Case Report: Fatal pneumonia as a manifestation of X-linked hypohidrotic ectodermal dysplasia: clinical phenotype and genotype characterization of a novel EDA frameshift variant in a four-generation pedigree.

BACKGROUND: Clinically, X-linked hypohidrotic ectodermal dysplasia is identified by its classic triad of hypohidrosis, hypotrichosis, and oligodontia. Nevertheless, the true threat to patient survival often stems from respiratory complications that extend beyond these obvious ectodermal traits. Mechanistically, ectodysplasin A (EDA) variants impair skin appendages and respiratory submucosal glands, undermining mucociliary clearance. This vulnerability, exacerbated by thermoregulatory instability from sweat gland dysfunction, establishes a pathological environment prone to severe infections, leaving infants at high risk for life-threatening fungal pneumonia and sepsis. Despite high early-life mortality, this potential lethality is frequently overlooked in pediatrics because glandular defects are nearly invisible on standard imaging.

CASE PRESENTATION: The proband was a male infant aged approximately 74 days. After birth, he repeatedly developed a fever and was hospitalized. Imaging confirmed pulmonary infection, and pathogen examination revealed Fusarium, Saccharomyces cerevisiae, and Achromobacter xylosoxidans. Given the patient's typical clinical features of ectodermal dysplasia, whole exome sequencing was performed with consent. Results showed a novel hemizygous frameshift variant, c.916delC (p.Gln306ArgfsTer2), in EDA. Subsequently, Sanger sequencing was performed on the direct relatives of the proband, and detailed clinical phenotype assessment and medical history collection were conducted for 17 members spanning four generations of the pedigree. Lineage analysis showed that transmission of this variant exhibited perfect cosegregation with the disease phenotype in the family, consistent with X-linked recessive inheritance. Unfortunately, the proband died at 2 years and 6 months from severe pneumonia.

CONCLUSION: This study identified a novel pathogenic EDA variant c.916delC, expanding the pathogenic variation spectrum of this gene. Through detailed family case reports and combined with imaging and pathogen evidence, we observe and suggest that underdeveloped respiratory mucosal glands and skin heat dissipation disorders may be an important pathological basis for fatal pneumonia and multiple infections in infants and young children with X-linked hypohidrotic ectodermal dysplasia. This discovery emphasizes the necessity of increasing clinical awareness of respiratory system involvement in such children, and suggests that adopting active temperature management, airway care, and reasonable anti-infection strategies in the early stages of diagnosis and treatment has important clinical reference value for improving the prognosis of children.