Atypical Femoral Fracture in Osteoporosis Pseudoglioma Syndrome Associated with Two Novel Compound Heterozygous Mutations in <i>LRP5</i>

Alonso, Nerea; Soares, Dinesh C.; McCloskey, Eugène; Summers, Gregory D.; Ralston, Stuart H.; Gregson, Celia L

doi:10.1002/jbmr.2403

Cited by 28 publications

(20 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This fracture occurred three years after A3 had discontinued bisphosphonate treatment and was similar to a fracture reported in another OPPG patient, described as an atypical femur fracture in a patient who had not been treated with any anti-resorptive therapy [18]. This prior report brings into question whether the subtrochanteric femur fracture in our case was associated with her prior bisphosphonate treatment or with the underlying disease itself.…”

Section: Discussionsupporting

confidence: 80%

Fractures on bisphosphonates in osteoporosis pseudoglioma syndrome (OPPG): pQCT shows poor bone density and structure

Streeten

Ramirez

Eliades

et al. 2015

Bone

View full text Add to dashboard Cite

Osteoporosis pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder of childhood osteoporosis and blindness due to inactivating mutations in LDL receptor-like protein 5 (LRP5). We and others have reported improvement in areal bone mineral density (aBMD) by DXA in OPPG on short term bisphosphonates. Long-term data on bisphosphonate use in OPPG and measures of volumetric BMD (vBMD) and cortical structure are not available. In addition, no long-term DXA data on untreated OPPG is available. The aims of this study were to: (1) record low trauma fractures and longitudinal aBMD by DXA in 5 OPPG patients on chronic bisphosphonate treatment, and in 4 OPPG patients never treated (2) to perform tibia peripheral quantitative CT (pQCT) to evaluate volumetric bone mineral density (vBMD), cortical structure and calf muscle area in 6 OPPG patients and 14 unaffected first degree family members. pQCT results were converted to sex-specific Z-scores for age and adjusted for tibia length based on data in >700 reference participants. We observed 4 fractures (3 femoral shafts) in 3 OPPG patients while on bisphosphonates, after each achieved significant improvement in aBMD. OPPG participants had significantly lower mean trabecular vBMD (−1.51 vs. 0.17, p = 0.002), cortical area (−2.36 vs. 0.37; p < 0.001) and periosteal circumference (−1.86 vs. −0.31, p = 0.001) Z-scores, compared with unaffected participants and had a trend toward lower muscle area Z-score (−0.69 vs. 0.47, p = 0.12). These data demonstrate substantial bone fragility despite improvements in aBMD. The pQCT data provide insight into the fragility with substantial deficits in trabecular vBMD and cortical dimensions, consistent with OPPG effects on bone formation. Treatment that improves bone quality is needed to reduce fractures in OPPG.

show abstract

Section: Discussionsupporting

confidence: 80%

Fractures on bisphosphonates in osteoporosis pseudoglioma syndrome (OPPG): pQCT shows poor bone density and structure

Streeten

Ramirez

Eliades

et al. 2015

Bone

View full text Add to dashboard Cite

show abstract

“…Osteoporosis pseudoglioma syndrome (OPPG) : OPPG is a rare, autosomal recessive form of juvenile osteoporosis caused by a loss‐of‐function mutation in the LRP5 gene . We identified a single case report of an AFF occurring in a 40‐year‐old bisphosphonate‐naïve male with OPPG, who had multiple fragility fractures since childhood and evidence of low bone turnover on bone biopsy . This is the only report of an AFF occurring in a genetic condition with primary osteoblast dysfunction.…”

