This male infant was born at term and had uneventful perinatal and postnatal periods until about 4 months of age. His birth weight was 2.8 kg. Unfortunately, he was not screened for the presence of TREC at birth, as current national neonatal screening programs in the UAE does not include testing for primary immunodeficiencies. At birth, he received the routine BCG and hepatitis B vaccines. At 2 and 4 months of age, he received the routine DTaP (diphtheria, tetanus, acellular pertussis), HiB (haemophilus influenzae type b conjugate), and 13-valent pneumococcal conjugate, rotavirus (RV1,Rotarix ), and oral IP (inactivated polio) vaccines. At 41/2 months, he developed severe respiratory infection and refractory diarrhea, which required hospitalization and intravenous antibiotics. His blood and stool cultures were negative. The stool was positive for rotavirus. His chest radiographs showed bilateral infiltrations, and the thymus was not visible (Figure 1(a)). On admission, his neutrophil count was 10.5 x 109/L and lymphocyte count was 10.4 x 109/L, with a normal hemoglobin concentration and platelet count. His serum IgE and IgA were unmeasurable, IgG <0.5 g/L (normal, 3.5 to 12.2), and IgM = 0.14 (normal, 0.18 to 1.08). He was started on a regular intravenous gammaglobulin infusion. The results of his lymphocyte immunophenotyping were as follows: total lymphocyte count, 3,715/microL; CD3+, 96 cells/microL (normal: 2,530 to 4,510); CD4+, 82 cells/microL (normal: 1,640 to 2,980); CD8+, 1 cell/microL (normal: 780 to 1,500); CD19+, 3,000 cells/microL (normal: 1,160 to 2,420); and NK, 514 cells/microL.
Diagnostic (whole) exome sequencing revealed two pathogenic variants: homozygous NM_000732.4(CD3D):c.128G > A, p.Trp43* (VCV000643120.1; pathogenic; https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi?REQUEST=CCDS&DATA=CCDS8394) and hemizygous NM_001287344.1 (BTK):c.80G > A, p.Gly27Asp (novel). Pathologic variants of CD3D (CD3 antigen, delta subunit, autosomal recessive; MIM#186790) cause "immunodeficiency type 19" (MIM#615617). His CD3D variant creates a premature stop-gain, resulting in a loss-of-function due to absent protein product. Pathologic variants of BTK (Bruton agammaglobulinemia tyrosine kinase; MIM#300300), on the other hand, cause "agammaglobulinemia, X-linked 1 (MIM#300755) and "isolated growth hormone deficiency, type III, with agammaglobulinemia" (MIM#307200). His novel BTK variant had conflicting predictions of interpretation: MutationTaster: 0.810 (pathogenic), LoFtool: 0.953 (pathogenic), and CADD: 7.6 (benign).
The parents, second cousins, had four healthy boys and one healthy daughter. They also had a daughter who passed away at the age of 4 months of an undetermined disease. The mother had four miscarriages in the first trimester. In addition, she and six of her sisters had hypothyroidism; one sister also had autoimmune hepatitis.
Over the following six weeks, he continued to suffer from high-fever, dyspnea (requiring oxygen), maculopapular rash, severe oral thrush, poor feeding, severe diarrhea, failure-to-thrive, and E. coli urosepsis. On physical examination, he had moderate hepatomegaly, mild splenomegaly, and palpable left axillary lymph nodes; the largest measured about 2 cm in diameter. Neck, chest, and abdominal CT scans confirmed generalized lymphadenopathy, including his left axillary lymph nodes (Figure 1(b)). Excisional left axillary lymph node biopsy showed numerous acid-fast bacilli (AFB), consistent with tuberculous (TB) lymphadenitis (Figure 2). As expected, IGRA (Interferon Gamma Release Assay) was negative.
His BCG-related lymphadenitis and systemic TB infection were treated with rifampicin, isoniazid, ethambutol, and pyridoxine. He was maintained on regular immunoglobulin infusion, trimethoprim-sulfamethoxazole for Pneumocystis jiroveci prophylaxis, fluconazole for fungal prophylaxis, and broad-spectrum antibiotics. His brother was a 10/10 HLA match. Bone marrow transplantation was performed before 8 months of age.