382 J. N. Harvey et a / .
References Angervall, L., Enerback, L. & Knutson, H. (1973) Chondrosarcoma of soft tissue origin. Cancer, 32,507-5 13. Charhon, S.A., Chapuy, M.C., Delvin, E.E., Valentin-Opran, A., Edouard, C.M. & Meunier, P.J. (1983) Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma with special reference to osteomalacia. Cancer, 51,918-924. Drezner, M.K. & Feinglos, M.N. (1977) Osteomalacia due to 1,25 di-hydroxy cholecalciferol deficiency: association with a giant cell tumour of bone. Journal of Clinical Investigation, 60,1046-1053. Firth, R.G., Grant, C.S. & Riggs, B.L. (1985) Development of hypercalcaemic hyperparathyroidism after long-term phosphate supplementation. American Journal of Medicine, 78,669-673. Fraser, D.R. & Kodicek, E. (1970) Unique biosynthesis by kidney of a biologically active vitamin D metabolite. Nature, 228,764-766. Hauge, B.N. (1955) Vitamin D resistant osteomalacia. Acra Medica Scandinmica, 153,271-282. Hosking, D.J., Chamberlain, M.J. & Shortland-Webb, W.R. (1975) Osteomalacia and carcinoma of prostate with major redistribution of skeletal calcium. British Journal of Radiology, 48,451456. Krane, S.M. (1965) Case records of the Massachusetts General Hospital. New England Journal of Medicine, 273,494-504. Linovitz, R.J., Resnick, D., Keissling, P., Kondon, J.J., Sehler, B., Nejdl, R.J., Rowe, J.H. & Deftos, L.J. (1976) Tumor-induced osteomalacia and rickets: a surgically curable syndrome. Journal of Bone and Joinr Surgery, 58,419423. Lyles, K.W., Berry, W.R., Haussler, M., Harrelson, J.M. & Drezner, M.K. (1980) Hypophosphataemic osteomalacia: association with prostatic carcinoma. Annals of Internal Medicine, 93,275-278.
Clinical Endocrinology (1992) 37
Miyauchi A,, Fukase, M., Tsutsumi, M. & Fujita, T. (1988) Hemangiopericytoma-induced osteomalacia: tumor transplantation in nude mice causes hypophosphatemia and tumor extracts inhibit renal 25-hydroxyvitaminD I-hydroxylase activity. Journal of Clrhical Endocrinology and Metabolism, 67,4653. Nomura, G., Koshino, Y.,Morimoto, H., Kida, H., Nomura, S. & Tamai, K.(1982) Vitamin D resistant hypophosphataemic osteomalacia associated with osteosarcoma of the mandible: report of a case. Japanese Journal of Medicine, 21, 35-39. Raskin, P., McClain, C.J. & Medsger, T.A. (1973) Hypocalcemia associated with metastatic bone disease. Archives of Internal Medicine, 132, 539-543. Ryan, E.A. & Reiss, E. (1984) Oncogenous osteomalacia. Review of the world literature of 42 cases and report of two new cases. American Journal of Medicine, 77, 501-512. Segre, G.V. & Dickersin, G.R. (1989) Case records of the Massachusetts General Hospital. New England Journal of Medicine, 321, 1812- 1821. Stanbury, S . W.(1972) Osteomalacia. Clinics in Endocrinology and Metabolism, 1:1,239-266. Taylor, H.C., Fallon, M.D. & Velasco, M.E. (1984) Oncogenic osteomalacia and inappropriate antidiuretic hormone secretion due to oat-cell carcinoma. Annals of Internal Medicine, 101,786788. Willis, R.A. (1967) Parhology of Tumours, Fourth edition. Butterworths, London. Wyman, A.L., Paradinas, F.J. & Daly, J.R. (1977) Hypophosphataemic osteomalacia associated with a malignant tumour of the tibia: report of a case. Journal of Clinical Parhology. 30,328-335.