Section: Resultsmentioning

confidence: 99%

Genetic Risk Factors for Atypical Femoral Fractures (AFFs): A Systematic Review

Nguyen¹,

Laarschot

Verkerk

et al. 2018

JBMR Plus

View full text Add to dashboard Cite

Atypical femoral fractures (AFFs) are uncommon and have been associated particularly with long‐term antiresorptive therapy, including bisphosphonates. Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate‐naïve individuals and in monogenetic bone disorders has led to the hypothesis that genetic factors predispose to AFF. Our aim was to review and summarize the evidence for genetic factors in individuals with AFF. We conducted structured literature searches and hand‐searching of conference abstracts/reference lists for key words relating to AFF and identified 2566 citations. Two individuals independently reviewed citations for (i) cases of AFF in monogenetic bone diseases and (ii) genetic studies in individuals with AFF. AFFs were reported in 23 individuals with the following 7 monogenetic bone disorders (gene): osteogenesis imperfecta (COL1A1/COL1A2), pycnodysostosis (CTSK), hypophosphatasia (ALPL), X‐linked osteoporosis (PLS3), osteopetrosis, X‐linked hypophosphatemia (PHEX), and osteoporosis pseudoglioma syndrome (LRP5). In 8 cases (35%), the monogenetic bone disorder was uncovered after the AFF occurred. Cases of bisphosphonate‐naïve AFF were reported in pycnodysostosis, hypophosphatasia, osteopetrosis, X‐linked hypophosphatemia, and osteoporosis pseudoglioma syndrome. A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases using exon array analysis. A whole‐exome sequencing study in 3 sisters with AFFs showed, among 37 shared genetic variants, a p.Asp188Tyr mutation in the GGPS1 gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. Two studies completed targeted ALPL gene sequencing, an ALPL heterozygous mutation was found in 1 case of a cohort of 11 AFFs, whereas the second study comprising 10 AFF cases did not find mutations in ALPL. Targeted sequencing of ALPL, COL1A1, COL1A2, and SOX9 genes in 5 cases of AFF identified a variant in COL1A2 in 1 case. These findings suggest a genetic susceptibility for AFFs. A large multicenter collaborative study of well‐phenotyped AFF cases and controls is needed to understand the role of genetics in this uncommon condition. © 2017 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

show abstract

“…In contrast, loss‐of‐function LRP5 mutations cause osteoporosis pseudoglioma syndrome (OPPG; MIM# 259770), an autosomal recessive condition of congenital blindness and severe childhood osteoporosis with skeletal fragility . Heterozygous carriers have been reported to have low bone mineral density (BMD) . Most OPPG and low BMD–associated mutations have been described in the second and third β‐propeller domains .…”

Section: Introductionmentioning

confidence: 99%

“…(19) Heterozygous carriers have been reported to have low bone mineral density (BMD). (20) Most OPPG and low BMD-associated mutations have been described in the second and third b-propeller domains. (16) Loss-of-function SOST mutations cause sclerosteosis, a rare condition of excessive bone overgrowth (MIM# 269500); a downstream deletion is thought to be responsible for the milder phenotype of van Buchem's disease (VBD) (MIM# 239100).…”

Section: Introductionmentioning

confidence: 99%

Mutations in Known Monogenic High Bone Mass Loci Only Explain a Small Proportion of High Bone Mass Cases

Gregson

Wheeler

Hardcastle

et al. 2015

Journal of Bone and Mineral Research

Self Cite

View full text Add to dashboard Cite

High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52‐kb intronic deletion 3′). Family members were assessed for HBM segregation with identified variants. Three‐dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (∼prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non‐LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5‐HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST‐LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z‐scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z‐scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small proportion (∼3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance. © 2015 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

show abstract

Atypical Femoral Fracture in Osteoporosis Pseudoglioma Syndrome Associated with Two Novel Compound Heterozygous Mutations in LRP5

Cited by 28 publications

References 64 publications

Fractures on bisphosphonates in osteoporosis pseudoglioma syndrome (OPPG): pQCT shows poor bone density and structure

Fractures on bisphosphonates in osteoporosis pseudoglioma syndrome (OPPG): pQCT shows poor bone density and structure

Genetic Risk Factors for Atypical Femoral Fractures (AFFs): A Systematic Review

Mutations in Known Monogenic High Bone Mass Loci Only Explain a Small Proportion of High Bone Mass Cases

Contact Info

Product

Resources

About