鰓耳腎症候群

Branchio-oto-renal (BOR) syndrome is an autosomal dominant condition characterized by variable malformations including hearing loss and renal dysfunction. Variants in SIX1 or its activating co-factor EYA1 are causative in about 50% of patients. Some patients carrying BOR variants also present with craniosynostosis, indicating that cranial skeletal dysmorphologies could be an under-diagnosed feature. To date, most studies on the role of SIX1 have focused on its role in the cranial placode-based development of the inner ear, whereas its role in the neural crest cells of the mandibular arch, which will give rise to the jaws and middle ear ossicles, is less well characterized. Here, we present novel expression profiles of three putative SIX1 co-factors (PA2G4, MCRS1, and SOBP) in the developing mouse first pharyngeal arch and tooth. SIX1 colocalizes with PA2G4, MCRS1, and SOBP within the oral domain of the mandibular arch and during odontogenesis, although each exhibits a distinct expression pattern. Functional analyses revealed that SOBP binds SIX1, EYA1, and EYA2 and represses both SIX1 + EYA1 and SIX1 + EYA2 transcriptional activity, whereas MCRS1 binds only SIX1 and selectively represses SIX1 + EYA2 activity. In contrast, PA2G4 does not bind SIX1, yet modulates SIX1 + EYA2 activity. We further show that SIX1 is required for proper expression of Pa2g4, Mcrs1, and Sobp in the mouse mandibular arch. Collectively, these results demonstrate that regulation of SIX1 + EYA transcriptional activity is highly context dependent, occurs through both direct and indirect mechanisms, and differs between SIX1 + EYA1 and SIX1 + EYA2 complexes. These findings reveal species-specific differences and uncover a level of regulatory complexity not previously identified in Xenopus studies.

BACKGROUND AND PURPOSE: As the endolymphatic (ES) undergoes normal postnatal maturation, the surrounding vestibular aqueduct (VA) undergoes a corresponding change in morphology, quantified by its angular trajectory (ATVA). In adult temporal bones with Meniere's disease (MD), a fetal orientation ATVA (≥140°) indicates underlying ES hypoplasia and defines the so called hypoplastic disease endotype (MD-hp). However, ES hypoplasia has also been described histologically in other inner ear syndromes and congenital conditions, independent of MD. We aimed to investigate whether ATVA ≥140° occurs in mature temporal bones beyond its established association with the MD-hp endotype. MATERIALS AND METHODS: Retrospective retrieval of CT scans performed on patients over age 12 years at Massachusetts Eye and Ear between January 2016 and December 2024 was conducted, with search terms encompassing diseases previously described to be associated with temporal bone anomalies. CT studies that did not allow adequate assessment of the VA were excluded. Two neuroradiologists blinded to clinical information independently performed ATVA measurements, with consensus interpretation rendered for disagreements in ATVA categories (adult, intermediate, or fetal orientation). RESULTS: 103 patients with congenital temporal bone anomalies were identified. 98 patients (190 ears) met inclusion criteria. Fetal VA orientation (ATVA ≥140°) was identified in 8 ears from 6 patients. Intermediate VA orientation (ATVA 121°-139°) was identified in 19 ears from 15 patients. Among 8 patients with branchio-oto-renal (BOR) syndrome, 2 patients had bilateral fetal orientation ATVA and 2 patients had mixed fetal/intermediate orientation ATVA. Among 11 patients with trisomy 21, 5 demonstrated unilateral abnormal ATVA. Higher than 120° ATVA values were also observed in CHARGE syndrome, Apert syndrome, and Chiari I malformation. Review of clinical records did not show a diagnosis of MD within our cohort. CONCLUSIONS: Fetal and intermediate ATVA orientations were observed in several congenital temporal bone anomalies without documented MD. These findings further support that abnormal ATVA reflects altered VA/ES developmental morphology and is not exclusive to the MD-hp endotype. Accordingly, fetal orientation ATVA should be interpreted within the broader clinical and radiologic context, particularly in the presence of additional congenital abnormalities.

