Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2001 Jan;38(1):1–6. doi: 10.1136/jmg.38.1.1

SHOX haploinsufficiency and overdosage: impact of gonadal function status

T Ogata 1, N Matsuo 1, G Nishimura 1
PMCID: PMC1734713  PMID: 11134233

Abstract

Since its discovery in 1997, knowledge about the SHOX gene has rapidly increased. In this review, we summarise clinical features and diagnostic and therapeutic implications in SHOX haploinsufficiency and overdosage. SHOX haploinsufficiency usually results in mesomelic short stature and Turner skeletal features, including Madelung deformity with puberty, in subjects with normal gonadal function. Thus, identification of early or mild signs of Madelung deformity is pivotal for the diagnosis, and gonadal suppression therapy may serve to mitigate the clinical features. By contrast, SHOX overdosage usually leads to long limbs and tall stature resulting from continued growth into the late teens in subjects with gonadal dysgenesis. Thus, the combination of tall stature and poor pubertal development is the key to diagnosis, and oestrogen therapy can help the prevention of unfavourably tall stature as well as the induction of sexual development. These findings, in conjunction with skeletal assessment in Turner syndrome and expression analysis during human embryogenesis, imply that SHOX functions as a repressor for growth plate fusion and skeletal maturation in the distal limbs and, thus, counteracts the skeletal maturing effects of oestrogens.


