Novel LRP5 Variant Associated to Osteoporosis Pseudoglioma Syndrome

SCAGLIA, P; CASSINELLI, H; AZA-CARMONA, M; SZLAGO, M; REY, R; BRASLAVSKY, D; RUIZ SCHENSTROM, O; NEVADO BLANCO, J; ARBERAS, C; BERGADÁ, I; SANGUINETI, N; FERNÁNDEZ, MC; LAPUNZINA, P; HEATH, K

Cusco

Congreso; XXVI Reunión anual de la Sociedad Latinoamericana de Endorinologia Pediatrica; 2018

Sociedad Latinoamericana de Endocrinologia Pediatrica

Background: Osteoporosis is a complex disorder, influencedby environmental and genetic factors. Primary osteoporosis is arare early onset disorder with high morbidity and mortality. Wntsignaling pathway is involved in bone remodeling regulation.Case Report: Boy born from consanguineous parents with historyof retinal detachment in the maternal line. Delivered at term,AGA with microcephaly. Bilateral congenital retinal folds causedhim progressive irreversible vision loss and microophthalmy.Since 5 y he developed two vertebral and four low trauma longbone fractures. Referred at 8.6 y, he presented normal weight,height and growth velocity, Tanner stage I, microcephaly andbulky vision. White sclera, normal teeth, absence of hyperlaxity,slight kyphosis and adequate neurodevelopment were observed.DEXA demonstrated low bone mineral density (BMD): L2-L40.370 g/m2 (Zscore ?3.9 SDS); bone metabolism markers withinnormal range (calcium 10.3 mg/dL; phosphate 4.9 mg/dL; magnesium1.9 mg/dL; ALP 195 IU/L; bone-ALP 61.5 ng/L; PTH 54 pg/ml; 25OHvitamin D 24 ng/ml; CTX 1231 pg/ml; Calcium/Creatinine0.2; PTR 91%). Secondary causes of osteoporosis were ruledout. After two years of Zoledronic acid every six months and specificexercises, his BMD has improved to ?2.2 SDS,Conclusions: LRP5 is a single-span transmembrane protein requiredfor Wnt/βcatenin signaling pathway, relevant for fetal andpostnatal osteogenesis. We identified a novel homozygous LRP5loss-of-function mutation in this patient, which causes autosomalrecessive Osteoporosis-pseudoglioma syndrome (OPPG, OMIM259770). Scarce information exists regarding osteoporosis treatmentin children. Understanding the molecular mechanisms underlyingprimary osteoporosis is important for improving screeningof comorbidities, genetic counselling and development of noveltherapies. Affected vertebras slightly reshaped without fracturesrecurrence. SNP-array showed loss of heterozygosity in 11p15.1-11q13.3, containing the low-density lipoprotein receptor-relatedprotein-5 gene (LRP5), a gene expressed in fetal ocular macrophagesand osteoblasts. A novel homozygous nonsense variant(NM_002335.3:c.441G>A, p.Trp147Ter) was identified in LRP5using a skeletal dysplasia NGS panel. Parents, heterozygous for thisvariant, have normal BMD.