Repeated admissions with atypical infections lead to clinical suspicion of immunodeficiency and decreased CD3 and CD4, as well as impaired LTT results, suggested SCID. Microcephaly, developmental delay and FTT guided us to specific subtypes of SCID associated with these symptoms such as Cernunnos deficiency and radio-sensitive genetic mutations. Combination of microcephaly, recurrent infections with opportunistic and atypical microorganism while receiving prophylactic antibiotics, FTT, lymphopenia, decreased IgA, IgE and IgG levels, T− B − NK+ flow cytometry and impaired LTT in the patient were all clues to immunodeficiency. As implied in introduction, mutations in DCLRE1C gene, LIG4 gene, XRCC4 gene, PRKDC gene and NHEJ1 gene are associated with T− B− NK+ subgroup of SCID (1, 3, 4, 6). Mutation in NHEJ1 gene causes Cernunnos deficiency which results in pre-T cell receptor defect by impairment of VDJ recombination pathway. Microcephaly and growth retardation are common clinical features of DNA ligase IV and Cernunnos/XLF deficiency and are not reported in Artemis and PRKDC defects.(7) Recio et al. reported that not only mutations in Cernunnos gene show variable clinical features but also the immunological profile would vary (5). Mild to severe T-cell lymphopenia was para clinically investigated in patients with NHEJ1 mutations in which the CD4 + and/or CD8 + number would be impaired (5). The genetic mutation in our case was in splicing site of NHEJ third intron detected by WES. It is of great importance as it is a novel mutation, not previously reported, compatible with patient’s phenotype.
The most common clinical manifestations of Cernunnos deficiency are growth retardation, microcephaly, recurrent opportunistic infections, radio-sensitivity, dysmorphic faces (bird-like) and developmental delay that were all compatible with our case (2, 8). To the best of our knowledge, there is no reported evidence for the sensorineural hearing loss in patients with cernunnos immunodeficiency.
Concurrent lymphopenia, with decreased IgA, IgE, IgG levels and normal IgM level dedicated an impaired V(D)J recombination.(7) Normal IgM level is justifiable by antibody production activity of remnant B cells and Cernunnos might play a role in class switch recombination (CSR), in addition to V(D)J recombination in the literature.(9) Yazdani et al. reported that 14.8% of Cernunnos deficiency cases have normal or increased levels of some immunoglobulin subtypes.(8)
Another interesting finding that should be highlighted in the case is hypothyroidism that has been less reported in Cernunnos deficient patients (8).
This case is the second reported Iranian case of Cernunnos deficiency. The first case, reported by Yazdani et al. was a 3-year-old girl presented by BCGosis, oral thrush, recurrent infections, FTT, microcephaly and lymphopenia, with normal B cell count, IgA, and IgM concentration but decreased IgG levels (8).
There are not so many therapeutic strategies for Cernunnos deficiency and hematopoietic stem cell transplantation (HSCT) is the only present curative treatment with promising results and expected survival rates of 90%.(10) HSCT can be conducted by HLA identical related or unrelated donor.(10, 11) In the absence of proper HSCT most of Cernunnos deficiency cases only survive the first years of life and after then will expire due to septic shock.(8)
In case of concurrent autoimmune manifestations steroids are often useful for managing the patient’s signs and symptoms but definitive treatment is again HSCT.(12)
Ultimately in any patient with recurrent infections, birdlike face, microcephaly, FTT and hypogammaglobinemia SCIDs with radiosensitive genetic mutations such as Cernunnos-XLF and ligase IV mutations should be suspected strongly.