Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, with a wide range of clinical manifestations. It is caused by pathogenic variants in the CYP21A2 gene causing deficiency of steroid 21-hydroxylase enzyme. Knowledge of the variant spectrum, which varies significantly across populations and ethnic groups, is essential for developing effective screening strategies to improve the diagnosis of 21-hydroxylase deficiency, provide accurate prognosis and reproductive options. CYP21A2 gene was amplified by highly specific primer pairs. Sequencing, multiplex ligation dependent probe amplification (MLPA) and fragment analysis were employed to determine pathogenic variants (including point variants and large deletion duplications) in 315 unrelated Asian Indian patients with CAH. Variants were detected in 94.3
Mendelian susceptibility to mycobacterial disease (MSMD), caused by IL12RB1 or IL12B mutations, typically presents with intra-cellular infections such as BCG-adenitis or Salmonella. Rarely, patients with IL12RB1/IL12B defects can exhibit cutaneous manifestations such as Henoch-Schonlein purpura (HSP). This study aimed to evaluate such vasculitic manifestations in genetically confirmed cases with MSMD in India and review the literature for similar associations. We included nine patients with genetically proven MSMD presenting with features of HSP-like small vessel vasculitis from pediatric immunology clinics across three tertiary care centers in India. Clinical, laboratory, histopathological, and genetic data were recorded using a structured proforma. Skin biopsy findings, IgA levels, renal involvement, and infection history were analyzed. Additionally, a literature review was performed using PubMed, Scopus, and Google Scholar databases to identify similar reported cases. In our cohort, eight patients had IL12RB1 defect, and one had IL12B defect. All had maculopapular purpuric rash in lower limbs, predominantly in the anterior aspect of legs and posterior thighs resembling the rash of HSP. Leukocytoclastic vasculitis was observed in 77.7% patients (n = 7), with two out of five had IgA deposits in dermo-epidermal junction. Concurrent infections due to Salmonella sp. and Pandorea apista were documented in 44.4% (n = 4) and 22.2% (n = 2), respectively. Treatment focused on antimicrobial therapy led to clinical improvement. The HSP-like vasculitic rash usually occurred in setting of underlying bacterial infections in patients with particularly IL12RB1/IL12B defects. These skin lesions can also be considered as one of the potential clinical clues for underlying IL12RB/IL12B defects.
Rapid nucleic acid amplification tests (NAAT), such as Xpert MTB/Rif, Xpert Ultra, and Xpert MTB/XDR, are critical for diagnosing pediatric tuberculosis (TB) and detecting drug resistance. However, rifampicin indeterminate (RI) results, particularly in samples with trace Mycobacterium tuberculosis (MTB) load, pose a clinical challenge. Current guidelines do not recommend performing Xpert MTB/XDR in patients with prior trace calls on Xpert Ultra. The aim of this study is to analyze the drug-resistance results on Xpert MTB/Rif or Ultra and Xpert MTB/XDR, particularly the results of Xpert MTB/XDR in those patients with prior RI results on Xpert MTB/Rif or Ultra and in those with trace calls on Xpert Ultra.Table 1:Samples tested and the type of tuberculosis in the patients based on the results of Xpert MTB/Rif or Ultra and Xpert MTB/XDR assaysTable 2:Results of Xpert MTB/Rif or Ultra assay (rifampicin resistance, MTB load) and Xpert MTB/XDR panelNote: MTB- Mycobacterium tuberculosis, RR- Rifampicin resistant, RI- Rifampicin indeterminate, RS- Rifampicin sensitive, *Plain- refers to Xpert MTB/Rif, INH- Isoniazid, FQ- Fluoroquinolone, Amk- Amikacin, Kan- Kanamycin, Cap- Capreomycin, Eto- Ethionamide. A retrospective study was conducted at a pediatric TB clinic in Mumbai, India, including 89 children less than 18 years of age, diagnosed with TB, between October 2020 and August 2024. All patients were positive on Xpert MTB/Rif or Ultra and underwent Xpert MTB/XDR testing. Data on rifampicin resistance, MTB load, and resistance to other drugs were analyzed. Fifty-six(62.92%) patients were rifampicin resistant (RR), 12(13.5%) were RI, and 21(23.6%) were rifampicin sensitive(RS). Xpert MTB/XDR did not detect Mycobacetrium tuberculosis(MTB) in 4(7.14%) patients with RR, 4(33.3%) patients with RI, and 3(14.29%) patients with RS results. Of 12 RI results on Xpert MTB/Rif or Ultra, 