Neurol Genet 2019 Dec 29;5(6):370. Epub 2019 Oct 29.
Clinical Genetics Branch (S.B., N.G., B.P.A., S.A.S.) and Biostatistics Branch (A.F.B.), Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville; Office of the Clinical Director (M.P.), National Institute of Mental Health, National Institutes of Health, Bethesda, MD; Department of Neurology (A.G.), Children's National Medical Center, Washington, DC; and Department of Radiology and Imaging Sciences (E.H.B.), Clinical Center, National Institutes of Health, Bethesda, MD.
Objective: We systematically evaluated CNS manifestations in patients with inherited telomere biology disorders (TBDs) to better understand the clinical and biological consequences of germline aberrations in telomere biology.
Methods: Forty-four participants with TBDs (31 dyskeratosis congenita, 12 Hoyeraal-Hreidarsson syndrome, and 1 Revesz syndrome) enrolled in an institutional review board-approved longitudinal cohort study underwent detailed clinical assessments, brain MRI, and genetic testing. Lymphocyte telomere length Z-scores were calculated to adjust for age.
Results: In this cohort, 25/44 (57%) patients with a TBD had at least 1 structural brain abnormality or variant, most commonly cerebellar hypoplasia (39%). Twenty-one patients (48%) had neurodevelopmental disorder or psychomotor abnormality. Twelve had psychiatric diagnoses, including depression and/or anxiety disorders. Other findings such as hypomyelination, prominent cisterna magna, and cavum septum pellucidum were more frequent than in the general population ( < 0.001). Shorter lymphocyte telomere length was associated with an increased number of MRI findings ( = 0.02) and neurodevelopmental abnormalities ( < 0.001). Patients with autosomal recessive or X-linked TBDs had more neurologic findings than those with autosomal dominant disease.
Conclusions: Structural brain abnormalities and variants are common in TBDs, as are neurologic and psychiatric symptoms. The connection between neurodevelopment and telomere biology warrants future study.