Article Text

XX males SRY negative: a confirmed cause of infertility
  1. Annalisa Vetro1,
  2. Roberto Ciccone1,
  3. Roberto Giorda2,
  4. Maria Grazia Patricelli3,
  5. Erika Della Mina1,
  6. Antonella Forlino4,
  7. Orsetta Zuffardi1,5
  1. 1Medical Genetics, University of Pavia, Pavia, Italy
  2. 2Molecular Biology, IRCCS E. Medea, Bosisio Parini, Lecco, Italy
  3. 3Clinical Genetics, Diagnostica e Ricerca San Raffaele, Milano, Italy
  4. 4Department of Biochemistry, University of Pavia, Pavia, Italy
  5. 5IRCCS C. Mondino National Neurological Institute Foundation, Pavia, Italy
  1. Correspondence to Dr Orsetta Zuffardi, Medical Genetics, University of Pavia, via Forlanini 14, 27100 Pavia, Italy; zuffardi{at}


Background SOX9 is a widely expressed transcription factor playing several relevant functions during development and essential for testes differentiation. It is considered to be the direct target gene of the protein encoded by SRY and its overexpression in an XX murine gonad can lead to male development in the absence of Sry. Recently, a family was reported with a 178 kb duplication in the gene desert region ending about 500 kb upstream of SOX9 in which 46,XY duplicated persons were completely normal and fertile whereas the 46,XX ones were males who came to clinical attention because of infertility.

Methods and results We report a family with two azoospermic brothers, both 46,XX, SRY negative, having a 96 kb triplication 500 kb upstream of SOX9. Both subjects have been analyzed trough oligonucleotide array-CGH and the triplication was confirmed and characterised through qPCR, defining the minimal region of amplification upstream of SOX9 associated with 46,XX infertile males, SRY negative.

Conclusions Our results confirm that even in absence of SRY, complete male differentiation may occur, possibly driven by overexpression of SOX9 in the gonadal ridge, as a consequence of the amplification of a gene desert region. We hypothesize that this region contains gonadal specific long-range regulation elements whose alteration may impair the normal sex development. Our data show that normal XX males, with alteration in copy number or, possibly, in the critical sequence upstream to SOX9 are a new category of infertility inherited in a dominant way with expression limited to the XX background.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: and

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  • Funding The work was supported by the MIUR 2008XA48SC and Cariplo 2007 to AF and Progetto Regione Lombardia (code SAL/45) to AF and OZ.

  • Competing interests None to declare.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by University of Pavia Ethical Committee, Pavia, Italy.

  • Provenance and peer review Not commissioned; externally peer reviewed.