ESPE Abstracts (2018) 89 P-P1-036

Novel LRP5 Loss-of-function Mutation Causes Osteoporosis-pseudoglioma Syndrome

Debora Braslavskya, Paula Scagliaa, Nora Sanguinetia, Hamilton Cassinellia, Olivia Ruiz Schenstroma, Romina Armandob, Claudia Arberasb, Miriam Aza-Carmonac,d,e, Julian Nevado-Blancoc,e, Pablo Daniel Lapunzina-Badíac,d,e, Karen E Heathc,d,e, Rodolfo Reya & Ignacio Bergadáa

aCentro de Investigaciones Endocrinológicas ‘Dr. César Bergadá’ (CEDIE) CONICET- FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; bServicio de Genética, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; cInstitute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autonóma de Madrid, IdiPAZ, Madrid, Spain; dSkeletal dysplasia Multidisciplinary Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain; eCIBERER, ISCIII, Madrid, Spain

Background: Osteoporosis is a complex disorder, influenced by both environmental and genetic factors. Primary osteoporosis is a rare early onset disorder with high morbidity and mortality. Wnt signaling pathway has been shown to be involved in the regulation of bone remodeling.

Case: Native Argentinean boy born from a consanguineous family with history of retinal detachment in the maternal line. Delivered at term, birth weight 2900 g (−0.95 SDS), birth length 50.5 cm (0.06 SDS), microcephaly (head circumference −1.93 SDS). Bilateral congenital retinal folds caused him progressive irreversible vision loss and acquired microophthalmy. Since the age of 5 y he developed four low trauma long bone fractures and two vertebral fractures. Referred at 8.6 y, weight 27.4 kg (P50), height 129 cm (P50), normal growth velocity, Tanner stage I, microcephaly and bulky vision. White sclera, normal teeth, absence of hyperlaxity, slight kyphosis and adequate neurodevelopment were observed. Dual-energy X-ray absorptiometry (DXA) demonstrated low bone mineral density (BMD): Lunar L2-L4: 0.370 g/m2 (Z score −3.9 SDS) and measurement of bone metabolism markers were within 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; PTH 54 pg/ml; 25OH vitamin D 24 ng/ml; CTX 1231 pg/ml; urine Calcium/Creatinine ratio 0.2; PTR 91%). Known secondary causes of osteoporosis were ruled out. There is no history of familial fractures and his parents have normal BMD. After two years of Zoledronic acid: 0.0125 mg/kg/dose every six months and specific exercises, 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 in chromosomal region 11p15.1-11q13.3, containing the low-density lipoprotein receptor-related protein-5 gene (LRP5), a gene expressed 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 a skeletal dysplasia NGS panel, SkeletalSeq.V7. Both parents are heterozygous for this variant.

Conclusions: LRP5 is a single-span transmembrane protein required for Wnt/βcatenin signaling pathway, relevant for fetal and postnatal osteogenesis. We identified a novel homozygous LRP5 loss-of-function mutation, which causes autosomal recessive Osteoporosis-pseudoglioma syndrome (OPPG, MIM 259770). Scarce information exists regarding OPPG treatment in children. Thus, understanding the molecular mechanisms underlying primary osteoporosis is important for improving screening for co-morbidities, genetic counselling and development of novel therapies.