Case Report: Hyper IgM Syndrome Identified by Whole Genome Sequencing in a Young Syrian Man Presenting With Atypical, Severe and Recurrent Mucosal Leishmaniasis

Abstract

A previously healthy 19-year-old Syrian man presented with atypical and severe mucosal leishmaniasis caused by Leishmania tropica. During a 2-year period, he had three severe relapses despite various treatment strategies, including liposomal amphotericin B and Miltefosine. Because of the unusual clinical presentation, potential underlying immunodeficiency was investigated. Normal T and NK cell counts were found. The B cell count was slightly elevated at 0.7 × 10⁹ cells/L (0.09 × 10⁹ to 0.57 × 10⁹ cells/L), but the proportions of memory and isotype switched memory B cells were severely diminished IgG levels were low, at 309 mg/dL (610-1490 mg/dL). The initial IgM and IgA levels were within normal range, but the IgA levels decreased to 57 mg/dL (70-430 mg/dL) during follow up. Common variable immunodeficiency (CVID) was initially suspected, because the immunological results of low IgG and IgA, low switched memory B cells, no profound T cell deficiency found and absence of secondary cause of hypogammaglobulinemia were compatible with this diagnosis (ESID 2019). However, the highly unusual and severe clinical presentation of L. tropica is not suggestive of B-cell deficiency or CVID. Eventually a pathogenic nonsense variant in the CD40 ligand gene [p.(Arg11^∗)] was identified by whole genome sequencing, thus enabling the diagnosis of X-linked hyper IgM syndrome. This case illustrates and supports the potential for the use of whole genome sequencing in accurate diagnosis of primary immunodeficiencies.

Keywords: diagnostic; genetics; hyper IgM syndrome; immunodeficiency; leishmaniasis; whole genome sequencing.

FIGURE 1

Clinical pictures from oropharyngoscopy and laryngoscopy from the third relapse. (A) Before treatment. The oral cavity and oropharyngeal isthmus show swelling, papilloma-like lesions, and eroded uvula. (B) Before treatment. Swelling of the epiglottis vestibular folds and aryepiglottic folds are seen. (C) One month after treatment. Near-normal findings.

FIGURE 2

Timeline of the clinical events and treatment strategies. LAB, liposomal amphotericin B; IVIG, intravenous immunoglobulin; SCIG, subcutaneous immunoglobulin.

FIGURE 3

Reduction in cell surface levels of CD40L in CD4pos T cells from the index patient compared with a control individual. (A) CD40L expression after PMA/ionomycin stimulation (light red/light green) on CD4pos T-cells and on unstimulated (dark red/dark green) CD4pos T-cells from the index patient (red colors) compared with healthy control (green colors). (B) Control of PMA/ionomycin stimulation monitored by CD69 upregulation on CD4pos T cells in the patient (light red) and a healthy control (light green). PE, phycoerythrin; PerCP, peridinin chlorophyll protein complex.