WNT1-associated osteogenesis imperfecta with atrophic frontal lobes and arachnoid cysts


A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.

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We thank our patients and their families for their kind cooperation and for allowing us to use their medical and dental information for the benefit of others. We thank Dr. Mark Lubinky for his comments on vascular disruptions related to WNT1 effects on angiogenesis. This work was supported by The Center of Excellence in Medical Genetics Research, Chiang Mai University; the Thailand Research Fund; The Dental Association of Thailand; and The Faculty of Dentistry, Chiang Mai University.

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Correspondence to Piranit Nik Kantaputra.

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Kantaputra, P.N., Sirirungruangsarn, Y., Visrutaratna, P. et al. WNT1-associated osteogenesis imperfecta with atrophic frontal lobes and arachnoid cysts. J Hum Genet 64, 291–296 (2019) doi:10.1038/s10038-019-0565-9

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