ICCBH2019 Poster Presentations (1) (226 abstracts)
Osteogenesis imperfecta type 15 with neurological phenotype associated with homozygous WNT1 mutation and uniparental isodisomy for chromosome 12
Belinda Crowe 1 , Mark Heathfield 1 , Karen Edwards 1 , Chris Clark 1 , Emilie Hupin 1 , Alex Bultitude 1 , Alistair Calder 2 , Melissa Lees 3 , Ri Liesner 4 , Jeremy Allgrove 1 & Catherine DeVile 1
1Highly Specialised Osteogenesis Imperfecta Service, The Wolfson Neurodisability Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; 2Department of Paediatric Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; 3Clinical Genetics Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; 4Haemophilia Comprehensive Care Centre, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Background: Osteogenesis imperfecta (OI) type 15 is a rare autosomal recessive form caused by WNT1 mutations. In addition to bone fragility it may be associated with neurological impairment. We report a unique case of OI type 15 in a child with uniparental isodisomy for chromosome 12 who also has von Willebrand disease type 2N, congenital ptosis, early onset scoliosis and a movement disorder.
Presenting Problem: A female infant was delivered normally at 42 weeks’ gestation to healthy, unrelated parents following unremarkable antenatal scans. On day two she was not moving her right arm and right humeral and incidental right prenatal clavicle fractures were identified. Skeletal survey at 12 weeks revealed multiple healing rib and long bone fractures, multi-level vertebral compression fractures and left convexity thoracic scoliosis; no Wormian bones. Aged four months she had white sclerae, congenital left ptosis, no hypermobility, and abnormal extensor posturing of neck and trunk. CGH microarray revealed uniparental isodisomy for chromosome 12. OI genetic testing identified a homozygous novel pathogenic duplication c.216dup in exon 2 of WNT1 on chromosome 12, predicted to cause a truncated protein. Father is heterozygous. In addition, von Willebrand disease type 2N was identified, with homozygous c.2561G>A substitution in exon 20 of VWF, also on chromosome 12. Neuroimaging was normal.
Clinical management: Aged 12 months she started pamidronate. Latest spine x-ray aged 22 months revealed improved modelling at most vertebral levels, despite ongoing long bone fractures. Her movement disorder has evolved, with orolingual dyskinesia triggered by pain and excitement causing recurrent lip and tongue biting, and involuntary limb posturing apparent on activity. Her scoliosis is stable and managed with specialist seating and an OI Lycra suit.
Discussion: The precise mechanism linking WNT1 mutations with OI is not fully understood, however the Wnt signalling pathway is one of the key regulators of bone homeostasis and osteoblast activity. The role of bisphosphonates in this setting is less clear, however this child has responded positively. The neurological phenotypic spectrum associated with WNT1 is also not yet fully characterised. Further study is required to determine optimum therapeutic options and achieve best possible quality of life.
Disclosure: The authors declared no competing interests.
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Bone Abstracts
ISSN 2052-1219 (online)
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