The Cleft Palate–Craniofacial Journal 52(1) pp. 62–65 January 2015 Ó Copyright 2015 American Cleft Palate–Craniofacial Association

ORIGINAL ARTICLE Cleft Lip and/or Palate and Auricular Malformations Samuli Suutarla, M.D., Jorma Rautio, M.D., Ph.D., Tuomas Klockars, M.D., Ph.D. Objective: To study the relationship between cleft lip and/or palate and auricular malformations in Finnish patients with cleft. Design: Retrospective analysis of patients with an external ear malformation and either a cleft lip with or without a cleft palate (CL6P) or an isolated cleft palate (CP). Setting: Tertiary referral clinic. Patients: Review of hospital records of 100 patients from the register of 8200 patients with cleft in the Cleft and Craniofacial Centre at the Helsinki University Central Hospital. Main Outcome Measures: Proportions of variable auricular malformations among CL6P and CP patients. Results: Microtia is the most common auricular malformation among patients with cleft and is almost equally prevalent with both CL6P and CP. The prevalence of microtia increases as the severity of CL6P increases. The combination of microtia and CL6P or CP is frequently found with both oculo-auriculo-vertebral spectrum and Treacher Collins syndrome. Conclusions: Microtia seems to be the most common auricular malformation among patients with cleft. The prevalence of microtia seems to increase as the severity of CL6P increases, whereas in isolated CP microtia seems to occur independently. KEY WORDS:

auricular malformation, cleft lip, cleft palate, microtia

Many orofacial structures, including the lips and the palate, derive from the first pharyngeal arches. Differentiation of these structures begins in the fifth and sixth gestational week. The external ear and the middle ear arise mainly from the first and second pharyngeal arches and the intervening pharyngeal clefts and pouches. The auricle develops from six auricular hillocks arising on the surfaces of the first and second pharyngeal arches during the fifth gestational week. These hillocks are fused to form the pinna by gestational week 12 (Larsen’s Human Embryology, 2009). Because of embryogenesis, it is logical that orofacial malformations may be concurrently expressed with malformations of the external or the middle ear (Hartung and Schweckendiek, 1973). Disorders associated with orofacial clefts and auricular malformations include oculo-auriculo-vertebral spectrum (OAVS) and Treacher Collins syndrome (TCS). OAVS consists of morphogenetic defects of the first and second branchial arches, leading to significantly high phenotypic variation (Keogh et al., 2007). Microtia, hemifacial microsomia, and Goldenhar syndrome are considered to be different degrees of this spectrum. The prevalence of CL6P among patients with OAVS has been estimated to be 7% to 15% (Gorlin et al., 1989). TCS is an autosomal dominant disorder with a highly variable phenotype. Microtia is common, and CP occurs in approximately one third of patients with TCS (Dixon, 1995). In addition to OAVS and TCS, the combination of CL6P or CP and ear malformations can occur in a number of syndromes (or sequence/spectrum) that appear less frequently

Orofacial clefts are common congenital craniofacial malformations; the global incidence is 1 in 700–800 live births (Tolarova and Cervenka, 1998; Rahimov et al. 2012). The incidence is higher in Finland, where approximately 1 in 450 live births have orofacial clefts because of the high frequency of cleft palate in the Finnish population (The Finnish Register of Congenital Malformations, http:// www.thl.fi/fi/statistics/congenitalmalformations). Approximately 30% of cleft lip with or without cleft palate (CL6P) cases and 50% of cleft palate only (CP) cases are associated with a syndrome (Murray, 2002). Auricular malformations can be associated with craniofacial syndromes and may aid in syndrome diagnosis. Typical auricular malformations include cup ears, microtia, preauricular tags, and fistulas (Hunter and Yotsuyanagi, 2005; Roth et al, 2008).