3(25%) had very low MTB load and 9(75%) had trace MTB load. Of the 9 samples with trace results, Xpert MTB/XDR detected MTB in 5(55.56%) of which 2(40%) had pan-indeterminate drug-resistance results on Xpert MTB/XDR, 2(40%) were pan-sensitive on Xpert MTB/XDR, and 1(20%) was sensitive to isoniazid and fluoroquinolones, but resistant to second-line injectable drugs and ethionamide. Thus, 3 out of 9(33.33%) patients with trace calls had actionable results on Xpert MTB/XDR. Both, RI results on Xpert MTB/Rif or Ultra and non-detection of MTB on Xpert MTB/XDR, are associated with lower MTB-loads on Xpert MTB/Rif or Ultra. Xpert MTB/XDR is useful in clinical decision-making in one-third of the patients with prior RI trace calls on Xpert Ultra and may be useful in devising an antitubercular therapy regimen when a second sample may not be easily available for testing. All Authors: No reported disclosures
Fanconi Anemia (FA) is a rare autosomal recessive disorder; characterized by bone marrow failure, congenital malformation, and a markedly increased risk of cancers. Despite well characterized genetic defects in the FA/BRCA pathway, the mechanisms underlining variable disease severity and cancer susceptibility remains unknown. We studied the role of global DNA methylation and its implication in the cancer predisposition in FA. Chromosomal breakage analysis from peripheral blood cultures induced with Mitomycin C. Mutational analysis using NGS, MLPA and Sanger sequencing. Genome-wide DNA methylation profiling was performed using Illumina Infinium Methylation EPIC 850k Bead Chip Array and gene expression was validated by qPCR. Global DNA methylation profiling revealed a significant hyper-methylation pattern in FA patients as compared to the controls. Pathway enrichment and gene ontology analysis revealed the hyper-methylated genes were associated with the mTOR, WNT, cell adhesion and non-homologous end joining pathways, while hypo-methylated genes were enriched in NF-kb, MAPK, Calcium and JAK-STAT signalling pathways. Validation of top candidate genes showed significant downregulation of FAM65B, NKAPL, ITGAM, CDIP1 and CDKN1b genes which are involved in tumour suppression, immune regulation and cell-cycle control. Protein-Protein interaction analysis demonstrated that these genes are indirectly linked through the p53 and TNF- α signalling axes, contributing to a pro-inflammatory microenvironment that may promotes the emergence of pre-leukemic clones in FA. These results suggest that aberrant DNA methylation may play a role in cancer predisposition in FA by silencing key regulatory genes and may represent as promising candidates for prediction of cancer progression.
Abstract Background Extra-pulmonary tuberculosis presenting as a gluteal abscess is uncommon in children and poses diagnostic and therapeutic challenges. The emergence of drug-resistant tuberculosis further complicates management, leading to recurrent abscesses and bone involvement such as sacral osteomyelitis. Case Presentation A 16-year-old female presented with a two-month history of painful swelling over the left gluteal region and difficulty in walking, without fever, trauma, or TB contact. She had weight loss and poor appetite. Examination revealed a firm, tender swelling with dilated veins. Ultrasonography showed a large multiloculated collection, and MRI of the pelvis revealed a thick-walled abscess extending into the presacral region with sacral nerve root enhancement. Aspiration yielded 300 ml of pus, and the Xpert/Rif assay detected Mycobacterium tuberculosis with rifampicin resistance; subsequent testing confirmed INH and fluoroquinolone resistance, consistent with Pre-XDR-TB. The patient was initiated on a second-line antitubercular regimen including bedaquiline, linezolid, clofazimine, and cycloserine. Despite initial improvement, she developed recurrent abscesses requiring multiple drainage procedures. An MRI of the spine later showed sacral osteomyelitis with presacral and epidural extension. Ethionamide and Delamanid were sequentially added, leading to gradual clinical improvement with continued follow-up. Discussion This case illustrates the diagnostic complexity and therapeutic difficulty of pre-XDR-tubercular abscess with sacral osteomyelitis in an adolescent. Conclusion Early imaging, microbiological confirmation, individualized multidrug therapy, and vigilant monitoring are crucial for favorable outcomes in recurrent extrapulmonary tuberculosis. Learning points
