Hoyeraal-Hreidarsson syndrome is a severe multisystem disorder that is characterized by bone-marrow failure, intrauterine growth retardation, microcephaly, immunodeficiency, and cerebellar atrophy. This rare disease shares clinical features with dyskeratosis congenita and, together, they are recognized as a group of disorders caused by telomere dysfunction. As the genetic background of dyskeratosis congenita or Hoyeraal-Hreidarsson syndrome has expanded rapidly, multiple causative genes and inheritance patterns pose a great challenge to their genetic diagnosis.
A 3-month-old boy was referred for head titubation and tremulous movements of the trunk. Multiple petechiae also developed on his face and trunk at the age of 5 months. Extensive evaluation, including brain magnetic resonance imaging, hematologic tests, and bone-marrow evaluation, revealed cerebellar atrophy and aplastic anemia. His elder brother exhibited a similar clinical presentation and died from sepsis after hematopoietic stem cell transplantation. Although skin pigmentation or nail dystrophy was not evident, Hoyeraal-Hreidarsson syndrome was suggested as a differential diagnosis. Instead of the conventional gene-specific approach with Sanger sequencing, we used whole-exome sequencing for the genetic diagnosis of this patient with possible Hoyeraal-Hreidarsson syndrome and successfully identified a missense mutation (c.146C>T, p.Thr49Me) in DKC1.
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This case suggests that whole-exome sequencing is particularly useful for the genetic diagnosis of extremely rare diseases with genetic heterogeneity, although there are many limitations, including cost and uneven or suboptimal coverage, to the application of this method as a routine genetic diagnosis.