Dr. Suutarla is M.D., ENT Department, Kymenlaakso Central Hospital, Kotka, Finland. Dr. Rautio is M.D., Ph.D., Cleft and Craniofacial Centre, Helsinki University Hospital, Helsinki, Finland. Dr. Klockars is M.D., Ph.D., ENT Clinic and Cleft and Craniofacial Centre, Helsinki University Hospital, Helsinki, Finland. This study was financially supported by special government subsidies for health sciences research awarded by Kymenlaakso Central Hospital. This support was conducted to the writing of this manuscript. Submitted March 2013; Revised July 2013; Accepted September 2013. Address correspondence to: Dr. Samuli Suutarla, Laajasalonkaari 2B, 00840 Helsinki, Finland. E-mail [email protected]fi. DOI: 10.1597/13-069 62

Suutarla et al., CLEFTS AND AURICULAR MALFORMATIONS

TABLE 1 Studies Dealing With Cleft Lip and Palate and Ear Growth Disturbances Author

Year

Number of Patients

Study Design

Hajnis et al. Hartung and Schweckendiek Farkas et al. Lilius Nathan et al.

1968 1973

110 21

Anthropometry Clinical observation

1973 1992 2008

145 345 (29 ears) 50

Anthropometry Hospital chart review Anthropometry

The statistical analysis was done by an independent statistician (Timo Pessi, Datawell oy, Espoo, Finland). The study was approved by the ethics committee of the Helsinki University Central Hospital. RESULTS

There are numerous reports on orofacial clefts and associated malformations, but only a few focus on clefts and auricular malformations (Table 1). The aim of our research was to study the relationship between auricular malformations and cleft lip and/or palate (CL/P) in Finnish patients with cleft. MATERIALS

AND

METHODS

The Cleft and Craniofacial Centre at the Helsinki University Central Hospital has prospectively collected data in an institutional cleft register since 1995. Retrospective data, starting from the year 1950, has also been added to the register. It presently contains data from almost 8200 patients with cleft, including such information as patient gender, date of birth, siblings, birth order, birth weight, relatives with clefts, cleft type, and cleft surgery. From this register, we searched for all patients with CL6P or CP and external ear malformation, resulting in 122 patients with CL/P and auricular malformation. The hospital records were examined, and patients with incomplete records were excluded, resulting in 100 patients that could be used for further analyses. The data that were collected included gender, birthplace, birth weight, birth length, gestational weeks, gestation problems, type of cleft, site of cleft, type and severity of ear malformation, audiometrics, imaging, chromosomal analyses, other anomalies or diseases, cleft operations, number of siblings, and anomalies among family members. Facial or lateral photographs of 62 patients were used in the analyses, and cross-tabling was used to test whether a certain ear anomaly is associated with a certain subtype of cleft. We used v2 tests to analyze whether a specific ear anomaly was associated with a certain type of cleft (cleft lip versus cleft palate). TABLE 2

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Of the 100 patients, 48 were male and 52 were female. The proportion of CP and CL6P was 66% and 34%, respectively, and there was no difference in sex distribution. These results are in concordance with the distribution in the whole cleft register. The ear malformation was bilateral in 47% (31/66) of the patients with CP and 35% (12/34) of the patients with CL6P. Cleft lip and unilateral ear malformation occurred on the ipsilateral side in 82% (18/22) of the patients with CL6P. In 45 of 100 patients (45%) the cleft and ear malformation was related to a recognized syndrome. The distribution of ear malformations in different types of clefts is presented in Table 2. Microtia was almost equally prevalent in both CP and CL6P. Skin tags occur more with cleft lip, particularly with cleft lip with or without cleft alveolus, and prominent ears were associated with isolated CP. The prevalence of microtia seemed to increase with the severity of CL6P, but there was not a similar trend with CP. The distribution of ear malformations among syndromic patients is presented in Table 3. The combination of microtia and CL6P was frequently found in both OAVS and TCS. The distribution of clefts in syndromic patients is shown in Table 4. Isolated CP was slightly more common in the OAVS group, whereas patients with TCS almost exclusively had CP. DISCUSSION There are numerous studies on the association of oral clefts and congenital malformations but few focus on clefts and auricular malformations (Table 1). Hajnis and Farkas (1968) compared the ears of patients with cleft with noncleft standards. Both the width and length and the most conspicuous anomalies of the auricle were recorded. Despite meticulous work, definitive conclusions could not be drawn. Hartung and Schweckendiek (1973) reviewed

