A Case of Dyskeratosis Congenita: A Unifying Diagnosis for a Patient with Agammaglobulinemia

Abstract

IntroductionTelomeres are the nucleotide repeat-protein complexes that cap DNA to prevent its degradation. Telomere length decreases with each cell cycle until a critical point is reached and senescence is triggered. High mitotically active cells utilize the protein telomerase to maintain a constant telomere length for continuous cellular division. Dyskeratosis congenita (DC) is a disease resulting from pathologic mutation in genes regulating this process. One such gene is poly(A)-specific ribonuclease (PARN) which stabilizes telomerase. DC can result in severe complications involving the brain, lungs, liver, intestines, skin and bone marrow (BM). BM failure results in combined immunodeficiency by age 30 and is the primary cause of mortality.Case Description: A 36-year-old male with hypogammaglobulinemia, seizure disorder, avascular necrosis of the hip, and inflammatory bowel disorder presented with hematochezia and dyspnea. His immunodeficiency was diagnosed at age 10. He had multiple prior hospitalizations for pneumonia, sinusitis, and meningitis. Exam was notable for thrush and digit clubbing. His labs showed normal WBC, low lymphocyte count, and absent immunoglobulins. His CD19+ B-cells were non-detectable, while CD4+T cells and CD16+/CD56+ NK cells were low. BM biopsy showed absent CD20+ B cells. CT head showed cerebral atrophy. He was found to be CMV/HSV positive on endoscopic biopsy. Invitae primary immunodeficiency panel showed two variants in the PARN gene, Gain (Exons 19–21) [likely pathogenic] and Gain (Exons 1–18) [uncertain significance]. Telomere length, performed by Repeat Diagnostics Inc., was at the first percentile, which in the context of multiple organ defects and immunodeficiency confirmed a diagnosis of DC. His condition eventually deteriorated, and he died of multifocal Aspergillus and Candida pneumonia. His siblings and children were referred to genetics. DiscussionThe diagnosis of DC is often a diagnosis of childhood/adolescence. This case describes a patient with poor follow up presenting to the hospital with infection, found to have agammaglobulinemia and the terminal features of DC. This case demonstrates the utility of immunology presence in the inpatient setting, the benefits of inpatient genetic testing, and the importance of noting the difference between hypogammaglobinemia and agammaglobulinemia for infectious implications as well as diagnostic purposes.