Classification of hereditary disorders of sexual development.

We have recently proposed a classification of the disorders of sexual development 
based upon the presumed site of action of the abnormal gene 
during embryogenesis. These disorders, which may be either genetic or nongenetic 
in nature, are the result of disturbances in the physiology of 
sexual differentiation during embryogenesis. The purpose of this review is to 
summarize the current physiologic concepts of normal sexual differentiation, to review 
the known hereditary disorders of sexual development, and to consider briefly 
the implications that these mutations have for the understanding of normal 
sexual differentiation. The translation of genetic sex into phenotypic sex is 
a complex process. Since some 19 hereditary, single-gene determined disorders of 
sexual development are currently recognized that involve loci on both the 
autosomes and the X chromosome, it can be inferred that at 
a minimum 19 genes and hence 19 discrete biochemical steps are 
involved in this process. At least 10 mutations result in male 
pseudohermaphroditism, whereas only 2 mutations are known to cause female pseudohermaphroditism. 
The predominance of male type of mutation is the result of 
the fact that the formation of the male phenotype is actively 
induced by the secretions of the fetal testis whereas the formation 
of the female phenotype does not require secretion from the fetal 
ovary. The end result of these mutations that involve the formation 
and action of testosterone can be similar, and it requires anatomic, 
endocrinologic, and genetic study of individual patients to identify the mutant 
genes involved. Undoubtedly, many more as yet unidentified genes must participate 
in sexual differentiation. The identification of these genes will depend on 
the continued delineation of new simply inherited clinical syndromes. Any fundamental 
understanding of the programming of events in phenotypic differentiation will require 
not only the identification of the genes involved but the elucidation 
of the molecular mechanisms by which each of these genes is 
expressed. 