Normal and Abnormal Sexual Differentiation: From Genes to Patient

[[Author Photo]] The exponential growth in molecular biology over the last 15 years has vastly expanded our knowledge of the mechanisms of sex determination and differentiation and greatly improved our management of patients with ambiguous genitalia. Simultaneously, the ever-increasing number of detailed phenotypes being described today in clinical practice are serving as privileged models for the identification of new genes, giving us a new and unique approach to research. Moreover, knockouts of specific genes in complementary animal studies are further enlarging the spectrum of genes suspected of being involved in these disorders.

This special issue of Seminars in Reproductive Medicine was designed to present the full range of current knowledge on disorders of sex differentiation-from genes to patient-with an emphasis on the most recent scientific data and their impact on clinical management of patients. In this field today more than ever, research and clinical concerns are inextricably bound.

I would like to express my deepest gratitude to all the leaders in our field who, despite their many responsibilities, took the time to make valuable contributions to this effort.

Dr. M. Fellous is Professor of Genetics at the Institut Pasteur in Paris and Director of an INSERM Research Unit. He has spent his professional life studying the molecular genetics of sex determination and has contributed significantly to this field by identifying several genes implicated in sex determination. He has also made substantial contributions by developing the concept of gene cascade, now widely acknowledged by all groups.

Professor Gary Warme is a pediatric endocrinologist at the Royal Children's Hospital of Parkville, Australia. He has wide experience in managing patients with male or female pseudohermaphroditism. He is also involved in a research group dedicated to the molecular genetics of the androgen receptor. His general overview of the endocrinology of sex differentiation reported in this issue will be helpful for diagnosis and management of individuals with disorders of sex differentiation.

Management of newborns with ambiguous genitalia is difficult and stressful. Based on 20 years of experience on a multidisciplinary team as a pediatric endocrinologist, as well as as a molecular biologist, I present here the general rules that must be followed to avoid conflictual debate between health professionals and parents about the sex of rearing.

Pr. E. Vilain, from the Department of Human Genetics and Pediatrics at UCLA (United States), was trained in Dr. Fellous' laboratory and then moved to Los Angeles to develop a group for clinical practice and research in pediatric endocrinology. He has been involved in the molecular genetics of disorders of sex determination and his contribution to this issue is valuable.

Professor A. Themmen from Erasmus University, Rotterdam, The Netherlands, was the first to identify an inactivating LH receptor mutation in a familial form of male pseudohermaphroditism. Since then, he has accumulated a significant amount of data on aberrant function of the LH receptor.

Dr.W. Miller is Professor of Pediatrics at UCSF in San Francisco. He has successfully developed his research in the field of the molecular biology of steroid hormone synthesis. He is particularly noted for his identification of StAR function, the molecular modeling of P450C17, and the molecular genetics of P450C21. His experience in disorders of androgen biosynthesis is considerable.

For the last 10 years, our group has been involved in the study of over 1300 patients with ambiguous genitalia from all over the world. Besides the identification of mutations of the 5α-reductase gene and the androgen receptor gene, we developed molecular tools to study the structure-function relationship of AR.

Dr. I. Hughes is Professor of Pediatrics at the University of Cambridge, England. He is an international specialist in childhood adrenal diseases as well as in disorders of sex differentiation. His contribution to this issue on P450C21 defects is important from clinical, biological, and molecular perspectives.

Professor D. Dewailly is Chairman of the Department of Endocrinology at the Lille University Hospital, France. He is a specialist in reproductive medicine. He has vast clinical experience with female hyperandrogenism and especially with the clinical and biological phenotype in late-onset 21-OH deficiency.

Doctor M. Peter is a pediatric endocrinologist who trained with Professor Sippel in Kiel, Germany. He has extensive experience with the clinical and biological aspects of 11β-OH deficiency as well as its molecular genetics.

Professor J. Simard is Chairman of the Oncology and Molecular Endocrinology Research Center in Quebec City, Canada. Among his several research activities in molecular genetics, he significantly contributed to our understanding of the pathophysiology of 3βHSD/ DS-D

@affil4:⁴ isomerase deficiency.

Pr. P. Mullis is Professor of Pediatric Endocrinology at Bern University Children's Hospital in Switzerland. His group has identified one of the five mutations of the aromatase/P450arom gene. He is today one of the leading specialists on the role of estrogen in children.

Dr. L. Gooeren is Professor of Endocrinology at the Hospital of the Vrije Universiteit Medical Center in Amsterdam, The Netherlands. He is one of the world's specialists on human sexual identity. He shares in this issue some of his wide experience from the study of transexualism and the impact of sex-atypical hormone exposure on brain functions.

Dr. A. Wisniewski is a Ph.D. working with Professor Cl. Migeon at the Division of Pediatric Endocrinology of the Johns Hopkins Hospital in Baltimore, Maryland. Professor Cl. Migeon has one of the most extensive experiences in the field of disorders of sex differentiation, from clinical, biological, and molecular points of view. They report here their experience in the follow-up of micropenis and male pseudohermaphroditism due to complete androgen insensitivity.

Doctor J. Toppari is an Academy Scientist at the Department of Pediatrics and Physiology of the University of Turku, Finland. He is a specialist on testis physiology and has been involved in several European collaborative projects on the impact of environmental endocrine disruptors on child development.

My sincerest wish is that scientists and clinicians alike will appreciate the value of this approach and that it will enlighten both in their respective areas of expertise.