American Journal of Medical Genetics 43:970-975 (1992)

Branchio-Oto-RenalSyndrome: Further Delineation of an Underdiagnosed Syndrome David Chitayat, Kathy A. Hodgkinson, Moy-Fong Chen, George D. Haber, Shigeto Nakishima, and Isamu Sando Department of Pediatrics, Division of Medical Genetics, Montreal Children's Hospital and the Centre for Human Genetics, McGill University (D.C., K.A.H.) and Departments of Obstetrics and Gynecology (G.H.) and Pathology (M.-F.C.),The Royal Victoria Hospital (M.F.C., G.H.), Montreal, Quebec, Canada; The Elizabeth McCullough Knowles Laboratory, Department of Otolaryngology, The Eye and Ear Institute of Pittsburgh (S.N., IS.), Pittsburgh, Pennsylvania We report on a woman who was diagnosed with branchio-oto-renal(BOR) syndrome after 2 pregnancies complicated by oligohydramnios due to renal hypoplasia and agenesis. Both babies died neonatally of pulmonary hypoplasia. Histopathology of the temporal bones of the second child showed marked immaturity of the middle ear cleft, ossicles, facial nerve and canal, and cochlear nerve. Maternal renal ultrasound study was normal although intravenous pyelography indicated renal hypoplasia. The frequency of BOR syndrome among cases of recurrent fetal renal hypoplasialdysplasia or agenesis is unknown, and parental renal ultrasonography may not identify a heritable renal defect. Investigations should include a family history, and examination of relatives to look for preauricular pits, lacrimal duct stenosis, and branchial fistulae andlor cysts. Hearing studies and IVP may be indicated. o 1992 Wiley-Lisa, Inc.

KEY WORDS BOR syndrome, oligohydramnios, renal hypoplasia/dysplasidagenesis,branchial fistulae/ cysts, lacrimal duct stenosis, preauricular pits, temporal bone, cochlear nerve, facial nerve, Potter sequence

Received for publication July 5 , 1991; revision received November 19, 1991. Address reprints to D. Chitayat, M.D., The Prenatal Diagnosis Program, Department of Medical Genetics, Division of Clinical Genetics, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, M5G 1x8,Canada.

0 1992 Wiley-Liss, Inc.

INTRODUCTION Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder which consists of conductive, sensorineural, or mixed hearing loss; preauricular pits, auricular abnormalities, and lateral cervical fistulas, cysts, or sinuses; renal anomalies; nasolacrimal duct stenosis or fistulae; and characteristic facial appearance [Melnick et al., 1976; Fkaser et al., 1978, 19801. Cases without renal manifestations are known although it is unresolved whether they are a different entity (BOsyndrome) or manifestations of the same single gene disorder [F'raser et al., 1983; Greenberg et al., 19881. The minimal diagnostic criteria of BOR syndrome are unknown. Some patients present prenatally with severe oligohydramnios due to renal hypoplasialdysplasia or agenesis; others present with mild manifestations such as small kidneys. Since the spectrum of this syndrome is broad, its contribution to the familial or recurrent cases of renal agenesis or hypoplasia may be high. We report on a female who presented with fetal renal abnormalities in 2 pregnancies. This Ied to the diagnosis of BOR syndrome and appropriate genetic counseling. Detailed histopathological studies of the temporal bones of her second child documented abnormalities of the middle and inner ear and the facial nerve. CLINICAL REPORT Due to recurrent oligohydramnios noted in both pregnancies, a 26-year-old, G2P1 woman (Fig. 1) was referred for genetic counseling during her second pregnancy. She had several relatives with manifestations of BOR syndrome (Fig. 2). The proposita's hearing problems were first diagnosed a t age 5 years when an abnormality of the right ossicular mass and antral region was found. She had normal mobile ear ossicles and stapedial footplate although the round window reflex could not be demonstrated. Her hearing loss was bilateral and mixed with the conductive element more severe. At 14 years the ossicular chain was surrounded by scar tissue and the stapes

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Fig. 1. The proposita (111-16).Note the anteverted pinnae,the facial features,and right preauricularpit (highlighted by arrow).

