HUMAN DEVELOPMENTAL DISORDERS OF THE EAR.
The human ear is mainly responsible for hearing but also aids in vestibular movement and balance. Its ability to detect not only auditory signals but also positional awareness in relation to gravity as well as acceleration makes it quite a unique organ.
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Evolutionary studies suggest the modern ear is a culmination of convergent evolution from both early vertebrates and invertebrates 600 million years ago. The vertebrate ear was described to resemble a single epithelium shaped “doughnut” organ for gravistatic perception with associated epithelia for angular perception whereas a simple sac reminiscent of semi-circular canals for angular acceleration in invertebrates. Subsequent gene expansion through duplication and diversification events are thus theorised to have led to rise of additional hearing function which now is prominently associated to the organ. (Fritzsch et al., 2010).
The sub-departments of the ear namely inner, middle and outer ear function in unison to transform sound stimuli into nerve impulses. Auditory transduction thus incorporates components of all these departments for collection, amplification and conversion sound waves into action potential and hence when these areas are affected disorders mostly resulting in hearing loss are observed. (Heine et al, 2004).
During human embryogenesis initial ear development begins from the thickening of ectoderm to form the otic placode which invaginates into the otic vesicle. The otic vesicle develops into majority of the inner ear and compartmentalises into dorsal and ventral demarcations which give rise to major sensory organs like utricle and semi-circular canals for vestibular movement and saccule and cochlear duct for hearing respectively. Additionally, it associates with three bony condensations from the first and second pharyngeal arch that become the ossicles of the middle ear. Complete development of the ear is evident when the external pinna of the fully formed. Migration of the first and second pharyngeal arch inward gives rise to the external acoustic meatus, which is the space between them while their auricular derivatives form whole exterior of the ear. In a nutshell, the specialisation of the otic ectoderm drives the vital sensory processes, effector and supporting cells required for normal ear functionality (Pansky, Medical Embryology Review, 2018). Morphogenesis into these sensory organs is modulated by multiple signalling through bone morphogenic protein, growth factors, sonic hedge-hog, wingless/integrated and other regulatory pathways. (Fritzsch et al., 2010).
Knowledge of the key process involved in this development were ascertained via mouse models. For a long time, processes and genes affecting inner ear development had remained elusive with respect to detailed information garnered for the middle and exterior sections.
Paint-fill methods along with gene analyses have been utilised to study the development of mouse inner ear which have contributed to current understanding of the human version. In 1998, a research group injected white latex paint into membranous auricular labyrinth of mouse inner ear at various stages in development, while labelling key regions of the cochlea, saccule, utricle for visualisation. Further, adopting molecular markers bone morphogenic protein (BMP4) and lunatic fringe(fng) they were able to analyse the forementioned structures in early and late development. Prior literature had already established the role of BMP4 as a marker for sensory organs in chicken inner ear and linked similar expression patterns in otocysts of xenopus and mouse, while Fng had been connected to formation of demarcations predominantly in the otic vesicle where it restrictively expressed in both models. Their results revealed that the posterior cristae was the first sensory organ to manifest approximately 11 days into embryogenesis followed by superior, lateral crista and macula utriculi drawing a correlation a common evolutionary ancestor. (Morsli et al, 1998)
Recent experimentation has expanded on our knowledge of the other genes involved in the development of the inner ear such as transcriptional factors LHX3 and SOX2 implicated in the modulation of differentiation of primordial inner ear cells into essential hair cells and supporting cells in both auditory and vestibular processes. (Hume et al 2007). Research insects has established vital role of bHLH genes in neuronal and sensory development and their interaction with Sox2 and non‐neuronal bHLH genes to progress proliferation. (Fritzsch et al., 2010). Knockout and frameshift mutations of PAX2 gene encoding transcriptional factor pax2 have also elucidated on its role in cochlear development and ability to rescue its agenesis. (Burton et al, 2004). These researches have shed more light on mechanisms regulating morphogenesis of mammalian inner ear.
