PMC6413717_01
Clinical and laboratory features in mother and daughter with Toxoplasmosis and APDS2. (A) Brain CT in the patient's daughter at 3 months of age, showing marked hydrocephalus with enlarged lateral and third ventricles, profound brain atrophy and basal ganglia calcifications. (B) Chromatogram demonstrating heterozygosity for the c.1425+1g > a at the PIK3R1 locus in the patient and her daughter. (C) Analysis of phospho-S6 in CD20+ cells from a healthy control, the mother, and the daughter at resting conditions (top) and upon in vitro activation with anti-IgM (bottom).
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F1
There were concerns for craniosyntosis, occasional episodes of staring and myoclonic jerks that led to a brain CT scan at 3 months of age that showed marked hydrocephalus, enlarged lateral and third ventricles, and extensive cerebral atrophy (Figure 1A). Whole exome gene sequencing with targeted analysis of 362 PID genes (Table 1) identified a heterozygous mutation at an essential donor splice site of PIK3R1 (NM_181523.2:c.1425+1g> a), which was confirmed with Sanger sequencing (Figure 1B). Functional studies on the patient's CD8+ and her daughter's CD20+ cells confirmed an increased S6 phosphorylation after IL-2 and anti-IgM stimulation (Figure 1C), which suggests hyperactivation of the PI3K-mTOR signaling pathway.
Lymph node histopathology in the mother with APDS2. (A) Hematoxylin & Eosin stained section show an ill-defined secondary follicle with "naked"germinal center; bottom left shows a cluster of monocytoid cells with pale cytoplasm (magnification, 10x). In the inlet, CMV positive cells are identified by immunohistochemistry (magnification, 40x). (B) Double immunohistochemisrty staining for CD4+ (in brown) and CD8+ (in red) T cells (magnification, 10x). (C) Immunohistochemistry staining for PD-1 highlights numerous T-follicular helper cells within the germinal centers (stronger expression) as well as in the interfollicular areas (magnification, 10X). (D-F) Immunohistochemical stains for CD20+
(D), IgM+
(E), and IgG+ cells (F) showing a marked increase of IgM positive plasma cells over IgG (magnification, 4x).
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F2
T follicular helper (TFH) cells, a striking predominance of IgM+ plasma cells (with few IgG+ plasma cells), and abnormal germinal centers (Figure 2). The proportion of CD4+ CXCR5+ CD45RA- CD25- TFH cells was also markedly increased in circulation in the patient as compared to two healthy controls (41.7 vs. 13.7% and 16.6%).