Commentary
Tumour induced osteomalacia M. Hewison, R. Karmall and J. L. H. O’Rlordan University College and Middlesex School of Medicine, London
Recognition of osteomalacia as a serious case of disability is regrettably often delayed unreasonably. Establishing the cause of osteomalacia again often takes far too long and the contribution of hypophosphataemia to the problem is frequently underestimated or overlooked, perhaps being attributed without adequate support to be due to secondary hyperparathyroidism. Considering how often serum phosCorrespondence: Dr M. Hewison, Department of Medicine, University College and Middlesex School of Medicine, 5th Floor, Jules Thorn Institute, The Middlesex Hospital, Mortimer Street, London WIM 8AA, UK.
phate is measured, remarkably few decisions are made on the basis of it (apart from treatment of hyperphosphataemia in chronic renal failure), and this makes it all the worse that measurement of serum phosphate is ignored when it actually gives the key to the problem. It is reasonable in an adult with late-onset hypophosphataemic osteomalacia to proceed on the basis that the condition is due to the presence of a tumour, leading to a renal tubular leak, if there is no family history of X-linked hypophosphataemic rickets. In this issue of the Journal, Harvey et al. (1992) describe a case in which there was a malignant chondroblastoma associated with hypophosphataemic osteomalacia; that tumour is also called
Turnour induced osteornalacia 383
a ‘mixed tumour of the thyroid gland’. More commonly, the tumour causing this syndrome is an haemangiopericytoma, though a variety of tumours can cause it. In the case described by Harvey et al. the symptoms of osteomalacia existed for a couple of years before a tumour was found in the neck and resection of the tumour led to clinical improvement for about 6 years. The diagnosis of osteomalacia seems only to have been made 12 years after symptoms first began. It is important to realize that the tumours causing the syndrome of ‘oncogenous osteomalacia’ can occur anywhere-on the sole of the foot, the anterior abdominal wall, the back of the neck, in the nasal sinuses, or within the skull. Careful clinical examination for odd lumps is essential and may need to be supplemented with CT or MRI scans, which may reveal an unexpected tumour. Even so, the tumour may not be detectable for many years after the diagnosis of hypophosphataemic osteomalacia has been made. Examination and investigation have to be repeated periodically. If a tumour can be found and resected, then long-lasting cure is often (but not always) feasible. If no tumour can be found, then a reasonable response to combination of phosphate supplement and treatment with the active form of vitamin D, namely 1,25-dihydroxyvitarnin D (1 ,25(OH)2D), can be effectiveat least for a while. There are two biochemical features that are the hallmark of this condition. One of them has already been mentioned, namely hypophosphataemia; the other is the presence of a low circulating concentration of 1,25(OH)2D. Unless a patient is ingesting (albeit covertly) phosphate binders then hypophosphataemia is due to a renal tubular defect in phosphate handling, a so-called ‘phosphate leak’, leading to phosphaturia and resulting in hypophosphataemia. In animal experiments, hypophosphataemia stimulates lahydroxylation, so the low circulating concentration of I ,25(OH)zD in patients with oncogenous osteomalacia can be regarded as paradoxical. The low 1,25(OH)2Dcould be due to either suppression of lu-hydroxylation or to accelerated destruction of 1,25(OH)2D.Another striking feature of the syndrome is the rapid rise in 1,25(OH)2D that occurs when the tumour is resected. Within hours, theconcentration of 1,25(OH)zD can become supranormal. The rise in 1,25(OH)2D (Fig. 1) seems to precede the rise in phosphate and so might be thought to be independent of phosphate. The concentration of 1,25(OH)?D can remain elevated for many months after the resection of the tumour (for reasons that are not clear) and can persist until the bone disease has healed. Since resection of the tumour leads to a rise in phosphate and a rise in 1,25(OH)2D,it is reasonable to suggest that the tumour was secreting a hormone that was stimulating phosphate excretion and leading to a reduction of
1,25(OH)2D. This syndrome would therefore be due to a hormone excess. Characterization of this hormone (or hormones) is not at all easy as the tumours are difficult to maintain in tissue culture. An important contribution was that of Miyauchi et al. (1988) who were able to maintain for a short while one of these tumours in athymic nude mice. They were able to demonstrate hypophosphataemia in the recipient mice and extracts of the tumour were shown to inhibit 1a-hydroxylase activity in cultured mouse kidney cells. This
500 400
300 200 I00
0 1.0
0.5
0
1.5
I 2 3 , 4
5
I. 0 0.5
I000
-25
0
25
50
75
100
125
150
Time before and after surgery (days) Fig. 1 Changes in serum 1,25(OH)zD, phosphate and alkaline phosphatase in a patient with a malignant fibrohistiocytoma of the right frontal sinus causing hypophosphataemic osteomalacia. Within 12 hours of a right fronto-ethmoidectomy 1,25(OH)lDlevels were supranormal whereas serum phosphate rose more slowly and became normal after 5 days. Serum 1,25(OH)2Dremained above normal for 4 months while the bone disease was healing. Serum calcium remained in the low/normal region after removal of the tumour. Insets show expansion of 1,25(OH)2D and phosphate results for the first 5 days after surgery. The patient had been diagnosed as having osteomalacia 4 years earlier and since then had been treated with loo00 units vitamin D daily. Thismay explain why serum 1,25(OH)zDlevels were not depressed.
