DIAS-LOGAN SYNDROME: DELINEATING A NEWLY RECOGNISED DISORDER OF TRANSCRIPTIONAL REGULATION

Purpose of study Dias-Logan syndrome is a recently described condition characterised by intellectual disability (ID) and persistence of fetal haemoglobin (HbF). It is caused by haploinsufficiency of BCL11A, on 2 p16.1, encoding a transcription factor belonging to the SWI/SNF chromatin remodelling complex. We describe 3 newly diagnosed patients, and discuss additional clinical features and pathogenesis. Methods used We reviewed the medical records of our patients with changes in BCL11A and those in the literature, and assessed the frequency of the main manifestations. Summary of results Our patients, aged 8–11 y, presented with hypotonia (3/3), ID (3/3), persistence of HbF (3/3), brain abnormalities (3/3), strabismus (2/3), and seizures (2/3). Two of them had de novo deletions involving BCL11A, and one had a de novo pathogenic variant in BCL11A. By review of the literature, we found 13 additional individuals with point mutations and 25 with 2 p15p16.1 microdeletions, aged 21 m–32 y. Including our patients, the most frequent manifestations were ID (100%), varying from mild to profound, persistent HbF (100%), distinctive facial features (95%), hypotonia (84%), microcephaly (63%), abnormal brain MRI (71%), consisting of cortical dysplasia, corpus callosum hypoplasia, or cerebellar hypoplasia, and growth delay (42%). Epilepsy was present in 15%: age at onset ranged 2 m–3 y, and seizures were drug-resistant in most cases. Interestingly, in half of the patients the facial gestalt resembled Alfa Thalassemia Intellectual Disability (ATRX), a condition caused by mutations in a gene encoding another SWI/SNF-like protein. Conclusions Our study expands the phenotype of BCL11A mutations to include early onset seizures and brain abnormalities, and the overlapping manifestations between Dias-Logan syndrome and ATRX syndrome suggest convergence on a common pathway of transcription regulation of haemoglobin genes.