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

Abstract

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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References

  1. 1.

    Keupp K, Beleggia F, Kayserili H, Barnes AM, Steiner M, Semler O, et al. Am J Hum Genet. 2013;92:565–74.

  2. 2.

    Laine CM, Joeng KS, Campeau PM, Kiviranta R, Tarkkonen K, Grover M, et al. WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Eng J Med. 2013;368:1809–16.

  3. 3.

    Pyott SM, Tran TT, Leistritz DF, Pepin MG, Mendelsohn NJ, Temme RT, et al. WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta. Am J Hum Genet. 2013;92:590–7.

  4. 4.

    Daneman R, Agalliu D, Zhou L, Kuhnert F, Kuo CJ, Barres BA. Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc Natl Acad Sci USA. 2009;2009:641–6.

  5. 5.

    Aldinger KA, Mendelsohn NJ, Chung BH, Zhang W, Cohn DH, Fernandez B, et al. Variable brain phenotype primarily affects the brainstem and cerebellum in patients with osteogenesis imperfecta caused by recessive WNT1 mutations. J Med Genet. 2016;53:427–30.

  6. 6.

    Navarro-Garberi M, Bueno C, Martinez S. Wnt1 signal determines the patterning of the diencephalic dorso-ventral axis. Brain Struct Funct. 2016;221:3693–708.

  7. 7.

    Meng H, Li F, Hu R, Yuan Y, Gong G, Hu S, et al. Deferoxamine all eviates chronic hydrocephalus after intraventricular hemorrhage through iron chelation and Wnt1/Wnt3a inhibition. Brain Res. 2015;1602:44–52.

  8. 8.

    Kantaputra PN, Kapoor S, Verma P, Intachai W, Ketudat Cairns JR. Split hand–foot malformation and a novel WNT10B mutation. Eur J Med Genet. 2018;61:372–5.

  9. 9.

    Benbir G, Kara S, Yalcinkaya BC, Karlıkaya G, Tuysuz B, Kocer N, et al. Unilateral cerebellar hypoplasia with different clinical features. Cerebellum. 2011;10:49–60.

  10. 10.

    Massoud M, Cagneaux M, Garel C, Varene N, Moutard ML, Billette T, et al. Prenatal unilateral cerebellar hypoplasia in a series of 26 cases: significance and implications for prenatal diagnosis. Ultrasound Obstet Gynecol. 2014;2014:447–54.

  11. 11.

    McMahon AP, Bradley A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell. 1990;62:1073–85.

  12. 12.

    Thomas KR, Musci TS, Neumann PE, Capecchi MR. Swaying is a mutant allele of the proto-oncogene Wnt-1. Cell. 1991;67:969–76.

  13. 13.

    Joeng KS, Lee YC, Jiang MM, Bertin TK, Chen Y, Abraham AM, et al. The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations. Hum Mol Genet. 2014;23:4035–42.

  14. 14.

    Danielian PS, McMahon AP. Engrailed-1 as a target of the Wnt-1 signalling pathway in vertebrate midbrain development. Nature. 1996;383:332–4.

  15. 15.

    Wurst W, Auerbach AB, Joyner AL. Multiple developmental defects in Engrailed-1 mutant mice: an early mid-hindbrain deletion and patterning defects in forelimbs and sternum. Development. 1994;120:2065–75.

  16. 16.

    Sgaier SK, Lao Z, Villanueva MP, Berenshteyn F, Stephen D, Turnbull RK, et al. Genetic subdivision of the tectum and cerebellum into functionally related regions based on differential sensitivity to engrailed proteins. Development. 2007;134:2325–35.

  17. 17.

    McMahon AP, Joyner AL, Bradley A, McMahon JA. The midbrain–hindbrain phenotype of Wnt-1-/Wnt-1- mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum. Cell. 1992;69:581–95.

  18. 18.

    Fahiminiya S, Majewski J, Mort J, Moffatt P, Glorieux FH, Rauch F. Mutations in WNT1 are a cause of osteogenesis imperfecta. J Med Genet. 2013;50:345–8.

  19. 19.

    Won JY, Jang WY, Lee HR, Park SY, Kim WY, Park JH, et al. Novel missense loss-of-function mutations of WNT1 in an autosomal recessive Osteogenesis imperfecta patient. Eur J Med Genet. 2017;60:411–5.

  20. 20.

    Wurst W, Prakash N. Wnt1-regulated genetic networks in midbrain dopaminergic neuron development. J Mol Cell Biol. 2014;6:34–41.

  21. 21.

    Rowitch DH, Danielian PS, McMahon AP, Zec N. Cystic malformation of the posterior cerebellar vermis transgenic mice that ectopically express engrailed-1, a homeodomain transcription factor. Teratology. 1990;60:22–8.

  22. 22.

    Faqeih E, Shaheen R, Alkuraya FS. WNT1 mutation with recessive osteogenesis imperfecta and profound neurological phenotype. J Med Genet. 2013;50:491–2.

  23. 23.

    Tole S, Hébert J. Telencephalic patterning. In Rubenstein JLR, Rakic P, editors. Patterning and Cell Type Specification in Developing CNS and PNS. San Diego: Academic Press; 2013.p. 3–24.

  24. 24.

    Palomo T, Al-Jallad H, Moffatt P, Glorieux FH, Lentle B, Roschger P, et al. Skeletal characteristics associated with homozygous and heterozygous WNT1 mutations. Bone. 2014;67:63–70.

  25. 25.

    Rauch F. The brains of the bones: how osteocytes use WNT1 to control bone formation. J Clin Invest. 2017;127:2539–40.

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Acknowledgments

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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