Novel LRP5 Loss-Of-Function Mutation Causes Osteoporosis-Pseudoglioma Syndrome

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

Atenas

Congreso; 57th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE); 2018

European Society for Paediatric Endocrinology (ESPE)

Background: Osteoporosis is a complex disorder, influencedby both environmental and genetic factors. Primary osteoporosisis a rare early onset disorder with high morbidity and mortality.Wnt signaling pathway has been shown to be involved in the regulationof bone remodeling.Case: Native Argentinean boy born from a consanguineousfamily with history of retinal detachment in the maternal line. Deliveredat term, birth weight 2900 g (-0.95 SDS), birth length 50.5cm (0.06 SDS), microcephaly (head circumference -1.93 SDS). Bilateralcongenital retinal folds caused him progressive irreversiblevision loss and acquired microophthalmy.Since the age of 5 y he developed four low trauma long bonefractures and two vertebral fractures. Referred at 8.6 y, weight 27.4kg (P50), height 129 cm (P50), normal growth velocity, Tannerstage I, microcephaly and bulky vision. White sclera, normal teeth,absence of hyperlaxity, slight kyphosis and adequate neurodevelopmentwere observed.Dual-energy X-ray absorptiometry (DXA) demonstrated lowbone mineral density (BMD): Lunar L2-L4: 0.370 g/m2 (Z score-3.9 SDS) and measurement of bone metabolism markers werewithin normal range (calcium 10.3 mg/dL; phosphate 4.9 mg/dL;magnesium 1.9 mg/dL; ALP 195 IU/L; bone ALP 61.5 ng/L; PTH54 pg/ml; 25OH vitamin D 24 ng/ml; CTX 1231 pg/ml; urine Calcium/Creatinine ratio 0.2; PTR 91%). Known secondary causesof osteoporosis were ruled out. There is no history of familialfractures and his parents have normal BMD. After two years ofZoledronic acid: 0.0125 mg/kg/dose every six months and specificexercises, his BMD has improved to 0.522 g/m2 (Zscore -2.2 SDS),affected vertebras slightly reshaped without fractures recurrence.SNP array (850k, Illumina) showed loss of heterozygosity inchromosomal region 11p15.1-11q13.3, containing the low-densitylipoprotein receptor-related protein-5 gene (LRP5), a geneexpressed in fetal ocular macrophages and in osteoblasts, thus,our first candidate gene. A novel homozygous nonsense variant(NM_002335.3:c.441G>A, p.Trp147Ter) was identified using askeletal dysplasia NGS panel, SkeletalSeq.V7. Both parents areheterozygous for this variant.Conclusions: LRP5 is a single-span transmembrane protein requiredfor Wnt/βcatenin signaling pathway, relevant for fetal and postnatal osteogenesis. We identified a novel homozygous LRP5loss-of-function mutation, which causes autosomal recessive Osteoporosis-pseudoglioma syndrome (OPPG, MIM 259770). Scarceinformation exists regarding OPPG treatment in children. Thus,understanding the molecular mechanisms underlying primary osteoporosisis important for improving screening for co-morbidities,genetic counselling and development of novel therapies.