Clinical features of three girls with mosaic genome-wide paternal uniparental isodisomy

Authors

  • Jennifer M. Kalish,

    1. The Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    2. The Department of Cell and Developmental Biology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Laura K. Conlin,

    1. The Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Tricia R. Bhatti,

    1. The Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    2. The Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Holly A. Dubbs,

    1. The Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Mary Catherine Harris,

    1. The Division of Neonatalogy, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Kosuke Izumi,

    1. The Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Sogol Mostoufi-Moab,

    1. The Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania
    2. The Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    3. The Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Surabhi Mulchandani,

    1. The Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Sulagna Saitta,

    1. The Department of Pediatrics, Medical Genetics Institute Cedars-Sinai Medical Center, Geffen School of Medicine at UCLA, Los Angeles, California
    Search for more papers by this author
  • Lisa J. States,

    1. The Department of Radiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Daniel T. Swarr,

    1. The Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    2. The Division of Neonatalogy, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Alisha B. Wilkens,

    1. The Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Elaine H. Zackai,

    1. The Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Kristin Zelley,

    1. The Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Marisa S. Bartolomei,

    1. The Department of Cell and Developmental Biology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Kim E. Nichols,

    1. The Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania
    2. The Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Andrew A. Palladino,

    1. The Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania
    2. The Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Nancy B. Spinner,

    1. The Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author
  • Matthew A. Deardorff

    Corresponding author
    1. The Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania
    • The Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    Search for more papers by this author

  • Conflict of interest: none.

Correspondence to:

Matthew A. Deardorff, M.D., Ph.D., Division of Genetics, The Children's Hospital of Philadelphia, 1002B Abramson Research Center, 3615 Civic Center Blvd., Philadelphia, PA 19104.

Email: deardorff@email.chop.edu

Abstract

Here we describe three subjects with mosaic genome-wide paternal uniparental isodisomy (GWpUPD) each of whom presented initially with overgrowth, hemihyperplasia (HH), and hyperinsulinism (HI). Due to the severity of findings and the presence of additional features, SNP array testing was performed, which demonstrated mosaic GWpUPD. Comparing these individuals to 10 other live-born subjects reported in the literature, the predominant phenotype is that of pUPD11 and notable for a very high incidence of tumor development. Our subjects developed non-metastatic tumors of the adrenal gland, kidney, and/or liver. All three subjects had pancreatic hyperplasia resulting in HI. Notably, our subjects to date display minimal features of other diseases associated with paternal UPD loci. Both children who survived the neonatal period have displayed near-normal cognitive development, likely due to a favorable tissue distribution of the mosaicism. To understand the range of UPD mosaicism levels, we studied multiple tissues using SNP array analysis and detected levels of 5–95%, roughly correlating with the extent of tissue involvement. Given the rapidity of tumor growth and the difficulty distinguishing malignant and benign tumors in these GWpUPD subjects, we have utilized increased frequency of ultrasound (US) and alpha-fetoprotein (AFP) screening in the first years of life. Because of a later age of onset of additional tumors, continued tumor surveillance into adolescence may need to be considered in these rare patients. © 2013 Wiley Periodicals, Inc.

Ancillary