Novel pathogenic variants in FOXP3 in fetuses with echogenic bowel and skin desquamation identified by ultrasound

Abstract

Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare, X-linked recessive disease that affects regulatory T cells (Tregs) resulting in diarrhea, enteropathy, eczema, and insulin-dependent diabetes mellitus. IPEX syndrome is caused by pathogenic alterations in FOXP3 located at Xp11.23. FOXP3 encodes a transcription factor that interacts with several partners, including NFAT and NF-κB, and is necessary for the proper cellular differentiation of Tregs. Although variable, the vast majority of IPEX syndrome patients have onset of disease during infancy with severe enteropathy. Only five families with prenatal presentation of IPEX syndrome have been reported. Here, we present two additional prenatal onset cases with novel inherited frameshift pathogenic variants in FOXP3 that generate premature stop codons. Ultrasound findings in the first patient identified echogenic bowel, echogenic debris, scalp edema, and hydrops. In the second patient, ultrasound findings included polyhydramnios with echogenic debris, prominent fluid-filled loops of bowel, and echogenic bowel. These cases further broaden the phenotypic spectrum of IPEX syndrome by describing previously unappreciated prenatal ultrasound findings associated with the disease.

Keywords: FOXP3; IPEX; X-linked; prenatal.

Figure 1

Outpouching of skin detected by prenatal ultrasound in patient 1. A) 3D image of the face of the fetus at 23 weeks gestation. Several outpouches are identified. B) 2D sagittal image of the fetus at 26 weeks gestation. Skin peeling is identified by arrows. C) Infant pathology images show that the skin was partially sloughed with underlying erythema but the remaining epidermis appeared to be tight and shiny. D) Skin biopsy specimen (hematoxylin-eosin, 50X magnification). The epidermis is mostly absent or necrotic. The milia are represented by the pink cells, and a mixed inflammatory infiltrate in the dermis is present, including a few inflammatory giant cells. E) The pathogenic alteration in FOXP3 (c.749delA) was present in the proband in the hemizygous state. Targeted analysis of family members revealed that this alteration was maternally inherited and appears de novo in the maternal grandmother.

Figure 2

Prenatal ultrasounds reveal desquamation in patient 2. A) A sagittal profile view of the fetus at 32 weeks. Dense echogenic amniotic fluid is identified. A hyperechoic jet of particulate material is pushed from the fetal nose with fetal breathing motion. B) A transverse view of the fetal abdomen at 32 weeks demonstrates prominent loops of bowel with echogenic debris in the lumen. On real-time images, peristalsis with transit of particulate material within the bowel was observed. C) Fluid index measurement at 34 weeks shows the volume and hyperechoic nature of the amniotic fluid. This fetus had marked polyhydramnios in the third trimester.