X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED)

Implicated Genomic Region

EDA

The EDA gene (ectodysplasin A) is located on the X chromosome at Xq13.1. This gene provides the blueprint for producing the protein ectodysplasin-A, which belongs to the tumor necrosis factor (TNF) ligand superfamily.
There are multiple isoforms of this protein, but the most critical is EDA-A1. During early fetal development, EDA-A1 activates a receptor called EDAR (ectodysplasin A receptor), which acts like a switch to ensure the proper formation of ectodermal-derived tissues such as skin, hair, teeth, sweat glands, and mucous glands.
When the EDA gene is abnormal, the EDA-A1 protein is either not produced or is produced in a defective form that cannot function properly. This disrupts cell-to-cell signaling, particularly between epithelial and mesenchymal cells, leading to abnormal development of ectodermal-derived structures such as hair, teeth, and sweat glands. This process results in X-linked hypohidrotic ectodermal dysplasia (XLHED).

Disorder Name 

The official name of this disorder is X-linked hypohidrotic ectodermal dysplasia (XLHED). The term “ectodermal dysplasia” refers to developmental abnormalities of tissues derived from the ectoderm, such as skin and teeth.
In English, the disorder is also called Christ-Siemens-Touraine syndrome.
Because the disorder is caused by mutations in a gene located on the X chromosome, it occurs more frequently in males. Females, who have two X chromosomes, often have milder symptoms or may not show obvious symptoms at all.

Overview

This disorder occurs due to the congenital failure of multiple ectoderm-derived tissues to develop normally. The three classic symptoms are:

• Hypotrichosis: sparse, thin, and soft hair.
  
• Hypohidrosis or Anhidrosis: difficulty sweating, leading to impaired temperature regulation.
  
• Hypodontia or Oligodontia: missing teeth or fewer-than-normal teeth, often with abnormal tooth shape.
  

In addition to these core signs, other symptoms can include dry skin prone to eczema, dry nasal mucosa leading to chronic rhinitis or nasal congestion, and frequent respiratory infections.
Some affected individuals also exhibit distinct facial features, such as a prominent forehead, a flattened nasal bridge (saddle nose), everted lips, and sometimes hypoplastic or absent nipples.
Importantly, intellectual development and overall growth are typically normal, which can be reassuring for families.

Epidemiology

XLHED is a rare disorder, but it is the most common form among the various ectodermal dysplasias.
It is estimated to affect approximately 1 in 5,000 to 10,000 live births, with a clear predominance in males. This is because the EDA gene is located on the X chromosome, and boys, having only one X chromosome, will manifest symptoms if the gene carries a mutation.
For example, a Danish study reported that 2.8 cases per 100,000 live-born boys were affected. Data from Europe suggest a prevalence of 1 to 9 per million people.
While most cases are X-linked (XLHED), rare cases of autosomal dominant or autosomal recessive forms have been reported, caused by mutations in other genes such as EDAR, EDARADD, or WNT10A.
In females (carriers), due to the mechanism of X-chromosome inactivation, some cells express the normal EDA gene while others do not, leading to wide variability in clinical expression.

Etiology

XLHED is primarily caused by mutations in the EDA gene. These mutations result in either the absence of EDA-A1 protein production or the production of a dysfunctional protein.
Several mutation types have been identified, for example:

• Furin cleavage site mutations: prevent secretion of the EDA protein, affecting sweat gland and tooth development (e.g., p.Arg153Cys).
  
• TNF homology domain mutations: disrupt the binding of EDA to the EDAR receptor, thereby blocking signaling (e.g., p.Lys263Gln).
  

Regardless of the mutation type, the critical EDA → EDAR → EDARADD → NF-κB signaling pathway is disrupted, preventing proper “design and construction” of ectoderm-derived organs during early embryogenesis.
In rare cases, mutations in EDAR, EDARADD, or WNT10A can cause similar symptoms in autosomal forms, though with different inheritance patterns.

Symptoms

The three hallmark symptoms, often referred to as the “classic triad,” include:

• Hypotrichosis: hair that is sparse, soft, fine, and often light in color. Growth may be slow, and eyebrows and eyelashes can be thin or absent.
  