Distribution of Ear Malformations in Different Types of Clefts* n

Clef lip all Cleft lip Cleft lip and alveolus Cleft lip and palate Palatal cleft all Soft palate Soft þ hard palate Submucous palatal cleft

34 8 5 21 66 10 37 19

Microtia 38% 0% 40% 52% 46% 40% 46% 47%

(13/34) (0/8) (2/5) (11/21) (30/66) (4/10) (17/37) (9/19)

* Miscellaneous includes microtia, malposition of pinna, missing lobulus, cup ear, and so on.

Skin Tag 26% 50% 60% 9% 9% 20% 11% 0%

(9/34) (4/8) (3/5) (2/21) (6/66) (2/10) (4/37) (0/19)

Prominent Ear 15% 12% 0% 19% 27% 20% 27% 32%

(5/34) (1/8) (0/5) (4/21) (18/66) (2/20) (10/37) (6/19)

Miscellaneous 21% 38% 0% 19% 18% 20% 16% 29%

(7/34 (3/8) (0/5) (4/21) (12/66) (2/10) (6/37) (4/14)

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Cleft Palate–Craniofacial Journal, January 2015, Vol. 52 No. 1

TABLE 3

Distribution of Ear Malformations Among Syndromic Patients*

Oculo-auriculo-vertebral spectrum Treacher Collins syndrome Other

n

Microtia

Skin Tag

Prominent Ear

Miscellaneous

24 7 14

63% (15/24) 100% (7/7) 50% (7/14)

12% (3/24) 0 0

8% (2/24) 0 21% (3/14)

17% (4/24) 0 29% (4/14)

* Miscellaneous includes microtia, malposition of pinna, missing lobulus, cup ear, and so on.

1400 patients with cleft lip or palate or transverse facial cleft and found 21 patients with ear malformations. They concluded that patients with cleft have ear malformations more frequently than patients without cleft. They also reported that the incidence of ear anomalies was 0.6% in the cleft lip and palate (CLP) group and 1.6% in the CP group. Farkas and Lindsay (1973) studied the size, shape, angle, protrusion, and location of pinna, and validated their hypothesis that in the case of growth disturbances of the face, qualitatively similar damage may be present in the auricles. Lilius (1992) studied cleft-associated anomalies and syndromes in Finland, and his work was essentially based on the same patient records that were used in this study. He found 29 ear anomalies out of 1586 patients with cleft. Unsurprisingly, this was roughly the same proportion found in this study. Nathan et al. (2008) did an anthropometric study of the ears of nonsyndromic children with CLP. The control group consisted of age-matched children without craniofacial anomalies. The significant findings were that the vertical length and protrusion of the auricle were greater in the control group. They also suggested that auricular growth may be altered in patients with cleft. According to a literature search (PubMed and Ovid MEDLINE), our patient data are larger than in any of the previous studies. In addition, we have analyzed different cleft types and syndromic patients, particularly those with OAVS and TCS (both were looked at separately). One main goal was to find out if a specific auricular malformation is associated with a certain cleft type. The prevalence of microtia increases as the severity of cleft increases from cleft lip through cleft lip and alvelous to CLP. Microtia was seen in 52% (11/21) of the patients known to have an ear malformation in conjunction with CLP but only in 40% (2/5) of patients with cleft lip and alveolus; furthermore, microtia was found in no patients with cleft lip only. However, the prevalence of microtia was not dependent on the type of isolated cleft palate (Table 2). TABLE 4