384
M. Hewison et el.
effect was resistant to trypsin treatment which suggested that the hormone was a small peptide, although further characterization was not possible and it is not clear whether the putative hormone has any normal physiological role in phosphate homeostasis and regulation of vitamin D metabolism. It is tempting to compare this with the hormone that causes hypercalcaemia in malignancy: ‘parathyroid hormone-related-peptide’ (PTHrP) which was first found in malignant tumours, but is now known to have physiological roles, for example in fetal calcium homeostasis (Rodda et uf., 1988). Another study, by Fukomoto et al. (1989), has shown that extracts of tumours responsible for hypercalcaemia of malignancy are able to inhibit directly the production of 1,25(OH)*D and it is therefore interesting to speculate on whether this lwhydroxylase inhibitory activity is due to one of the alternative PTHrP gene products or whether it is a completely different substance. Oncogenous osteomalacia can also be compared with Xlinked hypophosphataemic rickets. This is also characterized by a renal tubular defect in phosphate handling and it is sometimes said that the concentrations of I ,25(OH)*D are inappropriately low in this condition. The gene causing this condition is on the short arm of the X-chromosome and close flanking markers have been identified (Rowe et ul., 1992). An important advance in phosphate metabolism recently has been the cloning of the sodium-dependent phosphate transporter in the rabbit kidney (Werner et al., 1991). The chromosomal localization of the gene for that transporter is not yet clear, but if it were on the X-chromosome it might be relevant to X-linked hypophosphataemic rickets. There are animal models for that condition, the HYP mouse and the GYR mouse; both of these get rickets due to hypophosphataemia; the GYR mouse in addition shows gyratory behaviour. These mice might have a primary renal tubular defect
Clinical Endocrinology (1992) 37
causing the phosphate leak, but there is also some evidence (from parabiosis studies) that the disorder might be due to a humoral factor (Meyer et nl., 1989). If that were the case oncogenous osteomalacia and X-linked hypophosphataemia might have a common endocrine basis. References Fukomoto, S., Matsumoto, T., Yamoto, H., Kawashima, H., Ueyama, Y., Tamaoki, N. & Ogata, E. (1989) Suppression of serum 1,25-dihydroxyvitamin D in humoral hypercalcaemia of malignancy is caused by elaboration of a factor that inhibits renal 1,25-dihydroxyvitamin Dj production. Endocrinology, 124,20572062. Harvey, J.N., Gray, C. & Belchetz, P.E. (1992) Oncogenous osteomalacia and malignancy. Clinical Endocrinology, 37, 379384. Meyer (Jr), R.A., Meyer, M.H. & Gray, R.W. (1989) Parabiosis suggests a humoral factor is involved in X-linked hypophosphataemia in mice. Journal of Bone and Mineral Research, 4,493-500. Miyauchi, A., Fukase, M., Tsutsumi, M. & Fujita, T. (1988) Hemangiopericytoma-induced osteomalacia: tumor transplantation in nude mice causes hypophosphataemia and tumor extracts inhibit renal 25-hydroxyvitamin D I-alpha-hydroxylase activity. Journal of Clinical Endocrinology and Metabolism, 67,4653. Rodda,C.P.,Heath, J.A., Ebeling,P.R.,Moseley, J.M.,Care,A.D., Caple, I.W. & Martin, T.J. (1988) Regulation of fetal calcium metabolism: evidence for a novel parathyroid hormone-related protein promoting placental calcium transport. Journal of Bone and Mineral Research, 3 (Suppl.), 571 (abstract). Rowe, P.S.N., Read, A.P., Mountford, R.,Benham, F., Kruse, T.A., Camarino, G., Davies, K.E. & ORiordan, J.L.H. (1992) DNA markers for hypophosphataemic rickets and possible locus heterogeneity. Human Genetics (in press). Werner, A., Moore, M.L., Mante, N., Biber, J., Semenza, G. & Murer, H. (199t) Cloning and expression of cDNA for Na/Pi cotransport system of kidney cortex. Proceedings of the National Academy of Sciences USA, 88,9608-9612.
