He also had recurrent febrile illnesses associated with abdominal pain and mesenteric lymphadenitis that were diagnosed as typhoid fever on many occasions based on a very high antibody titer on Widal test (culture not done) (  Figure 1B  ). On each occasion, his condition improved remarkably after treatment. There was no history of other infections (pneumonia, otitis media, nor skin, bone, or joint infections). The patient's new TB condition started 6 weeks before referral to the Pediatric Tropical and Infectious Diseases unit. He appeared to have normal growth with a weight of 20 kg (10th) and a height of 118 cm (25th). He presented with high-grade fever, mainly at night with sweating, which improved with oral paracetamol. He also had severe abdominal pain disturbing his sleep and daily living activity, but there was no abdominal distension, diarrhea, constipation, or vomiting. The mother noted that the patient had significant weight loss and fatigability. Two weeks later, the patient developed a cough, which started dry and then became productive with thick mucoid sputum without blood. He did not suffer from chest pain or shortness of breath. In this occasion (January 2022), his diagnosis was disseminated TB (  Figure 1B  ). His family history was remarkable for the affection of four other members (  Figure 1A : III-1, III-5, III-11, IV-2, and IV-4) across two generations including his father (  Figure 1A : III-5), with a similar condition. The patient's father (  Figure 1A : III-5), who was 40 years old at the time of presentation of the proband, had recurrent TB adenitis since early childhood, which was diagnosed based on histopathology and acid-fast Bacillus (AFB) stain. Furthermore, the proband's parents reported that the father had three episodes of meningitis. One of these was cerebrospinal fluid (CSF)-confirmed tuberculous meningitis. In two occasions, failure of therapy was followed by the detection of Aspergillus fungal hyphae on the CSF. As a result of complicated TB and fungal meningitis, the father is now deaf, blind, and with shunted hydrocephalus. The patient's mother (III-6) aged 35 years is phenotypically healthy, is not blood related to the father, and is not from the same region. After taking a detailed family history, the mother mentioned a similar presentation of disseminated BCG infection leading to early infantile death in one of her own cousins (  Figure 1A : III-11). There is a positive family history of recurrent adenitis among members of the patient's paternal family including his paternal aunt (III-1) and paternal cousin (IV-2) (  Figure 1A  ).
To investigate the patient's abdominal complaints, an abdominal ultrasound scan was requested for the patient. This showed minimal intra-abdominal fluid and mesenteric and para-aortic lymph node adenitis, which was reported as highly suggestive of abdominal TB based on his previous history. The chest x-ray showed bilateral prominent hilar lymph nodes ( Figure 1C  ). The diagnosis of TB infection was further confirmed with PCRs using IS6110 and mtp40 primers on blood and sputum, respectively. Immunological investigation revealed elevated immunoglobulin G (IgG) for his age, 2,117 mg/dl (normal range: 380-1,400 mg/dl). IgG subclasses and specific antibody titers for protein and polysaccharide vaccines were not done, as they are unavailable in Sudan. The patient's IgM and IgE levels were normal at 69 mg/dl (normal range: 37-225 mg/dl) and 53 IU/ml (normal range up to 155 IU/ml), respectively. His IgA level was low, 19 mg/dl (normal range: 30-250 mg/dl), dihydrorhodamine reduction (DHR) test by flow cytometer showed normal oxidative burst, and the patient's complete blood count and lymphocyte subset are shown in  Tables 1  and  Table 2 , respectively.
Primary immunodeficiency genetic testing performed on the NextSeq Illumina platform revealed two pathogenic homozygous variants in IL12RB1 gene of our patient at Exon 9, c.913A>T (p. Lys305*). This IL12RB1 mutation is associated with autosomal recessive MSMD, which is reported by Altare et al.. This sequence change creates a premature translational stop signal (p.Lys305*) in the IL12RB1 gene, which is expected to result in an absent or disrupted protein product. Such loss-of-function mutations in IL12RB1 are pathogenic (PMID: 9603733, 12591909). The patient's variant was not present in population databases (gnomAD no frequency), but this premature translational stop signal was observed in individuals with clinical features of MSMD (PMID: 9603732; Invitae). ClinVar also contained an entry for this variant (Variation ID: 488832). The father's genotype showed the same homozygous pathogenic variants in IL12RB1 Exon 9, c.913A>T (p. Lys305*), and interestingly, the mother, who is not blood related to the father, is a carrier for the same mutation. The patient is now on anti-TB drugs and planned to continue treatment for 2 years and then for bone marrow transplant.