Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT)

Abstract

Background: Nijmegen breakage syndrome (NBS) is a combined primary immunodeficiency with DNA repair defect, microcephaly, and other phenotypical features. It predominantly occurs in Slavic populations that have a high frequency of carriers with the causative NBN gene c.657_661del5 mutation. Due to the rarity of the disease in the rest of the world, studies of NBS patients are few. Here, we report a prospective study of a cohort of Russian NBS patients.

Methods: 35 Russian NBS patients of ages 1-19 years, referred to our Center between years 2012 and 2016, were prospectively studied.

Results: Despite the fact that in 80% of the patients microcephaly was diagnosed at birth or shortly thereafter, the average delay of NBS diagnosis was 6.5 years. Though 80% of the patients had laboratory signs of immunodeficiency, only 51% of the patients experienced significant infections. Autoimmune complications including interstitial lymphocytic lung disease and skin granulomas were noted in 34%, malignancies-in 57% of the patients. T-cell excision circle (TREC)/kappa-deleting recombination excision circle (KREC) levels were low in the majority of patients studied. Lower KREC levels correlated with autoimmune and oncological complications. Fifteen patients underwent hematopoietic stem cell transplantation (HSCT), 10 of them were alive and well, with good graft function. Three patients in the HSCT group and five non-transplanted patients died; tumor progression being the main cause of death. The probability of the overall survival since NBS diagnosis was 0.76 in the HSCT group and 0.3 in the non-transplanted group.

Conclusion: Based on our findings of low TRECs in most NBS patients, independent of their age, TREC detection can be potentially useful for detection of NBS patients during neonatal screening. KREC concentration can be used as a prognostic marker of disease severity. HSCT is a viable treatment option in NBS and should be especially considered in patients with low KREC numbers early on, before development of life-threatening complications.

Keywords: Nijmegen breakage syndrome; T-cell excision circle; granuloma; hematopoietic stem cell transplantation; kappa-deleting recombination excision circle; malignancy.

Figure 1

Macroscopic and microscopic images of granulomatous lesion in a boy with Nijmegen Breakage Syndrome: (A) at referral, after multiple courses of antibiotics and topical steroids, (B) after conditioning for hematopoietic stem cell transplantation, (C) skin histology demonstrating perivascular and diffuse, mixed-cell infiltrate in superficial and deep dermis. H&E stain, 40× magnification, (D) skin histology demonstrating palisaded inflammatory infiltrates consisting of histocytes, lymphocytes, and neutrophils, associated with basophilic alterations of collagen. H&E stain, 400× magnification.

Figure 2

T-cell excision circle (TREC) and kappa-deleting recombination excision circle (KREC) levels in various groups of Nijmegen Breakage Syndrome (NBS) patients. (A,B) TREC and KREC levels in NBS patients with and without infection. (C,D) TREC and KREC levels in NBS patients with and without autoimmune complications. (E,F) TREC and KREC levels in NBS patients with and without malignancies. (G,H) Age-dependent distribution of TREC and KREC levels in NBS patients. Asterisk indicates statistically significant difference between the groups. TREC/KREC levels are expressed per 10⁵ cells. Note logarithmical scale of the graphs.

Figure 3

The probability of the overall survival since Nijmegen breakage syndrome (NBS) diagnosis in 15 patients who underwent hematopoietic stem cell transplantation (HSCT) and in 20 non-transplanted patients (expressed as percentage ± SD). Probability of overall survival was estimated by the Kaplan-Meier product limit and were expressed as percentage ± standard deviation. The two-sided log-rank test was used for comparisons.