E-Poster Presentation ESA-SRB-ANZBMS 2021

Precision medicine in the bone clinic – its time is now. (#728)

Matthew Balcerek 1 , Andrea Fernandes 1 , Diane Jensen 2 3 , Craig Munns 4 , Syndia Lazarus 1 5 , Emma Duncan 6
  1. Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Herston, QLD, 4029
  2. Department of Endocrinology and Diabetes, Queensland Chilren's Hospital, South Brisbane, Queensland, Australia
  3. School of Clinical Medicine, Paediatrics and Child Health, The University of Queensland, Herston, Queensland, Australia
  4. Endocrinology, The Children's Hospital at Westmead, Westmead, NSW, Australia
  5. School of Clinical Medicine - Royal Brisbane Clinical Unit, The University of Queensland, Herston, Qld, Australia
  6. Department of Twin Research & Genetic Epidemiology, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom

Case Description

The proband was referred to paediatric endocrinology at age 4 years with recurrent low trauma fractures including a left humeral spiral fracture at age 14 months, right wrist fracture at age 3 years, and recurrent metatarsal fractures aged 4 years. Bone densitometry demonstrated z scores of -1.8 (TBLH), -1.7 (AP spine), -3.3 (left total femur), and -3.1 (right total femur).

 

Her maternal uncle, grandfather and grandmother had severe osteoporosis on bone density and multiple low trauma fractures. Her mother had osteopaenia without fracture. A heritable bone fragility disorder was suspected.

 

The proband underwent panel sequencing for brittle bone disorders which identified a PLS3 variant (heterozygous c.653A>G p. (Asp218Gly)) not previously reported in clinical or population databases, considered a variant of uncertain clinical significance (VUS). PLS3 mutations are associated with X-linked osteogenesis imperfecta (1, 2).

 

A collaborative effort between treating endocrinologists facilitated cascade testing (via Sanger sequencing) which demonstrated appropriate segregation of the PLS3 variant with phenotype, supporting this variant as likely pathogenic.

 

Discussion

Identifying monogenic causes of bone fragility benefits both patient and clinician through a better understanding of aetiology, prognosis, treatment approaches, and genetic counselling.

 

In the absence of an identifiable secondary cause, clinicians should have a low threshold for performing genetic testing in individuals with recurrent fragility fractures (particularly if presenting at young age or in men), those with extra-skeletal manifestations, and individuals with a suggestive family history. A lack of family history, however, should not dissuade genetic testing given up to two-thirds of COL1A1 and one-third of COL1A2 mutations occur de novo (3).

 

The time to incorporate genetic testing as part of routine care in the bone clinic is now. However, for this to occur, public laboratories need to be adequately resourced to facilitate timely turnaround, and ensure rebates are available for equitable access.

  1. Mortier GR, Cohn DH, Cormier-Daire V, Hall C, Krakow D, Mundlos S, et al. Nosology and classification of genetic skeletal disorders: 2019 revision. Am J Med Genet A. 2019;179(12):2393-419.
  2. Hu J, Li LJ, Zheng WB, Zhao DC, Wang O, Jiang Y, et al. A novel mutation in PLS3 causes extremely rare X-linked osteogenesis imperfecta. Mol Genet Genomic Med. 2020;8(12):e1525.
  3. Zhytnik L, Maasalu K, Duy BH, Pashenko A, Khmyzov S, Reimann E, et al. De novo and inherited pathogenic variants in collagen-related osteogenesis imperfecta. Mol Genet Genomic Med. 2019;7(3):e559.