Acta Oto-Laryngologica, 2011; 131: 11171122

CASE REPORT

Four systems involved with congenital abnormalities: A new type of syndromic hearing loss ADOC Wangs syndrome?
QIUJU WANG1*, FEI-FAN ZHAO1* & YONG-BING SHI2
1

Department of Otorhinolaryngology/Head and Neck Surgery, Institute of Otolaryngology, Chinese PLA Institute of Otolaryngology, Chinese People Liberation Army General Hospital, Beijing, China and 2Department of Otolaryngology Head/Neck Surgery, Oregon Health & Science University, Portland, USA

Abstract Syndromic hearing impairment encompasses hundreds of phenotypes. We identied a young female patient affected by the unique combination of dysplasia of the auricular system, patent ductus arteriosus (PDA), choroideremia, and enamel hypoplasia. The patient was treated with PDA ligature and left exploratory tympanotomy. Impairment in all four systems suggests a correlation with the neural crest. It is presumed that all of the features result from the same origin, probably through autosomal recessive inheritance or a novel mutation during the embryonic period. When audio-dento-oculo-cardio systems are involved, we suggest that this new syndrome can be named ADOC Wangs syndrome, summarizing the disorders of the four systems and indicative of the founding person (Dr Wang, the rst and corresponding author of the paper).

Keywords: Enamel hypoplasia, choroideremia, patent ductus arteriosus, congenital auricular organ dysplasia, syndromic hereditary hearing impairment, neural crest

Introduction More than 400 types of syndromic hearing impairment (SHI) have been reported, and new types are continually discovered [1]. While sensorineural hearing loss is common in SHI, conductive or mixed loss can happen, especially in syndromes with outer and middle ear anomalies. Eye, teeth, and heart defects are commonly associated with SHI in various combinations [2], as seen in, for example, CHARGE syndrome, AxenfeldRiegeranomaly, and otodental syndrome. Patent ductus arteriosus (PDA) is an especially commonly reported cardiac anomaly in SHI, and enamel abnormality is the most common dental defect in SHI [3]. However, presentation of simultaneous abnormalities of the ear, eye, teeth, and heart is rare. Oculo-facio-cardio-dental syndrome may be an example, which is characterized by canine gigantism, radiculomegaly, abnormal enamel,

congenital cataract, long narrow face, high nasal bridge with broad nasal tip and long philtrum, mild cardiac defects, and mild sensorineural hearing loss [4]. The gene for this syndrome is mapped to Xp11.2-p21.2 and allelic with Lenz microphthalmia [5]. A recent study on a family with brittle cornea syndrome presented two patients who also suffered dental anomalies, hearing loss, and minor cardiac defects besides the typical corneal abnormalities. Dental involvement in these two patients included crowding in the mandible and linear enamel hypoplasia on mandibular canines. Cardiac ndings were mainly mild valve insufciencies. Audiometrically, the patients demonstrated mild to moderate conductive or mixed hearing loss over mid and low frequencies, with vertigo in one patient. The study showed a novel missense mutation of ZNF469 associated with this mainly connective tissue disorder [3]. It is generally agreed that most malformation syndromes

Correspondence: Prof. Qiuju Wang MD PhD, Department of Otolaryngology, Head & Neck Surgery, Chinese People Liberation Army Institute of Otolaryngology, Chinese People Liberation Army General Hospital, 28 Fuxing Road, Beijing 100853, China. Fax: +86 10 68172228. E-mail: wqcr@263.net *These authors contributed equally to the paper.

(Received 22 February 2011; accepted 28 March 2011)

ISSN 0001-6489 print/ISSN 1651-2251 online 2011 Informa Healthcare DOI: 10.3109/00016489.2011.589405

