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PEDIATRICS Vol. 108 No. 2 August 2001, p. e32

ELECTRONIC ARTICLE:
Syndromic Ear Anomalies and Renal Ultrasounds

Raymond Y. Wang, MD*, Dawn L. Earl, RN, CPNPDagger , Robert O. Ruder, MD§, and John M. Graham Jr, MD, ScDDagger

From the * University of California-Los Angeles, School of Medicine; Dagger  Department of Medical Genetics, Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Burns and Allen Research Institute, Cedars-Sinai Medical Center and Department of Pediatrics, University of California-Los Angeles; and § Department of Plastic and Reconstructive Surgery, Cedars-Sinai Medical Center, University of California-Los Angeles, Los Angeles, California.


    ABSTRACT
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Abstract
Methods
Results
Discussion
References

Objective.  Although many pediatricians pursue renal ultrasonography when patients are noted to have external ear malformations, there is much confusion over which specific ear malformations do and do not require imaging. The objective of this study was to delineate characteristics of a child with external ear malformations that suggest a greater risk of renal anomalies. We highlight several multiple congenital anomaly (MCA) syndromes that should be considered in a patient who has both ear and renal anomalies.

Methods.  Charts of patients who had ear anomalies and were seen for clinical genetics evaluations between 1981 and 2000 at Cedars-Sinai Medical Center in Los Angeles and Dartmouth-Hitchcock Medical Center in New Hampshire were reviewed retrospectively. Only patients who underwent renal ultrasound were included in the chart review. The literature was reviewed for the epidemiology of renal anomalies in the general population and in MCA syndromes with external ear anomalies. We defined a child as having an external ear anomaly when he or she had any of the following: preauricular pits and tags; microtia; anotia; or cup, lop, and other forms of dysplastic ears. A child was defined as having a renal anomaly if an ultrasound revealed any of the following: unilateral or bilateral renal agenesis; hypoplasia; crossed ectopia; horseshoe, pelvic, cystic kidney; hydronephrosis; duplicated ureters; megaureter; or vesicoureteric reflux.

Results.  Because clinical genetics assessments were made by the same clinician at both sites (J.M.G.), data were combined. A total of 42 patients with ear anomalies received renal ultrasound; 12 (29%) of them displayed renal anomalies. Of the 12 patients with renal anomalies, 11 (92%) also received a diagnosis of MCA syndrome. Eleven of 33 patients (33%) with MCA syndromes had renal anomalies, whereas 1 of 9 patients (11%) with isolated ear anomalies had renal anomalies. Specific disorders seen were CHARGE association, Townes-Brocks syndrome, branchio-oto-renal syndrome, Nager syndrome, and diabetic embryopathy.

Conclusions.  We conclude that ear malformations are associated with an increased frequency of clinically significant structural renal anomalies compared with the general population. This is due to the observation that auricular malformations often are associated with specific MCA syndromes that have high incidences of renal anomalies. These include CHARGE association, Townes-Brocks syndrome, branchio-oto-renal syndrome, Nager syndrome, Miller syndrome, and diabetic embryopathy. Patients with auricular anomalies should be assessed carefully for accompanying dysmorphic features, including facial asymmetry; colobomas of the lid, iris, and retina; choanal atresia; jaw hypoplasia; branchial cysts or sinuses; cardiac murmurs; distal limb anomalies; and imperforate or anteriorly placed anus. If any of these features are present, then a renal ultrasound is useful not only in discovering renal anomalies but also in the diagnosis and management of MCA syndromes themselves. A renal ultrasound should be performed in patients with isolated preauricular pits, cup ears, or any other ear anomaly accompanied by 1 or more of the following: other malformations or dysmorphic features, a family history of deafness, auricular and/or renal malformations, or a maternal history of gestational diabetes. In the absence of these findings, renal ultrasonography is not indicated.  Key words:  external ear, renal, anomalies, ultrasound.

