Introduction: There is a scarcity of data on height as well as bone densitometry in humans with NOGGIN mutations. Methods: In 2 families with symphalangism, anthropometry, bone densitometry and genetic analysis of the NOGGIN gene were performed. Results: In family A, the height standard deviation scores of the affected father and son were –0.4 and 3.5, respectively. In family B, the height standard deviation scores of the affected father, twin daughters and another daughter were 1.7, 1.8, 2.4 and 1.8, respectively. In the children, percentage predicted bone mineral content (BMC) for height at the appendicular sites (total femur, femoral neck) was lower than at an axial site lumbar spine. In the 2 fathers, median bone mineral density at total femur and femoral neck was –0.3 standard deviation scores (–0.7, 0.2) and at lumbar spine the scores were –0.4 and 0.9. The children had median tibial and radial speed of sound velocities of –2.1 (–0.9 to –6.4) and –1.4 (–0.2 to –4.9), respectively. DNA analysis revealed a novel missense mutation in family A and family B, resulting in a Met190Val substitution and a Pro42Arg substitution, respectively. Conclusion: Heterozygous gene mutations in NOGGIN are associated with tall stature in children but not necessarily in adults. The appendicular BMC and speed of sound may be low in affected children but normalises by adulthood. However, axial BMC seems normal in childhood and is high in adulthood.

1.
Chen D, Ji X, Harris MA, Feng JQ, Karsenty G, Celeste AJ, Rosen V, Mundy GR, Harris SE: Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J Cell Biol 1998;142:295–305.
2.
Wall NA, Hogan BLM: TCF-B related genes in development. Curr Opin Genet Dev 1994;4:517–522.
3.
Canalis E, Economides AN, Gazzerro E: Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev 2003;24:218–235.
4.
Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN, Kwiatkowski W, Baban K, Affolter M, Vale WW, Belmonte JC, Choe S: Structural basis of BMP signaling inhibition by Noggin, a novel twelve-membered cystine knot protein. J Bone Joint Surg Am 2003;85(suppl 3):52–58.
5.
Polymeropoulos MH, Poush J, Rubenstein JR, Francomano CA: Localization of the gene (SYM1) for proximal symphalangism to human chromosome 17q21-q22. Genomics 1995;27:225–229.
6.
Brunet LJ, McMahon JA, McMahon AP, Harland RM: Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 1998;280:1455–1457.
7.
Wijgerde M, Karp S, McMahon J, McMahon AP: Noggin antagonism of BMP4 signaling controls development of the axial skeleton in the mouse. Dev Biol 2005;286:149–157.
8.
Cushing H: Hereditary anchylosis of proximal phalangeal joints (symphalangism). Genetics 1916;1:90–106.
9.
Krakow D, Reinker K, Powell B, Cantor R, Priore MA, Garber A, Lachman RS, Rimoin DL, Cohn DH: Localization of a multiple synostoses–syndrome disease gene to chromosome 17q21–22. Am J Hum Genet 1998;63:120–124.
10.
Gong Y, Krakow D, Marcelino J, Wilkin D, Chitayat D, Babul-Hirji R, Hudgins L, Cremers CW, Cremers FPM, Brunner HG, Reinker K, Rimoin DL, Cohn DH, Goodman FR, Reardon W, Patton M, Francomano CA, Warman ML: Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet 1999;21:302–304.
11.
Marcelino J, Sciortino CM, Romero MF, Ulatowski LM, Ballock RT, Economides AN, Eimon PM, Harland RM, Warman ML: Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding. Proc Natl Acad Sci USA 2001;98:11353–11358.
12.
Dixon ME, Armstrong P, Stevens DB, Bamshad M: Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism. Genet Med 2001;3:349–353.
13.
Takahashi T, Takahashi I, Komatsu M, Sawaishi Y, Nishimura G, Saito H, Takada G: Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome. Clin Gen 2001;60:447–451.
14.
Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ, Moroi SE, Milunsky JM, Lesperance MM: Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin. Am J Hum Genet 2002;71:618–624.
15.
Mangino M, Flex E, Digilio MC, Giannotti A, Dallapiccola B: Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism. Hum Mutat 2002;19:308.
16.
Styne DM: The physiology of puberty; in Brook CGD, Hindmarsh PC (eds): Clinical Pediatric Endocrinology, ed 4. Oxford, Blackwell Science, 2001, pp 140–164.
17.
Gluer CC: Quantitative ultrasound techniques for the assessment of osteoporosis: expert agreement on current status. The International Quantitative Ultrasound Consensus Group. J Bone Miner Res 1997;12:1280–1288.
18.
Zadik Z, Price D, Diamond G: Pediatric reference curves for multi-site quantitative ultrasound and its modulators. Osteoporos Int 2003;14:857–862.
19.
Felder B, Stegmann K, Schultealbert A, Geller F, Strehl E, Ermert A, Koch MC: Evaluation of BMP4 and its specific inhibitor NOG as candidates in human neural tube defects (NTDs). Eur J Hum Genet 2002;10:753–756.
20.
Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN, Kwiatkowski W, Affolter M, Vale WW, Belmonte JC, Choe S: Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 2002;420:636–642.
21.
Minina E, Wenzel HM, Kreschel C, Karp S, Gaffield W, McMahon AP, Vortkamp A: BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development 2001;128:4523–4534.
22.
King JA, Marker PC, Seung KJ, Kingsley DM: BMP5 and the molecular, skeletal, and soft-tissue alterations in short ear mice. Dev Biol 1994;166:112–122.
23.
Wu XB, Li Y, Schneider A, Yu W, Rajendren G, Iqbal J, Yamamoto M, Alam M, Brunet LJ, Blair HC, Zaidi M, Abe E: Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice. J Clin Invest 2003;112:924–934.
24.
Cao J, Venton L, Sakata T, Halloran BP: Expression of RANKL and OPG correlates with age-related bone loss in male C57BL/6 mice. J Bone Miner Res 2003;18:270–277.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.