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result from mutation in a class of genes. In this report, we present a case of a young female patient with PDA, auricular defects with hearing loss, choroideremia, and enamel hypoplasia, which we believe may represent a previously unidentied SHI involving multiple systems. Case report Clinical features The patient was a girl born on August 6, 2002, and her code was case 20063152 in our database. The girl had a history of brief birth stroke due to aspiration and an Apgar score of 7. During pregnancy, there were no potential environmental hazards and the mother did not experience any harmful conditions. The delivery was cesarean. The girls mother was 29 years old at her birth and the father was 31. She presented with cardiac murmurs at birth and was diagnosed as having PDA. At the age of 2 years, she was found to have congenital hearing impairment. As she grew up to the age of 7 years, dental and ocular abnormalities emerged consecutively. Her family had no similar cases, including all paternal and maternal relatives, from grandfather to cousins (14 individuals). She has no siblings. Thorough consultation and examination by different clinical departments, including ophthalmology, dentistry, and cardiology were conducted. The examination results, including physical examination and inspection by instruments and operational ndings, are summarized below. She has normal craniofacial manifestation, and we will clarify the abnormal complex in each system. Auditory system Her family described her poor hearing and speech development when she was 2 years old, and unsteady walking when she began to walk after 2.5 years. To improve the subjects hearing, she was admitted to the hospital again in July 2007. Physical examination showed low antilobium on both sides, a defect of the left membrane covering approximately half the area of the entire tympanic membrane. Development seemed normal, but she has difculty in speaking, even with the help of hearing aids. Slight ataxia was also noted. A pure-tone audiogram (Figure 1) showed that the subject had conductive hearing loss. In both ears, the pure-tone average (PTA) of air conduction was 75 dB and the average airbone gap was 60 dB. With hearing aids, the PTA of air conduction was improved to approximately 25 dB (Figure 2). A Rinne test yielded a negative result for the left side but a positive result

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Figure 1. Pure-tone audiogram of unaided ears before operation showed conductive hearing loss. The blue line indicates the hearing level of the left ear, while the red line indicates the right ear. The upper signals indicate the bone conduction and the lower lines indicate air conduction.

for the right side. A Weber test revealed a preference for the left side. The conductive loss in this patient is slightly worse on the left at lower frequencies, which may explain the lateralized Webers test because the frequency of the tuning fork (250 Hz) happened to be in these frequency ranges. A tympanic curve indicated that there was negative pressure in both middle ears. A double stapes acoustic reex could not be elicited. The auditory brainstem response (ABR) was elicited with normal waves and nerve function was thought to be normal. A high-resolution computed tomography (CT) reconstruction showed that the left cochlea, left malleus, and facial nerve canal were basically normal (Figure 3).
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Figure 2. Pure-tone audiogram with hearing aids show that the deafness could be improved.

New type of syndromic hearing loss ADOC Wangs syndrome The subject agreed to left ear exploratory tympanotomy and was found to have the following malformations: absence of stapes, osseous atresia of the fenestra vestibule, osseous xation of the neck of malleus to paries tympanica, and an abnormal branch of the facial nerve exposed on the surface of the atresic oval window. A window was surgically opened in the vestibular wall and an articial auricular bone, a Teon column, was placed in this window. These abnormalities were not observable in a CT scan. At 2-year follow-up, there was no improvement of hearing level (Figure 4). Dental system Examination of her teeth displayed saprodontia of deciduous teeth and enamel hypoplasia of permanent teeth (Figure 5). Ocular system Both eyes appeared esotropic and exhibited choroideremia. According to examination of visual acuity, the left eye was 0.5 and the right eye was 0.1. Cardiovascular system To treat her PDA, the patient was admitted to the Chinese People Liberation Army General Hospital at the age of 3 years and was treated with PDA ligature on October 28, 2005. The benecial effects of this
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procedure were notable and her cardiac murmurs disappeared. A urinary system examination did not yield any abnormal results, and ultrasonic inspection of both kidneys found no abnormalities. Circulatory system examination revealed PDA, which had been previously repaired, a normal EEG, and a normal appearance of the heart shadow and aortic arch from a chest X-ray. The patients skeleton and motor system had slight ataxia but displayed neither skeletal nor muscular abnormalities. Due to her multiple disorders, we suspected that the subject had SHI. Discussion The patient presented with abnormalities involving four systems. The auricular malformations and the PDA were congenital diseases that likely arose during embryonic development, whereas the choroideremia and the enamel hypoplasia were acquired or delayed diseases that developed after birth. Although the time of onset was not simultaneous, is seems likely that disease development involved an inherent signaling system that evokes the breakout of the four different systems in proper order. With this possibility in mind, we analyzed each system retrospectively to identify consistent pathopoiesis factors. We rst consider the auditory system. The pure tone audiometry showed an airbone conduction difference of >60 dB, but it could be corrected by the hearing aids. The CT scan did not nd any
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Figure 3. (a, b, and c) CT reconstruction shows basically normal left malleus, cochlea, and facial nerve canal. (d) The left anterior semicircular canal was decreased in size, which suggested abnormality of the left inner ear.

