Disorders of Sex Development: Challenges for the Future

Abstract

The perpetual challenge in the diagnosis and management of patients with disorders of sex development (DSD), to paraphrase the adage, is that as our circle of knowledge in the genetic mechanisms of DSD expands, so does the circumference of darkness surrounding it. New technologies (comparative genomic hybridization, sequencing by hybridization, and next generation sequencing) are rapidly generating massive amounts of information on the pathogenesis of DSD (1). The caveat is that identifying a pathogenic mutation may not predict the clinical picture because phenotype can be highly variable, even within the same family (2). Oligogenic modulators, developmental switches, epigenetic influences, environmental stimuli, and even imbalanced cis-regulation of mutant vs. wild-type alleles when mutations are present in a heterozygous state may also be contributing factors to the variable expression of phenotype (3). A major step forward in organizing the molecular and clinical information was the recent change in nomenclature and classification of DSD. In 2006, the Pediatric Endocrine Society (formerly known as the Lawson and Wilkins Pediatric Endocrine Society) and the European Society for Pediatric Endocrinology consensus group defined DSD as congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical, and broadly classified DSD into three groups based upon cytogenetic, hormonal, gonadal histology, and clinical findings: 46,XY DSD, 46,XX DSD, and sex chromosome DSD (4). The classification reflected the natural history of the diagnostic process in which the sex chromosomes are the usual starting point for investigations of a child with atypical genitalia. As our genetic and endocrine understanding of unclassified or syndromic conditions improves, the DSD classification, which continues to gain wide acceptance across the globe (5), has the flexibility to incorporate them into its current structure. But there is still a long way to go to where the genetic information can be used to predict long-term outcomes to provide personalized care for the DSD patient. In some DSD, clinical diagnosis can be confirmed by hormonal and molecular testing. For example, in complete androgen insensitivity syndrome there is an 80 – 90% chance that a 46,XY infant with normal female genitalia and normal testosterone synthesis will have a mutation in androgen receptor gene (6). Similarly, the majority of 46,XX presenting with virilized genitalia will have congenital adrenal hyperplasia with a mutation in CYP21A2 where genotype-phenotype correlations are excellent (7). In cases of XY DSD with partially virilized genitalia, a molecular diagnosis has been relatively elusive so that diagnosis is guided by a thorough clinical, biochemical, and anatomical evaluation of the affected infant. For instance, only about 20% of these cases associated with normal androgen synthesis will have a mutation in the androgen receptor gene (6). Discordance between molecular changes and functional in vitro transactivation studies complicate even further the efforts for attributing the particular DSD phenotype to the identified gene change. Furthermore, such functional studies continue to remain in the realms of research laboratories, and their large-scale clinical utility remains unclear. The recent identification of mutations associated with DSD in a poorly characterized MAPK sig-