• Hypohidrosis or Anhidrosis: absent or reduced sweat glands, leading to impaired temperature regulation, particularly dangerous in infants, who may experience life-threatening hyperthermia in hot environments.
  
• Hypodontia or Oligodontia: reduced number of teeth, delayed eruption, and peg-shaped or conical teeth.
  

Other common features include:

• Dry skin, prone to eczema.
  
• Dry nasal and oral mucosa, leading to chronic rhinitis, nasal congestion, and frequent respiratory infections.
  
• Characteristic facial features: prominent forehead, saddle nose, everted lips.
  
• Sparse eyebrows and eyelashes.
  
• Hypoplastic or absent nipples.
  
• Dry eyes (keratoconjunctivitis sicca), missing meibomian glands, and recurrent eye irritation.
  

Increased susceptibility to infections due to immune irregularities.

Testing & Diagnosis

Diagnosis is typically based on clinical findings, but genetic testing provides confirmation.

Prenatal diagnosis: for families with a history of XLHED, ultrasound between 20 and 24 weeks gestation may detect tooth bud development; genetic testing is also an option.

Physical examination: assessment of hair quantity and quality, sweating ability, and number and shape of teeth.

Iodine-starch sweat test: iodine and starch are applied to the skin to visualize areas where sweat is produced.

Dental imaging: X-rays to evaluate missing teeth and tooth root abnormalities (such as taurodontism).

Carrier testing in females: may reveal mosaic sweat gland patterns.

Genetic testing: sequencing of the EDA gene and analysis of deletions/duplications; if negative, testing for EDAR, EDARADD, or WNT10A mutations.

Functional tests: sweat function testing, blood EDA protein levels (using AlphaLISA), and Western blotting.

Treatment & Management

Currently, there is no definitive cure for XLHED. Treatment focuses on supportive management:

• Temperature regulation: maintaining a cool environment, using fans and cooling devices, and ensuring hydration to avoid overheating.
  
• Dental care: early fitting of dentures (prosthetic teeth) to assist with chewing, speech, and appearance; orthodontics or dental implants may be considered in older children.
  
• Skin care: moisturizers to reduce dryness; anti-inflammatory treatments for eczema.
  
• Eye and nasal care: artificial tears for dry eyes; humidifiers and nasal care for dryness and inflammation.
  

Nutritional support: tailored feeding support for infants with difficulties in chewing or swallowing.

Experimental Therapy

Fc-EDA (also known as ER004) is an emerging experimental therapy. It is a fusion protein that combines EDA-A1 with an IgG1 antibody. The therapy is administered in utero during fetal development.
Treatment is typically given around 25–26 weeks of gestation, injecting Fc-EDA into the amniotic fluid, where it is absorbed by the fetus to restore the signaling pathway necessary for the development of sweat glands and teeth.
Early studies have shown that this treatment restores sweat gland function, allowing normal sweating and thermoregulation after birth, and has also shown positive effects on dental development.
However, it is important to note that postnatal administration is ineffective; the treatment must be given prenatally.
The EDELIFE clinical trial (ClinicalTrials.gov: NCT04980638) is ongoing and is expected to continue collecting safety and efficacy data through 2025.

Prognosis

With appropriate management and support, children with XLHED typically have normal intellectual and physical development. While daily life may require adjustments and additional support, most children attend school and participate in regular activities.
Infants, however, are at higher risk of serious complications due to impaired thermoregulation and recurrent infections, making early monitoring and medical interventions critical.
As children grow, dental abnormalities, dry skin, and differences in physical appearance may cause psychosocial challenges, highlighting the importance of psychological and social support.
Emerging therapies such as Fc-EDA offer promising potential for significantly improving sweat gland function and dental development in the future.

Helpful Terms

• Ectoderm: The outermost germ layer of the embryo that forms skin, hair, teeth, and glands.
  
• Hypohidrosis: Reduced sweating, causing difficulty in cooling the body.
  
• Anhidrosis: Complete absence of sweating, risking dangerous overheating.
  
• Hypotrichosis: Sparse, thin hair, sometimes including sparse eyebrows or eyelashes.
  
• Hypodontia: Congenital absence of some teeth, impacting chewing and speech.
  
