Audiologic and Otologic Clinical Manifestations of Loeys‐Dietz Syndrome: A Heritable Connective Tissue Disorder

Abstract

Objective Loeys-Dietz syndrome (LDS) is a rare genetic connective tissue disorder resulting from TGF-ß signaling pathway defects and characterized by a wide spectrum of aortic aneurysm, arterial tortuosity, and various extravascular abnormalities. This study describes the audiologic, otologic, and craniofacial manifestations of LDS. Study Design Consecutive cross-sectional study. Setting Tertiary medical research institute. Methods Audiologic and clinical evaluations were conducted among 36 patients (mean ± SD age, 24 ± 17 years; 54% female) with genetically confirmed LDS. Cases were categorized into genetically based LDS types 1 to 4 ( TGFBR1, TGFBR2, SMAD3, TGFB2, respectively). Audiometric characteristics included degree and type of hearing loss: subclinical, conductive, mixed, and sensorineural. Results LDS types 1 to 4 included 11, 13, 5, and 7 patients, respectively. In LDS-1, 27% had bilateral conductive hearing loss; 9%, unilateral mixed; and 36%, subclinical. In LDS-2, 38% had conductive hearing loss and 38% subclinical. In LDS-3 and LDS-4, 40% and 43% had bilateral sensorineural hearing loss, respectively. Degree of hearing loss ranged from mild to moderate. Bifid uvula was observed only in LDS-1 (55%) and LDS-2 (62%). Submucosal/hard cleft palates were primarily in LDS-1 and LDS-2. Posttympanostomy tympanic membrane perforations occurred in 45% (10/22 ears) of LDS-1 and LDS-2. There were 4 cases of cholesteatoma: 3 middle ear (LDS-1 and LDS-2) and 1 external ear canal (LDS-3). Conclusion Conductive hearing loss, bifid uvula/cleft palate, and posttympanostomy tympanic membrane perforation are more common in LDS-1 and LDS-2 than LDS-3 and LDS-4, while sensorineural hearing loss was present only in LDS-3 and LDS-4. These LDS-associated key clinical presentations may facilitate an early diagnosis of LDS and thus prompt intervention to prevent related detrimental outcomes.

Regeneration of Hair Cells from Endogenous Otic Progenitors in the Adult Mammalian Cochlea: Understanding Its Origins and Future Directions

“…BMPs belong to the TGFβ superfamily. In humans, mutations in TGFβ or its receptor are associated with hearing loss, such as in Loeys-Dietz syndrome and Ehler-Danlos syndrome [95,96]. In mice, BMPs are already expressed in early cochlear development from E9 onwards, together-but not always co-expressed-with the lunatic fringe (Lfng) [97][98][99][100].…”

“…Conditional knockout of BMP receptors in the inner ear causes lack of cochlear development and lack of differentiation of cells in the prosensory domain, hallmarked by the absence of P27kip expression [100]. In developing chicks, BMP signaling inhibition by Noggin causes an increased size of sensory patches without changes in cell proliferation in E3.5-4 [99] but a reduction in hair cells and supporting cell counts in E15-16 [96]. On the other hand, the addition of exogenous BMP4 in developing chick otic vesicles in vitro showed a reduction in sensory patches and a marked decline in cell proliferation in E3.5-4 [99] but an increase in hair cell counts in E15-16 [97].…”