SIX1 variants underlying branchio-oto-renal syndrome occur in the SIX domain (SD) or homeodomain (HD). We tested whether different variants - V17E (SD), Y129C (HD) - cause distinct developmental phenotypes in Xenopus embryos with reduced Six1 in comparison to wild-type Six1 (Six1WT). In Six1 morphants, Six1WT restored neural crest and preplacodal gene expression; V17E restored foxd3 and irx1 better than Y129C, and Y129C restored sox11 better than V17E. In six1-null otic vesicles, Six1WT partially restored tbx1 and sobp, V17E was less effective and Y129C was least effective; all three restored dlx5. In six1 heterozygotes, Six1WT and Y129C had similar pleiotropic effects on tbx1, whereas V17E had no effect; Six1WT restored dlx5 expression, V17E was less effective and Y129C was most deficient. In six1-null tadpoles, reduced cranial cartilage volume and individual cartilage abnormalities were rescued by Six1WT, less so by V17E and not by Y129C. In heterozygotes and wild types, Y129C caused a higher frequency of abnormal cartilages compared to Six1WT or V17E. Thus, variants with different functional deficits have distinguishable effects in both nulls and heterozygotes on the formation of the tissues affected in branchio-oto-renal syndrome.

BACKGROUND: Second branchial cleft anomalies are the most common congenital cervical malformations, accounting for approximately 90% of branchial cleft lesions. They usually present unilaterally, while bilateral involvement is exceedingly rare and most often associated with genetic syndromes such as branchio-oto-renal (BOR) syndrome. CASE PRESENTATION: We report the case of an 8-year-old Moroccan boy with no relevant past medical history who presented with bilateral, low-lying paramedian cervical fistulas that had been recurrently infected since early childhood. Clinical examination revealed two small external openings with intermittent mucopurulent discharge. Audiological evaluation was normal, and renal ultrasonography excluded any associated anomalies. The patient underwent complete surgical excision of both tracts in a single-stage procedure. The postoperative course was uneventful, and no recurrence was observed during follow-up. CONCLUSION: This case highlights the exceptional occurrence of bilateral second branchial cleft fistulas in the absence of syndromic features. A systematic preoperative evaluation, including auditory and renal assessment, is essential. Complete surgical excision remains the gold standard to prevent recurrence and recurrent infections.

Hearing loss (HL) is the most prevalent sensory disorder globally and a major public health challenge in Brazil, affecting over 1.5 million individuals. While over 150 HL-associated genes have been identified, the genetic architecture in underrepresented populations remains poorly defined, often limiting diagnostic yield and precision medicine. We assessed the diagnostic performance of a comprehensive 218-gene HL panel in 99 Brazilian probands (78 non-syndromic; 21 syndromic) who had previously tested negative for GJB2/GJB6 (DFNB1) and MT-RNR1 (m.1555A>G) and did not have ear malformations. Targeted next-generation sequencing was followed by variant interpretation according to ACMG/AMP guidelines, segregation analysis, and longitudinal phenotypic re-evaluation. Integration of Brazil-specific allele-frequency data was used to refine variant classification. A molecular diagnosis or a candidate variant was identified in 61 probands, yielding an overall diagnostic yield of 43%-62%, depending on classification stringency. We identified 19 novel variants across 15 genes, with MYO7A and MYO15A as the most frequently implicated. Notably, 10.4% of patients initially diagnosed with non-syndromic HL carried pathogenic or likely pathogenic variants in syndromic genes (PEX6, BSND, USH1C, and WFS1), necessitating clinical reclassification. Segregation analysis and phenotypic reassessment further enabled the reclassification of three variants of uncertain significance (VUS). In syndromic cases, a molecular diagnosis was established in 41% of cases, including Usher, Waardenburg, Branchio-oto-renal, and Bartter syndromes. This first large-scale clinical genetic evaluation of hearing loss in Brazil demonstrates that comprehensive gene panels incorporating population-specific data significantly improve diagnostic accuracy. Our findings broaden the mutational landscape of HL-associated genes, reinforce the value of integrated genetic approaches for underrepresented populations, and underscore their direct impact on patient care and clinical management.