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footplate was fixed. Recent studies have shown moderately severe mixed hearing loss in the right ear, and severe to profound hearing loss in the left ear. Her first pregnancy a t 25 years was complicated by oligohydramnios detected at 23 weeks gestation. The kidneys were undetectable and the bladder was small. At 31 weeks, amniotic fluid decreased and a t 34 weeks, fetal bradycardia necessitated emergency cesarean section. Apgar scores were 4 and 4 a t 1 and 5 minutes respectively. Respiratory distress due to pulmonary hypoplasia occurred and the male infant died at 4 hours. At autopsy, weight was 2,140 g (50th centile); there was agenesis of the left kidney, a hypoplastic/dysplastic

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right kidney, hypoplasia of the lungs, [combined weight 24 g (< - 2 SD)] a small bladder, and preductal coarctation of the aorta. Both ureters were identified. The face was reported not to show the Potter sequence and chromosomes were normal (46,XY). The couple was given a low recurrence risk. During the second pregnancy oligohydramnios was detected at 18weeks of gestation, although both kidneys and bladder were seen. At 26 weeks, the kidneys were undetectable, the bladder was small, and the oligohydramnios was severe. Amniocentesis was normal (46,XY), and the couple decided to carry the baby to term. Delivery was vaginal and spontaneous at 41

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Chitayat et al. weeks gestation. Birthweight was 3,120 g (25-50th centile), length 49.5 cm (50th centile), and OFC 33.5 cm (25-50th centile). There was redundant skin over the hands and feet, hyperextensible metacarpopharyngeal and interpharyngeal joints, pes planovalgus, prominent heels (Fig. 3), and bilateral preauricular pits (Fig. 4). Flat face, retrognathia, joint contractures and undescended testes were absent. The child died 6 hours after birth of respiratory insufficiency. At autopsy there was agenesis of the right kidney, severe hypoplasia of the left kidney [l.1g (normal combined weight for body weight = 25 & 5 g)] (Fig. 51, and severe pulmonary hypoplasia [combined weight 30.95 g (normal for body weight = 55 ? 13 g)]. Both ureters and bladder were identified. Histopathology of the temporal bones showed large amounts of mesenchymal tissue occupying about 50%of the middle ear cleft. The malleus and incus were bulky with moderate amounts of bone marrow. The facial nerve was hypoplastic and accompanied by a large dehiscence of the bony canal (Fig. 6). Some of the spiral ganglion cells of the cochlea were dislocated to the fundus of the internal auditory canal (Fig. 7). Maternal renal ultrasound scan post delivery showed a smaller left kidney than the right (10 cm vs. 12 cm) although within normal limits. Intravenous pyelogram documented 4-5 calyces in the left kidney suggestive of congenital hypoplasia although cortical thickness was normal. Some manifestations of BOR syndrome were noted including a long narrow “myopathic” face, hypo-

Fig. 3. IV-9.Note the prognathia, lack of joint contraetures, and prominent heels.

Fig. 4. Lateral projection of the head and neck of IV-9.Note the preauricular pit.

Fig. 5. Abdominal autopsy of IV-9 revealed right-sided renal agenesis and severe left renal hypoplasia with the two normally positioned ureters (arrows) and bladder (B).

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Fig. 6. Middle ear (left side). Larger amount of mesenchymaltissue (MT). Facial nerve (F)accompanied by large dehiscence of the bony canal. Note that its diameter is almost the same as the chorda tympani (c).I, Incus; LSC, lateral semicircular canal.

plastic malar areas, preauricular pits, and prognathism (Fig. 1).

DISCUSSION The first report of the combination of preauricular pits, branchial fistulas, and hearing impairment was by Heusinger in 1864, although it was not until 1976 that the association with renal anomalies was noted [Melnick et al., 19761. Since then the designation branchio-oto-renal or BOR syndrome has been used. Its frequency has been estimated at about 1 in 40,000 with severe renal manifestations expected in 6% of heterozygotes [baser et al., 19801. The most obvious findings in BOR syndrome are the auricular abnormalities and preauricular pits as well as the branchial fistulas and cysts. These have a common embryologicorigin in the branchial arch apparatus. The auricle develops from six hillocks at the dorsal end of the first and second branchial arches which surround the first pharyngeal cleft. Auricular anomalies probably represent abnormal differentiation of the hillocks [Melnick and Myrianthopoulos, 19791. Malformation of the middle ear ossicles represents abnormal differentiation of the first and second pharyngeal arches, the malleus and incus derivatives of the former, and the stapes of the latter. Branchial fistulae, sinuses, or cysts originate from incomplete obliteration of the second pharyngeal cleft [Hunter, 19741. Remnants of cleft epithelium form a tract which may have an orifice in the skin, in the tonsillar fossa, in both, or in neither of these sites. However, in 50%of hearing impaired BOR patients the cause of the hearing loss is sensorineural, and Mondini dysplasia has been reported several times [Melnick et al., 1976;

