Intrauterine IPEX.

Area of Science:

• Immunology
• Genetics
• Neonatology

Background:

• Immune dysregulation, poly-L-histidine, poly-L-lysine, and eotaxin (IPEX) syndrome can manifest prenatally.
• Intrauterine IPEX represents the earliest known human autoimmune diseases.
• Understanding intrauterine IPEX is crucial for early diagnosis and management of severe autoimmune conditions.

Purpose of the Study:

• To review clinical, histopathologic, and genetic findings of intrauterine IPEX.
• To investigate the spectrum of FOXP3 mutations and their phenotypic consequences.
• To explore genotype-phenotype correlations in intrauterine IPEX and related Tregopathies.

Main Methods:

• Retrospective review of 21 individuals with intrauterine IPEX from 11 families.
• Analysis of clinical presentations, histopathology, and FOXP3 genetic mutations.
• Comparative analysis with mouse models (scurfy) and other monogenic Tregopathies (IL2RB mutations).

Main Results:

• Recurrent fetal death (hydrops) was the most common presentation (13/21).
• Fetal and perinatal onset IPEX cases showed severe phenotypes, with no milder later-onset forms observed.
• Nine FOXP3 mutations were identified, with six causing protein truncation; however, no strict genotype-phenotype correlation was found.
• Mouse models and IL2RB mutation cases also showed variable severity.

Conclusions:

• Intrauterine IPEX represents a distinct subgroup of IPEX with the most severe clinical manifestations.
• While FOXP3 and IL2RB mutations are implicated, phenotype variability exists even with identical mutations.
• Further research is needed to elucidate the factors contributing to the divergent severity in intrauterine IPEX.