| 1. |
- Laine, Christine M., et al.
(författare)
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A Novel Splice Mutation in PLS3 Causes X-linked Early Onset Low-Turnover Osteoporosis
- 2015
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431. ; 30:3, s. 437-445
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors play an important role in the development of osteoporosis. Several monogenic forms of osteoporosis have been recognized, most recently an X-chromosomal form resulting from mutations in the gene encoding plastin 3 (PLS3). PLS3 is a protein involved in actin bundle formation in the cytoskeleton. We present a large family with early onset osteoporosis and X-linked inheritance. Phenotyping was performed on 19 family members and whole-exome sequencing on 7 family members (5 with a diagnosis of early onset osteoporosis and 2 with normal bone parameters). Osteoporosis had its onset in childhood and was characterized by recurrent peripheral fractures, low bone mineral density (BMD), vertebral compression fractures, and significant height loss in adulthood. Males were in general more severely affected than females. Bone histomorphometry findings in 4 males and 1 female showed severe trabecular osteoporosis, low amount of osteoid, and decreased mineral apposition rate, indicating impaired bone formation; resorption parameters were increased in some. All affected subjects shared a single base substitution (c.73-24T>A) in intron 2 of PLS3 on Xq23. The mutation, confirmed by Sanger sequencing, segregated according to the skeletal phenotype. The mutation introduces a new acceptor splice site with a predicted splice score of 0.99 and, thereby, as confirmed by cDNA sequencing, induces the insertion of 22 bases between exons 2 and 3, causing a frameshift and premature termination of mRNA translation (p.Asp25Alafs(not asymptotic to)17). The mutation affects the first N-terminal calcium-binding EF-hand domain and abolishes all calcium-and actinbinding domains of the protein. Our results confirm the role of PLS3 mutations in early onset osteoporosis. The mechanism whereby PLS3 affects bone health is unclear, but it may be linked to osteocyte dendrite function and skeletal mechanosensing. Future studies are needed to elucidate the role of PLS3 in osteoporosis and to define optimal treatment. (C) 2014 American Society for Bone and Mineral Research.
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| 2. |
- Makitie, R. E., et al.
(författare)
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Skeletal Characteristics of WNT1 Osteoporosis in Children and Young Adults
- 2016
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 31:9, s. 1734-1742
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Tidskriftsartikel (refereegranskat)abstract
- WNT proteins comprise a 19-member glycoprotein family that act in several developmental and regenerative processes. In bone, WNT proteins regulate osteoblast differentiation and maintain bone health by activating the canonical WNT/-catenin pathway. We reported a heterozygous missense mutation c.652T>G (p.C218G) in WNT1 exon 4 as the cause for severe early-onset, autosomal dominant osteoporosis. The initial study concerned a large Finnish family with 10 affected adults. Here we report clinical findings of the WNT1 osteoporosis in 8 children and young adults (median age 14 years; range 10 to 30 years) in two families, all with the p.C218G mutation in WNT1. Clinical assessments showed no apparent dysmorphia or features similar to typical osteogenesis imperfecta (OI). Biochemistry revealed no changes in parameters of calcium metabolism and bone turnover markers. Fracture frequencies varied, but all subjects had sustained at least one fracture and 4 had a pathological fracture history. Plain radiographs showed osteopenic appearance, loss in vertebral height, and thin diaphyses of the long bones. Bone densitometry showed the BMD to be below normal median in all subjects and the bone mass deficit seemed to be more severe in older participants. Bone histomorphometry revealed a low turnover osteoporosis in 2 subjects at ages 14 and 16 years. These findings are congruent with earlier findings in adult patients and indicate that WNT1 osteoporosis causes significant skeletal changes already in early childhood and impairs bone mass gain during pubertal years. Genetic testing of children or close relatives of affected individuals is recommended for appropriate preventive measures. (c) 2016 American Society for Bone and Mineral Research.
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| 3. |
- Valimaki, V. V., et al.