References Angervall, L., Enerback, L. & Knutson, H. (1973) Chondrosarcoma of soft tissue origin. Cancer, 32,507-5 13. Charhon, S.A., Chapuy, M.C., Delvin, E.E., Valentin-Opran, A., Edouard, C.M. & Meunier, P.J. (1983) Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma with special reference to osteomalacia. Cancer, 51,918-924. Drezner, M.K. & Feinglos, M.N. (1977) Osteomalacia due to 1,25 di-hydroxy cholecalciferol deficiency: association with a giant cell tumour of bone. Journal of Clinical Investigation, 60,1046-1053. Firth, R.G., Grant, C.S. & Riggs, B.L. (1985) Development of hypercalcaemic hyperparathyroidism after long-term phosphate supplementation. American Journal of Medicine, 78,669-673. Fraser, D.R. & Kodicek, E. (1970) Unique biosynthesis by kidney of a biologically active vitamin D metabolite. Nature, 228,764-766. Hauge, B.N. (1955) Vitamin D resistant osteomalacia. Acra Medica Scandinmica, 153,271-282. Hosking, D.J., Chamberlain, M.J. & Shortland-Webb, W.R. (1975) Osteomalacia and carcinoma of prostate with major redistribution of skeletal calcium. British Journal of Radiology, 48,451456. Krane, S.M. (1965) Case records of the Massachusetts General Hospital. New England Journal of Medicine, 273,494-504. Linovitz, R.J., Resnick, D., Keissling, P., Kondon, J.J., Sehler, B., Nejdl, R.J., Rowe, J.H. & Deftos, L.J. (1976) Tumor-induced osteomalacia and rickets: a surgically curable syndrome. Journal of Bone and Joinr Surgery, 58,419423. Lyles, K.W., Berry, W.R., Haussler, M., Harrelson, J.M. & Drezner, M.K. (1980) Hypophosphataemic osteomalacia: association with prostatic carcinoma. Annals of Internal Medicine, 93,275-278.
Clinical Endocrinology (1992) 37
Miyauchi A,, Fukase, M., Tsutsumi, M. & Fujita, T. (1988) Hemangiopericytoma-induced osteomalacia: tumor transplantation in nude mice causes hypophosphatemia and tumor extracts inhibit renal 25-hydroxyvitaminD I-hydroxylase activity. Journal of Clrhical Endocrinology and Metabolism, 67,4653. Nomura, G., Koshino, Y.,Morimoto, H., Kida, H., Nomura, S. & Tamai, K.(1982) Vitamin D resistant hypophosphataemic osteomalacia associated with osteosarcoma of the mandible: report of a case. Japanese Journal of Medicine, 21, 35-39. Raskin, P., McClain, C.J. & Medsger, T.A. (1973) Hypocalcemia associated with metastatic bone disease. Archives of Internal Medicine, 132, 539-543. Ryan, E.A. & Reiss, E. (1984) Oncogenous osteomalacia. Review of the world literature of 42 cases and report of two new cases. American Journal of Medicine, 77, 501-512. Segre, G.V. & Dickersin, G.R. (1989) Case records of the Massachusetts General Hospital. New England Journal of Medicine, 321, 1812- 1821. Stanbury, S . W.(1972) Osteomalacia. Clinics in Endocrinology and Metabolism, 1:1,239-266. Taylor, H.C., Fallon, M.D. & Velasco, M.E. (1984) Oncogenic osteomalacia and inappropriate antidiuretic hormone secretion due to oat-cell carcinoma. Annals of Internal Medicine, 101,786788. Willis, R.A. (1967) Parhology of Tumours, Fourth edition. Butterworths, London. Wyman, A.L., Paradinas, F.J. & Daly, J.R. (1977) Hypophosphataemic osteomalacia associated with a malignant tumour of the tibia: report of a case. Journal of Clinical Parhology. 30,328-335.
