A Novel CDC42 Variant with Impaired Thymopoiesis, IL-7R Signaling, PAK1 Binding, and TCR Repertoire Diversity.

Genetic variants in cell division cycle 42 (CDC42) can manifest with dysmorphic features, autoinflammation, hemophagocytic lymphohistiocytosis, and thrombocytopenia, whereas defective thymopoiesis is a rare disease manifestation. We report a novel CDC42 missense variant (c.46A > G, p.Lys16Glu) resulting in infection and HPV-driven carcinogenesis in the mosaic mother and impaired thymopoiesis and profound T cell lymphopenia in the heterozygous daughter identified through newborn screening for SCID. We found that surface expression of IL-7Rα (CD127) was decreased, consistent with reduced IL-7-induced STAT5 phosphorylation and accelerated apoptotic T cell death. Consistent with the vital role of IL-7 in regulating thymopoiesis, both patients displayed reduced T cell receptor CDR3 repertoires. Moreover, the CDC42 variant prevented binding to the downstream effector, p21-activated kinase (PAK)1, suggesting this impaired interaction to underlie reduced IL-7Rα expression and signaling. Here, we provide the first report of severely compromised thymopoiesis and perturbed IL-7Rα signaling caused by a novel CDC42 variant and presenting with diverging clinical and immunological phenotypes in patients.

Short bi-iliac distance in prenatal Ullrich-Turner syndrome.

The purpose of the present study is to evaluate the bi-iliac distance and the caudo-cranial position of the iliac bones in Ullrich-Turner syndrome (UTS) fetuses compared to recently published standards for normal fetuses. Whole-body radiographs in antero-posterior projections of 24 UTS fetuses (crown-rump lengths, 106-220 mm) were included in the study. From each radiograph, two horizontal (outer and inner bi-iliac distances) and two vertical (caudo-cranial) positions compared to the vertebral column were measured to estimate the position of the iliac bones. The present investigation revealed that both the outer and inner bi-iliac distances were significantly shorter in UTS fetuses than in normal fetuses. We also found that for the inner bi-iliac distance, the growth rate in UTS fetuses was significantly lower than in normal fetuses. This finding suggests not only a lesser growth but also a different growth pattern compared to normal fetuses. Regarding the caudo-cranial position of the iliac bones compared to the lower vertebral column, there was no significant difference for the lower caudo-cranial position, but the upper caudo-cranial position was significantly lower in UTS fetuses than in normal fetuses. The bi-iliac distance and the iliac bone position have not previously been described in Ullrich-Turner syndrome fetuses.