Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects

A. F. Daly, Bo Yuan, Frederic Fina, J. H. Caberg, G. Trivellin, L. Rostomyan, Wouter De Herder, L. Naves, D. Metzger, Thomas Cuny, Wolfgang Rabl, Nalini S. Shah, Marie Lise Jaffrain Rea, Maria Chiara Zatelli, Fabio R. Faucz, E. Castermans, Isabelle Nanni-Metellus, Maya Lodish, Ammar Muhammad, L. PalmeiraIulia Potorac, Giovanna Mantovani, Sebastian J C M M Neggers, Marc Klein, Anne Barlier, P. Liu, L'houcine Ouafik, Vincent Bours, James R. Lupski, Constantine A. Stratakis, A. Beckers

Research output: Contribution to journalArticlepeer-review


Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG)syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101. We studied XLAG syndrome patients (n = 18)to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2 ratio (LR)compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8% These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR)technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV)threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

Original languageEnglish
Pages (from-to)221-233
Number of pages13
JournalEndocrine-Related Cancer
Issue number4
Publication statusPublished - Apr 1 2016


  • Gigantism
  • Molecular genetics
  • Mosaicism
  • Pituitary
  • X-LAG syndrome

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research


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