High-Bone-Mass Disease and LRP5
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Boyden et al. (May 16, 2002, issue)1 report cosegregation of a syndrome of high bone density, jaw enlargement, and torus palatinus with a missense mutation — a G-to-T substitution at position 512, encoding a glycine-to-valine substitution at amino acid residue 171 (G171V) — in the gene encoding low-density lipoprotein receptor–related protein 5 (LRP5). This autosomal dominant condition seemed benign, enhancing skeletal mass without causing complications of osteopetrosis. Genealogic studies showed no relationship with the healthy kindred with high bone mass described in 1997 by Johnson et al.2 and documented as having the identical LRP5 V171 mutation by Little et al., also in 2002.3 Increased Wnt signaling, leading to stimulation of osteoblasts by diminished antagonism of LRP5 by Dickkopf (Dkk), seemed to account for both the syndromic and the nonsyndromic phenotypes.1,4 (Osteoporosis–pseudoglioma, characterized by low bone mass and congenital blindness, is caused by autosomal recessive inheritance of deactivating mutations in LRP5.4) However, in 2003, Van Wesenbeeck et al.5 reported six novel LRP5 missense mutations, also involving LRP5's first "B-propeller" module, in persons from the Americas and Europe, some of whom had clinically significant dense bone disease.
A 37-year-old woman was referred in 2003 because of "osteopetrosis." Congenital unilateral strabismus had required surgical correction when she was four years of age. Bell's palsy persisted after a sudden onset at the age of nine months. When she was 20 years old, pseudotumor cerebri that caused worsening headaches, visual problems, vomiting, and papilledema responded to medical therapy. When the patient was 32 years old, trigeminal neuralgia that had intensified over a four-year period improved after microvascular decompression. Magnetic resonance imaging, performed to evaluate headaches she had had since childhood, disclosed a type I Chiari malformation (Figure 1A). She had forgetfulness, recurrent eye twitching, blurred vision, impaired phonation, vertigo, and tinnitus, as well as pounding and nauseating headaches. Moving to an elevation of 2900 m (9500 ft) in Colorado had brought transient relief. Osseous tori had encased her dentition since adolescence, twice necessitating bone-chip removal from her gums (Figure 1B). Torus palatinus caused some dysphagia. Diffuse bone pain, fatigue, and paresthesias in the extremities had been treated with morphine for six months. Only her mother, who had died from fallopian cancer, reportedly had had "thickened bones" as well as headaches, fatigue, leg pains, and similar dental findings. The patient had an elongated face, broad zygomas, and a wide and deep mandible.
Figure 1. Radiographic Studies.
A magnetic resonance imaging scan (Panel A) shows a markedly thickened calvarium that obliterates the diploic space (thin arrows). All the calvarial bones are affected. A type I Chiari malformation (dashed line and thick arrow) features a 4-to-6-mm cerebellar tonsil herniation. A computed tomographic scan (Panel B) shows mandibular (and maxillary) teeth encased in excessive bone, both buccally and lingually. Also visible is the thickened outer cortex of the jaw with unusual, anterior bone excrescences arising from the superficial aspects of the alveolar ridges (arrows). This study also revealed a small torus palatinus (not shown).
Radiographs revealed a dense skeleton, marked thickening of the skull, including the calvarium and base, and cortical widening that narrowed the medullary cavities of the long bones (endosteal hyperostosis). The z scores for bone mineral density, assessed by dual-energy x-ray absorptiometry (Lunar DPX-L), were 6.1 and 7.4 in the total hip and from L1 to L7 in the spine, respectively (approximately 175 percent of the average scores among age-matched women). Biochemical measures of skeletal formation, serum bone-specific alkaline phosphatase (9 IU per liter [normal range, 3 to 38]) and osteocalcin (11.4 pg per milliliter [normal range, 3.1 to 13.7]) suggested that osteoblast activity was normal. Polymerase-chain-reaction amplification and sequencing of exons 2, 3, and 4 of LRP5 and adjacent splice sites revealed heterozygosity for the G512T mutation (LRP5 V171).
As yet unknown nutritional, environmental, or (more likely) genetic factors condition the effects of LRP5 V171 such that gain of function of LRP5 and increased Wnt signaling in bone may not always be benign.