Many studies in the literature have noted a significant association between renal anomalies and various ear anomalies. Ear pits and tags, perhaps the most common minor ear malformation, occur with a frequency of 5 to 6 per 1000 live births.1,2 In the pediatric population, structural renal anomalies occur in 1 to 3 per 100 live births.3-5 Kohelet and Arbel6 noted that among 70 consecutive children who had isolated preauricular tags and were examined by renal ultrasonography, 6 (8.6%) had urinary tract abnormalities (5 with hydronephrosis, 1 with horseshoe kidney). In a separate study, among 69 children who had preauricular sinuses and were examined by renal ultrasound, 3 (4.3%) demonstrated renal anomalies (2 with hydronephrosis, 1 with branchio-oto-renal (BOR) syndrome and an absent left kidney and hypoplastic right kidney).7 A recent study3 of 32 589 consecutive live births, still births, and abortions over 10 years in the Mainz Congenital Birth Defect Monitoring System noted a 1.2% prevalence of renal anomalies. External ear anomalies of all types, including deformations from fetal constraint, were found in 19.0% of all newborns, compared with 23.8% in newborns with renal malformations, showing a slightly significant increased risk (odds ratio: 1.3) for renal anomalies in children with ear anomalies. After patients with syndromic diagnoses were excluded, there continued to be a strong association between auricular pits or cup ears and specific renal anomalies but no association between auricular tags and renal defects.3

Given the wealth of data indicating an association between ear and renal anomalies, the question is, "Should all children with ear anomalies receive renal ultrasonography?" We note that in children with ear anomalies, defects within all other organ systems occur with a frequency of 5% to 40%.1,28-10 We also note that ear and renal anomalies are components of many multiple congenital anomaly (MCA) syndromes. We present here data from our own genetics clinic regarding MCA syndrome diagnoses and the incidence of renal anomalies in patients with ear anomalies. We then review some of the more significant MCA syndromes with ear and renal anomalies.

    METHODS
Top
Abstract
Methods
Results
Discussion
References

Charts of patients who had ear anomalies and were seen for clinical genetics evaluations at Cedars-Sinai Medical Center and Dartmouth-Hitchcock Medical Center between 1981 and 2000 were reviewed retrospectively. Only patients who underwent renal ultrasound were included in the chart review. Because clinical genetics assessments were made by the same clinician at both sites (J.M.G.), data were combined. The literature regarding MCA syndromes with ear anomalies was reviewed for epidemiology and reports of associated renal anomalies.

    RESULTS
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Abstract
Methods
Results
Discussion
References

A total of 42 patients with ear anomalies received a renal ultrasound; 12 (29%) of them displayed renal anomalies. These results are summarized in Table 1. Of the 12 patients with renal anomalies, 11 (92%) also received a diagnosis of MCA syndrome. Percentages of renal anomalies in patients with an MCA syndrome are summarized in Table 2.

                              
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TABLE 1
Percentages of Patients Seen at Cedars-Sinai and Dartmouth-Hitchcock Genetics Clinic With Renal Anomalies

                              
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TABLE 2
Percentages of Patients With MCA Syndrome and Renal Anomalies

Clinical Syndromes With Associated Renal Anomalies

CHARGE Association/Syndrome The majority of patients with CHARGE association represent sporadic occurrences in an otherwise normal family, with several reports supporting the possibility of autosomal dominant transmission. CHARGE association encompasses a wide spectrum of nonrandomly associated malformations, which include coloboma of iris or retina (80%-90%), heart defects (75%-80%; commonly conotruncal), atresia choanae (50%-60%), retarded growth (70%) and development (100%), genital hypoplasia (70%-80%), and ear defects (90%).11 Figure 1 shows the triangular concha, prominent antihelix, and absent lobule characteristic of CHARGE ears. Renal anomalies occur in 15% to 25% of patients with CHARGE association. Also commonly seen are cleft lip and/or cleft palate (15%-20%) and tracheoesophageal fistula with esophageal atresia (15%-20%).11


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  		Fig. 1.   Top, typical child with CHARGE association illustrating low-set, posteriorly angulated ears with deficient cartilage and absent lobules. Note the iris colobomas and facial asymmetry in this patient. Bottom, 4 pairs of ears from children affected with CHARGE association demonstrating typical auricular dysmorphology and asymmetry.

