Intrauterine IPEX

Abstract

IPEX is one of the few Inborn Errors of Immunity that may manifest in the fetal period, and its intrauterine forms certainly represent the earliest human autoimmune diseases. Here, we review the clinical, histopathologic, and genetic findings from 21 individuals in 11 unrelated families, with nine different mutations, described as cases of intrauterine IPEX. Recurrent male fetal death (multigenerational in five families) due to hydrops in the midsemester of pregnancy was the commonest presentation (13/21). Noteworthy, in the affected families, there were only fetal- or perinatal-onset cases, with no affected individuals presenting milder forms with later-life manifestation. Most alive births were preterm (5/6). Skin desquamation and intrauterine growth restriction were observed in part of the cases. Fetal ultrasonography showed hyperechoic bowel or dilated bowel loops in the five cases with available imaging data. Histopathology showed multi-visceral infiltrates with T lymphocytes and other cells, including eosinophils, the pancreas being affected in most of the cases (11/21) and as early as at 18 weeks of gestational age. Regarding the nine FOXP3 mutations found in these cases, six determine protein truncation and three predictably impair protein function. Having found distinct presentations for the same FOXP3 mutation in different families, we resorted to the mouse system and showed that the scurfy mutation also shows divergent severity of phenotype and age of death in C57BL/6 and BALB/c backgrounds. We also reviewed age-of-onset data from other monogenic Tregopathies leading to IPEX-like phenotypes. In monogenic IPEX-like syndromes, the intrauterine onset was only observed in two kindreds with IL2RB mutations, with two stillbirths and two premature neonates who did not survive. In conclusion, intrauterine IPEX cases seem to constitute a particular IPEX subgroup, certainly with the most severe clinical presentation, although no strict mutation-phenotype correlations could be drawn for these cases.

Keywords: IL2RB; IPEX; IPEX-like syndromes; fetal ultrasonography; immune fetal hydrops; intrauterine fetal deaths; neonatal-onset autoimmune diabetes; recurrent male miscarriages.

Figure 1

Clinical, imaging, and molecular findings in 21 fetuses or neonates with intrauterine IPEX from 11 unrelated families. FOXP3 mutation site, protein alteration, and the number of the cases were indicated below the timelines. US-ultrasonography; E-exon; Triangle-miscarriages; †-death.

Figure 2

FOXP3 gene structure showing the regulatory regions, the repressor domain, the zinc-finger domain, the leucine-zipper domain, the LZ-FHK loop, and the forkhead domain. The regulatory regions that are target sites for DNA methylation are indicated by blue and green arrows; and for histone modifications by green arrows. The exon localization of the mutations identified in intrauterine IPEX fetuses or neonates from 11 families is depicted. Annotations refer to coding sequence and protein alteration positions; family ID appears between parenthesis.

Figure 3

Work-flow diagram for the prenatal identification of intrauterine-onset IPEX. The size of the letters in the ellipse of the ultrasound observation is proportional to the number of the affected cases.