Evidence for digenic inheritance in some cases of Antley-Bixler syndrome?
William Reardona, Anne Smithb, John W Honourc, Peter Hindmarshd, Debipriya Dasc, Gill Rumsbyc, Isabelle Nelsonb, Sue Malcolmb, Lesley Adèse, David Sillencee, Dhavendra Kumarf, Celia DeLozier-Blanchetg, Shane McKeeh, Thaddeus Kellyi, Wallace L McKeehanj, Michael Baraitsera, Robin M Wintera
a Department of Clinical Genetics, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK, b Molecular Genetics Unit, Institute of Child Health, London, UK, c Department of Chemical Pathology, University College London Hospitals, London, UK, d London Centre for Paediatric Endocrinology, University College Hospital, London, UK, e Departments of Clinical Genetics and Paediatrics and Child Health, New Children's Hospital, Parramatta, NSW 2124, Australia, f Centre for Human Genetics, Sheffield Children's Hospital, 117 Manchester Road, Sheffield S10 5DN, UK, g Division of Medical Genetics, University of Geneva CMU, 1 rue Michel-Servet CH-1211, Geneva 4, Switzerland, h Clinical Genetics Unit, Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG UK, i Division of Medical Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA, j Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A&M University, System Health Science Center, 2121 Holcombe Blvd, Houston, TX 77030, USA
Correspondence to: Dr Reardon
Revised version received 19 August
1999;
Accepted for publication 27 August 1999
The Antley-Bixler syndrome has been thought to be caused
by an autosomal recessive gene. However, patients with this phenotype have been reported with a new dominant mutation at the
FGFR2 locus as well as in the offspring of
mothers taking the antifungal agent fluconazole during early pregnancy.
In addition to the craniosynostosis and joint ankylosis which are the
clinical hallmarks of the condition, many patients, especially females,
have genital abnormalities. We now report abnormalities of steroid
biogenesis in seven of 16 patients with an Antley-Bixler phenotype.
Additionally, we identify FGFR2 mutations in
seven of these 16 patients, including one patient with abnormal
steroidogenesis. These findings, suggesting that some cases of
Antley-Bixler syndrome are the outcome of two distinct genetic events,
allow a hypothesis to be formulated under which we may explain all the
differing and seemingly contradictory circumstances in which the
Antley-Bixler phenotype has been recognised.
Keywords: Antley-Bixler syndrome; FGFR; congenital adrenal hyperplasia; CYP21 deficiency
© 2000 by J Med Genet
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