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Intrauterine IPEX.

Magda Carneiro-Sampaio1, Carlos Alberto Moreira-Filho1, Silvia Yumi Bando1

  • 1Laboratory of Medical Investigation (LIM-36, HCFMUSP), Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

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|December 17, 2020
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Summary

Intrauterine IPEX, an early autoimmune disease, often causes fetal death and severe neonatal complications. Genetic mutations in FOXP3 and IL2RB are implicated, but strict genotype-phenotype correlations remain elusive.

Keywords:
IL2RBIPEXIPEX-like syndromesfetal ultrasonographyimmune fetal hydropsintrauterine fetal deathsneonatal-onset autoimmune diabetesrecurrent male miscarriages

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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.