Normal ear is delineated by specific convexities and concavities that allow its recognition. Features such as helix, anti-helix, tragus, anti-tragus, lobule, scapha and concha, among others have a defined appearance that when modified are defined as an anomaly. Occuring in about 5% of worldwide population ear anomalies are quite common. Perhaps more frequent is the presence of these altered features at birth. Congenital ear anomalies have been well studied particularly those affecting the external ear. (W.H.O, 2018)
Microtia-anotia, underdeveloped pinna, exists as a spectrum of features with innocuous effects on one end and very severe effects on the other. Capable of affecting one or both ears it is often reported in new-borns (Luquetti et al, 2011). Mild malformations are subject to non-surgical treatments such as otoplasty and ear moulding which takes advantage of soft infant ear cartilage prone to reshaping. This has been effective for prominent ear, Stahl`s ear, Lop ear, Cryptotia all relatively mild variants of the disease which most often are aesthetic hindrances but do not impair functionality. However, anotia is a more severe anomaly and results in aplasia of the ear leading to complete deafness of affected ear. Thus full reconstruction surgery involving either harvesting rib cartilages and carving it into ear construct (brent et al, 1999) or reconstruction of the ear using a polyethylene plastic implant(Reinisch et al, 2009), implemented in these cases.
Fig1.illustrates the different grades I,II, III and IV with increased severety. Auricle is relativelt normal in I but pinna is prominent. The pinna in II is smaller than normal. In grade III, the overall structure is minute and features such the tragus and concha are degenerated. Grade IV is the typical anotic ear with the entire ear and auditory canal missing.
Figure from: Alasti, F. and Van Camp, G. (2009). Genetics of microtia and associated syndromes. Journal of Medical Genetics, 46(6), pp.361-369.
Aetiology of Microtia has been investigated prominently. Numerous literatures have provided compelling evidence on environmental factors that promote hereditary risk in neonates, such as high exposure to retinoids, alcohol and even infamous drugs such as thalidomide of women during pregnancy. Focusing on the genetic aspect, the disorder cannot be attributed any single specific gene or pathway, however evidence of high concordance in monozygotic twins in comparison to dizygote, reports of single gene mutations leading to variant phenotypes and induced mutation of aforementioned genes needed in mouse (eg. Gsc and Prx1 mutants) have all resulted in some characteristical features of microtia. (Luquetti et al, 2011).
Similarly, to microtia many disorders of the middle and inner ear are multifactorial, and their aetiology have not been well described. For instance, Ménière’s disease (MD) an inner ear disease exhibiting tinnitus, vertigo and sensorineural hearing loss is thought to develop from gene imbalances that disrupt fluid homeostasis nevertheless, the pathophysiological mechanism remains unknown (Hietikko et al, 2013).
Inversely disorders like CHARGE, Lesch-Nylan and LAMM have defined genetic inputs. CHARGE, so named after it sign and symptoms is specific to the CHD7 gene and sporadic. Children with CHARGE beside the other disease phenotypes also have low-set underdeveloped ears. (NHS 2018) Lesch-Nylan on the other hand is brought about by deficient hypoxanthine–guanine phosphoribosyl transferase (HPRT) enzyme originating from deletions, missense and nonsense mutation in male exclusively expressed X chromosome.
Labyrinthine aplasia, microtia, and microdontia (LAMM syndrome) arise from pathogenic variant in autosomal recessive mutations of fibroblast growth factor 3 (FGF3) gene. Typically bilateral it affects both ears and teeth and subjects infants to motor delays and sensorineural deafness. Investigation with both patients with mutated FGf3 and animal knockouts suggested overarching expression and signalling of FGF3 during development to stimulate division and maturation of vestibular sensory organs, teeth and auricular orientation. (Riazuddin et al, 2011)
A) Grade I microtia with inverted ears. C) CT scan of bilateral petrous bone aplasia
B) Microdontia with unusual spacing
It is evident that there is a scarcity of information regarding mechanistic principles governing many developmental anomalies of the ear. Genome-wide studies have identified more than 2000 loci implicated in ear disorders enabling us map various genes to disease phenotype. (Hietikko et al, 2013) Moreover, advancement in genetic screening have facilitated diagnosis of variant disease. The complexity of the developmental process originating from a simple otic placode tissue into a highly specialised multi-functional organ, the network of numerous genes/proteins functioning at in a converging spatio-temporal manner to achieve this final state imparts a whole new appreciation for the biological process and inspire further research into areas that are still a mystery.
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