Meena Balasubramanian1,2, Nadja Fratzl-Zelman3, Rory O'Sullivan4, Mary Bull5, Nicola Fa Peel5, Rebecca C Pollitt6, Rebecca Jones7, Elizabeth Milne8, Kath Smith6, Paul Roschger3, Klaus Klaushofer3, Nicholas J Bishop9. 1. Highly Specialised Severe, Complex & Atypical OI Service, Sheffield Children's NHS Foundation Trust, UK. 2. Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, UK. 3. Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre, Meidling, 1st Med. Dept. Hanusch Hospital, 1140 Vienna, Austria. 4. Medical School, University of Sheffield, UK. 5. Metabolic Bone Centre, Northern General Hospital, Sheffield, UK. 6. Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, UK. 7. Department of Psychology, Sheffield Children's NHS Foundation Trust, UK. 8. Department of Psychology, University of Sheffield, UK. 9. Academic Unit of Child Health, University of Sheffield, UK.
Abstract
BACKGROUND: Idiopathic Juvenile Osteoporosis (IJO) refers to significantly lower than expected bone mass manifesting in childhood with no identifiable aetiology. IJO classically presents in early pubertal period with multiple fractures including metaphyseal and vertebral crush fractures, and low bone-mass. METHODS: Here we describe two patients and provide information on their clinical phenotype, genotype and bone material analysis in one of the patients. RESULTS: Patient 1: 40-year old adult male diagnosed with IJO in childhood who re-presented with a hip fracture as an adult. Genetic analysis identified a pathogenic PLS3 hemizygous variant, c.1765del in exon 16. Patient 2: 15-year old boy with multiple vertebral fractures and bone biopsy findings suggestive of IJO who also has a diagnosis of autism spectrum disorder. Genetic analysis identified a maternally inherited PLS3 pathogenic c.1295T>A variant in exon 12. Analyses of the transiliac bone sample revealed severe reduction of trabecular volume and bone turnover indices and elevated bone matrix mineralisation. DISCUSSION: We propose that genetic testing for PLS3 should be undertaken in patients presenting with a current or previous history of IJO as this has implications for genetic counselling and cascade screening. The extensive evaluation of the transiliac biopsy sample of Patient 2 revealed a novel bone phenotype. CONCLUSION: This report includes a review of IJO and genetic causes of osteoporosis, and suggests that existing cases of IJO should be screened for PLS3. Through analysis of bone material properties in Patient 2, we can conclude that PLS3 does have a role in bone mineralisation.
BACKGROUND:Idiopathic Juvenile Osteoporosis (IJO) refers to significantly lower than expected bone mass manifesting in childhood with no identifiable aetiology. IJO classically presents in early pubertal period with multiple fractures including metaphyseal and vertebral crush fractures, and low bone-mass. METHODS: Here we describe two patients and provide information on their clinical phenotype, genotype and bone material analysis in one of the patients. RESULTS:Patient 1: 40-year old adult male diagnosed with IJO in childhood who re-presented with a hip fracture as an adult. Genetic analysis identified a pathogenic PLS3 hemizygous variant, c.1765del in exon 16. Patient 2: 15-year old boy with multiple vertebral fractures and bone biopsy findings suggestive of IJO who also has a diagnosis of autism spectrum disorder. Genetic analysis identified a maternally inherited PLS3 pathogenic c.1295T>A variant in exon 12. Analyses of the transiliac bone sample revealed severe reduction of trabecular volume and bone turnover indices and elevated bone matrix mineralisation. DISCUSSION: We propose that genetic testing for PLS3 should be undertaken in patients presenting with a current or previous history of IJO as this has implications for genetic counselling and cascade screening. The extensive evaluation of the transiliac biopsy sample of Patient 2 revealed a novel bone phenotype. CONCLUSION: This report includes a review of IJO and genetic causes of osteoporosis, and suggests that existing cases of IJO should be screened for PLS3. Through analysis of bone material properties in Patient 2, we can conclude that PLS3 does have a role in bone mineralisation.
Authors: Christopher L Schwebach; Elena Kudryashova; Weili Zheng; Matthew Orchard; Harper Smith; Lucas A Runyan; Edward H Egelman; Dmitri S Kudryashov Journal: Bone Res Date: 2020-05-22 Impact factor: 13.567
Authors: Scott E Youlten; John P Kemp; John G Logan; Elena J Ghirardello; Claudio M Sergio; Michael R G Dack; Siobhan E Guilfoyle; Victoria D Leitch; Natalie C Butterfield; Davide Komla-Ebri; Ryan C Chai; Alexander P Corr; James T Smith; Sindhu T Mohanty; John A Morris; Michelle M McDonald; Julian M W Quinn; Amelia R McGlade; Nenad Bartonicek; Matt Jansson; Konstantinos Hatzikotoulas; Melita D Irving; Ana Beleza-Meireles; Fernando Rivadeneira; Emma Duncan; J Brent Richards; David J Adams; Christopher J Lelliott; Robert Brink; Tri Giang Phan; John A Eisman; David M Evans; Eleftheria Zeggini; Paul A Baldock; J H Duncan Bassett; Graham R Williams; Peter I Croucher Journal: Nat Commun Date: 2021-05-05 Impact factor: 14.919
Authors: Sanne Treurniet; Elisabeth M W Eekhoff; Felix N Schmidt; Dimitra Micha; Björn Busse; Nathalie Bravenboer Journal: Front Endocrinol (Lausanne) Date: 2020-06-23 Impact factor: 5.555
Authors: Christopher L Schwebach; Elena Kudryashova; Weili Zheng; Matthew Orchard; Harper Smith; Lucas A Runyan; Edward H Egelman; Dmitri S Kudryashov Journal: Bone Res Date: 2020-05-22 Impact factor: 13.567