Facial clefting and oroauditory pathway manifestations in ankyloblepharon–ectodermal defects-cleft lip/palate (AEC) syndrome†
How to cite this article: Cole P, Hatef DA, Kaufman Y, Magruder A, Bree A, Friedman E, Sindwani R, Hollier Jr LH. 2009. Facial clefting and oroauditory pathway manifestations in ankyloblepharon–ectodermal defects-cleft lip/palate (AEC) syndrome. Am J Med Genet Part A 149A:1910–1915.
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. © 2009 Wiley-Liss, Inc.
The ectodermal dysplasias (EDs) are a group of syndromes which all have the abnormal development of two or more ectodermally derived tissues as a common denominator [Lamartine, 2003]. Because the ectoderm gives rise to the skin, hair, nails, dental enamel, and central and peripheral nervous systems, these patients can have abnormal development in these ectodermally derived structures [Priolo et al., 2001]. EDs are relatively uncommon, with a reported incidence between 0.1 and 7 in 10,000 for the most common subtype, hypohidrotic ED [Freire-Maia and Pinheiro, 1984; Daniel et al., 2002].
Ankyloblepharon–ectodermal defects-cleft lip/palate (AEC) syndrome (Hay–Wells syndrome, OMIM 106220) is one of the rarer ED subtypes. The condition was first recognized by Hay and Wells in 1976. These authors described cleft lip/palate and congenital fusion of the eyelids in association with ED [Hay and Wells, 1976]. In addition to the abnormal anatomic development, chronic inflammation is also associated with the oro-auricular pathway malformations [Macias et al., 2006], and may produce a compound effect.
Chronic sinusitis, longstanding otitis media, hearing loss, and feeding difficulties are common findings in AEC patients [Cabiling et al., 2007]. Although these findings may be attributed to the syndrome itself, other explanations are also possible. Because of the palatal clefting, which is seen almost ubiquitously in these patients, it could be theorized that these otolaryngologic pathologies are secondary to the cleft palate with all of the others findings downstream complications. Much further study and examination is needed; however, this may be limited as the disease is exceedingly rare (Table I).
Table I. Detailed Patient Data
|5||Severe; PET × 5||Stenosis; no effusion||Moderate (35–70 dB); H/A||Yes; in therapy||Moderate||None||No cleft lip; submucous cleft—W/K repair no fistula||Present||Yes|
|7||Mild; no PET||Mild stenosis; no effusion||Moderate (40–65 dB); no H/A||Yes; no therapy||Mild; hyper-nasal||Moderate||Cleft lip—BM repair; unilateral cleft palate—W/K repair; palatal fistula||Unrepaired||Yes|
|19 months||Moderate; no PET||Mild stenosis||Mild (20–30 dB SAT); no H/A||Yes; no therapy||No||None||No cleft lip; unilateral cleft—W/K repair; no fistula||Unrepaired||No|
|30||Severe; PET × 8||No stenosis or effusion; TM retraction||Mild (30–40 dB); no H/A||No; no therapy||Mild||Mild||No cleft lip; isolated cleft—W/K repair; no fistula||Repaired; pharyngoplasty and flap||No|
|17||Moderate; PET × 3||Narrow canal; TM retraction||Moderate (20–60 dB); prior H/A||Yes; no therapy||No||Mild||No cleft lip; unilateral cleft palate—unknown repair type; no fistula||Repaired; pharyngeal flap||No|
|6||Mild; no PET||Severe stenosis; no effusion||Moderate to severe (60–90 dB); no H/A||Yes; no therapy||No; hyper-nasal||Moderate||Cleft lip—M repair; bilateral cleft palate—W/K repair; no fistula||Unrepaired||No|
|4 months||Severe; no PET||Otitis externa; no stenosis or effusion||Unable to test due to age||Unknown due to age||No||Unable to assess||Unrepaired cleft lip and bilateral cleft palate; no fistula||Unrepaired||No|
|10||Mild; PET × 1||Stahl's ear; no stenosis or effusion; TM retraction||Mild (25–35 dB); no H/A||Yes; no therapy||No; hyper-nasal||Severe||Cleft lip—M repair; isolated cleft palate—V + W/K repair; palatal fistula||Repaired; pharyngoplasty/bone graft/flap||No|
|7||Mild; PET × 2||No stenosis or effusion||Unable to test due to recent surgery; H/A||No; in therapy||No||Mild||Submucous cleft—unrepaired; no fistula||Present||No|
|4||Mild; PET × 1||No stenosis or effusion||Moderate on prior testing; H/A||Yes; in therapy||Mild; hyper-nasal||Mild||Cleft lip—M repair; unilateral cleft palate—W/K repair; no fistula||Repaired; superior pharyngeal flap||No|
