Case Report: Reactive Lymphohistiocytic Proliferation in Infant With a Novel Nonsense Variant of IL2RG Who Received BCG Vaccine

Abstract

We present here a male young infant with X-linked severe combined immunodeficiency (MIM#300400) due to the novel nonsense variant of IL2RG (interleukin 2 receptor, gamma; MIM#308380), NM_000206.2(IL2RG):c.820_823dup p.Ser275Asnfs^*29. He developed aggressive reactive lymphohistiocytic proliferation after receiving the live-attenuated Bacillus Calmette-Guérin (BCG) vaccine at birth. This report advocates for modifying the current practice of early use of BCG. The natural history of his disease also suggests considering IL2RG variants as a potential cause of "X-linked recessive Mendelian susceptibility to mycobacterial disease" (MSMD). His reactive lymphohistiocytic proliferation and massive hepatosplenomegaly simulated hemophagocytic lymphohistiocytosis (HLH, likely triggered by the BCG disease). This entity was masked by the absence of fever and markedly elevated inflammatory biomarkers. Thus, his findings stimulate discussion on the need to modify the diagnostic criteria of HLH, in order to accommodate conditions, such IL2RG variants that block systemic inflammation.

Keywords: BCG vaccine; IEI; IL2RG; Mendelian susceptibility to mycobacterial disease (MSMD); SCID; hemophagocytic lymphohistiocytosis (HLH); lymphohistiocytic proliferation; lymphoid proliferation.

Figure 1

The swelling near the right wrist with the inability to move the right little and ring figures are shown. The abdominal distension (massive hepatosplenomegaly), the BCG site and a subcutaneous nodule are also evident.

Figure 2

Radiographic images taken at about 3½ months of age. (A): Radiograph of the right forearm showing abnormal texture in the distal ulnar, with areas of bone destruction and resorption surrounded by soft tissue swelling. (B,C): MRI of the right forearm (with and without contrast) showing destructive bone lesion involving the ulnar with a large, enhancing soft tissue mass extending into the interosseous space, measuring 2.5 × 2.5 × 4.5 cm. The mass involves the diaphysis and distal metaphysis. There is periosteal reaction and edema in the surrounding soft tissue and subcutaneous fat. There is also abnormal signal and enhancement of the distal ulnar growth plate with displacement. (D,E): Chest radiograph and chest CT scan showing nodular lesions in both lungs. (F,G): Abdominal CT scan and ultrasound showing the right hepatic lobe exceeding the costal margin, measuring 8.6 cm craniocaudally. The spleen measures 7.0 cm in length and shows two focal hypodense lesions, the largest measuring 1.01 × 0.86 cm (arrowed).

Figure 3

Sections of routine stain from the soft tissue mass right distal ulna. (A) shows sheet of mononuclear cells of lymphocytes and histiocytes. (B) shows predominate lymphocytic infiltrate bone and skeletal muscle. (C) shows higher magnification of the right ulnar lesion routine stain section shows mononuclear cells predominantly of lymphocytes with scattered mitosis infiltrating skeletal muscle (skeletal muscle appears as eosinophilic striated tissue with peripheral nuclei at left side of the image). Most of the lymphocytes are B cell with CD20 positive immunohistochemical stain (D), mixed with few scattered T lymphocytes highlighted with CD3 immunohistochemical stain (E). Skin biopsy shows dermal inflammatory cells infiltrate, mainly of histiocytes with granulomatous inflammation (F).

Figure 4

A sequence alignment of the wild-type ILR2G and the variant ILR2G: p.Ser275Asnfs*29 proteins. The transmembrane region and the “Box 1 motif” regions of the wild-type protein are annotated along with the frameshifted sequence of the variant ILR2G. Amino acids are colored based on their polarity: blue - basic; red - acidic; green - polar; olive - hydrophobic.