Commentary
Tumour induced osteomalacia M. Hewison, R. Karmall and J. L. H. O’Rlordan University College and Middlesex School of Medicine, London
Recognition of osteomalacia as a serious case of disability is regrettably often delayed unreasonably. Establishing the cause of osteomalacia again often takes far too long and the contribution of hypophosphataemia to the problem is frequently underestimated or overlooked, perhaps being attributed without adequate support to be due to secondary hyperparathyroidism. Considering how often serum phosCorrespondence: Dr M. Hewison, Department of Medicine, University College and Middlesex School of Medicine, 5th Floor, Jules Thorn Institute, The Middlesex Hospital, Mortimer Street, London WIM 8AA, UK.
phate is measured, remarkably few decisions are made on the basis of it (apart from treatment of hyperphosphataemia in chronic renal failure), and this makes it all the worse that measurement of serum phosphate is ignored when it actually gives the key to the problem. It is reasonable in an adult with late-onset hypophosphataemic osteomalacia to proceed on the basis that the condition is due to the presence of a tumour, leading to a renal tubular leak, if there is no family history of X-linked hypophosphataemic rickets. In this issue of the Journal, Harvey et al. (1992) describe a case in which there was a malignant chondroblastoma associated with hypophosphataemic osteomalacia; that tumour is also called
Turnour induced osteornalacia 383
a ‘mixed tumour of the thyroid gland’. More commonly, the tumour causing this syndrome is an haemangiopericytoma, though a variety of tumours can cause it. In the case described by Harvey et al. the symptoms of osteomalacia existed for a couple of years before a tumour was found in the neck and resection of the tumour led to clinical improvement for about 6 years. The diagnosis of osteomalacia seems only to have been made 12 years after symptoms first began. It is important to realize that the tumours causing the syndrome of ‘oncogenous osteomalacia’ can occur anywhere-on the sole of the foot, the anterior abdominal wall, the back of the neck, in the nasal sinuses, or within the skull. Careful clinical examination for odd lumps is essential and may need to be supplemented with CT or MRI scans, which may reveal an unexpected tumour. Even so, the tumour may not be detectable for many years after the diagnosis of hypophosphataemic osteomalacia has been made. Examination and investigation have to be repeated periodically. If a tumour can be found and resected, then long-lasting cure is often (but not always) feasible. If no tumour can be found, then a reasonable response to combination of phosphate supplement and treatment with the active form of vitamin D, namely 1,25-dihydroxyvitarnin D (1 ,25(OH)2D), can be effectiveat least for a while. There are two biochemical features that are the hallmark of this condition. One of them has already been mentioned, namely hypophosphataemia; the other is the presence of a low circulating concentration of 1,25(OH)2D. Unless a patient is ingesting (albeit covertly) phosphate binders then hypophosphataemia is due to a renal tubular defect in phosphate handling, a so-called ‘phosphate leak’, leading to phosphaturia and resulting in hypophosphataemia. In animal experiments, hypophosphataemia stimulates lahydroxylation, so the low circulating concentration of I ,25(OH)zD in patients with oncogenous osteomalacia can be regarded as paradoxical. The low 1,25(OH)2Dcould be due to either suppression of lu-hydroxylation or to accelerated destruction of 1,25(OH)2D.Another striking feature of the syndrome is the rapid rise in 1,25(OH)2D that occurs when the tumour is resected. Within hours, theconcentration of 1,25(OH)zD can become supranormal. The rise in 1,25(OH)2D (Fig. 1) seems to precede the rise in phosphate and so might be thought to be independent of phosphate. The concentration of 1,25(OH)?D can remain elevated for many months after the resection of the tumour (for reasons that are not clear) and can persist until the bone disease has healed. Since resection of the tumour leads to a rise in phosphate and a rise in 1,25(OH)2D,it is reasonable to suggest that the tumour was secreting a hormone that was stimulating phosphate excretion and leading to a reduction of
1,25(OH)2D. This syndrome would therefore be due to a hormone excess. Characterization of this hormone (or hormones) is not at all easy as the tumours are difficult to maintain in tissue culture. An important contribution was that of Miyauchi et al. (1988) who were able to maintain for a short while one of these tumours in athymic nude mice. They were able to demonstrate hypophosphataemia in the recipient mice and extracts of the tumour were shown to inhibit 1a-hydroxylase activity in cultured mouse kidney cells. This
500 400
300 200 I00
0 1.0
0.5
0
1.5
I 2 3 , 4
5
I. 0 0.5
I000
-25
0
25
50
75
100
125
150
Time before and after surgery (days) Fig. 1 Changes in serum 1,25(OH)zD, phosphate and alkaline phosphatase in a patient with a malignant fibrohistiocytoma of the right frontal sinus causing hypophosphataemic osteomalacia. Within 12 hours of a right fronto-ethmoidectomy 1,25(OH)lDlevels were supranormal whereas serum phosphate rose more slowly and became normal after 5 days. Serum 1,25(OH)2Dremained above normal for 4 months while the bone disease was healing. Serum calcium remained in the low/normal region after removal of the tumour. Insets show expansion of 1,25(OH)2D and phosphate results for the first 5 days after surgery. The patient had been diagnosed as having osteomalacia 4 years earlier and since then had been treated with loo00 units vitamin D daily. Thismay explain why serum 1,25(OH)zDlevels were not depressed.
