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Kyriakie Sarafoglou, S. Faisal Ahmed, Disorders of Sex Development: Challenges for the Future, The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 7, 1 July 2012, Pages 2292–2294, https://doi.org/10.1210/jc.2012-2178
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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.
