Refinement of the 12q14 microdeletion syndrome: primordial dwarfism and developmental delay with or without osteopoikilosis (original) (raw)

European Journal of Human Genetics volume 17, pages 1141–1147 (2009)Cite this article

Abstract

In their studies on the molecular basis of osteopoikilosis, Menten et al have identified three individuals with microdeletions on chromosome 12q14.4, which removed several genes including LEMD3, the osteopoikilosis gene. In addition to osteopoikilosis, affected individuals had growth retardation and developmental delay. We now report a smaller 12q14.4 microdeletion in a boy with severe pre and postnatal growth failure, and mild developmental delay; the patient was small at birth and presented with poor feeding and failure to thrive during the first 2 years of life, similar to the phenotype of primordial dwarfism or severe Silver-Russell syndrome (SRS). The 12q14 deletion did not include LEMD3, and no signs of osteopoikilosis were observed on skeletal radiographs. Among the deleted genes, HMGA2 is of particular interest in relationship to the aberrant somatic growth in our patient, as HMGA2 variants have been linked to stature variations in the general population and loss of function of Hmga2 in the mouse results in the pygmy phenotype that combines pre and postnatal growth failure, with resistance to the adipogenic effect of overfeeding. Sequencing of the remaining HMGA2 allele in our patient showed a normal sequence, suggesting that HMGA2 haploinsufficiency may be sufficient to produce the aberrant growth phenotype. We conclude that the 12q14.4 microdeletion syndrome can occur with or without deletion of LEMD3 gene; in _LEMD3_-intact cases, the phenotype includes primordial short stature and failure to thrive with moderate developmental delay, but osteopoikilosis is absent. Such cases will likely be diagnosed as Silver-Russell-like or as primordial dwarfism.

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Acknowledgements

This study was supported by the German BMBF Rare Diseases network SKELNET (project GFGN01141901) and by the European Community (FP6, ‘EuroGrow’ project, LSHM-CT-2007–037471). Dr. Mari was recipient of a study grant from the Deutscher Akademischer Austauschdienst (DAAD) and of a research grant from the University of Siena (PAR 2006).

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Authors and Affiliations

  1. Centre for Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
    Francesca Mari, Pia Hermanns, Sheila Unger, Bernhard Zabel & Andrea Superti-Furga
  2. Department of Molecular Biology, Medical Genetics, University of Siena, Siena, Italy
    Francesca Mari & Alessandra Renieri
  3. Genetics and Molecular Medicine, University of Florence, Florence, Italy
    Maria L Giovannucci-Uzielli
  4. Department of Paediatrics, Pediatric Endocrinology Unit, University of Florence, Florence, Italy
    Fiorella Galluzzi
  5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    Daryl Scott & Brendan Lee

Authors

  1. Francesca Mari
  2. Pia Hermanns
  3. Maria L Giovannucci-Uzielli
  4. Fiorella Galluzzi
  5. Daryl Scott
  6. Brendan Lee
  7. Alessandra Renieri
  8. Sheila Unger
  9. Bernhard Zabel
  10. Andrea Superti-Furga

Corresponding author

Correspondence toAndrea Superti-Furga.

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Supplementary Information accompanies the paper on European Journal of Human Genetics website (http://www.nature.com/ejhg)

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Mari, F., Hermanns, P., Giovannucci-Uzielli, M. et al. Refinement of the 12q14 microdeletion syndrome: primordial dwarfism and developmental delay with or without osteopoikilosis.Eur J Hum Genet 17, 1141–1147 (2009). https://doi.org/10.1038/ejhg.2009.27

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