EDA – Ectodermal Dysplasia Syndrome

Ectodysplasin-A (EDA) is a tumor necrosis factor family ligand critical for the development of ectodermal appendages. Pathogenic variants in EDA disrupt signaling through its receptor EDAR and downstream NF-κB activation, leading to hypohidrotic ectodermal dysplasia (HED), the most common form of ectodermal dysplasia syndrome (MONDO:0019287).

Inheritance is X-linked recessive, with EDA mutations causing characteristic hypotrichosis, hypodontia and hypo/anhidrosis. Across >40 unrelated families, 44 probands harbor EDA variants with clear co-segregation ([PMID:20979233]), including two brothers with oligodontia and subtle ED signs ([PMID:26753551]) and de novo cases in isolated patients ([PMID:29184627]).

The EDA variant spectrum comprises missense, splice-site, frameshift and copy-number changes. A representative pathogenic change is c.896G>A (p.Gly299Asp) detected in a sporadic HED case ([PMID:26345974]). Recurrent alleles such as p.Arg289His and splice acceptor mutations underscore mutational hotspots.

Family studies demonstrate complete co-segregation of EDA alleles with disease in XLR pedigrees. Carrier females often exhibit mild hypodontia, supporting dosage sensitivity and confirming pathogenicity.

Functional assays reveal that missense mutations within the TNF homology domain impair trimerization and receptor binding ([PMID:11279189]), collagen domain deletions disturb multimer formation, and splice-site variants abrogate processing—all leading to deficient NF-κB signaling ([PMID:9736768]).

Limited conflicting evidence arises from twin cases negative for EDA mutations, indicating genetic heterogeneity and the need for broad-panel testing in ED phenotypes ([PMID:29184627]).

Integration of genetic and experimental data supports a Strong gene–disease association. EDA variant screening is recommended for diagnostic confirmation, family counseling, and patient stratification for emerging recombinant EDA therapies.

Key take-home: EDA mutation analysis is a robust and clinically actionable tool for diagnosing and managing ectodermal dysplasia syndrome.

References

• Human Mutation • 2011 • Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidotic ectodermal dysplasia cases. PMID:20979233
• Genetics and Molecular Research : GMR • 2015 • EDA mutation as a cause of hypohidrotic ectodermal dysplasia: a case report and review of the literature. PMID:26345974
• Journal of Orofacial Orthopedics • 2016 • Novel missense mutation in the EDA gene in a family affected by oligodontia. PMID:26753551
• Journal of Dental Research, Dental Clinics, Dental Prospects • 2017 • Medical sequencing of de novo ectodermal dysplasia in identical twins and evaluation of the potential eligibility for recombinant EDA therapy. PMID:29184627
• The Journal of Biological Chemistry • 2001 • Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A. PMID:11279189
• Human Molecular Genetics • 1998 • The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats. PMID:9736768

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