Abnormal apoptosis causes colitis and enteritis in patients with Hoyeraal–Hreidarsson syndrome due to DKC1 mutations

Abstract

Background: Hoyeraal–Hreidarsson syndrome (HHS), the severe clinical variant of X-linked dyskeratosis congenita, is caused by germline mutations in telomere associated genes. HHS usually manifests within the first years of life and is characterized by progressive bone marrow failure, immunodeficiency, neurological features including microcephaly and developmental delay, as well as intrauterine growth retardation. The typical mucocutaneous manifestations are nail dysplasia, lacy skin pigmentation, and oral leukoplakia. Importantly, gastrointestinal involvement is reported in most patients with HHS, and may be the presenting feature. Given the spectrum of gastrointestinal diseases with a similar presentation, recognizing the unique gastrointestinal histopathology of HHS may facilitate earlier diagnosis and treatment. Methods: This case series highlights the gastrointestinal pathology findings of 2 patients with HHS caused by DKC1 gene mutations. Results: Gastrointestinal biopsies reveal loss of mucosal glands, regenerative glandular alterations and increased colonic epithelial cell apoptosis. Immunostaining of biopsies for cleaved caspase 3, a marker of cellular apoptosis, demonstrates abnormal nonapical and random locations of enterocyte exit which was further exacerbated by enteritis. Conclusion: Gastrointestinal involvement is usually the presenting feature of patients with HHS. This case series highlights the important role on gastrointestinal histopathology in facilitating a diagnosis of HHS. Statement of novelty: Detailed gastrointestinal biopsy images associated with HHS involving DKC1 mutations.