Cochlear Implants Int. 2011 Sep 23;
Yogesh B, Nick G, Kathryn F, Ben H, Chris J, Nico J, David A, Martin B, Michelle W, Lesley C

OBJECTIVE: The objective of this study was to report surgical results and outcomes of cochlear implantation in a large series of children with syndromes from one centre. PATIENTS AND METHODS: All syndromic children who underwent cochlear implantation at Great Ormond Street Hospital, from January 2000 to December 2010 were included in this study. The surgical technique was analysed and audiological outcomes were collected. RESULTS: Over the 10-year period of this study, a total of 88 cochleas in 67 children with syndromes were implanted. The common syndromes implanted in this study were Ushers syndrome (23 patients, 33 cochleas), Wardenburgs syndrome (8 patients, 9 cochleas), Pendreds syndrome (4 patients, 4 cochleas), Jervell-Lange-Neilsen syndrome (3 patients, 4 cochleas), Enlarged vestibular aqueduct syndrome (4 patients, 7 cochleas), Cogans syndrome (3 patients, 4 cochleas), CHARGE (5 patients, 6 cochleas), and Branchio Oto Renal syndrome (3 patients, 4 cochleas). Pre-operative radiological inner ear anatomy was found to be abnormal in 28.4% (25/88) cochleas in this study group. Full insertion of the electrode was achieved in 93.1% (82/88) of cochleas, partial insertion in three cochleas, and insertion was abandoned in three cochleas. Early complications were seen in 6.8% (6/88) of implantations. All the 64/67 children who were implanted are still using the implant. CONCLUSION: Cochlear implantation in syndromic children is challenging in both its audiological and surgical aspects. Good surgical results and good audiological and speech outcomes were achieved in this study, and subjective improvement in quality of life was achieved in these patients.

Clin Nephrol. 2011 Oct; 76(4): 330-3
Nardi E, Palermo A, Cusimano P, Mulè G, Cerasola G

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disease clinically characterized by the coexistence of some or all of the following major disorders: deafness, cervical branchial fistulae, preauricular pits, and renal abnormalities. Most families with BOR syndrome have mutations on the EYA-1 gene on chromosome 8q. We present the case of a 23-year-old Italian woman without a familial history of BOR syndrome. The patient, who had hearing loss and a history of surgeries for correction of bilateral cervical branchial fistulae and bilateral preauricular pits, presented with renal impairment, hypertension and overt proteinuria. DNA sequencing showed a novel heterozygous mutation 1420-1421delCC in exon 14 of EYA-1 gene.

Int J Pediatr Otorhinolaryngol. 2011 Oct; 75(10): 1341-5
Johnston DR, Whittemore K, Poe D, Robson CD, Perez-Atayde AR

Described is the first case report, to our knowledge, of a middle-ear dermoid in a child with branchio-oto-renal (BOR) syndrome. Radiographic, pathologic, and intraoperative figures are shown. This was a diagnostic and surgical challenge as the presentation was similar to a congenital cholesteatoma and the child had numerous significant temporal bone abnormalities. After the intraoperative findings suggested a non-destructive process, the treatment strategy was altered. This case reiterates the need for a cautious, flexible operative approach in a syndromic child. Included is a relevant review of the literature and a detailed clinical analysis.

Ophthalmic Genet. 2011 Nov; 32(4): 250-5
Aliferis K, Stoetzel C, Pelletier V, Hellé S, Angioï-Duprez K, Vigneron J, Leheup B, Marion V, Dollfus H

Branchio-Oculo-Facial Syndrome (BOFS) is a rare autosomal dominant congenital disorder defined by branchial defects, ocular anomalies and craniofacial malformations, including variable degrees of cleft lip with or without cleft palate. In addition, temporal bone anomalies, renal and ectodermal manifestations can be present. Mutations in the TFAP2A gene have been reported in patients with BOFS, prompting phenotype-genotype studies because of the variable clinical spectrum.We report on a family (a mother, her daughter and son) with BOFS and significant variability in clinical expression. The daughter presents predominantly with an ocular phenotype of unilateral microphthalmia and bilateral chorioretinal colobomas, whereas her brother is more severely affected contrasting with the paucisymptomatic mother. TFAP2A molecular analysis revealed a novel frameshift mutation.We confirm the wide clinical spectrum of BOFS. The importance of upper lip examination in mild and paucisymptomatic cases is underlined. TFAP2A mutation spectrum is discussed and broadened by the report of the second frameshift mutation in this gene. Conclusion: Patients with BOFS and predominant ocular phenotypes can be underdiagnosed. In such cases, upper lip examination can be of important diagnostic value. TFAP2A analysis provides diagnostic confirmation and improves genetic counselling.