|15||Mild; PET × 2||No stenosis or effusion||Mild (30–40 dB); H/A||Yes; no therapy||No||Severe||Cleft lip—M repair; isolated cleft palate—W/K repair; no fistula||Repaired; pharyngeal flap||No|
|7||Mild; no PET||Stenosis; no effusion||Normal (10–20 dB); no H/A||Yes; in therapy||No||Mild||No cleft lip; isolated cleft palate—W/K repair; no fistula||Present||Yes|
|8||Moderate; PET × 1||No stenosis or effusion||Mild (15–35 dB); no H/A||Yes; no therapy||Mild||None||No cleft lip; isolated cleft palate—F repair; no fistula||Present||No|
|1||Moderate; no PET||Stenosis; no effusion||Moderate on prior testing; H/A||Yes; in therapy||No||None||No cleft lip; isolated cleft palate—W/K repair; no fistula||Unrepaired||Yes|
|4 months||Mild; no PET||Stenosis; no effusion||Unable to assess due to age||Unknown due to age||No||None with small nares||No cleft lip; unilateral cleft palate—unrepaired; no fistula||Unrepaired||Yes|
|22 months||Moderate; PET × 1||Stenosis and effusion||Mild (20–35 dB SAT); no H/A||Yes; in therapy||No||Moderate||Cleft lip—T repair; isolated cleft palate—W/K repair; no fistula||Unrepaired||No; poor feeding noted|
|22 months||Mild; PET × 1||No stenosis; acute otitis media||Mild (30–40 dB SAT); no H/A||Yes; in therapy||No||None||No cleft lip; submucous cleft—not repaired; no fistula||Unrepaired||No; poor feeding noted|
|8||Moderate; PET × 4||No stenosis or effusion||Moderate (15–60 dB); H/A||Yes; in therapy||Moderate||Moderate||Cleft lip—BM repair; bilateral cleft palate—W/K repair; no fistula||Unrepaired||No|
The International AEC Syndrome symposium convened at Baylor College of Medicine Department of Dermatology in Houston, Texas in 2006. Eighteen patients with AEC syndrome were evaluated at Texas Children's Hospital. Subjects provided medical, dental, and surgical histories. Questionnaires were completed regarding specific head and neck problems. Physicians and surgeons from the Departments of Plastic Surgery, Dermatology, and Otolaryngology examined all patients. All patients also underwent standard dental examinations [see Farrington and Lausten, 2009 in this issue]. Subjects additionally underwent audiologic evaluation utilizing standardized equipment including otoscopy, tympanometry, pure-tone air-conduction audiometry and pure-tone bone-conduction audiometry; results were graphed as standard audiograms. Speech and cognitive function was not specifically tested in our study due to limitations of time within the multidisciplinary evaluation format.
Eighteen of the patients were unanimously agreed to have ankyloblepharon–ectodermal defect-cleft lip/palate (AEC) syndrome, which was supported by the mutational analysis findings [see Rinne et al., 2009 in this issue]. Nine patients were male, and nine were female. Of 18 patients with AEC, patient age was approximately 7.5 years (range: 4 months–30 years). Nine out of 18 patients (50.0%) had a positive family history (either known sibling or parent cases).
Chronic ear infections were reported to be common by all patients. Otolaryngologic examination revealed 16 patients in whom otitis media, chronic scarring of the tympanic membrane, or ongoing inflammation within the ear canal was uncovered. Nine of the patients also had stenosis of the external auditory canal. Eleven of the 18 patients (61.11%) required PE tubes at least once. Several patients required several sets, with a range from 1 to 8 sets, with an average of 3.79 sets of PE tubes per patient in this group. Nine of 13 respondents subjectively reported hoarseness or voice problems: 6 reported mild problems, 2 moderate problems and 1 noted severe problems. On examination, eight subjects were noted to be hypernasal and/or hoarse with subjective ratings of hoarseness as mild in four subjects and moderate in two others.
Speech and Hearing Issues
Speech delays were subjectively reported by 14 of 16 verbal subjects or their family members, while eight of these children were engaged in regular speech therapy. Unfortunately, formal speech assessments were not performed in our study.
By history, 14 of 15 subjects (93.33%) reported subjective hearing impairment. On exam, 14 of 15 subjects who were able to be tested demonstrated conductive hearing loss (CHL). Of those with CHL, one had severe deficits (71–90 dB), six demonstrated moderate defects (41–70 db), and seven displayed mild hearing loss (21–40 dB). Seven subjects had hearing aids presently or in the past and tolerated them reasonably well.
Fourteen patients reported either active feeding problems or a history of feeding issues (77.78%). Five patients (27.77%) in this series required gastrostomy tube feeds. Additional growth, nutritional and gastrointestinal aspects of these subjects in reported by Motil and Fete in this special section [Motil and Fete, 2009 in this issue]. All but four patients had undergone cleft palate closure; two were too young for palatoplasty and the other two had submucous clefts.
Plastic Surgical Issues
As expected, there were a very high percentage of cleft lip and palate defects. All eighteen patients (100%) had some type of cleft palate. Sixteen were noted to have soft palate involvement, while 10 subjects had clefting of the hard palate. There were seven isolated cleft palates. There were also three submucous clefts. Eight of the patients were found to have a cleft lip (44.44%). Of these, three had bilateral cleft lip and palate, and five had unilateral cleft lip and palate.
Seven of the eight patients had repair or cheiloplasty of their cleft lips at the time of the study; four by the Millard technique, two by the bilateral Millard approach and one by the Tennison method. Fourteen patients had repair of their cleft palate or palatoplasties at the time of the study; one with partial repair, three not yet repaired due to their age and another an asymptomatic submucosal cleft. Of the 14 palatoplasties, 11 were repaired by the Wardill–Kilner method, 1 with a combination of a Vomer flap and Wardill–Kilner method, 1 by the Furlow technique, and another with an unknown repair type.
Nine patients had unrepaired velopharyngeal incompetence (VPI). Five subjects had undergone additional surgeries, including pharyngeal flaps, pharyngoplasty and bone grafting, to repair their VPI. Four of the subjects were noted to have velopharyngeal competence without surgical correction. Two patients were noted to have palatal fistulas in addition to their VPI.
Examination of the nasal septum revealed septal deviation in 11 subjects (61.11%). Two patients (11.11%) demonstrated severe septal deviation. Both of these patients had cleft lip and palate. Nine patients showed mild to moderate septal deviations. Four had moderate deviation, and all of these subjects had both cleft lip and palate. Six subjects had mild deviations; none had cleft lip and all had cleft palates, with two of the palatal clefts being submucosal.
CHL is a frequent finding in those with AEC syndrome; however, the underlying etiologies of the audiologic pathology remain unclear. Of 18 patients evaluated in the present study, 93.33% showed signs of decreased hearing. One patient with severe deficits also had a cleft lip and palate with unrepaired VPI, external auditory stenosis, and a history of mild otitis media not requiring PE tubes. Approximately one-thirds demonstrated moderate loss, and one-half showed mild hearing loss. Several etiologies have been proposed to explain this association. In review of patients with EDs, the broad category encompassing AEC syndrome, Shin and Hartnick 2004 suggested that absent cilia within the nose and abnormal Eustachian tube structure resulted in chronic infection and middle ear scarring. While these factors likely play a role in AEC-related hearing loss, we suspect that palatal clefting also makes a significant impact on hearing. We propose that cleft palate can be considered an indirect, upstream cause of CHL in this patient population. Because of the issues concerning absent cilia, inflammation, abnormal Eustachian tube structure, and clefting of the palate, the etiology of CHL in AEC patients is very likely multifactorial. This could explain why the hearing issues in these patients appears to be more severe than seen in patients with other EDs, such as EEC syndrome [Skarzynski and Podskarbi-Fayette, 2009]. Interestingly, systematic reviews of the literature have demonstrated that CHL is more frequently seen when these patients have a cleft palate [Roelfsema and Cobben, 1996]. The pediatrician and/or medical geneticist should be alerted to the possibility of more severe hearing issues in this group of patients, so that appropriate parental preparation and referrals can be performed. As hearing is an integral factor in speech development, this should also be assessed in these at-risk patients.
Pathological speech and language development were frequently noted in the study population. Nine of 13 subjects reported voice problems. Eight of the subjects were grossly noted to have hoarse or hypernasal speech during evaluation. Unfortunately, formal speech and cognitive evaluations were outside the scope of this study, but certainly more study is needed in this area.
The high reported incidence of speech pathology may also be related to the palatal abnormalities as well as the abnormal interplay of several complex processes. Ptok and Kiessling 2004 demonstrated abnormal CNS auditory tract formation in the setting of hearing loss. In addition, several studies have linked language defects to recurrent middle ear infection between the ages of 6 and 18 months [Friel-Patti and Finitzo, 1990]. In addition to these multifactorial issues, the relationship between palatal clefting and speech defects is well-documented. Characteristic articulation problems include enhanced nasal air emissions, a shift in location of articulation, and modified articulatory tension [Laitinen et al., 1998]. These patients demonstrate increased misarticulations when lingual-alveolar contact is required for dento-alveolar sounds. Laitinen et al. 1999 further described a higher incidence of posterior cross-bite and dento-alveolar misarticulations associated with cleft palate patients.
