Hearing loss in syndromic craniosynostoses: Otologic manifestations and clinical findings

Agochukwu, Nneamaka B.; Solomon, Benjamin D.; Muenke, Maximilian

doi:10.1016/j.ijporl.2014.09.019

Cited by 28 publications

(22 citation statements)

References 93 publications

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“…Also, inner and middle ear malformations have been described in CPS and AS patients ( Orvidas et al, 1999 ; Zhou et al, 2009 ). We speculate that aspects of the malformation seen in homozygous mice may contribute to the high incidence of hearing loss reported in FGFR2-related cases of syndromic craniosynostosis, including 74% of CPS patients ( Agochukwu et al, 2014 ) and warrants a more detailed investigation.…”

Section: Discussionmentioning

confidence: 95%

Analysis of the Fgfr2C342Y mouse model shows condensation defects due to misregulation of Sox9 expression in prechondrocytic mesenchyme

et al. 2017

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Syndromic craniosynostosis caused by mutations in FGFR2 is characterised by developmental pathology in both endochondral and membranous skeletogenesis. Detailed phenotypic characterisation of features in the membranous calvarium, the endochondral cranial base and other structures in the axial and appendicular skeleton has not been performed at embryonic stages. We investigated bone development in the Crouzon mouse model (Fgfr2C342Y) at pre- and post-ossification stages to improve understanding of the underlying pathogenesis. Phenotypic analysis was performed by whole-mount skeletal staining (Alcian Blue/Alizarin Red) and histological staining of sections of CD1 wild-type (WT), Fgfr2C342Y/+ heterozygous (HET) and Fgfr2C342Y/C342Y homozygous (HOM) mouse embryos from embryonic day (E)12.5-E17.5 stages. Gene expression (Sox9, Shh, Fgf10 and Runx2) was studied by in situ hybridisation and protein expression (COL2A1) by immunohistochemistry. Our analysis has identified severely decreased osteogenesis in parts of the craniofacial skeleton together with increased chondrogenesis in parts of the endochondral and cartilaginous skeleton in HOM embryos. The Sox9 expression domain in tracheal and basi-cranial chondrocytic precursors at E13.5 in HOM embryos is increased and expanded, correlating with the phenotypic observations which suggest FGFR2 signalling regulates Sox9 expression. Combined with abnormal staining of type II collagen in pre-chondrocytic mesenchyme, this is indicative of a mesenchymal condensation defect. An expanded spectrum of phenotypic features observed in the Fgfr2C342Y/C342Y mouse embryo paves the way towards better understanding the clinical attributes of human Crouzon–Pfeiffer syndrome. FGFR2 mutation results in impaired skeletogenesis; however, our findings suggest that many phenotypic aberrations stem from a primary failure of pre-chondrogenic/osteogenic mesenchymal condensation and link FGFR2 to SOX9, a principal regulator of skeletogenesis.

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Section: Discussionmentioning

confidence: 95%

Analysis of the Fgfr2C342Y mouse model shows condensation defects due to misregulation of Sox9 expression in prechondrocytic mesenchyme

et al. 2017

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“…The p.Ala391Glu variant does explain the choanal stenosis as it is observed in 41%–43% of individuals with CAN (Arnaud‐López et al, ; Schweitzer et al, ) as well as Chiari I formation (23%) and hearing loss (14%). Vertebral malformations are present with a lower frequency in CAN and broad thumbs and big toes as well as developmental delay are very rare (Agochukwu, Solomon, & Muenke, ). No predicted deleterious variants were identified by WES in any other genes involved in CS to explain a more severe phenotype.…”