Fitch et al., 1976; Cremers et al., 19801. This is not a branchial apparatus abnormality as the inner ear develops from the otocyst which is of ectodermal origin. In addition, renal, lacrimal duct, and facial nerve abnormalities are not problems related to the branchial arches or pharyngeal pouches as they are of a different embryonic origin. Temporal bone histopathology documented abnormalities which reflected delayed or arrested maturation of both the inner and middle ear as well as the facial and cochlear nerves. The malleus, incus, and stapes are initially surrounded by mesenchyme, contain large amounts of bone marrow, and reach their maximum size at 21 weeks gestation [Pearson, 19801. The ossicular bone marrow diminishes substantially at 25 weeks gestation and at birth is minimal. The mesenchyme at term occupies 19% of the middle ear [Takahara et al., 19861. In our patient the mesenchyme occupied 50% of the middle ear cleft, and both the malleus and incus contained excess amounts of bone marrow. The second pharyngeal pouch nerve (the facial nerve) was hypoplastic and its course in the temporal bone was affected. In normal development the facial canal is seen as a sulcus a t 4 months gestation [Anson and Donaldson, 19811. Facial nerve diameter is comparable in size to the chorda tympani a t 6.5 months gestation [Gasser, 19671, but a t birth is larger than the chorda tympani. In our patient, a t term, the facial nerve had the same diameter as the chorda tympani. The spiral ganglion cells, normally located in Rosenthal's canal of modiolus were found at the fundus of the internal auditory canal. Relocation of these cells has previously been noted in cases with multiple congenital anomalies [Sando et al., 19881.

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Chitayat et al. frequency of preauricular pits was not mentioned [Roodhooft et al., 19841; some of these families may have had BOR syndrome. Renal ultrasound studies showed no abnormality in the proposita although IVP indicated mild unilateral hypoplasia. Parental renal ultrasound studies after the detection of renal hypoplasiddysplasia or agenesis in the fetus or newborn may, therefore, not be sufficient to diagnose BOR syndrome. This report illustrates, as have others [Fitch et al., 1976; Greenberg et al., 19881, that not all cases with severe oligohydramnios present with a classic Potter phenotype [Potter, 19461.In our report the oligohydramnios progressed from mild to severe in parallel with the renal defect, and it may be that the initial urinary excretion in BOR individuals (who have both ureters and bladder) avoids some of the characteristic manifestations of Potter sequence. We conclude that first degree relatives of a newborn infant or fetus with renal agenesis, hypoplasia, or dysplasia, especially if the ureters and bladder are present, should have the following minimum studies: a family history noting preauricular pits, hearing problems, nasolacrimal ducts, and branchial fistulas or cysts; physical examination and renal ultrasonography. Ultrasound monitoring of future pregnancies is recommended. Functional urologic evaluation (IVP) and audiometric evaluation may also be considered. Further histopathological studies may help delineate the embryonic etiology of this underdiagnosed syndrome.

REFERENCES

Fig. 7. Cochlear nerve (CN) in the internal auditory canal (right side).Some of the spiral ganglion cells (SG)usually located in the canal were seen at the fundus of the internal auditory canal of modiolus (M) (IAC).

Minimal criteria for diagnosing BOR syndrome are not well established, and assigning unaffected status may be difficult. Individual 111-15 (Fig. 1) had oligohydramnios during her pregnancy which resolved at 28 weeks of gestation, and resulted in a male child (IV-7);results of renal ultrasound studies were normal. The proposita was undiagnosed despite a history of hearing loss and preauricular pits. This may relate to the evolution of the hearing impairment, from a mild, mainly conductive problem to a more severe mixed loss, with stapes fixation occurring over time. Unilateral preauricular pits occur in about 1%of the general population [Stewart et al., 19691. In some individuals they may be the only obvious manifestation. The spectrum of renal abnormalities in BOR syndrome ranges from mild hypoplasia to renal agenesis [Nevin, 1977;Dumas et al., 1982;Cote and O’Regan, 1982;Widderhoven et al., 1983; Carmi et al., 1983; Gimsing and Dyrmose, 1986; Greenberg et al., 19881. One study showed that 9% of the parents and siblings of 41 probands with bilateral renal agenesis and/or cystic dysplasia had renal malformations. Hearing studies however were not done, and the