Recent reports document increasing evidence for a syndromic subset of patients within the spectrum of CHARGE association displaying iris colobomas; choanal atresia; ear anomalies; and cranial nerve VII, IX, and X palsies with semicircular canal, cochlear, and temporal bone hypoplasia.12,13

CHARGE association has superficial similarity to renal-coloboma syndrome, which is caused by mutations in the PAX2 gene, and also to DiGeorge sequence, which can be caused by deletion of chromosome 22q11, but these genetic abnormalities have been eliminated as causes of CHARGE association.14

Townes-Brocks Syndrome Townes-Brocks syndrome (TBS), an autosomal dominant disorder, is caused by a mutation in the SALL1 transcription factor gene, which is expressed in the developing ear, limb buds, and excretory organs.15 Like many other autosomal dominant disorders, phenotypic expression is extremely variable but should include 2 or more of the following: bilateral external ear malformation (71%), hand malformations (56%), and imperforate anus or rectovaginal/rectourethral fistula (47%).16

Ear defects, seen in Figs 2 and 3, can include microtia; overfolded superior helix; "satyr," "lop," or "cup" ear; and preauricular pits or tags; some published cases of SALL1 mutations have had ears that resembled those seen in CHARGE association. Hand malformations consist mainly of preaxial ray defects, which can range from polydactyly of a biphalangeal thumb to triphalangeal thumb or thenar hypoplasia.17 Renal malformations have been noted in 27% of patients with TBS.16


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  		Fig. 2.   TBS proband with mild auricular anomaly and hypoplastic thumbs (also had imperforate anus).


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  		Fig. 3.   A second TBS proband demonstrating cup ears and hypoplastic thumbs (also had anteriorly placed anus and renal anomaly).

Considerable similarity also exists between TBS and BOR ear anomalies, and this has been emphasized in the clinical literature,18 along with 1 report of a 3-generation family with overlapping features of TBS and oculoauriculovertebral spectrum (OAVS) with triphalangeal thumbs, preauricular tags, abnormal tragus, overfolded superior helices, redundant anal skin in 2 individuals, micrognathia and macrostomia in 2 individuals, and epibulbar dermoids in all 3 individuals.19

Oculoauriculovertebral Spectrum OAVS encompasses a broad variety and severity of defects in structures derived from the first and second branchial arches. It is predominantly sporadic in occurrence, with reports of autosomal dominant transmission in only 1% to 2% of cases.

Commonly observed malformations in OAVS include epibulbar dermoids (benign growths on the medial/lateral aspects of the cornea), preauricular tags and pits, microtia with accompanying conductive hearing loss, and small jaw resulting in an asymmetric face.20 Patients with these features in conjunction with cleft lip and/or cleft palate and thoracic hemivertebrae are termed to have Goldenhar syndrome, a more severe form of OAVS.

The epidemiology of OAVS and isolated microtia/anotia (M/A) are similar, with a frequency of approximately 1.8 per 10 000 births; a male:female ratio of 3:2; and 70% to 90% unilateral involvement, of which 60% are right sided and 40% are left sided. Increasingly, isolated M/A is being considered as the mildest expression of OAVS.20,21

The largest collected population of patients with OAVS was found to have a 5% prevalence (16 of 294) of genitourinary malformations, but this study included renal malformations with genital defects such as hypospadias, hydrocele, chordae penis, cryptorchidism, and scrotal anomalies.20 Thus, it is unknown what portion of that 5% was accounted for by renal anomalies. Renal anomalies were noted in 4% of all cases of M/A.8-10

BOR Syndrome BOR syndrome, an autosomal dominant disorder, is caused by a mutation in the eyeless (EYA1) transcription factor gene and has a frequency of 1 in 40 000 live births. Approximately 60% of cases have branchial cysts or fistulas, usually found on the external lower third of the neck, at the median border of the sternocleidomastoid muscle (Fig 4), and 30% to 60% of patients with BOR have ear anomalies that range from severe microtia to small, lop or cupped ears with overfolded superior helices similar to TBS ears (Fig 5). Preauricular pits are present in 70% to 80% and sometimes can be the only external ear finding. At least 75% have conductive, sensorineural, or mixed hearing loss, and 12% to 20% have structural kidney anomalies.22


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  		Fig. 4.   BOR proband (IV 19) whose initial diagnosis with familial Goldenhar syndrome because of severe micrognathia, conjunctival dermoids, and microtia. A branchial cleft cyst is evident on the left side of his neck, just above his tracheostomy collar.


