ESPE Abstracts

Background: SET domain-containing 5 (SETD5) is an uncharacterized member of the protein lysine methyltransferase family, a group best known for its ability to methylate their substrate and, by that, regulate gene expression. Heterozygous pathogenic variants in SETD5 are known to cause neurodevelopmental delay. We present two children with pathogenic variants in SETD5 and vertebral fractures with low bone mass. Individual 1 This 15-year old male of Caucasian and Chinese origin first presented with delayed speech, irregular sleep, learning difficulties and aggression during the first years of life. After a fall at the playground at the age of 8 years he was referred to the pediatric bone clinic, where x-rays showed mild scoliosis and vertebral wedge fractures at T11, L2 and L3. Bone densitometry (DXA) revealed reduced lumbar spine bone mineral apparent density (BMAD) with a Z-score of -2,3, a subtotal BMD for height Z-score of -2,5 and subtotal BMC for height of -3,1. Notable skeletal features were hyperflexibility of elbows, thumbs and wrists alongside bilateral clubfoot and pes cavus. Whole exome sequencing revealed a pathogenic heterozygous SETD5 variant c.1498C>T (p.Gln500*het) in exon 13. Since he fulfilled the criteria for paediatric osteopororis, therapy with zoledronic acid was established. Individual 2 This 13-year old male of Latin American origin was born preterm at a gestational age of 25 weeks with bronchopulmonary dysplasia, bronchomalacia, larnygomalacia, bilateral inguinal hernia and unilateral renal hypoplasia. Brain MRI identified bilateral cerebellar hypoplasia. Aged 5, he had a febrile seizure. At the age of 13 years, he presented with persisting sternal pain with no evidence of trauma. Radiographs showed fissures of the sternum. Aged 14, following trivial fall, radiographs showed multiple vertebral fractures and anterior wedging of T6-T7 and possible fractures of T6 and T9 with suspected microfractures affecting the upper platforms of T5, T6 and T10. The DXA scan showed a low lumbar spine BMD with a Z-score of -1,9. As the criteria for pediatric osteoporosis was fulfilled, therapy with zoledronic acid was established. Whole exome sequencing revealed a pathogenic heterozygous c.1082G>A (p.Arg361Gln) variant in exon 11 of SETD5.

Conclusion: The combination of SETD5-associated neurodevelopmental delay and low bone mass has only recently been described. Our two cases corroborate this association. Neither of the patient had other risk factors for bone fragility nor was there a family history of fractures. We explore mechanism of action to ascertain how SETD5 affects bone metabolism and results in bone fragility.