Section: Discussionmentioning

confidence: 99%

Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans

Rymer

Shiang

Hsiung

et al. 2019

Molec Gen & Gen Med

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Background Craniosynostosis, or premature fusion of the skull sutures, is a group of disorders that can present in isolation (nonsyndromic) or be associated with other anomalies (syndromic). Delineation of syndromic craniosynostosis is confounded due to phenotypic overlap, variable expression as well as molecular heterogeneity. We report on an infant who presented at birth with multisuture synostosis, turribrachycephaly, midface hypoplasia, beaked nose, low set ears, a high palate and short squat appearing thumbs, and great toes without deviation. The additional MRI findings of choanal stenosis and a Chiari I malformation suggested a diagnosis of Pfeiffer syndrome. First tier molecular testing did not reveal a pathogenic variant. Methods Whole exome sequencing on DNA samples from the proband and her unaffected parents was utilized to delineate the variant causative for the Pfeiffer syndrome diagnosis. Results On whole exome sequencing, a de novo NM_000142.4:c.1428C>A missense variant causing a p.Ala391Glu amino acid change in FGFR3 has been identified. The p.Ala391Glu change has been predominantly identified in patients with Crouzon syndrome with acanthosis nigricans. Conclusions This finding illustrates the first reported case of a child with an overlap with Pfeiffer syndrome to have the p.Ala391Glu variant.

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“…FGF signaling is mediated by receptor tyrosine kinases (Fgf receptors, Fgfrs; Fgfr1‐4) 59 . A number of human craniosynostosis syndromes (such as Apert, Pfeiffer, Crouzon, Beare–Stevenson, and Jackson–Weiss syndromes) that are caused by pathogenic variants in FGF receptors can also display inner and middle ear defects 60,61 . Among the FGF ligands, Fgf8 is strongly expressed in arch surface ectoderm and the pharyngeal endoderm 62,63 .…”

Section: Direct and Indirect Roles Of Secreted Signaling Molecules Onmentioning

confidence: 99%

“…59 A number of human craniosynostosis syndromes (such as Apert, Pfeiffer, Crouzon, Beare-Stevenson, and Jackson-Weiss syndromes) that are caused by pathogenic variants in FGF receptors can also display inner and middle ear defects. 60,61 Among the FGF ligands, Fgf8 is strongly expressed in arch surface ectoderm and the pharyngeal endoderm. 62,63 Ectodermalspecific deletion of Fgf8 or hypomorphic Fgf8 mutants exhibit similar phenotypes, including a severely reduced or absent malleus, incus and tympanic ring which are due to the failure in neural crest cell survival.…”

Section: Fibroblast Growth Factormentioning

confidence: 99%

Uncovering the secreted signals and transcription factors regulating the development of mammalian middle ear ossicles

Ankamreddy

Bok

Groves

2020

Developmental Dynamics

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The mammalian middle ear comprises a chain of ossicles, the malleus, incus, and stapes that act as an impedance matching device during the transmission of sound from the tympanic membrane to the inner ear. These ossicles are derived from cranial neural crest cells that undergo endochondral ossification and subsequently differentiate into their final functional forms. Defects that occur during middle ear development can result in conductive hearing loss. In this review, we summarize studies describing the crucial roles played by signaling molecules such as sonic hedgehog, bone morphogenetic proteins, fibroblast growth factors, notch ligands, and chemokines during the differentiation of neural crest into the middle ear ossicles. In addition to these cell-extrinsic signals, we also discuss studies on the function of transcription factor genes such as Foxi3, Tbx1, Bapx1, Pou3f4, and Gsc in regulating the development and morphology of the middle ear ossicles.

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Hearing loss in syndromic craniosynostoses: Otologic manifestations and clinical findings

Cited by 28 publications

References 93 publications

Analysis of the Fgfr2C342Y mouse model shows condensation defects due to misregulation of Sox9 expression in prechondrocytic mesenchyme

Analysis of the Fgfr2C342Y mouse model shows condensation defects due to misregulation of Sox9 expression in prechondrocytic mesenchyme

Expanding the phenotype for the recurrent p.Ala391Glu variant in FGFR3: Beyond crouzon syndrome and acanthosis nigricans

Uncovering the secreted signals and transcription factors regulating the development of mammalian middle ear ossicles

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