Michael P. Whyte, M.D.
William H. Reinus, M.D.
Steven Mumm, Ph.D.
Washington University School of Medicine
St. Louis, MO 63110
References
Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 2002;346:1513-1521.
Johnson ML, Gong G, Kimberling W, Recker SM, Kimmel DB, Recker RB. Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13). Am J Hum Genet 1997;60:1326-1332.
Little RD, Carulli JP, Del Mastro RG, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone mass trait. Am J Hum Genet 2002;70:11-19.
Patel MS, Karsenty G. Regulation of bone formation and vision by LRP5. N Engl J Med 2002;346:1572-1574.
Van Wesenbeeck L, Cleiren E, Gram J, et al. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet 2003;72:763-771.
The authors reply: Whyte and colleagues describe a patient with the same G171V mutation in LRP5 that we previously reported in the Journal. Like mutation carriers in the kindred we studied, this patient had extremely high bone density, a wide and deep mandible, and torus palatinus. In addition, she had a number of prominent neurologic complications that arose from overgrowth of the facial bones and calvarium. Although neurologic sequelae are relatively common in endosteal hyperostosis and sclerosing bone dysplasias,1 this report extends the finding to carriers of LRP5 mutations.
After the publication of our article, three apparently unrelated kindreds with extremely high bone density came to our attention. We found that two of the kindreds had the same G171V mutation reported previously and that one had a novel mutation, N198S, which was also located in the first propeller domain of LRP5. We identified 10 mutation carriers in these kindreds (Figure 1). All the affected subjects had markedly elevated bone density. All but one (in Kindred K116) had torus palatinus, and the wide, deep mandible described previously was typical. There was no history of bone fracture.
Figure 1. Pedigrees of Three Kindreds with Extremely High Bone Density.
The specific LRP5 mutation in each kindred is indicated above the pedigree. Solid and open symbols denote subjects who had the mutation and those who did not, respectively; dotted symbols subjects who were not studied; squares male kindred members; circles female members; and arrows index subjects. The first number below each symbol is the subject's age, and the second number is the z score for bone density in the lumbar spine.
Like the patient described by Whyte and colleagues, four of the subjects had neurologic complications arising from abnormal growth of bones of the calvarium and spine. Kindred K116 was self-referred by an 83-year-old physician, who had noted the similarity of his own family to the kindred described in our article. He had mild deafness and sensorimotor neuropathy of uncertain cause. Another member of the kindred had dysphonia and required surgery for spinal stenosis. One member of Kindred K115 had deafness, and a deceased affected parent (not shown in the pedigree) had had deafness, sensorimotor neuropathy, and spinal stenosis. Finally, one member of Kindred K103 had hydromyelia, a complication of a type I Chiari malformation. Six other affected subjects reported no neurologic sequelae. The surgery mentioned above and a total-hip replacement (in the index subject in Kindred K116) were difficult to perform because of the extraordinary hardness of the bone encountered — a finding that confirmed the structural integrity of the dense bones in this syndrome.
These findings increase to eight the number of different mutations in LRP5 that cause high bone density. The remarkable clustering of these mutations in the first propeller domain of LRP52 supports efforts to develop small molecules that mimic the effects of these mutations as a means of treating or preventing osteoporosis. The finding that neurologic sequelae develop in some patients with this syndrome suggests that there are upper limits for the bone density levels one might seek to achieve with such treatment.
Lynn M. Boyden, Ph.D.
Karl Insogna, M.D.
Richard P. Lifton, M.D., Ph.D.
Yale University School of Medicine
New Haven, CT 06520
References
Perez-Vicente JA, Rodriguez de Castro E, Lafuente J, Mateo MM, Gimenez-Roldan S. Autosomal dominant endosteal hyperostosis: report of a Spanish family with neurological involvement. Clin Genet 1987;31:161-169.
Van Wesenbeeck L, Cleiren E, Gram J, et al. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet 2003;72:763-771.