Eur J Med Genet. 2011 Sep-Oct; 54(5): e484-8
Mosrati MA, Hammami B, Rebeh IB, Ayadi L, Dhouib L, Ben Mahfoudh K, Hakim B, Charfeddine I, Mnif J, Ghorbel A, Masmoudi S

Branchio-oto-renal (BOR) and Branchio-otic (BO) syndromes are dominant disorders characterized by variable hearing impairment (HI) and branchial defects. BOR includes additional kidney malformations. BO/BOR syndromes are genetically heterogeneous and caused by mutations in EYA1 and SIX1 genes. Mutation in SIX1 is responsible also for DFNA23, a locus for non-syndromic HI. Strikingly, the severity of the phenotype did not seem to correlate with the type of SIX1 mutation. Herein, we identified a novel mutation in SIX1 (p.E125K) in a Tunisian family with variable HI and preauricular pits. This mutation is located at the same position as the mutation identified in the Catwhesel (Cwe) mouse. No renal and branchial defects were observed in our family nor in Cwe/+ mice. A homology model revealed that the replacement of the Glutamate by a Lysine alters the electrostatic potential surface propriety which may affect the DNA-binding activity.

Eur J Dermatol. 2011 Mar-Apr; 21(2): 234-7
Yılmaz AE, Sarıfakıoglu E, Aydemır S, Taş T, Orün E, Aydemır H

Preauricular sinuses (ear pits) are common congenital abnormalities. The incidence of preauricular sinus is widely varied. Usually asymptomatic, they manifest as small hollows adjacent to the external ear near the anterior margin of the ascending limb of the helix, most frequently on the right side. Preauricular sinuses can be either inherited or sporadic. They may be bilateral, increasing the likelihood of being inherited, in 25-50% of cases. Preauricular sinuses are features of other conditions or syndromes in 3-10% of cases, primarily in association with deafness and branchio-oto-renal (BOR) syndrome. When other congenital anomalies coexist with these sinuses, auditory testing and renal ultrasound should be considered. A girl, who was three months and 20 days old, was presented because of the co-existence of a right infected preauricular sinus, nephrolithiasis, infantile eczema and a natal tooth.

Adv Otorhinolaryngol. 2011; 70: 75-83
Kimberling WJ, Borsa N, Smith RJ

There are several syndromes in which both hearing and renal function are impaired. The two best known are branchio-oto-renal (BOR) syndrome and Alport syndrome. These are reviewed along with several other rarer syndromes. BOR is especially important since it is likely to be first recognized by the otolaryngologist because of the hearing and branchial anomalies. It is important for the practicing otolaryngologist to recognize these disorders and to ensure that renal problems are being treated. In addition, the syndromes discussed here are all hereditary and referral to a clinical geneticist may be helpful to the individual and family.

Hum Mutat. 2011 Feb; 32(2): 183-90
Krug P, Morinière V, Marlin S, Koubi V, Gabriel HD, Colin E, Bonneau D, Salomon R, Antignac C, Heidet L

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial, ear, and renal anomalies. Over 80 mutations in EYA1 have been reported in BOR. Mutations in SIX1, a DNA binding protein that associates with EYA1, have been reported less frequently. One group has recently described four missense mutations in SIX5 in five unrelated patients with BOR. Here, we report a screening of these three genes in a cohort of 140 patients from 124 families with BOR. We identified 36 EYA1 mutations in 42 unrelated patients, 2 mutations, and 1 change of unknown significance in SIX1 in 3 unrelated patients, but no mutation in SIX5. We did not find correlation between genotype and phenotype, and observed a high phenotypic variability between and within BOR families. We show the difficulty in establishing a molecular diagnosis strategy in BOR syndrome: the screening focusing on patients with typical BOR would detect a mutation rate of 76%, but would also miss mutations in 9% of patients with atypical BOR. We detected a deletion removing three EYA1 exons in a patient who was previously reported to carry the SIX5 Thr552Met mutation. This led us to reconsider the role of SIX5 in the development of BOR.

Acta Otolaryngol. 2011 Apr; 131(4): 413-8
Noguchi Y, Ito T, Nishio A, Honda K, Kitamura K

A reported mutation in SIX1 was identified in a patient with familial hearing loss (HL), a left preauricular pit, and bilateral enlarged vestibular aqueducts (EVA). Although the characteristic symptoms of EVA including fluctuating HL and repetitive vertigo were not seen in the patient, further studies are needed to clarify the association between EVA and such symptoms.To study the audiovestibular functions, and to identify the causative gene in a patient with branchio-oto syndrome.We enrolled a 30-year-old female in whom HL was pointed out at the age of 6 years. She visited our department at the age of 21 years, and had not experienced any progression of her HL, tinnitus, or vertigo. Pure-tone audiograms showed bilateral moderate mixed HL with no apparent progression during a 9-year follow-up period. Audiovestibular examinations included distortion product otoacoustic emissions (DPOAEs), electrocochleography (ECochG), and electronystagmography (ENG). Direct sequencing was utilized to screen for SIX1, EYA1, SLC26A4, GJB2, and mitochondrial DNA MTRNR1 including 1555 position.The findings of DPOAEs, ECochG, and ENG indicated cochlear HL with no vestibular dysfunction. A previously reported mutation of a heterozygous c.386A > G (p.Y129C) in SIX1 was detected. No mutation was identified in EYA1, SLC26A4, GJB2, or MTRNR1.