Keywords: SHOX; oestrogens; clinical features; practical implications

Full Text

The Full Text of this article is available as a PDF (145.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Angsusingha K., Kenny F. M., Nankin H. R., Taylor F. H. Unconjugated estrone, estradiol and FSH and LH in prepubertal and pubertal males and females. J Clin Endocrinol Metab. 1974 Jul;39(1):63–68. doi: 10.1210/jcem-39-1-63. [DOI] [PubMed] [Google Scholar]
  2. Belin V., Cusin V., Viot G., Girlich D., Toutain A., Moncla A., Vekemans M., Le Merrer M., Munnich A., Cormier-Daire V. SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). Nat Genet. 1998 May;19(1):67–69. doi: 10.1038/ng0198-67. [DOI] [PubMed] [Google Scholar]
  3. Betts P. R., Butler G. E., Donaldson M. D., Dunger D. B., Johnston D. I., Kelnar C. J., Kirk J., Price D. A., Wilton P. A decade of growth hormone treatment in girls with Turner syndrome in the UK. UK KIGS Executive Group. Arch Dis Child. 1999 Mar;80(3):221–225. doi: 10.1136/adc.80.3.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Binder G., Schwarze C. P., Ranke M. B. Identification of short stature caused by SHOX defects and therapeutic effect of recombinant human growth hormone. J Clin Endocrinol Metab. 2000 Jan;85(1):245–249. doi: 10.1210/jcem.85.1.6375. [DOI] [PubMed] [Google Scholar]
  5. Brook C. G., Mürset G., Zachmann M., Prader A. Growth in children with 45,XO Turner's syndrome. Arch Dis Child. 1974 Oct;49(10):789–795. doi: 10.1136/adc.49.10.789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Clement-Jones M., Schiller S., Rao E., Blaschke R. J., Zuniga A., Zeller R., Robson S. C., Binder G., Glass I., Strachan T. The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Hum Mol Genet. 2000 Mar 22;9(5):695–702. doi: 10.1093/hmg/9.5.695. [DOI] [PubMed] [Google Scholar]
  7. Curry C. J., Magenis R. E., Brown M., Lanman J. T., Jr, Tsai J., O'Lague P., Goodfellow P., Mohandas T., Bergner E. A., Shapiro L. J. Inherited chondrodysplasia punctata due to a deletion of the terminal short arm of an X chromosome. N Engl J Med. 1984 Oct 18;311(16):1010–1015. doi: 10.1056/NEJM198410183111603. [DOI] [PubMed] [Google Scholar]
  8. Davis R. M. Localisation of male determining factors in man: a thorough review of structural anomalies of the Y chromosome. J Med Genet. 1981 Jun;18(3):161–195. doi: 10.1136/jmg.18.3.161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dawe C., Wynne-Davies R., Fulford G. E. Clinical variation in dyschondrosteosis. A report on 13 individuals in 8 families. J Bone Joint Surg Br. 1982;64(3):377–381. doi: 10.1302/0301-620X.64B3.7096409. [DOI] [PubMed] [Google Scholar]
  10. Dewald G., Spurbeck J. L., Gordon H. Replication patterns of three isodicentric X chromosomes and an X isochromosome in human lymphocytes. Am J Med Genet. 1978;1(4):445–460. doi: 10.1002/ajmg.1320010407. [DOI] [PubMed] [Google Scholar]
  11. Even L., Bronstein V., Hochberg Z. Bone maturation in girls with Turner's syndrome. Eur J Endocrinol. 1998 Jan;138(1):59–62. doi: 10.1530/eje.0.1380059. [DOI] [PubMed] [Google Scholar]
  12. Henry A., Thorburn M. J. Madelung's deformity. A clinical and cytogenetic study. J Bone Joint Surg Br. 1967 Feb;49(1):66–73. [PubMed] [Google Scholar]
  13. Kosho T., Muroya K., Nagai T., Fujimoto M., Yokoya S., Sakamoto H., Hirano T., Terasaki H., Ohashi H., Nishimura G. Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the development of Turner syndrome. J Clin Endocrinol Metab. 1999 Dec;84(12):4613–4621. doi: 10.1210/jcem.84.12.6289. [DOI] [PubMed] [Google Scholar]
  14. LANGER L. O., Jr DYSCHONDROSTEOSIS, A HEREDITABLE BONE DYSPLASIA WITH CHARACTERISTIC ROENTGENOGRAPHIC FEATURES. Am J Roentgenol Radium Ther Nucl Med. 1965 Sep;95:178–188. doi: 10.2214/ajr.95.1.178. [DOI] [PubMed] [Google Scholar]
  15. Leppig K. A., Brown C. J., Bressler S. L., Gustashaw K., Pagon R. A., Willard H. F., Disteche C. M. Mapping of the distal boundary of the X-inactivation center in a rearranged X chromosome from a female expressing XIST. Hum Mol Genet. 1993 Jul;2(7):883–887. doi: 10.1093/hmg/2.7.883. [DOI] [PubMed] [Google Scholar]
  16. Lichtenstein J. R., Sundaram M., Burdge R. Sex-influenced expression of Madelung's deformity in a family of dyschondrosteosis. J Med Genet. 1980 Feb;17(1):41–43. doi: 10.1136/jmg.17.1.41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. MacGillivray M. H., Morishima A., Conte F., Grumbach M., Smith E. P. Pediatric endocrinology update: an overview. The essential roles of estrogens in pubertal growth, epiphyseal fusion and bone turnover: lessons from mutations in the genes for aromatase and the estrogen receptor. Horm Res. 1998;49 (Suppl 1):2–8. doi: 10.1159/000053061. [DOI] [PubMed] [Google Scholar]
  18. Ogata T., Kosho T., Wakui K., Fukushima Y., Yoshimoto M., Miharu N. Short stature homeobox-containing gene duplication on the der(X) chromosome in a female with 45,X/46,X, der(X), gonadal dysgenesis, and tall stature. J Clin Endocrinol Metab. 2000 Aug;85(8):2927–2930. doi: 10.1210/jcem.85.8.6745. [DOI] [PubMed] [Google Scholar]
  19. Ogata T., Matsuo N. Sex chromosome aberrations and stature: deduction of the principal factors involved in the determination of adult height. Hum Genet. 1993 Jul;91(6):551–562. doi: 10.1007/BF00205079. [DOI] [PubMed] [Google Scholar]
  20. Preger L., Steinbach H. L., Moskowitz P., Scully A. L., Goldberg M. B. Roentgenographic abnormalities in phenotypic females with gonadal dysgenesis. A comparison of chromatin positive patients and chromatin negative patients. Am J Roentgenol Radium Ther Nucl Med. 1968 Dec;104(4):899–910. doi: 10.2214/ajr.104.4.899. [DOI] [PubMed] [Google Scholar]
  21. Rao E., Weiss B., Fukami M., Rump A., Niesler B., Mertz A., Muroya K., Binder G., Kirsch S., Winkelmann M. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet. 1997 May;16(1):54–63. doi: 10.1038/ng0597-54. [DOI] [PubMed] [Google Scholar]
  22. Rappold G. A. The pseudoautosomal regions of the human sex chromosomes. Hum Genet. 1993 Oct;92(4):315–324. doi: 10.1007/BF01247327. [DOI] [PubMed] [Google Scholar]
  23. Rivera H., Rivas F., Garcia-Esquivel L., Moller M., Cantú J. M. Ovarian dysgenesis due to an idic(X)(q2803). Ann Genet. 1987;30(2):98–100. [PubMed] [Google Scholar]
  24. Robertson J., Faed M. J., Lamont M. A., Crowder A. M. Isodicentric X chromosome in a moderately tall patient with gonadal dysgenesis: lack of effect of functional centromere on inactivation pattern. J Med Genet. 1982 Dec;19(6):463–465. doi: 10.1136/jmg.19.6.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rouyer F., de la Chapelle A., Andersson M., Weissenbach J. An interspersed repeated sequence specific for human subtelomeric regions. EMBO J. 1990 Feb;9(2):505–514. doi: 10.1002/j.1460-2075.1990.tb08137.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schibler D., Brook C. G., Kind H. P., Zachmann M., Prader A. Growth and body proportions in 54 boys and men with Klinefelter's syndrome. Helv Paediatr Acta. 1974 Oct;29(4):325–333. [PubMed] [Google Scholar]
  27. Schiller S., Spranger S., Schechinger B., Fukami M., Merker S., Drop S. L., Tröger J., Knoblauch H., Kunze J., Seidel J. Phenotypic variation and genetic heterogeneity in Léri-Weill syndrome. Eur J Hum Genet. 2000 Jan;8(1):54–62. doi: 10.1038/sj.ejhg.5200402. [DOI] [PubMed] [Google Scholar]
  28. Shanske A., Ellison J., Vuguin P., Dowling P., Wasserman E., Heinrich J., Saenger P. Deletion of the pseudoautosomal region in a male with a unique Y;13 translocation and short stature. Am J Med Genet. 1999 Jan 1;82(1):34–39. [PubMed] [Google Scholar]
  29. Shears D. J., Vassal H. J., Goodman F. R., Palmer R. W., Reardon W., Superti-Furga A., Scambler P. J., Winter R. M. Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nat Genet. 1998 May;19(1):70–73. doi: 10.1038/ng0198-70. [DOI] [PubMed] [Google Scholar]
  30. Therman E., Sarto G. E., Patau K. Apparently isodicentric but functionally monocentric X chromosome in man. Am J Hum Genet. 1974 Jan;26(1):83–92. [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES