Hypohidrotic ectodermal dysplasia: clinical and molecular review

Reyes-Reali, Julia; Mendoza-Ramos, María Isabel; Garrido-Guerrero, Efraín; Méndez-Catalá, Claudia Fabiola; Méndez-Cruz, Adolfo René; Pozo-Molina, Glustein

doi:10.1111/ijd.14048

Cited by 73 publications

(69 citation statements)

References 42 publications

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“…Ectodermal dysplasias (ED) are a family of disorders characterized by aplasia or dysplasia of two or more ectoderm‐derived structures such as hair, teeth, nails and sweat glands. Hypohidrotic and anihidrotic ED, the most common forms of ED are characterized by the triad of hypotrichosis, hypodontia/oligodontia, abnormally shaped teeth and reduced ability to sweat (hypohidrosis) . Hypohidrotic ED is genetically heterogeneous.…”

Section: Introductionmentioning

confidence: 99%

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LEF1 haploinsufficiency causes ectodermal dysplasia

et al. 2020

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Ectodermal dysplasias are a family of genodermatoses commonly associated with variants in the ectodysplasin/NF‐κB or the Wnt/β‐catenin pathways. Both pathways are involved in signal transduction from ectoderm to mesenchyme during the development of ectoderm‐derived structures. Wnt/β‐catenin pathway requires the lymphoid enhancer‐binding factor 1 (LEF1), a nuclear mediator, to activate target gene expression. In mice, targeted inactivation of the LEF1 gene results in a complete block of development of multiple ectodermal appendages. We report two unrelated patients with 4q25 de novo deletion encompassing LEF1, associated with severe oligodontia of primary and permanent dentition, hypotrichosis and hypohidrosis compatible with hypohidrotic ectodermal dysplasia. Taurodontism and a particular alveolar bone defect were also observed in both patients. So far, no pathogenic variants or variations involving the LEF1 gene have been reported in human. We provide further evidence for LEF1 haploinsufficiency role in ectodermal dysplasia and delineate its clinical phenotype.

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Section: Introductionmentioning

confidence: 99%

“…When activated, the IKK complex releases the transcriptional activator NF‐κB causing upregulation of the NF‐κB signaling pathway . Variants in EDA cause X‐linked ED and variants in EDAR or EDARADD cause both autosomal recessive (AR) and autosomal dominant (AD) forms …”

Section: Introductionmentioning

confidence: 99%

LEF1 haploinsufficiency causes ectodermal dysplasia

et al. 2020

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“…It is likely that dental caries is caused by enamel defects or salivary gland malfunction. Numerous clinical studies have previously described the possible relationship between enamel defects and HED (AlNuaimi & Mansoor, 2019; Ambarkova, Jovanovska, Bajraktarova, Batra, & Popovski, 2017; Reyes‐Reali et al., 2018; Rojas & da Silva, 2015). An in vitro study using rat dental epithelial stem cells indicated that NF‐κB is involved in regulating the expression of amelogenesis‐related proteins (Liang et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

Overactivation of the NF‐κB pathway impairs molar enamel formation

et al. 2020

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Objective Hypohidrotic ectodermal dysplasia (HED) is a hereditary disorder characterized by abnormal structures and functions of the ectoderm‐derived organs, including teeth. HED patients exhibit a variety of dental symptoms, such as hypodontia. Although disruption of the EDA/EDAR/EDARADD/NF‐κB pathway is known to be responsible for HED, it remains unclear whether this pathway is involved in the process of enamel formation. Experimental subjects and methods To address this question, we examined the mice overexpressing Ikkβ (an essential component required for the activation of NF‐κB pathway) under the keratin 5 promoter (K5‐Ikkβ). Results Upregulation of the NF‐κB pathway was confirmed in the ameloblasts of K5‐Ikkβ mice. Premature abrasion was observed in the molars of K5‐Ikkβ mice, which was accompanied by less mineralized enamel. However, no significant changes were observed in the enamel thickness and the pattern of enamel rods in K5‐Ikkβ mice. Klk4 expression was significantly upregulated in the ameloblasts of K5‐Ikkβ mice at the maturation stage, and the expression of its substrate, amelogenin, was remarkably reduced. This suggests that abnormal enamel observed in K5‐Ikkβ mice was likely due to the compromised degradation of enamel protein at the maturation stage. Conclusion Therefore, we could conclude that the overactivation of the NF‐κB pathway impairs the process of amelogenesis.

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“…The ectodysplasin-A (Eda) pathway is known to be involved in the formation of several ectodermal organs, including hair and mammary glands (Mikkola, 2008), but has not been extensively studied in the LG context (Pispa et al, 2003). Eda loss-of-function (Eda −/− ) mutation in mammals, which leads to X-linked hypohidrotic ectodermal dysplasia (XLHED, MIM 305100) in humans (Bayés et al, 1998;Headon et al, 2001;Kowalczyk et al, 2011;Srivastava et al, 1997), is characterized by severe symptoms, including hair, tooth, sweat gland and salivary gland hypoplasia (for reviews, see Lefebvre and Mikkola, 2014;Reyes-Reali et al, 2018). Moreover, LG defects in XLHED patients lead to dry eye diseases (Dietz et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

et al. 2019

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A lack of ectodysplasin-A (Eda) signaling leads to dry eye symptoms, which have so far only been associated with altered Meibomian glands. Here, we used loss-of-function (Eda −/−) mutant mice to unravel the impact of Eda signaling on lacrimal gland formation, maturation and subsequent physiological function. Our study demonstrates that Eda activity is dispensable during lacrimal gland embryonic development. However, using a transcriptomic approach, we show that the Eda pathway is necessary for proper cell terminal differentiation in lacrimal gland epithelium and correlated with modified expression of secreted factors commonly found in the tear film. Finally, we discovered that lacrimal glands present a bilateral reduction of Eda signaling activity in response to unilateral corneal injury. This observation hints towards a role for the Eda pathway in controlling the switch from basal to reflex tears, to support corneal wound healing. Collectively, our data suggest a crucial implication of Eda signaling in the cornea-lacrimal gland feedback loop, both in physiological and pathophysiological conditions. Our findings demonstrate that Eda downstream targets could help alleviate dry eye symptoms.

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Hypohidrotic ectodermal dysplasia: clinical and molecular review

Cited by 73 publications

References 42 publications

LEF1 haploinsufficiency causes ectodermal dysplasia

LEF1 haploinsufficiency causes ectodermal dysplasia

Overactivation of the NF‐κB pathway impairs molar enamel formation

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

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