This 5-month-old male infant was born at term to asymptomatic, non-consanguineous emirati parents who belonged to the same tribal descent. The pregnancy and delivery were uneventful. His birth weight was 2.75 kg. He had received the BCG vaccine in the upper left arm at birth (0.05 mL, intradermal injection; manufactured by Serum Institute of India Pvt. Ltd., India). He had a healthy 16-month-old sibling, who had an oozing discharge from the BCG vaccine site for 2 months; he was currently asymptomatic. Otherwise, the family history is negative for any type of IEI.
His growth and development were normal. He was never genuinely febrile during the entire course of this illness; his temperatures were always <= 37.2 C. At 31/2 months of age, he developed a tender swelling in the right lower forearm (Figure 1). Abdominal examination revealed massive hepatosplenomegaly. The skin examination was remarkable for a prominent BCG scar (Figure 1), and skin-colored soft nodules such as the one in the lateral chest cage (Figure 1). He had mild cough; but on examination, he had no shortness-of-breath and his breath sounds and oxygen saturation were normal.
His complete blood counts were remarkable for profound lymphopenia (mean +- SD lymphocyte count = 84 +- 55 per muL (median = 70; range = 20-210; n = 18). His serum IgA level was 0.08 g/L (normal, 0.1-0.83), IgG 1.94 g/L (normal, 2.27-13.8), IgM 0.16 g/L (normal, 0.10-1.45), and IgE 3.0 (normal, <= 15). Lymphocyte subset analysis was requested, but the test failed due to inadequate lymphocytes. His serum C-reactive protein (CRP) was 7.5 +- 3.5 mg/L (n = 8), erythrocyte sedimentation rate (ESR) 26 mm/hr, ferritin 87 +- 8 mug/L (n = 3), and triglyceride 1.54 +- 0.41 mmol/L (normal, 0.25-0.85). Urinalysis, coagulation profile, renal function, and hepatic function were normal. Blood cultures were negative. Bronchoalveolar lavage culture showed normal upper respiratory flora; the Grocott-Gomori's methenamine silver (GMS) stain for fungal elements was suspicious for Pneumocystis jiroveci, while the acid-fast bacillus (AFB) stain was negative.
Radiograph and magnetic resonance imaging (MRI) of the right forearm showed areas of bone destruction (resorption) in the distal ulnar, surrounded by a soft tissue mass (Figure 2). Chest radiograph and chest CT showed nodular lesions in the lungs (Figure 2). Ultrasound and computed tomography (CT) scan of the abdomen showed organomegaly with two focal hypodense splenic lesions (Figure 2).
Biopsies of the right forearm soft tissue mass and the ulnar bone lesion revealed "reactive lymphohistiocytic proliferation," as a part of infection such as the administered live vaccine BCG. Morphologically, the specimens showed infiltrating lymphohistiocytic proliferations by small-to-medium size mature/activated B cells [PD1 (programmed cell death protein 1) positive] of non-germinal center origin intermixed with normal histiocytes (Figures 3A-E). For both specimens, fluorescence in-situ hybridization (FISH) panel for B cell lymphoma [detects rearrangements involving IGH (immunoglobulin heavy chain; MIM#146910), C-MYC (MYC protooncogene, bHLH transcription factor; MIM#190080), BCL2 (B-cell lymphoma 2; MIM#603167), BCL6 (B-cell lymphoma 6; MIM#109565), CCND1 (cyclin D1; MIM#168461), and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation gene 1 paracaspase; MIM#604860)] was negative. Immunohistochemical stains of CD10, BCL6, CD30, C-MYC, CD34, TdT, myeloperoxidase, Cyclin D1, AE1/AE3 (bind to cytokeratins and serve as a marker of carcinomas), S100 proteins, CD99, myogenin, desmin, and MyoD1 were also negative. The Ki-67 stain was positive in about 50% of the cells. In-situ hybridization with EBV encoded mRNA was negative.
Biopsy of a skin nodule revealed dermal histiocytic infiltrate forming granuloma (Figure 3F).
Acid-fast bacillus (AFB) stain was negative for mycobacterium tuberculosis, and Grocott-Gomori's methenamine silver (GMS) stain was negative for fungal elements. Bone marrow biopsy showed cellular marrow (>90%) with trilineage hematopoiesis, adequate maturation, and T cell depletion.
Diagnostic exome sequencing revealed the hemizygous, pathogenic, novel non-sense variant of exon 6 of IL2RG (interleukin 2 receptor, gamma; MIM#308380): NM_ 000206.2(IL2RG):c.820_823dup, p.Ser275Asnfs*29. This novel variant causes "severe combined immunodeficiency, X-linked" (SCIDX1 or XSCID; MIM#300400). This IL2RG variant was not detected in the mother's blood sample. Thus, the variant was assumed de novo in the affected infant. Germline mosaicism, however, could not be excluded. It is also important to note that the only significant variant reported on his diagnostic exome sequencing test was that involving the IL2RG gene. In addition, there was no clinically relevant copy number variant by NGS-CNV (copy number variation detection by next generation sequencing read counts) analysis.
His management included intravenous immunoglobulin, sulfamethoxazole-trimethoprim, isoniazid, rifampin, vancomycin, piperacillin/tazobactam, azithromycin, and amphotericin B liposomal. He continued breastfeeding and occasionally required oxygen supplementation by nasal cannula. He had no human leukocyte antigen (HLA) identical match. Thus, he was transferred to a transplant center for parental donor haploidentical hematopoietic stem cell transplantation (HSCT).