Anson BJ, Donaldson JA (1981): “Surgical Anatomy of the Temporal Bone.” Philadelphia: Saunders, pp 150-155. Carmi R, Binshtock M, Abeliovich D, Bar-Ziv J (1983):The Branchiooto-renal (BOR) syndrome: Report of bilateral renal agenesis in three sibs. Am J Med Genet 14:625-627. CGte A, O h g a n S (1982): The branchio-oto-renal syndrome. Am J Nephrol 2:144-146. Cremers CW, Fikkers-Van Noord M (1980):The earpits-deafnesssyndrome. Clinical and genetic aspects. Int J Pediatr Otorhinolaryngol 2:309-322. Dumas R, Uziel A, Baldet P, Segond A (1982):Glomerularlesionsin the branchio-oto-renal(BOR)syndrome.Int J Pediatr Nephrol3:67-70. Fitch N, Lindsay JR, Srolovitz H (1976): The temporal bone in the preauricular pit, cervical fistula, hearing loss syndrome. Ann Otol Rhinol Laryngol 85:268-275. Fraser FC, Ling D, Clogg D, Nogrady B (1978):Genetic aspects of the BOR syndrome-branchial fistula, ear pits, hearing loss, and renal anomalies. Am J Med Genet 2:241-252. Fraser FC, Sproule JR, Halal F (1980): Frequency of the branchio-otorenal (BOR)syndrome in children with profound hearing loss. Am J Med Genet 7:341-349. Fraser FC, Aym6 S,Halal F, Sproule J (1983): Autosomal dominant duplicationof the renal collectingsystem, hearing loss and external ear anomalies: A new syndrome? Am J Med Genet 14:473-478. Gasser RF (1967):The developmentof the facial nerve in man. Ann Otol Rhinol Laryngol 76:37-56. Gimsing S, Dyrmose J (1986): Branchio-oto-renaldysplasia in three families. Ann Otol Rhinol Laryngol 95:421-426. Greenberg CR, TrevenenCL, Evans J A (1988):The BOR syndromeand renal agenesis-prenatal diagnosis and future clinical delineation. Prenat Diagn 8:103-108. Heusinger CF (1864):Hals-Kiemen-Fisteln von noch nicht beobachteter Form. Virchows Arch Path01 Anat Physiol 29:358-380. Hunter AGW (1974):Inheritance of branchial sinuses and preauricular fistulae. Teratology 9:225-228.

Branchio-Oh-RenalSyndrome Melnick M, Bixler D, Nance WE, Silk K, Yune H (1976): Familial branchio-oto-renal dysplasia: A new addition to the branchial arch syndromes. Clin Genet 925-34. Melnick M, Myrianthopoulos NC (1979):External ear malformations: Epidemiology, genetics and natural history. Birth Defects 15:l-29. Nevin NC (1977): Hereditary deafness associated with branchial fistulae and external ear malformations. J Laryngol Otol 91: 709-716. Pearson AA (1980):Developmental anatomy of the ear. In English GM “Otolaryngology,” Vol. 1. Hagerstown, MD: Harper & Row, pp 20-34. Potter EL (1946):Facial characteristics of infants with bilateral renal agenesis. Am J Obstet Gynecol 41:855-888. Roodhooft AM, Birnholz JC, Holmes IB (1984): Familial nature of

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congenital absence and severe dysgenesis of both kidneys. N Engl J Med 310:1341-1345. Sando I, Shibahara Y, Takagi A, Takahara T, Yamaguchi N (1988): Frequency and localisation of congenital anomalies of the middle and inner ears: A human temporal bone histopathological study. Int J Pediatr Otorhinolaryngol 16:l-22. Stewart AL, Keay AJ, Smith PG (1969):Congenital malformations; a detailed study of 2,500 liveborn infants. Ann Hum Genet 32:353360. Takahara T, Sando I, Hashida Y, Shibahara Y (1986): Mesenchyme remaining in human temporal bones. Otolaryngol Head Neck Surg 95:349-357. Widderhoven J, Monnens L, Assmann K, Cremers C (1983): Renal disorders in the branchio-oto-renal syndrome. Helv Paediatr Acta 38513-522.

Branchio-oto-renal syndrome: further delineation of an underdiagnosed syndrome.

We report on a woman who was diagnosed with branchio-oto-renal (BOR) syndrome after 2 pregnancies complicated by oligohydramnios due to renal hypoplas...
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