(författare)
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Teriparatide Treatment in Patients With WNT1 or PLS3 Mutation-Related Early-Onset Osteoporosis: A Pilot Study
- 2017
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 102:2, s. 535-544
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Tidskriftsartikel (refereegranskat)abstract
- Context: We previously identified 2 Finnish families with dominantly inherited, low-turnover osteoporosis caused by mutations in WNT1 or PLS3. Objective, Design, and Setting: This prospective, longitudinal, uncontrolled study was undertaken to evaluate whether these patients respond to teriparatide. Patients and Intervention: We recruited 6 adults (median age, 54 years); 3 with a WNT1 missense mutation, c.652T>G, and 3 with a PLS3 splice mutation, c.73-24T>A, to receive teriparatide 20 mg daily for 24 months. Five patients had previously used bisphosphonates. Main Outcome Measures: Outcome measures included lumbar spine and hip bone mineral density (BMD) by dual-energy X-ray absorptiometry, distal radius peripheral quantitative computed tomography, spinal radiography, serum bone turnover markers, paired iliac crest biopsies. Results: All patients showed increases in formation markers procollagen type 1 amino-terminal propeptide (90% to 398%) and osteocalcin (50% to 280%) and in resorption markers cross-linked C-terminal telopeptide of type I collagen (58% to 457%) and tartrate-resistant acid phosphatase 5b (20% to 68%) in first 6 months. Lumbar spine BMD increased 5.2% to 7.9% in 5 patients and femoral neck BMD 2.6% to 7.8% in 4 patients in 24 months. Distal radius cortical volumetric BMD decreased 5.4% to 26.1%. In histomorphometric analyses, osteoid indices increased more consistently in patients with WNT1 vs PLS3 mutation. Eroded surface decreased 44% to 100% in all patients. Adipocyte number increased in 5 patients studied. Conclusions: Patients with WNT1 or PLS3 mutation-related osteoporosis responded to teriparatide treatment. Future studies are needed to evaluate whether observed changes translate to fracture resistance.
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| 4. |
- Wesseling-Perry, K., et al.
(författare)
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Osteocyte Protein Expression Is Altered in Low-Turnover Osteoporosis Caused by Mutations in WNT1 and PLS3
- 2017
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 102:7, s. 2340-2348
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Tidskriftsartikel (refereegranskat)abstract
- Context: Osteocytes express proteins that regulate bone remodeling and mineralization. Objective: To evaluate the relationship between osteocyte-specific protein expression and bone histology in patients with monogenic osteoporosis due to wingless integration site 1 (WNT1) or plastin 3 (PLS3) mutations. Design and Setting: Cross-sectional cohort study at a university hospital. Participants: Six patients (four males; ages: 14 to 72 years) with a heterozygous WNT1 mutation and five patients (four males; ages: 9 to 70 years) with a heterozygous/hemizygous PLS3 mutation. Methods and Main Outcome Measures: Immunohistochemistry was performed for fibroblast growth factor 23 (FGF23), dentin matrix protein 1 (DMP1), sclerostin, and phosphorylated (phospho-)beta-catenin in iliac crest samples and compared with bone histomorphometry. Results: FGF23 expression in WNT1 patients was 243% that observed in PLS3 patients (P < 0.01). DMP1, sclerostin, and phospho-beta-catenin expression did not differ between groups. Serum phosphate correlated inversely with FGF23 expression (r = -0.79, P = 0.01) and serum ionized calcium correlated inversely with sclerostin expression (r = -0.60, P = 0.05). Phospho-beta-catenin expression correlated inversely with DMP1 expression (r = -0.88, P < 0.001), osteoid volume/bone volume (r = -0.68, P = 0.02), and bone formation rate (r = -0.78, P < 0.01). FGF23 expression did not correlate with DMP1 expression, sclerostin expression, or bone histomorphometry. Marrow adiposity was higher in WNT1 than in PLS3 patients (P = 0.04). Conclusions: Mutations that disrupt WNT signaling and osteocytic mechanosensing affect osteocyte protein expression. Abnormal osteocyte function may play a role in the pathogenesis of monogenetic forms of osteoporosis.
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| 5. |
- Pekkinen, M., et al.
(författare)
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FGF23 gene variation and its association with phosphate homeostasis and bone mineral density in Finnish children and adolescents
- 2015
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 1873-2763 .- 8756-3282. ; 71, s. 124-30
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Tidskriftsartikel (refereegranskat)abstract
- Fibroblast growth factor 23 (FGF23), a bone-derived hormone, participates in the hormonal bone-parathyroid-kidney axis, which is modulated by PTH, 1,25-dihydroxyvitamin D, plasma phosphate (Pi), and diet. Inappropriately high serum FGF23, seen in certain genetic and acquired disorders, results in urinary phosphate wasting and impaired bone mineralization. This study investigated the impact of FGF23 gene variation on phosphate homeostasis and bone health. The study included 183 children and adolescents (110 girls) aged 7-19 years (median 13.2years). Urine and blood parameters of calcium and phosphate homeostasis were analyzed. Bone characteristics were quantified by DXA and peripheral quantitative computed tomography (pQCT). Genetic FGF23 variation was assessed by direct sequencing of coding exons and flanking intronic regions. Nine FGF23 polymorphisms were detected; three of them were common: rs3832879 (c.212-37insC), rs7955866 (c.716C>T, p.T239M) and rs11063112 (c.2185A>T). Four different haplotypes and six different diplotypes were observed among these three polymorphisms. The variations in FGF23 significantly associated with plasma PTH and urinary Pi excretion, even after adjusting for relevant covariates. FGF23 variations independently associated with total hip BMD Z-score, but not with other bone outcomes. In instrument analysis, genetic variance in FGF23 was considered a weak instrument as it only induced small variations in circulating FGF23, PTH and Pi concentrations (F statistic less than 10). The observed associations between FGF23 variations and circulating PTH, and Pi excretion and total hip BMD Z-scores suggest that FGF23 polymorphisms may play a role in mineral homeostasis and bone metabolism.
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| 6. |
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| 7. |
- Kontogeorgos, Georgios, et al.
(författare)
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Normocalcaemic, vitamin D-sufficient hyperparathyroidism - high prevalence and low morbidity in the general population: A long-term follow-up study, the WHO MONICA project, Gothenburg, Sweden
- 2015
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 83:2, s. 277-284
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveThere is limited knowledge about the natural history of normocalcaemic, vitamin D-sufficient hyperparathyroidism (nHPT). The aim was to study the prevalence of nHPT and its relation to morbidity. DesignCross-sectional and retrospective study at the Sahlgrenska University Hospital, Gothenburg, Sweden. SubjectsA random population of 608 men and women, age 25-64years, was studied in 1995 as part of the WHO MONICA study and reinvestigated in 2008 (n=410, of whom 277 were vitamin D sufficient). MeasurementsA serum intact parathyroid hormone (S-PTH) 60ng/l was considered as HPT, S-calcium 215-249mmol/l as normocalcaemia and S-25(OH)D50nmol/l as vitamin D sufficiency. Data on fractures, stroke and myocardial infarction were retrieved until 2013, that is a 17-year follow-up. ResultsThe prevalence of nHPT was 20% in 1995 (age 25-64) and 110% in 2008 (age 38-79). S-PTH was positively correlated with age and BMI. After adjustment for these variables, a high S-PTH level (60ng/l) at follow-up was associated with previously low S-25(OH)D, high osteocalcin, S-PTH and both past and presently treated hypertension. No relation was seen with creatinine, cystatin C, malabsorption markers, thyroid function, glucose, insulin, lipids, calcaneal quantitative ultrasound, fractures, myocardial infarction, stroke or death at follow-up. ConclusionsThis small random population study showed that nHPT was common, 11% at follow-up. Only one individual developed mild hypercalcaemia in 13years. Previous S-PTH was predictive of nHPT and hypertension was prevalent, but no increase in hard end-points was seen over a 17-year period.
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| 8. |
- Laine, Christine M., et al.
(författare)
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Case report: fast reversal of severe osteoporosis after correction of excessive levothyroxine treatment and long-term follow-up.
- 2017
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Ingår i: Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. - : Springer Science and Business Media LLC. - 1433-2965. ; 28:7, s. 2247-2250
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Tidskriftsartikel (refereegranskat)abstract
- This case report describes a 38-year-old woman, who presented with bilateral femoral stress fractures and osteoporosis after years of excessive levothyroxine treatment. Her bone health was restored rapidly and long-lasting with the reduction of levothyroxine dosage. No bone-active treatment was warranted.Hyperthyroidism is a known risk factor for osteoporosis and fractures. Recent studies on patients with serum thyrotropin-suppressive therapy have not, however, indicated adverse effects on bone during long-term follow-up.This case report describes long-term follow-up data of a clinically euthyreoid patient, who developed symptomatic osteoporosis due to excessive levothyroxine treatment.After correction of levothyroxine dosage, her bone mineral density (BMD) and previously elevated serum osteocalcin levels normalized rapidly and she remained free from fractures during 23 years of follow-up over menopause.Excessive TSH suppression contributed to the secondary osteoporosis in this patient; BMD normalized after dose reduction of levothyroxine and no fractures occurred during 23 years' follow-up. Some patients develop severe osteoporosis if they are over-substituted with levothyroxine, and decent follow-up of patients with levothyroxine supplementation is mandatory.
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