Early-onset primary antibody deficiency resembling common variable immunodeficiency challenges the diagnosis of Wiedeman-Steiner and Roifman syndromes

Abstract

Syndromic primary immunodeficiencies are rare genetic disorders that affect both the immune system and other organ systems. More often, the immune defect is not the major clinical problem and is sometimes only recognized after a diagnosis has been made based on extra-immunological abnormalities. Here, we report two sibling pairs with syndromic primary immunodeficiencies that exceptionally presented with a phenotype resembling early-onset common variable immunodeficiency, while extra-immunological characteristics were not apparent at that time. Additional features not typically associated with common variable immunodeficiency were diagnosed only later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed KMT2A-associated Wiedemann-Steiner syndrome in one sibling pair and their mother. In the other sibling pair, targeted testing of the known disease gene for Roifman syndrome (RNU4ATAC) provided a definite diagnosis. With this study, we underline the importance of an early-stage and thorough genetic assessment in paediatric patients with a common variable immunodeficiency phenotype, to establish a conclusive diagnosis and guide patient management. In addition, this study extends the mutational and immunophenotypical spectrum of Wiedemann-Steiner and Roifman syndromes and highlights potential directions for future pathophysiological research.

Figure 1

Family A with KMT2A-associated Wiedemann-Steiner syndrome (WSS). (a) Pedigree of family A. (b) Skipping of KMT2A exon 28. Gel electrophoresis of the KMT2A cDNA region containing exon 28 revealed a second shorter transcript in the three affected individuals. HC1 and HC2 represent two healthy controls; GAPDH was used as reference target. In-frame deletion of exon 28 was confirmed by cDNA sequencing; c.10755 and c.10835 indicate the start respectively stop position of exon 28. (c) KMT2A protein domains (adapted from ref. 9). KMT2A is cleaved in an N-terminal (KMT2A-N) and C-terminal (KMT2A-C) fragment, which form a non-covalently associated complex. Deletion of the amino acids encoded by exon 28 may disrupt the interaction site between the two fragments.

Figure 2

Family B with RNU4ATAC-associated Roifman syndrome (RS). (a) Pedigree of family B. (b) Representative retinal images of the RS patients. Panel I, composite retinal image of fundus of left eye (LE) of patient II:1: note inferior outer retinal atrophy with greyish hue and intraretinal pigment migration of the spicular type in inferior retina; mottled aspect of retinal pigment epithelium, more pronounced in inferotemporal area. Panel II, blue light autofluorescence image of LE of patient II:1 showing hyperautofluorescent delineation of inferior atrophic zone, as well as superior to optic disc, illustrating more widespread disease than can be seen on white light fundoscopic image only. Panel III, similar image of right eye (RE) of patient II:1 as in Panel II. Panel IV, fundus picture of detail of superonasal midperiphery of RE of patient II:2. Despite a normal full-field flash electroretinography, recent fundus examination at 14 years of age showed a mild mottling of pigment epithelium suggestive of early stage retinal dystrophy. (c) U4atac snRNA showing structural elements, conserved positions and location of variants associated with RS (adapted from ref. 8). The here-reported variant that has not been previously associated with RS is shown in red.

Figure 3

cTfh cells, BAFF-R expression and TACI expression in WSS and RS patients. (a) Family A patients with KMT2A-associated Wiedemann-Steiner syndrome (WSS). The twins (II:2, II:3) were 8 years old and the mother (I:2) was 43 years old at time of analysis. (b) Family B patients with RNU4ATAC-associated Roifman syndrome (RS). At time of analysis, the patients (II:1, II:2) were 14 and 11 years old, respectively. Flow cytometric immunophenotyping was performed on patients’ PBMCs in comparison with age-matched healthy controls (HC). T cells were gated as CD3⁺ and B cells as CD19⁺CD20⁺ in total PBMCs. Circulating follicular helper T (cTfh) cells were gated as CXCR5⁺CD45RO⁺ in CD4⁺ T cells. BAFF-R and TACI expression were measured on B cells. Relative mean fluorescence intensity (MFI) was calculated by dividing the MFI of the positive population by the MFI of the Fluorescence Minus One (FMO) population. Graphs of the HC groups represent mean ± standard deviation. BAFF-R: B cell activating factor-receptor, cTfh: circulating follicular helper T, expr: expression, TACI: transmembrane activator and calcium modulator and cyclophilin ligand interactor.