Giorgia Bucciol, Belgium
KU Leuven Laboratory of Inborn Errors of Immunity, department of Microbiology and ImmunologyPresenter of 2 Presentations
A NOVEL MUTATION IN BLM UNDERLYING BLOOM SYNDROME
Abstract
Background and Aims
Autosomal recessive mutations in BLM underlie Bloom syndrome, a prototypical chromosomal instability syndrome resulting in growth retardation, cancer and immunodeficiency. Other features include a typical face, various skin lesions, diabetes mellitus, and infertility. To date, more than 60 pathogenic variants in BLM have been identified. Despite the lack of definitive treatment, early diagnosis is crucial for optimal follow-up of patients, especially regarding their increased cancer susceptibility.
Methods
Whole exome sequencing (WES) was performed in a 14-year-old girl with high-pitched voice, long and narrow face, microcephaly, recurrent respiratory tract infections, hypogammaglobulinemia, short stature and early-onset type 2 diabetes mellitus. She didn’t have skin manifestations, including the prototypic sun-induced face rash.
Results
WES identified a novel private homozygous variant in BLM (p.L753X), causing a stop gain in the DNA helicase domain and predicted to be pathogenic by in silico prediction methods (CADD score 38, MSC 0.08). Functional validation of the variant is ongoing.
Conclusions
We report a novel mutation in BLM in a teenager with some phenotypic manifestations of Bloom syndrome, but lacking the usual skin manifestations.
LIFE-THREATENING H1N1 INFLUENZA INFECTION IN A PATIENT WITH LEAKY SCID ASSOCIATED WITH COMPOUND HETEROZYGOUS RAG1 MUTATION
Abstract
Background and Aims
Hypomorphic defects in RAG1 underlie leaky SCID, ranging from Omenn syndrome to atypical presentations of combined immunodeficiency. Hypomorphic RAG1 mutations also cause an atypical SCID characterized by chronic CMV infection, autoimmunity and expansion of TCRγδ T cells.
Methods
We report the clinical course and outcome of a child with hypomorphic RAG1 defects.
Results
A 16-month-old girl with failure to thrive presented with pneumonia and ARDS due to H1N1 Influenza. A month later, she developed CMV and Pneumocystis jirovecii pneumonia, hepatosplenomegaly, autoimmune hemolytic anemia (AHIA) and pancreatitis. Previously, she had suffered from bronchiolitis requiring O2-therapy and had developed vaccine-related disease after Rotavirus and VZV vaccine. Her work-up showed moderate T and B lymphopenia with normal NK cells, excess of memory T and of TCRγδ T cells (53% of T cells), hypergammaglobulinemia, absent thymus on CT scan, and restricted TCR-V-beta repertoire. Whole exome sequencing revealed compound heterozygous missense mutations in RAG1 (p.R410Q, p.H612R). She received haploidentical HSCT after myeloablative conditioning, resulting in full engraftment. Three months post-HSCT she experienced graft loss with CMV reactivation and recurrence of AHIA, not responding to unconditioned stem cell boost and a course of bortezomib. She then developed fulminant hemophagocytic lymphohistiocytosis which was sadly fatal despite high dose steroid therapy, a second haploidentical HSCT and extensive antiviral therapy.
Conclusions
We report a patient presenting with life-threatening flu, which led to the diagnosis of leaky SCID associated with AIHA, pancreatitis and HLH. This highlights the importance of timely diagnosis of SCID and the wide spectrum of presentation of hypomorphic RAG mutations.