Ann Otol Rhinol Laryngol. 2010 Dec; 119(12): 806-14
Thomeer HG, Crins TT, Kamsteeg EJ, Buijsman W, Cruysberg JR, Knoers NV, Cremers CW

We report on the clinical presentation of branchio-oculo-facial (BOF) syndrome in 2 patients with mutations in the TFAP2A gene (OMIM 107580). This TFAP2A gene was recently shown to be involved in the causation of BOF syndrome. An overview of the literature on BOF syndrome is given based on clinical reports written in the period during which mutation analysis was not yet available for BOF syndrome. We also give descriptions of the mutations in the TFAP2A gene in our 2 new patients with BOF syndrome. Congenital conductive hearing impairments are described, including hearing rehabilitation and the results of ear surgery.

Am J Med Genet A. 2011 Jan; 155A(1): 22-32
Milunsky JM, Maher TM, Zhao G, Wang Z, Mulliken JB, Chitayat D, Clemens M, Stalker HJ, Bauer M, Burch M, Chénier S, Cunningham ML, Drack AV, Janssens S, Karlea A, Klatt R, Kini U, Klein O, Lachmeijer AM, Megarbane A, Mendelsohn NJ, Meschino WS, Mortier GR, Parkash S, Ray CR, Roberts A, Roberts A, Reardon W, Schnur RE, Smith R, Splitt M, Tezcan K, Whiteford ML, Wong DA, Zori R, Lin AE

Branchio-oculo-facial syndrome (BOFS; OMIM#113620) is a rare autosomal dominant craniofacial disorder with variable expression. Major features include cutaneous and ocular abnormalities, characteristic facies, renal, ectodermal, and temporal bone anomalies. Having determined that mutations involving TFAP2A result in BOFS, we studied a total of 30 families (41 affected individuals); 26/30 (87%) fulfilled our cardinal diagnostic criteria. The original family with the 3.2 Mb deletion including the TFAP2A gene remains the only BOFS family without the typical CL/P and the only family with a deletion. We have identified a hotspot region in the highly conserved exons 4 and 5 of TFAP2A that harbors missense mutations in 27/30 (90%) families. Several of these mutations are recurrent. Mosaicism was detected in one family. To date, genetic heterogeneity has not been observed. Although the cardinal criteria for BOFS have been based on the presence of each of the core defects, an affected family member or thymic remnant, we documented TFAP2A mutations in three (10%) probands in our series without a classic cervical cutaneous defect or ectopic thymus. Temporal bone anomalies were identified in 3/5 patients investigated. The occurrence of CL/P, premature graying, coloboma, heterochromia irides, and ectopic thymus, are evidence for BOFS as a neurocristopathy. Intrafamilial clinical variability can be marked. Although there does not appear to be mutation-specific genotype-phenotype correlations at this time, more patients need to be studied. Clinical testing for TFAP2A mutations is now available and will assist geneticists in confirming the typical cases or excluding the diagnosis in atypical cases.

Pediatr Transplant. 2011 Feb; 15(1): E1-7
Narayan S, Tsai EW, Zhang Q, Wallace WD, Reed EF, Ettenger RB

Allograft rejection in HLA identical transplant recipients and in patients without detectable donor-specific anti-HLA antibodies has lead to the identification of non-HLA antigens as targets of the alloimmune response. MICA antigen has been recognized as an important non-HLA target in renal transplantation. Recent studies have shown that anti-MICA antibodies are associated with acute renal allograft rejection and failure. Current cross match procedures using donor lymphocytes fail to detect MICA antibodies. Transplant candidates are not routinely tested for pre-sensitization to MICA antigens nor are transplant donors typed for MICA alleles. Optimal classification and treatment of acute rejection associated with MICA antibody remains unknown. In this case report, we are the first to describe the clinical course and treatment of donor-specific MICA antibody associated with both Banff type II A ACR and AMR in a highly sensitized pediatric renal re-transplant recipient. This case also emphasizes the importance of pre-transplant screening for donor-specific MICA antibody especially in highly sensitized renal transplant patients.