The embryogenesis of microtia appears to be related to the severity of the CLP. The fusion of the lip begins earlier than that of the palate and the ear. One might speculate that if the disturbance in embryogenesis ceases before the palate and ear structures start to build up, only the lip is affected. If the disturbance is more prolonged, the defect extends to the alveolar ridge and palate and possibly also results in auricular malformation. Microtia is the most common ear malformation among patients with cleft. The proportions of ear deformities are as follows: microtia, 43%; prominent ears, 23%; miscellaneous, 19%, and skin tag, 15%. However, the diagnosis of microtia is definite, whereas skin tags may be overlooked and underreported. In addition, there is no objective line between protruding and normal auricles. Microtia and prominent ears are slightly more prevalent in isolated cleft palate, whereas skin tags are more prevalent in CL6P. Almost half of our patients (45%) were syndromic (this is consistent with findings of previous studies). As expected, CP was clearly more syndrome related than CL6P (Table 4). An interesting exception is OAVS, where the difference in prevalence between CP and CL6P was insignificant. Although isolated CP and CL6P are thought to differ in their pathogenesis, they both appear to be almost equally associated with OAVS. In previous studies of OAVS, the frequency was 7% to 13% for CL6P and 10% to 17% for CP (Rollnick et al., 1987; D’Antonio et al., 1998; Tasse et al., 2005). In the report of Tasse et al. (2005), CLP was twice as common as cleft lip only. This is supported by our findings: six patients with CLP compared to two patients with cleft lip only. This must be interpreted carefully because of the small number of patients. It is also important to consider that the report of Tasse et al. (2005) is based on a German population, and the prevalence of clefts may differ from that in our cleft register. In our CP research, the frequency of more extended cleft (hard and soft palate) was higher among patients with OAVS. Based on our patient

Distribution of Orofacial Clefts in Patients With a Syndrome (or Sequence/Spectrum)*

Oculo-auriculo-vertebral spectrum (nc¼c24) Treacher Collins syndrome(nc¼c7) Other (nc¼c14)

Cleft Palate (All)

Soft Palate

Soft and Hard Palate

Submucous

Cleft Lip (All)

Cleft Lip

Cleft Lip and Alveolus

Cleft Lip and Palate

58% (14/24)

13% (3/24)

28% (7/24)

17% (4/24)

42% (10/24)

8% (2/24)

8% (2/24)

25% (6/24)

86% (6/7)

0% (0/7)

72% (5/7)

14% (1/7)

14% (1/7)

0% (0/7)

0% (0/7)

14% (1/7)

79% (11/14)

0% (0/14)

50% (7/14)

29% (4/14)

21% (3/14)

0% (0/14)

0% (0/14)

21% (3/14

* The other group consists of such rare and separate syndromes as chromosome 22q11 microdeletion, Klippel-Feil, Pallister-Killian, Pierre Robin sequence, Faetal alcohol syndrome, Turner, and some that are undefined.

Suutarla et al., CLEFTS AND AURICULAR MALFORMATIONS

data and previous reports, OAVS may be more common the more severe the cleft. Microtia and CP are typical for patients with TCS: external ear abnormalities are present in most patients (60%), and CP is found in 28% of patients: (Vazquez M-P [expert reviewer] Treacher Collins syndrome, Orphanet encyclopedia, May, 2011). In our patient data, bilateral microtia was the sole ear anomaly and was present in all patients with TCS. Only one of the patients with TCS had cleft lip. Our clinical findings were similar to those of previous reports (Jones, 2005; Trainor et al., 2009). Our analysis does have limitations. Retrospective analysis has restrictions, and sufficient clinical photographs were only available for 62% (62/100) of patients. In the remaining patients, our classification of ear malformations was based on written explanations of ear deformities. To avoid misconceptions, only unequivocal cases were included in this study. In addition, the subgrouping of clefts and ear deformities was essential, but it resulted in small sample sizes and diminished statistical strength. Consequently, the number of observations in each group was too small to detect differences statistically. CONCLUSIONS Microtia seemed to be the most common auricular malformation among patients with cleft. The prevalence of microtia seemed to increase with the severity of CL6P, whereas this was not the case with isolated CP. REFERENCES D’Antonio LL, Rice RD, Fink SC. Evaluation of pharyngeal and laryngeal structure and function in patients with oculo-auriculovertebral spectrum. Cleft Palate Craniofac J. 1998;35:333–341. Dixon MJ. Treacher Collins syndrome. J Med Genet. 1995;32:806–808. Farkas LG, Lindsay WK. Ear morphology in cleft lip and palate anomaly. Arch Otorhinolaryngol. 1973;206:57–68.

