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Meier-Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder.

Abstract
Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth.
AuthorsSonja A de Munnik, Barto J Otten, Jeroen Schoots, Louise S Bicknell, Salim Aftimos, Jumana Y Al-Aama, Yolande van Bever, Michael B Bober, George F Borm, Jill Clayton-Smith, Cheri L Deal, Alaa Y Edrees, Murray Feingold, Alan Fryer, Johanna M van Hagen, Raoul C Hennekam, Maaike C E Jansweijer, Diana Johnson, Sarina G Kant, John M Opitz, A Radha Ramadevi, Willie Reardon, Alison Ross, Pierre Sarda, Constance T R M Schrander-Stumpel, A Erik Sluiter, I Karen Temple, Paulien A Terhal, Annick Toutain, Carol A Wise, Michael Wright, David L Skidmore, Mark E Samuels, Lies H Hoefsloot, Nine V A M Knoers, Han G Brunner, Andrew P Jackson, Ernie M H F Bongers
JournalAmerican journal of medical genetics. Part A (Am J Med Genet A) Vol. 158A Issue 11 Pg. 2733-42 (Nov 2012) ISSN: 1552-4833 [Electronic] United States
PMID23023959 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Wiley Periodicals, Inc.
Chemical References
  • CDT1 protein, human
  • Cell Cycle Proteins
  • Origin Recognition Complex
  • Human Growth Hormone
Topics
  • Cell Cycle Proteins (genetics)
  • Child, Preschool
  • Cohort Studies
  • Congenital Microtia
  • Ear (abnormalities)
  • Female
  • Growth Charts
  • Growth Disorders (diagnosis, drug therapy, genetics)
  • Human Growth Hormone (blood, therapeutic use)
  • Humans
  • Infant
  • Male
  • Micrognathism (diagnosis, drug therapy, genetics)
  • Mutation
  • Origin Recognition Complex (genetics)
  • Patella (abnormalities)
  • Sexual Development (genetics)
  • Urogenital Abnormalities

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