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Figure 4. Pure-tone audiogram of unaided ears after operation showed little improvement.

obvious malformation in the middle and inner ears. Because most abnormalities in middle ears do not have positive signs in CT scan, and the preoperative examinations sustained the diagnosis of conductive hearing loss, the ndings implied that malformation of the middle ear was the key site. The operative ndings revealed the abnormalities of facial nerve and auditory ossicles. Then the auricular system was affected, including a slight malformation of the outer ear and obvious malformation of both the middle ears. Although the improvement in hearing from hearing aid use indicated that the conductive hearing loss could be corrected, surgery of the left ear did not improve the hearing ability. The reason for this failure was thought to be the failed connection of ossicles. If possible, left restoration or right exploratory surgery could be performed. We cannot be sure whether or not the patient will develop sensorineural hearing loss later in life because the long-term function of hair cells and spiral ganglia cannot be determined. Since the patient did not have scoliosis, hip

Figure 5. Examination of patients teeth: saprodontia of deciduous teeth and enamel hypoplasia of permanent teeth.

dislocation, or muscular malformation, we can exclude anatomic etiological factors. Thus, the dysplasia of the semicircular ducts may have correlations with ataxia. From a developmental aspect, the malleus and incus are derived from the rst branchial arch, the stapes is derived from the second branchial arch, and the facial nerve and the facial nerve duct are derived from multiple embryonic branches. The middle ear structures are basically derived from mesoderm, and they also cooperate with mesectoderm, which comes from neural crest cells belonging to the ectoderm. The genes expressed in branchial arches and the genes that direct the creation of branchial arches can both signicantly affect the morphology of the middle ear. These genes, which include the Hox family, the Dlx family, Prx 1, and Otx 2, also complement each other in guiding the specic differentiation of structures acquired from branchial arches. For instance, if the expression of Hox a2 in the second branchial arch is directionally disturbed, specic structures such as the stapes will disappear [6]. With this principle, genes correlated with the development of the middle ear can also affect the outer ear. As for the inner ear, the membranous and bony labyrinths have different sources, i.e. the former from ectoderm and the latter from mesoderm. We turn now to the dental system. The differential diagnosis of enamel hypoplasia associated with a specic systemic disorder or syndrome included hereditary enamel disorders and acquired defects. The present case had saprodontia in primary teeth and enamel hypoplasia only in permanent teeth, ruling out a congenital disease. The acquired disease usually stems from environmental inuences and develops gradually until a threshold is reached this is inconsistent with immediate onset of enamel hypoplasia in the patients permanent teeth. Enamel hypoplasia is associated with many known syndromes and congenital metabolic diseases, such as rubella syndrome, Down syndrome, ectodermal dysplasias, hypocalcemia, and vitamin D-dependent rickets. For example, Heimler et al. reported a family with enamel hypoplasia, sensorineural hearing loss, and leukonychia [7]. As mentioned above, the middle ear is mainly derived from mesoderm but modulated by ectoderm, and the enamel is derived from the ectoderm. Ectodermal dysplasia syndromes are dened as conditions in which two or more ectodermal organs are affected, and dental defects in these syndromes typically include multiple missing teeth as well as small and misshapen teeth. A novel tumor necrosis factor (TNF) pathway has recently been reported that regulates ectodermal organ development and is necessary for the formation of ectodermal placodes.

