Correspondence

High-Bone-Mass Disease and LRP5

N Engl J Med 2004; 350:2096-2099May 13, 2004

Article

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 1AFigure 1Radiographic Studies.). 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.

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

5 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   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
   CrossRef | Web of Science | Medline

3. 3

   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
   CrossRef | Web of Science | Medline

4. 4

   Patel MS, Karsenty G. Regulation of bone formation and vision by LRP5. N Engl J Med 2002;346:1572-1574
   Full Text | Web of Science | Medline

5. 5

   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
   CrossRef | Web of Science | Medline

Author/Editor Response

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 1Figure 1Pedigrees of Three Kindreds with Extremely High Bone Density.). 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.

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 LRP5 2 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

2 References

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   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
   CrossRef | Web of Science | Medline

2. 2

   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
   CrossRef | Web of Science | Medline

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