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  		Fig. 5.   Ears of affected siblings (top, IV 10 and IV 11; bottom, IV 16 and IV 21) of the BOR proband in Fig 4 again showing marked variability in ear dysmorphology. Only patient IV 21 had a detectable renal anomaly (single kidney). Note the preauricular pits of IV 11.

BOR has extremely variable expression, and even within the same family, affected individuals show differing phenotypes (Fig 6). Some members have kidney malformations, whereas others may have malformations so subtle that imaging cannot identify them. There are conflicting reports as to whether branchio-oto (BO) syndrome is a variant of BOR syndrome; some studies of BO families show linkage to EYA1,23 whereas others do not.24,25 Two other EYA1 homologs have been cloned, and it is possible that some cases of BO are caused by mutations in these other EYA genes or in other genes in the EYA signaling pathways.


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  		Fig. 6.   Pedigree of family in Fig 5 that demonstrated linkage to the EYA1 locus on 8q11 to 13. Note the marked variability in phenotypic expression.

Diabetic Embryopathy Infants of diabetic mothers (IDMs) have been noted to have malformations in a wide variety of organ systems as a result of the direct and indirect teratogenic effects of hyperglycemia on the developing embryo. This is evidenced by both studies in animal models and the observation that the risk for fetal malformations increases with elevations in glycosylated hemoglobin.26,27 In addition to macrosomia, infants who are born to mothers who have either chronic or gestational diabetes are at increased risk for dysplastic ears (Fig 7), holoprosencephaly, spine/rib malformations such as caudal dysgenesis, and renal/urinary defects (Martínez-Frías ML, unpublished data).5 Other defects ascribed to IDMs include respiratory hypoplasia, cardiovascular defects, gastrointestinal tract atresia, oculoauriculovertebral sequence, and limb reduction.5,28


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  		Fig. 7.   Two sporadic cases of lethal diabetic embryopathy with dysplastic ears. Top, case had vertebral defects and hypoplastic left heart. Bottom, case had rib and vertebral defects, DiGeorge sequence, single kidney, and pancreatic islet cell hyperplasia.

Treacher Collins Syndrome Treacher Collins syndrome (TCS) is an autosomal dominant condition caused by mutations in the treacle gene, the function of which has not been determined. TCS comprises mostly craniofacial abnormalities of structures derived from the first branchial arch, including downslanting palpebral fissures, lower lid colobomas, depressed cheekbones, bilateral microtia, conductive hearing loss, micrognathia, cleft palate, and pharyngeal hypoplasia. Renal anomalies are not recognized as part of this syndrome.29,30

Nager Syndrome Nager syndrome is a disorder whose craniofacial features are very similar to those of TCS. Mandibular hypoplasia tends to be more severe than that of TCS and commonly results in respiratory distress; however, limb defects, specifically preaxial anomalies (hypoplastic or absent thumbs and radii), are the principal distinguishing feature. Defects also can be seen in the lower extremities---hypoplastic halluces and other absent toes. Renal malformations were found in 7 of 78 (9%) of affected individuals.31-34 The mode of inheritance remains unclear; both autosomal dominant and autosomal recessive inheritance has been suggested.

Miller Syndrome Miller syndrome is extremely rare, with only 18 reported cases in the literature. Like Nager syndrome, craniofacial features are similar to TCS, but lower-lid ectropion is much more pronounced in Miller syndrome than in the other facial dysostoses. The cardinal finding of Miller syndrome is ulnar limb deficiencies such as ulnar hypoplasia and fifth finger and/or toe agenesis or underdevelopment. Reflux and hydronephrosis were noted in 1 of the 18 cases (5.5%).35

    DISCUSSION
Top
Abstract
Methods
Results
Discussion
References

In 1946, Edith Potter's association of crumpled, flattened ears with bilateral kidney agenesis36 led pediatricians to routinely order renal ultrasounds in children with virtually any type of ear anomaly. Although there are many articles in the literature about this subject, no set of uniform standards exists for determining which types of ear anomalies require renal imaging. Population studies do show an increased incidence of renal malformations in children with ear anomalies. The Mainz Congenital Birth Defect Monitoring System study suggested that minor ear anomalies are extremely common and that pits and cup ears are more likely to be associated with renal defects than ear tags in an otherwise normal-appearing infant.3 This may reflect detection of sporadic cases of occult BOR. Ear and renal anomalies often are components of other MCA syndromes, particularly CHARGE association, TBS, Nager syndrome, Miller syndrome, and diabetic embryopathy. Table 3 summarizes the history and examination findings found in patients with these syndromes. A patient with isolated preauricular pit(s), cup ears, or an ear anomaly accompanied by positive findings in any of these areas should undergo a renal ultrasound to aid in diagnosis of these syndromes. Otherwise, a renal ultrasound is not recommended.