New type of syndromic hearing loss ADOC Wangs syndrome Mutations in this pathway exhibit X-linked inheritance. The genes that cause teeth agenesis include the PAX and Msx families. PAX9 and Msx1, respective members of these two families, maintain the expression of bone morphogenetic protein 4 (BMP4), which guides the growth and formation of enamel. Another important human gene associated exclusively with teeth renewal is AXIN2 [8]. All of these genes can regulate ectodermal organ morphogenesis in nearly the same pathway during the embryonic and postnatal phases [9]. It is conceivable that enamel hypoplasia and choroideremia are under the same regulation in some developmental phases. Considering the ocular system, choroideremia, characterized by chorioretinal degeneration, is an X-linked recessive inherited disease. The choroid is derived from neural ectoderm and mesoderm. All mutations that have been identied in the choroideremia gene result in the truncation or absence of the normal protein product, Rab escort protein-1, which is a component of an enzyme complex that mediates correct intracellular vesicular transport. The Rab family proteins are GTP-binding proteins. As such, they belong to the G protein family, a large protein family regulated by GTP circulation [10]. Clinically, defects can be detected through low levels of cGMP upon blood examination, which result from a GTP circulation disorder and cause G protein dysfunction. The poor visual acuity caused by secondary esotropia is a symptom of this disease. Choroideremia is thought to be caused by a deletion mutation (402delT) or by the missense mutation (555A > G) in CHM gene. Merry et al. conrmed that choroideremia accompanied by middle ear dysplasia is a contiguous syndrome with mutation at Xq21 [11]. Finally we turn to the cardiovascular system. Congenital heart disease is the most common birth defect, and multifactorial inheritance has been postulated for the majority of these cases. If a newborn is found with this malformation, indomethacin can be given in the rst week, effectively closing the ductus arteriosus. PDA ligature is the most effective treatment. Although the cardiac system mainly develops from mesoderm, neural crest-related factors also play an important role in the formation of PDA. In cardiovascular system development, remodeling of the outow tract and pharyngeal arches to create separate pulmonary and systemic circulatory systems is necessary. In this process, neural crest cells play an important role to form smooth muscles and provide signals to regulate the cardiogenic mesoderm [12]. PDA is a disorder that arises during this remodeling. Isolated PDA has been associated with many etiological factors. Genetic factors contributing to PDA have been located on chromosome 5 without identication of a specic gene. However, on chromosome

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6p12-p21, PDA contributing mutations in TFAP2B, which encodes a neural crest-related helix-span-helix transcription factor, were identied by positional cloning studies [13]. There have been several reported families with congenital heart disease and hearing loss. Le Caignec et al. reported a large family with mild-to-severe combined hearing loss, congenital heart defects, and posterior embryotoxon, in which the heart defects included peripheral pulmonary stenosis and Fallots syndrome [14]. The investigators identied JAG1 as the responsible gene and characterized it as a contiguous gene syndrome. A novel missense mutation was identied in the extracellular domain of JAG1 in the rst of the 16 epidermal-growth-factor (EGF)-like domains, which demonstrated that mutations in JAG1 could cause hearing loss [14]. Forney et al. also reported a case of congenital heart disease (mitral incompetence) and deafness (conductive hearing loss), but the signicant distinction was skeletal malformation, including cervical vertebral fusion and carpal bone fusion [15]. The PDA in our case may not have correlation with other abnormalities, because there has been no reported similar case and we did not have direct genetic proof. But at the same time, it could be presumed to be an accompanied part in this syndrome until we obtain further data. The abnormalities in the present case have heterogeneous embryologic origins in two blastoderms, including mesoderm (cardiovascular system, choroids, bony labyrinth, and main middle ear structures) and ectoderm (the facial nerve, membranous labyrinth, and dental enamel). Neural crest cells or neural crest-related factors appear to be affected in the developmental process. It is reasonable to conclude that some error occurred in the migration and location of neural crest cells, causing changes that manifested in the four affected systems. The occurrence of this single case and apparently unaffected parents may be consistent with autosomal recessive inheritance or just a novel mutation during the embryonic period. Because of the high cost of whole genome analysis, we were unable to identify a specic locus of association. The whole blood sample was conserved and prepared for future genetic study. As for the diagnosis of choroideremia, sequencing of CHM (REP1) gene will be the rst choice. In case of CHM mutation, audio and dental anomalies could be linked to a previous known syndrome [16]. JAG1 gene will be the second candidate gene in consideration of combination abnormalities of the heart and auditory system [14]. Although she has a normal facial features, perhaps this patient has a subtype of oculo-faciocardio-dental syndrome, and the BCOR gene also should be sequenced [5]. So, it will be important to