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Gorlin RJ, Cohen MM, Jr, Levin LS. Oculoauriculovertebral spectrum. In: Syndromes of the Head and Neck. 3rd ed. New York: McGraw-Hill; 1989:641–649. Hajnis K, Farkas LG. Basic auricular characteristics in children with cleft anomalies as compared with the standard. Acta Chir Plast. 1968;10(1):15–27. Hartung B, Schweckendiek W. Malformations of the ear in cleft palate patients. J Maxillofac Surg. 1973;1:253–258. Hunter AG, Yotsuyanagi T. The external ear: more attention to detail may aid syndrome diagnosis and contribute answers to embryological questions. Am J Med Genet A. 2005;135:237–250. Jones MC. Treacher Collins syndrome. In: Cassidy SB, Allanson JE, eds. Management of Genetic Syndromes. Hoboken, NJ: Wiley-Liss; 2005:547–554. Keogh IJ, Troulis MJ, Monroy AA, Eavey RD, Kaban LB. Isolated microtia as a marker for unsuspected hemifacial microsomia. Arch Otolaryngol Head Neck Surg. 2007;133:997–1001. Larsen’s Human Embryology. 4th ed. Schoenwolf GC, Bleyl SB, Brauer PR, Francis-West PH, eds. Philadelphia, PA: ChurchillLivingstone-Elsevier; 2009. Lilius GP. Clefts with associated anomalies and syndromes in Finland. Scand J Plast Reconstr Surg Hand Surg. 1992;26:185–196. Murray JC. Gene/environment causes of cleft lip and/or palate. Clin Genet. 2002;61:248–256. Nathan N, Latham K, Cooper J, Perlyn C, Gozlan I, Thaller SR. Anthropometry of the external ear in children with cleft lip and palate in comparison to age-matched controls. J Craniofac Surg. 2008;19:1391–1395. Rahimov F, Jugessur A, Murray JC. Genetics of nonsyndromic orofacial clefts. Cleft Palate Craniofac J. 2012;49:73–91. Rollnick BR, Kaye CI, Nagatoshi K, Hauck W, Martin AO. Oculoauriculovertebral dysplasia and variants: phenotypic characteristics of 294 patients. Am J Med Genet. 1987;26:361–375. Roth DA, Hildesheimer M, Bardenstein S. Preauricular skin tags and ear pits are associated with permanent hearing impairment in newborns. Pediatrics. 2008;122:e884–e890. Tasse C, Bohringer S, Fischer S, Ludecke HJ, Albrecht B, Horn D, ¨ ¨ Janecke A, Kling R, Konig R, Lorenz B, et al. Oculo-auriculo¨ vertebral spectrum (OAVS): clinical evaluation and severity scoring of 53 patients and proposal for a new classification. Eur J Med Genet. 2005;48:397–411. Tolarova MM, Cervenka J. Classification and birth prevalence of orofacial clefts. Am J Med Genet. 1998;75:126–137. Trainor PA, Dixon J, Dixon MJ. Treacher Collins syndrome: etiology, pathogenesis and prevention. Eur J Hum Genet. 2009;17:275–283.

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