                              
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TABLE 3
Areas to Focus on in Initial Evaluation of a Patient With an External Ear Anomaly

Finally, because of the profoundly deleterious effects of delayed diagnosis of hearing impairment on a child's communication and social development, audiologic testing and intervention are crucial in the workup of any child with an ear anomaly. A significant percentage of children (see Table 4) with ear anomalies have some degree of hearing loss, and early detection and referral to an ear, nose, and throat specialist for management often are necessary.

                              
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TABLE 4
Prevalence of Hearing Loss in Various MCA Syndromes and Ear Anomalies

Because the incidence of ear malformations is relatively rare---almost 1.3 per 10 000 live births---it is difficult for 1 center to conduct a prospective population study large enough to accumulate sufficient numbers of children with ear anomalies to analyze. Our study was limited by review of only our clinic patients with ear anomalies, which introduces selection bias in that their ears (or other organ systems) had to be anomalous enough to have been referred for a clinical genetics evaluation. Also, patients who had not undergone renal ultrasonography were excluded, which would affect our calculated incidence of renal malformations; however, our numbers agree with the figures given in review articles of large numbers of children with these syndromes and thereby provide some guidelines for how to decide which children with ear anomalies might benefit from renal ultrasonography.

Ear and kidney development has been characterized in great detail, and we now know that embryologically, ear and kidney primordia arise at different times and develop at different rates. Therefore, the association between ear and kidney anomalies usually is not due to an isolated insult to the embryo that affects both developing structures at the same time. Prolonged embryonic insults, such as those seen in IDMs, may cause defects not just in ears and kidneys but also in many other organ systems. This reflects the ongoing teratogenesis of toxic metabolites on all developing structures of the embryo. Recent identification of genes that are responsible for BOR and TBS, along with gene expression studies of these genes, has shown that these genes are expressed in developing ear and kidney structures at different times during morphogenesis.37 Temporally and spatially asynchronous gene expression is proving to be a recurring theme in embryogenesis. One example is the nested expression of Hox genes that provide patterning for the medial-lateral axis of the limbs, branchial arches, and somitomeres, all of which arise at different times in development. PAX2 expression, another regulatory gene in the same signaling pathway as EYA1, in optic placodes and nephrogenic tissues is yet another example of this type of expression. The discovery of EYA1 and SALL1 offer insight into why BOR, TBS, and other syndromes demonstrate ear, kidney, and other organ malformations.

    ACKNOWLEDGMENTS

This study received support from SHARE's Childhood Disability Center, the Steven Spielberg Pediatric Research Center, the Cedars-Sinai Burns and Allen Research Institute, the Skeletal Dysplasias NIH/NICHD Program Project Grant (HD22657), and the Medical Genetics NIH/NIGMS Training Program Grant (GM08243).

We thank Barbara Lawson for her support with this manuscript.

    FOOTNOTES

Received for publication Jan 18, 2001; accepted Apr 9, 2001.

Reprint requests to (J.M.G.) 444 S San Vicente Blvd, Ste 1001, Mark Goodson Building, Cedars-Sinai Medical Center, Los Angeles, CA 90048.

    ABBREVIATIONS

BOR, branchio-oto-renal; MCA, multiple congenital anomaly; TBS, Townes-Brocks Syndrome; OAVS, oculoauriculovertebral spectrum; M/A, microtia/anotia; IDM, infant of a diabetic mother; TCS, Treacher Collins syndrome.

    REFERENCES
Top
Abstract
Methods
Results
Discussion
References
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Pediatrics (ISSN 0031 4005). Copyright ©2001 by the American Academy of Pediatrics


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