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[4] McGovern E, AL-Mudaffer M, McMahon C, Brosnahan D, Fleming P, Reardon W. Oculo-facio-cardio-dental syndrome in a mother and daughter. Int J Oral Maxillofac Surg 2006; 35:10602. [5] Hilton E, Johnston J, Whalen S, Okamoto N, Hatsukawa Y, Nishio J, et al. BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects. Eur J Hum Genet 2009;17:132535. [6] Keynes R, Lumsden A. Segmentation and the origin of regional diversity in the vertebrate central nervous system. Neuron 1990;4:19. [7] Heimler A, Fox JE, Hershey JE, Crespi P. Sensorineural hearing loss, enamel hypoplasia, and nail abnormalities in sibs. Am J Med Genet 1991;39:1925. [8] Thesleff I. The genetic basis of tooth development and dental defects. Am J Med Genet 2006;140:25305. [9] Huysseune A, Thesleff I. Continuous tooth replacement: the possible involvement of epithelial stem cells. Bioessays 2004; 26:66571. [10] MacDonald IM, Sereda C, McTaggart K, Mah D. Choroideremia gene testing. Expert Rev Mol Diagn 2004;4:47884. [11] Merry DE, Lesko JG, Sosnoski DM, Lewis RA, Lubinsky M, Trask B, et al. Choroideremia and deafness with stapes xation: a contiguous gene deletion syndrome in Xq21. Am J Hum Genet 1989;45:53040. [12] Brown CB, Baldwin HS. Neural crest contribution to the cardiovascular system. Adv Exp Med Biol 2006;589:13454. [13] Vaughan CJ, Basson CT. Molecular determinants of atrial and ventricular septal defects and patent ductus arteriosus. Am J Med Genet 2000;97:3049. [14] Le Caignec C, Lefevre M, Schott JJ, Chaventre A, Gayet M, Calais C, et al. Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the rst epidermal-growth-factor-like domain of jagged 1. Am J Hum Genet 2002;71:1806. [15] Forney WR, Robinson SJ, Pascoe DJ. Congenital heart disease, deafness, and skeletal malformations: a new syndrome? J Pediatr 1966;68:1426. [16] Poloschek CM, Kloeckener-Gruissem B, Hansen LL, Bach M, Berger W. Syndromic choroideremia: sublocalization of phenotypes associated with Martin-Probst deafness mental retardation syndrome. Invest Ophthalmol Vis Sci 2008;49:4096104.

review additional case reports and determine a specic associated gene locus in order to verify the association of these abnormalities as a new inherited syndrome. Conclusion The congenital defects that occurred in four systems have intrinsic developmental correlations. Although we do not have direct genetic proof, it is planned to name this specic type of syndromic hearing loss ADOC Wangs syndrome. Acknowledgments We thank the patients and their families for their cooperation during this work. This work was supported by grants from the National Natural Science Foundation of China, Key Project (no. 30830104), the National Natural Science Foundation of China (grant 30771203), and Beijing Nature Science Technology Major Project (7070002). Declaration of interest: The authors report no conicts of interest. The authors alone are responsible for the content and writing of this paper. References
[1] Friedman TB, Schultz JM, Ben-Yosef T, Pryor SP, Lagziel A, Fisher RA, et al. Recent advances in the understanding of syndromic forms of hearing loss. Ear Hear 2003; 24:289302. [2] http://www.ambrygen.com/clinical_diagnostic_and_carrier_testing/PDFforms/Chromosomal_Microarray_Disorder_List.pdf. [3] Christensen AE, Knappskog PM, Midtb M, Gjesdal CG, Mengel-From J, Morling N, et al. Brittle cornea syndrome associated with a missense mutation in the zinc-nger 469 gene. Invest Ophthalmol Vis Sci 2010;51:4752.

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