濞ｅ洠鍓濇导鍛閸涱剛杩旈柛娆忓€介埀顒€鍠涚槐婵囩▔瀹ュ棛鈧垶骞嬮幇顏呭床濞达絾娲戠粻锝咁嚈妤︽鍞撮柕鍡曠劍鐢綊鎳￠幇顓炵仐闁圭ǹ娲ょ槐鈺呭Υ閸屾稒鐎紒鏃傚Х婢ф寮堕崘銊ф剑濞存粌楠哥敮顐︽媼濡炲墽绋婇柡澶婂暕濮瑰鏁嶅畝鍐仧闁诡喓鍔忛缁樼▔閻戞﹩鍔冮柡鍌氭矗缁楀鈧绮忛～锕傚绩鐠鸿櫣绉垮〒姘☉閵囧洨鈧娉涢崢銈囨嫻瑜版帗顫夐悹鍥︾串缁辨繄鎷犻悜钘変粡濞寸姾鍩栭崹銊╂偨娴ｅ啰妯堥梺顐ｆ皑閻擄繝骞嬮幋婊勭拨闁挎稑鏈崹婊勭椤掍焦鏆柛鎺嶅嵆閳ь剚姘ㄩ悡锟犲触鎼搭垳绀夊ù鍏兼皑閻濇盯宕￠崘鑼闁诡喓鍔庡▓鎴炴媴濠婂啯鎯傚ù鐘插濠€鎵磾閹寸姷褰查柛鎺斿█濞呭酣濡撮敓锟�A 37-year-old woman was referred in 2003 because of "osteopetrosis." Congenital unilateral strabismus had required surgical correction when she was four years of age. Bell's palsy persisted after a sudden onset at the age of nine months. When she was 20 years old, pseudotumor cerebri that caused worsening headaches, visual problems, vomiting, and papilledema responded to medical therapy. When the patient was 32 years old, trigeminal neuralgia that had intensified over a four-year period improved after microvascular decompression. Magnetic resonance imaging, performed to evaluate headaches she had had since childhood, disclosed a type I Chiari malformation (Figure 1A). She had forgetfulness, recurrent eye twitching, blurred vision, impaired phonation, vertigo, and tinnitus, as well as pounding and nauseating headaches. Moving to an elevation of 2900 m (9500 ft) in Colorado had brought transient relief. Osseous tori had encased her dentition since adolescence, twice necessitating bone-chip removal from her gums (Figure 1B). Torus palatinus caused some dysphagia. Diffuse bone pain, fatigue, and paresthesias in the extremities had been treated with morphine for six months. Only her mother, who had died from fallopian cancer, reportedly had had "thickened bones" as well as headaches, fatigue, leg pains, and similar dental findings. The patient had an elongated face, broad zygomas, and a wide and deep mandible.
Figure 1. Radiographic Studies.
A magnetic resonance imaging scan (Panel A) shows a markedly thickened calvarium that obliterates the diploic space (thin arrows). All the calvarial bones are affected. A type I Chiari malformation (dashed line and thick arrow) features a 4-to-6-mm cerebellar tonsil herniation. A computed tomographic scan (Panel B) shows mandibular (and maxillary) teeth encased in excessive bone, both buccally and lingually. Also visible is the thickened outer cortex of the jaw with unusual, anterior bone excrescences arising from the superficial aspects of the alveolar ridges (arrows). This study also revealed a small torus palatinus (not shown).
Radiographs revealed a dense skeleton, marked thickening of the skull, including the calvarium and base, and cortical widening that narrowed the medullary cavities of the long bones (endosteal hyperostosis). The z scores for bone mineral density, assessed by dual-energy x-ray absorptiometry (Lunar DPX-L), were 6.1 and 7.4 in the total hip and from L1 to L7 in the spine, respectively (approximately 175 percent of the average scores among age-matched women). Biochemical measures of skeletal formation, serum bone-specific alkaline phosphatase (9 IU per liter [normal range, 3 to 38]) and osteocalcin (11.4 pg per milliliter [normal range, 3.1 to 13.7]) suggested that osteoblast activity was normal. Polymerase-chain-reaction amplification and sequencing of exons 2, 3, and 4 of LRP5 and adjacent splice sites revealed heterozygosity for the G512T mutation (LRP5 V171).
As yet unknown nutritional, environmental, or (more likely) genetic factors condition the effects of LRP5 V171 such that gain of function of LRP5 and increased Wnt signaling in bone may not always be benign.
Michael P. Whyte, M.D.
William H. Reinus, M.D.
Steven Mumm, Ph.D.