• Oligodontia: Missing many teeth, requiring early dental interventions.
  
• Ectodysplasin A: A signaling protein critical for the development of ectodermal tissues.
  
• EDA gene: Gene encoding ectodysplasin A, located on the X chromosome.
  
• X-linked inheritance: A genetic pattern where males are typically more severely affected, and females often have mild or no symptoms.
  
• EDAR receptor: A receptor protein that binds to ectodysplasin A to trigger developmental signaling.
  
• NF-κB pathway: A critical signaling pathway regulating cell differentiation and growth.
  
• Sweat testing: Tests to assess sweat gland function, such as the iodine-starch test.
  
• Genetic testing: Sequencing and analysis to detect mutations or copy number variations.
  
• Prenatal diagnosis: Testing performed during pregnancy to detect the disorder in the fetus.
  
• X-chromosome inactivation: A mechanism in females where one X chromosome is randomly silenced, causing variable symptom severity.
  
• Fc-EDA: A therapeutic fusion protein in experimental trials for prenatal treatment of XLHED.
  
• Intra-amniotic injection: Delivery of medication into amniotic fluid during pregnancy.
  
• Supportive care: Symptom management aimed at improving quality of life.
  
• Dentures: Prosthetic teeth used to replace missing teeth.
  
• Dry eye: Condition with reduced tear production, causing irritation or discomfort.
  
• Saddle nose: Flattened nasal bridge often seen in affected individuals.
  
• Hypoplastic nipples: Underdeveloped or absent nipples.
  
• Psychosocial support: Assistance for patients and families in coping with emotional, psychological, or social challenges.

References

• Schneider, H., Schweikl, C., Faschingbauer, F., Hadj-Rabia, S., & Schneider, P. (2023). A Causal Treatment for X-Linked Hypohidrotic Ectodermal Dysplasia: Long-Term Results of Short-Term Perinatal Ectodysplasin A1 Replacement. International journal of molecular sciences, 24(8), 7155. https://doi.org/10.3390/ijms24087155
• Faria-Teixeira, M. C., Tordera, C., Salvado E Silva, F., Vaz-Carneiro, A., & Iglesias-Linares, A. (2024). Craniofacial syndromes and class III phenotype: common genotype fingerprints? A scoping review and meta-analysis. Pediatric research, 95(6), 1455–1475. https://doi.org/10.1038/s41390-023-02907-5
• Huttner K. (2014). Future developments in XLHED treatment approaches. American journal of medical genetics. Part A, 164A(10), 2433–2436. https://doi.org/10.1002/ajmg.a.36499
• Wright JT, Grange DK, Fete M. Hypohidrotic Ectodermal Dysplasia. 2003 Apr 28 [Updated 2025 Mar 20]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1112/
• Yang, R., Mei, Y., Jiang, Y., Li, H., Zhao, R., Sima, J., & Yao, Y. (2022). Ectodysplasin A (EDA) Signaling: From Skin Appendage to Multiple Diseases. International journal of molecular sciences, 23(16), 8911. https://doi.org/10.3390/ijms23168911
• Lee, Y. J., Kim, Y. J., Chae, W., Kim, S. H., & Kim, J. W. (2024). EDA Mutations Causing X-Linked Recessive Oligodontia with Variable Expression. Genes, 16(1), 12. https://doi.org/10.3390/genes16010012
• Alksere, B., Kornejeva, L., Grinfelde, I., Dzalbs, A., Enkure, D., Conka, U., Andersone, S., Blumberga, A., Nikitina-Zake, L., Kangare, L., Radovica-Spalvina, I., Vasiljeva, I., Gailite, L., Erenpreiss, J., & Fodina, V. (2021). A novel EDA variant causing X-linked hypohidrotic ectodermal dysplasia: Case report. Molecular genetics and metabolism reports, 29, 100796. https://doi.org/10.1016/j.ymgmr.2021.100796
• Wohlfart, S., Meiller, R., Hammersen, J. et al. Natural history of X-linked hypohidrotic ectodermal dysplasia: a 5-year follow-up study. Orphanet J Rare Dis 15, 7 (2020). https://doi.org/10.1186/s13023-019-1288-x
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