Autosomal Dominant Hyperostosis/Osteosclerosis with High Serum Alkaline Phosphatase Activity

Hernández-Cassis, Carlos; Vogel, Claudia K.; Hernandez, Tatiana P.; Econs, Michael J.; Iglesias, Melitza; Iglesias, A Lois; Levis, Silvina; Roos, Bernard A.; Howard, Guy A.; Gamarra, Antonio Iglesias

doi:10.1210/jc.2001-011428

Cited by 9 publications

(2 citation statements)

References 22 publications

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“…In 2003, some individuals diagnosed with these disorders were discovered to carry gain‐of‐function mutations in LRP5 , (2,4) suggesting a shared genetic etiology for these high bone mass conditions. A Columbian kindred with autosomal dominant endosteal hyperostosis had normal sequence for LRP5 exon 3, but exons 2 and 4 were not studied, (29) so LRP5 gain‐of‐function remains possible. Our patient's disorder is consistent with Worth disease and was found to be caused by a novel missense mutation in exon 2 of LRP5 .…”

Section: Discussionmentioning

confidence: 99%

Oropharyngeal Skeletal Disease Accompanying High Bone Mass and Novel LRP5 Mutation

Rickels

Zhang²,

Mumm

et al. 2005

Journal of Bone and Mineral Research

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Gain-of-function mutation in the gene encoding LRP5 causes high bone mass. A 59-year-old woman carrying a novel LRP5 missense mutation, Arg154Met, manifested skeletal disease affecting her oropharynx as well as dense bones, showing that exuberant LRP5 effects are not always benign.Introduction: Gain-of-function mutation (Gly171Val) of LDL receptor-related protein 5 (LRP5) was discovered in 2002 in two American kindreds with high bone mass and benign phenotypes. In 2003, however, skeletal disease was reported for individuals from the Americas and Europe carrying any of six novel LRP5 missense mutations affecting the same LRP5 protein domain. Furthermore, in 2004, we described a patient with neurologic complications from dense bones and extensive oropharyngeal exostoses caused by the Gly171Val defect. Materials and Methods:A 59-year-old woman was referred for dense bones. Three years before, mandibular buccal and lingual exostoses (osseous "tori") were removed because of infections from food trapping between the teeth and exostoses. Maxillary buccal and palatal exostoses were asymptomatic. Radiographic skeletal survey showed marked thickening of the skull base and diaphyses of long bones (endosteal hyperostosis). BMD Z scores assessed by DXA were +8.5 and +8.7 in the total hip and L 1 -L 4 spine (both ∼195% average control), respectively. LRP5 mutation analysis was carried out for the LRP5 domain known to cause high bone mass. Results: Biochemical evaluation excluded most secondary causes of dense bones, and male-to-male transmission in her family indicated autosomal dominant inheritance. PCR amplification and sequencing of LRP5 exons 2-4 and adjacent splice sites revealed heterozygosity for a new LRP5 missense mutation, Arg154Met. Conclusions: LRP5 Arg154Met is a novel defect that changes the same first "␤-propeller" module as the eight previously reported LRP5 gain-of-function missense mutations. Arg154Met alters a region important for LRP5 antagonism by dickkopf (Dkk). Therefore, our patient's extensive oropharyngeal exostoses and endosteal hyperostosis likely reflect increased Wnt signaling and show that exuberant LRP5 effects are not always benign.

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Section: Discussionmentioning

confidence: 99%

Oropharyngeal Skeletal Disease Accompanying High Bone Mass and Novel LRP5 Mutation

Rickels

Zhang²,

Mumm

et al. 2005

Journal of Bone and Mineral Research

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“…Most patients with LRP5 activating mutations had normal ALP (15/17), P1NP (3/6) and β-CTX (10/15) levels. Compared with control group with normal bone mass, there was no significant difference in the levels of bone formation markers: ALP and P1NP, while the bone resorption biomarker β-CTX was decreased or normal (Frost et al 2003 ; Hernandez-Cassis et al 2003 ). ADO I is in autosomal dominant inheritance.…”

