A De Novo Missense Variant in DKC1 Leading to Hoyeraal-Hreidarsson Syndrome

Hoyeraal-Hreidarsson syndrome (HHS) represents the most severe form of dyskeratosis congenita (DC), a telomere biology disorder caused by pathogenic variants in genes involved in telomere maintenance. DKC1 encodes dyskerin, a component of the telomerase ribonucleoprotein complex. HHS typically presents with intrauterine growth retardation, microcephaly, cerebellar hypoplasia, developmental delay, bone marrow failure, and immunodeficiency. A 12-month-old boy was admitted with failure to thrive and acute respiratory failure. His history included prematurity, intrauterine growth restriction, microcephaly, cerebellar vermis hypoplasia, and global developmental delay. Examination revealed profound growth failure (<0.01st percentile) without nail dysplasia, oral leukoplakia, or reticular skin hyperpigmentation. He tested positive for rhinovirus/enterovirus and adenovirus, complicated by adenoviremia. Laboratory evaluation showed pancytopenia and hypogammaglobulinemia. Bone marrow biopsy was negative for malignancy. Vaccine titers to tetanus, diphtheria, and pneumococcus were non-protective. Lymphocyte phenotyping revealed mild T cell lymphopenia with severely reduced B and natural killer (NK) cells; naïve-to-memory T cell ratios were normal. T cell proliferation to PHA was mildly decreased, and the T cell receptor repertoire was polyclonal. He received intravenous immunoglobulin and prophylactic antimicrobial therapy with pentamidine, acyclovir, and fluconazole. Genetic testing identified a hemizygous DKC1 missense variant, c.229A>G (p.Asn77Asp), absent in his mother, confirming a de novo origin. Telomere length analysis demonstrated critically short telomeres (<1st percentile) across lymphocyte and granulocyte subsets. The patient recovered from acute illness with hematologic improvement and was discharged for outpatient bone marrow transplant (BMT) evaluation. Current concerns center on persistent feeding difficulties and poor weight gain. This case describes a novel de novo DKC1 missense variant associated with classical features of HHS. It underscores the early presentation of severe telomere biology disorders before the full mucocutaneous triad of DC is evident. Recognition of HHS in infancy is essential for anticipatory management of marrow failure and immunodeficiency and to guide the timing of hematopoietic stem cell transplantation.