384
M. Hewison et el.
effect was resistant to trypsin treatment which suggested that the hormone was a small peptide, although further characterization was not possible and it is not clear whether the putative hormone has any normal physiological role in phosphate homeostasis and regulation of vitamin D metabolism. It is tempting to compare this with the hormone that causes hypercalcaemia in malignancy: ‘parathyroid hormone-related-peptide’ (PTHrP) which was first found in malignant tumours, but is now known to have physiological roles, for example in fetal calcium homeostasis (Rodda et uf., 1988). Another study, by Fukomoto et al. (1989), has shown that extracts of tumours responsible for hypercalcaemia of malignancy are able to inhibit directly the production of 1,25(OH)*D and it is therefore interesting to speculate on whether this lwhydroxylase inhibitory activity is due to one of the alternative PTHrP gene products or whether it is a completely different substance. Oncogenous osteomalacia can also be compared with Xlinked hypophosphataemic rickets. This is also characterized by a renal tubular defect in phosphate handling and it is sometimes said that the concentrations of I ,25(OH)*D are inappropriately low in this condition. The gene causing this condition is on the short arm of the X-chromosome and close flanking markers have been identified (Rowe et ul., 1992). An important advance in phosphate metabolism recently has been the cloning of the sodium-dependent phosphate transporter in the rabbit kidney (Werner et al., 1991). The chromosomal localization of the gene for that transporter is not yet clear, but if it were on the X-chromosome it might be relevant to X-linked hypophosphataemic rickets. There are animal models for that condition, the HYP mouse and the GYR mouse; both of these get rickets due to hypophosphataemia; the GYR mouse in addition shows gyratory behaviour. These mice might have a primary renal tubular defect
Clinical Endocrinology (1992) 37
causing the phosphate leak, but there is also some evidence (from parabiosis studies) that the disorder might be due to a humoral factor (Meyer et nl., 1989). If that were the case oncogenous osteomalacia and X-linked hypophosphataemia might have a common endocrine basis. References Fukomoto, S., Matsumoto, T., Yamoto, H., Kawashima, H., Ueyama, Y., Tamaoki, N. & Ogata, E. (1989) Suppression of serum 1,25-dihydroxyvitamin D in humoral hypercalcaemia of malignancy is caused by elaboration of a factor that inhibits renal 1,25-dihydroxyvitamin Dj production. Endocrinology, 124,20572062. Harvey, J.N., Gray, C. & Belchetz, P.E. (1992) Oncogenous osteomalacia and malignancy. Clinical Endocrinology, 37, 379384. Meyer (Jr), R.A., Meyer, M.H. & Gray, R.W. (1989) Parabiosis suggests a humoral factor is involved in X-linked hypophosphataemia in mice. Journal of Bone and Mineral Research, 4,493-500. Miyauchi, A., Fukase, M., Tsutsumi, M. & Fujita, T. (1988) Hemangiopericytoma-induced osteomalacia: tumor transplantation in nude mice causes hypophosphataemia and tumor extracts inhibit renal 25-hydroxyvitamin D I-alpha-hydroxylase activity. Journal of Clinical Endocrinology and Metabolism, 67,4653. Rodda,C.P.,Heath, J.A., Ebeling,P.R.,Moseley, J.M.,Care,A.D., Caple, I.W. & Martin, T.J. (1988) Regulation of fetal calcium metabolism: evidence for a novel parathyroid hormone-related protein promoting placental calcium transport. Journal of Bone and Mineral Research, 3 (Suppl.), 571 (abstract). Rowe, P.S.N., Read, A.P., Mountford, R.,Benham, F., Kruse, T.A., Camarino, G., Davies, K.E. & ORiordan, J.L.H. (1992) DNA markers for hypophosphataemic rickets and possible locus heterogeneity. Human Genetics (in press). Werner, A., Moore, M.L., Mante, N., Biber, J., Semenza, G. & Murer, H. (199t) Cloning and expression of cDNA for Na/Pi cotransport system of kidney cortex. Proceedings of the National Academy of Sciences USA, 88,9608-9612.
