child and family. Identifying the domains that may be impacted should help clinicians better screen for problems in functioning of children affected by AEC syndrome and their families.