Inflammation of the auditory pathway was common in the present study group. In all, 16 patients demonstrated either otitis media, scarring of the tympanic membrane, or inflammation within the external ear canal. A majority of the patients had required treatment with myringotomy and PE tubes; many needed several sets with an average of 3.79 sets per affected subject. In a review of patients with ED, Shin and Hartnick 2004 suggested that the high incidence of otitis media in hypohidrotic ectoderma dysplasia is due to hypoplastic mucous glands within the auditory pathway. Without proper gland function at these locations, the epidermis is vulnerable to repeated infection. The population of ED patients reviewed by those authors did not include AEC patients with clefts of the palate. Although the authors are correct in asserting that hypoplastic mucosa contributes to auditory problems, we posit it is an insufficient explanation in the AEC population.
Patients with AEC syndrome typically have clefts of the palate, and this condition is well known to be linked with CHLs [Proctor, 1973; Broen, 1996]. In the present study, 100% of the patients displayed palatal clefting and nearly half showed marked CHL. Past authors suggest that cleft-related CHL is directly related to recurrent otitis media, middle ear scarring, and tympanic membrane scarring [Goudy et al., 2006]. In turn, this longstanding inflammation is exacerbated by cleft-related: (1) levator veli palatini malpositioning, (2) tensor veli palatini malformation, and (3) abnormalities in auditory tube function [Seif and Dellon, 1978]. Abnormal tensor veli palatini insertion produces an anomalous, isometric contraction and this is ineffective in ventilating the middle ear space [Bluestone et al., 1975; Kitajiri et al., 1985]. Poor Eustachian tube function produces poor middle ear ventilation and this is thought to promote repeated infections at this location [Sando et al., 1991; Leuwer and Koch, 1999]. Over time, repeated middle ear infection produces local scarring and results in CHL [Swarts and Rood, 1990; Ptok and Kiessling, 2004].
Deviation of the nasal septum was a common defect in those with AEC syndrome. Eleven patients demonstrated some degree of septal deviation. Because the bony palate normally guides septal development, palatal clefting likely plays a significant role in contributing to this defect as well. It is thought that deviation to the noncleft side results when the cartilaginous tip is unable to grow into the skin of the nasal tip, leaving it to rest within the nasal aperture [Drettner, 1960]. As a result, bowing of both bony and cartilaginous septal portions often contribute to cleft-related nasal airway obstruction. In addition, septal deviation has been linked to abnormal paranasal sinus drainage patterns and chronic sinus infections [Drettner, 1960]; although, this is controversial. Compounding the displaced septum, scar tissue from palatal repair may draw septal components further into the cleft side airway [Byrd and Salomon, 2000].
Patients with cleft palate have difficulty maintaining an oral seal when suckling, require a longer period to feed, and they can then grow tired before ingesting needed nutrients. If the palatal defect remains as the child ages, eventually oral reflux into the nasal cavity may become problematic. As a result, these patients are often undernourished and below standardized body mass for their age. However, this does not explain the feeding problems seen in this patient group, as the number of subjects within our study group requiring gastrostomy tube placement is higher than would be expected in isolated cleft lip/palate cases [see Motil et al., 2009 this issue]. The ultimate solution to cleft-related feeding difficulty is typically palatal reconstruction, and this typically takes place around 1 year of age. This definitive palatoplasty reverses the problem, and thus tube feeds are almost never required in cleft palate patients. While clefting may help explain feeding difficulties prior to repair, it does not explain problems in the older, post-palatoplasty group. It is our estimation that an element of pharyngeal or esophageal compromise may also be at play; although impaired gastrointestinal absorption may also be a contributing factor. This is a topic for further evaluation.
We found that ankyloblepharon–ectodermal defect-cleft lip/palate (AEC) syndrome is associated with a wide variety of oral and auditory pathway abnormalities. A thorough review of our data leads us to suggest that many oroauditory problems in those with AEC syndrome are likely related in large part to palatal clefting. As described in those with classic palatal clefting, associated disorders include feeding difficulty, recurrent middle ear infection, and speech disarticulations. Increased tissue vulnerability associated with absent epidermal appendages may also play a role. In conjunction with this vulnerability, poor cleft-related middle ear ventilation likely predisposes those with AEC syndrome to chronic auditory pathway infection. Still, some abnormalities, such as persistent feeding difficulties following cleft closure suggest that additional factors may be involved. Much more study of AEC syndrome is needed, yet a heightened awareness of its many facets will provide caregivers needed information when evaluating those with this remarkable disease.
The authors would like to acknowledge the National Foundation for Ectodermal Dysplasias for their organization of this conference, their financial support of this study and their continued commitment to the assistance of these patients.