Central Nervous System Abnormalities in Dyskeratosis Congenita and Fanconi Anemia: Correlation with Clinical Phenotype and Aplastic Anemia.
Authors: Giri Neelam , Butman John A. , Keil Meg F. , Stratakis Constantine A. , Alter Blanche P. 
Published: April 2020

Abstract
Fanconi anemia (FA) and dyskeratosis congenita (DC) are characterized by bone marrow failure (BMF) and an increased risk of acute myeloid leukemia, myelodysplastic syndrome and epithelial cancers. While cerebellar hypoplasia has been reported in some patients with DC, and small pituitary size and midline brain anomalies in FA, systematic central nervous system (CNS) magnetic resonance imaging (MRI) and correlation with clinical phenotype and aplastic anemia (AA) are lacking. To investigate these associations we evaluated patients with DC and FA enrolled in the National Cancer Institute’s Inherited Bone Marrow Failure Syndrome study. DC: 16 patients, ages 1–23 yrs (median 9 yrs), had CNS MRI as a part of their evaluation. All had peripheral cytopenias; 11 with severe AA were on treatment with androgens or transfusions. 13/16 had at least 2 of the 3 features of the diagnostic triad (dystrophic nails, oral leukoplakia and reticulated skin pigmentation). Among 10 patients with microcephaly, 8 had developmental delay, 7 truncal ataxia and 6 had a severe phenotype with the Hoyeraal-Hreidarsson variant. 7/16 patients had moderate to severe cerebellar hypoplasia. Patients with cerebellar hypoplasia were significantly younger than those without (median age 6 yrs vs. 14 yrs respectively; p=0.01). All patients with cerebellar hypoplasia had truncal ataxia, developmental delay and microcephaly, whereas amongst those without hypoplasia 3 had microcephaly (p=0.01), none had ataxia and one had developmental delay (p=0.001). There was no correlation between the severity of AA and cerebellar hypoplasia (p=0.5). FA: 11 patients, ages 6–42 yrs (median 22 yrs) who were not on current treatment and 13 age and sex-matched controls underwent CNS MRI. 9 patients had cytopenias; 5 with severe AA had received prior treatment (3 bone marrow transplant, 2 transfusions). Pituitary height, width and area in patients with FA were compared with the NIH controls and pituitary heights were compared with published normal values. The mean pituitary height in the FA patients tended to be lower then the NIH or published controls (p=0.06 and p=0.09 respectively). However, the mean pituitary width and the mean pituitary area were significantly lower in patients with FA compared with the NIH controls (p=0.003). In all, 7/11 patients had small pituitary glands; one of these had pituitary stalk interruption and another had an absent septum pellucidum. 7 patients had one or more endocrine abnormalities: 4 growth hormone deficiency, 6 hypothyroidism, 7 hypogenitalia/hypogonadism and 6 short stature. An equal proportion of patients with a small pituitary had short stature, hypothyroidism and growth hormone deficiency when compared with those who had a normal pituitary gland (p=1.0). There was no correlation between small pituitary size and age (p=0.2), any endocrine abnormality (p=0.5) or severe AA (p=0.6). CNS abnormalities were detected by MRI in ∼ 50% of patients with DC or FA. In an age-dependent analysis, the cumulative incidence of AA was the same in those with or without cerebellar hypoplasia in DC and in those with or without a small pituitary in FA. We currently recommend that all patients with DC and FA undergo MRI of the brain and pituitary to more completely characterize the spectrum of CNS anomalies, and to determine whether there is an association with hematologic severity in a larger data set.