Washington University School of Medicine
St. Louis, MO 63110
References
Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 2002;346:1513-1521.
Johnson ML, Gong G, Kimberling W, Recker SM, Kimmel DB, Recker RB. Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13). Am J Hum Genet 1997;60:1326-1332.
Little RD, Carulli JP, Del Mastro RG, et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone mass trait. Am J Hum Genet 2002;70:11-19.
Patel MS, Karsenty G. Regulation of bone formation and vision by LRP5. N Engl J Med 2002;346:1572-1574.
Van Wesenbeeck L, Cleiren E, Gram J, et al. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet 2003;72:763-771.
The authors reply: Whyte and colleagues describe a patient with the same G171V mutation in LRP5 that we previously reported in the Journal. Like mutation carriers in the kindred we studied, this patient had extremely high bone density, a wide and deep mandible, and torus palatinus. In addition, she had a number of prominent neurologic complications that arose from overgrowth of the facial bones and calvarium. Although neurologic sequelae are relatively common in endosteal hyperostosis and sclerosing bone dysplasias,1 this report extends the finding to carriers of LRP5 mutations.
After the publication of our article, three apparently unrelated kindreds with extremely high bone density came to our attention. We found that two of the kindreds had the same G171V mutation reported previously and that one had a novel mutation, N198S, which was also located in the first propeller domain of LRP5. We identified 10 mutation carriers in these kindreds (Figure 1). All the affected subjects had markedly elevated bone density. All but one (in Kindred K116) had torus palatinus, and the wide, deep mandible described previously was typical. There was no history of bone fracture.
Figure 1. Pedigrees of Three Kindreds with Extremely High Bone Density.
The specific LRP5 mutation in each kindred is indicated above the pedigree. Solid and open symbols denote subjects who had the mutation and those who did not, respectively; dotted symbols subjects who were not studied; squares male kindred members; circles female members; and arrows index subjects. The first number below each symbol is the subject's age, and the second number is the z score for bone density in the lumbar spine.
Like the patient described by Whyte and colleagues, four of the subjects had neurologic complications arising from abnormal growth of bones of the calvarium and spine. Kindred K116 was self-referred by an 83-year-old physician, who had noted the similarity of his own family to the kindred described in our article. He had mild deafness and sensorimotor neuropathy of uncertain cause. Another member of the kindred had dysphonia and required surgery for spinal stenosis. One member of Kindred K115 had deafness, and a deceased affected parent (not shown in the pedigree) had had deafness, sensorimotor neuropathy, and spinal stenosis. Finally, one member of Kindred K103 had hydromyelia, a complication of a type I Chiari malformation. Six other affected subjects reported no neurologic sequelae. The surgery mentioned above and a total-hip replacement (in the index subject in Kindred K116) were difficult to perform because of the extraordinary hardness of the bone encountered — a finding that confirmed the structural integrity of the dense bones in this syndrome.
These findings increase to eight the number of different mutations in LRP5 that cause high bone density. The remarkable clustering of these mutations in the first propeller domain of LRP52 supports efforts to develop small molecules that mimic the effects of these mutations as a means of treating or preventing osteoporosis. The finding that neurologic sequelae develop in some patients with this syndrome suggests that there are upper limits for the bone density levels one might seek to achieve with such treatment.
Lynn M. Boyden, Ph.D.
Karl Insogna, M.D.
Richard P. Lifton, M.D., Ph.D.
Yale University School of Medicine
New Haven, CT 06520
References
Perez-Vicente JA, Rodriguez de Castro E, Lafuente J, Mateo MM, Gimenez-Roldan S. Autosomal dominant endosteal hyperostosis: report of a Spanish family with neurological involvement. Clin Genet 1987;31:161-169.
Van Wesenbeeck L, Cleiren E, Gram J, et al. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet 2003;72:763-771.
|
鐎甸偊鍠曟穱濠囧棘閸モ晝褰�
闁稿繗娅曢弫鐐烘儌閻愵剙顎�
閻犲洤瀚鎴﹀礄閻樻彃缍�
闁瑰吋绮庨崒銊╁即閺夋埈妯�
闁规亽鍔岄悺銊х磼濞嗘劖绠欓柛娆欐嫹
闁告梻濮撮崣鍡涘绩閹増顥�
|