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

Sonja 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. OpitzA. 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

Research output: Contribution to journalArticle

25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2733-2742
Number of pages10
JournalAmerican Journal of Medical Genetics, Part A
Volume158 A
Issue number11
DOIs
Publication statusPublished - Nov 2012

    Fingerprint

Keywords

  • Abnormal secondary sexual development
  • Ear-patella-short stature
  • Genital underdevelopment
  • Growth
  • Growth hormone therapy
  • Meier-Gorlin syndrome

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

de Munnik, S. A., Otten, B. J., Schoots, J., Bicknell, L. S., Aftimos, S., Al-Aama, J. Y., ... Bongers, E. M. H. F. (2012). Meier-Gorlin syndrome: Growth and secondary sexual development of a microcephalic primordial dwarfism disorder. American Journal of Medical Genetics, Part A, 158 A(11), 2733-2742. https://doi.org/10.1002/ajmg.a.35681