Section: Literature Review and Analysismentioning

confidence: 99%

Novel mutation in LRP5 gene cause rare osteosclerosis: cases studies and literature review

et al. 2023

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To study the effects of low-density lipoprotein receptor-related protein 5 (LRP5) gene mutations on bone, and to open up our view of LRP5 and Wnt pathways on bone mass regulation. Three patients with increased bone mineral density or thickened bone cortex were included, who were 30-year-old, 22-year-old and 50-year-old men, respectively. The latter two patients were son and father of a same family. The characteristics of bone X-rays were evaluated in detail. Bone turnover markers were detected, such as procollagen type 1 amino-terminal peptide (P1NP), alkaline phosphatase (ALP), and type 1 collagen carboxyl terminal peptide (β-CTX). Dual energy X-ray absorptiometry (DXA) was used to measure the bone mineral density (BMD) at lumbar spine and proximal femur of the patients. The targeted next-generation sequencing (NGS) technology was used to detect pathogenic gene mutations, which were further verified by Sanger sequencing. Moreover, the gene mutation spectrum and phenotypic characteristics of reported patients with LRP5 gain-of-function mutations were summarized by reviewing the literature. The main characteristics of the first patient were headache, facial paralysis, high BMD (lumbar vertebrae 1–4: 1.877 g/cm2, Z-score: 5.8; total hip: 1.705 g/cm2, Z-score: 5.7), slightly increased P1NP (87.0 ng/mL) and β-CTX (0.761 ng/mL) level, and with thickened bone cortex, especially the cranial vault. The latter two patients showed enlargement of the mandible and enlarged osseous prominence of the tours palatinus. X-rays showed that the bone cortex of skull and long bones were thickened. The bone turnover markers and BMD were normal. All three cases carried novel missense mutations in LRP5 gene, which were mutation in exon 3 (c.586 T > G, p.Trp196Gly) of the first patient, and mutation in exon 20 (c.4240C > A, p.Arg1414Ser) of the latter two patients. Combined with the reported literature, a total of 19 gain-of-function mutations in LRP5 were detected in 113 patients from 33 families. Hotspot mutations included c.724G > A, c.512G > T and c.758C > T. Furthermore, mutations in the exon 3 of LRP5 may cause severe phenotypes. LRP5 gain-of-function mutations can lead to rare autosomal dominant osteosclerosis type Ι (ADO Ι), which was characterized by increased bone mass and thickened bone cortex. In-depth research on the Wnt pathway will be benefit for discovering important mechanisms of bone mass regulation.

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Diffuse osteosclerosis in a patient with prostate cancer

Üstün

Özgür

et al. 2013

Osteoporos Int

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A 61-year-old man was referred to our outpatient clinic because of severe bilateral upper leg pain for 1 year. On admission, the patient had anemia and a high serum alkaline phosphatase level. Lumbar and femoral neck T-scores were +10.5 and +9.6, respectively. His radius 33 % T-score was -2.8. Plain radiographs of the patient's pelvis, spine, and long bones revealed osteosclerosis. The patient had previously undergone a prostate biopsy, which showed prostate adenocarcinoma (Gleason score 3 + 4). The patient's total and free prostate-specific antigen were very high. According to previous records, the patient did not have anemia, and his serum alkaline phosphatase (ALP) level was normal. An abdominal radiograph taken 2 years earlier revealed a normal spine and pelvic bone. Bone scintigraphy yielded nontypical findings for prostate cancer metastasis. Computed tomography of the patient's thorax and abdomen showed heterogeneous sclerotic areas in all bones consistent with prostate cancer metastasis. A bone marrow biopsy disclosed disseminated carcinomatosis of bone marrow in association with prostate cancer. Clinicians should be aware of the possibility of prostate malignancy as a cause of high bone mineral density (BMD), even in the absence of typical localized findings on plain radiographs.

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Autosomal Dominant Hyperostosis/Osteosclerosis with High Serum Alkaline Phosphatase Activity

Cited by 9 publications

References 22 publications

Oropharyngeal Skeletal Disease Accompanying High Bone Mass and Novel LRP5 Mutation

Oropharyngeal Skeletal Disease Accompanying High Bone Mass and Novel LRP5 Mutation

Novel mutation in LRP5 gene cause rare osteosclerosis: cases studies and literature review

Diffuse osteosclerosis in a patient with prostate cancer

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