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Increasing the Diagnosis Rate in Patients with Disorders of Sex Development (DSD)
Jill D. Jacobson, MD, Julie Strickland, MD, MPH, Laurie Smith, MD, Anna Egan, PhD, Laurel Willig, MD, Emily G. Farrow, PhD, Carol J. Saunders, PhD, Stephen F. Kingsmore, MD, Terri Luetjen, RN, John M. Gatti, MD.
Children's Mercy Hospital, Kansas City, MO, USA.

Background: The 2006 Endocrine Society Consensus Statement for Disorders of Sexual Development (DSD) states that fewer than 50% of undervirilized males receive definitive diagnoses, and only 20% of patients overall receive molecular diagnoses. One objective of our multidisciplinary DSD clinic was to increase our molecular and biochemical diagnosis rate.
Methods: From 2008 to 2013, 91 patients with DSD were evaluated. We utilized a detailed testing algorithm designed to maximize our biochemical and molecular diagnosis rate. Upon IRB approval, we identified 37 undervirilized males, 43 overvirilized females, and 11 patients with sex chromosome mosaicism.
Results: We identified biochemical or molecular causes in 19 of 37 (51%) of undervirilized males. Of 37 undervirilized males: one patient was diagnosed with Klinefelter syndrome by karytotype. Targeted genetic analysis based on clinical suspicion yielded 10 definitive causes: androgen receptor gene(n=3), NR5A1 (n=2) SOX9 (n=1), the Beckwith Wiedeman syndrome gene (n=1), SRD5A2 (n=2) and congenital dyserythroblastic anemia (n=1). One patient had hypogonadotropic hypogonadism associated with an ectopic pituitary gland. Microarray and/or custom array analysis were performed on the remaining 17 genetic males who had not received molecular diagnoses. Microarray analysis demonstrated duplications or deletions expected to be associated with genital ambiguity in 4 patients. Targeted gene panel testing by next generation sequencing (TaGSCAN) identified causative mutations in 3 patients, one in OPHN1, and 2 in NR5A1. An additional patient was found to have a heterozygous mutation in GNRHR using this panel, which is not known to be causative. The remaining 9 undervirilized males who had DNA available and who had not received molecular diagnoses are undergoing whole exome sequencing (WES). To date, only one undervirilized male has undergone all tests, including WES without receiving a diagnosis. With respect to virilized females, 26 of 43 (60%) received molecular or biochemical diagnoses. Of these, one patient was diagnosed with Down syndrome by a routine karyotype. Twenty-one patients were diagnosed with CAH (n=21). Targeted gene analysis yielded the following diagnoses: Beckwith Wiedeman syndrome (n=1), Smith Magenis syndrome (n=2). Altogether, including the patients with sex chromosome mosaicism, we achieved a molecular or biochemical diagnosis rate of 62%.
Conclusions: A combination of routine karyotyping, targeted genetic testing, microarray testing, and targeted genome sequencing can provide definitive diagnoses in more than half of patients with DSD. Whole exome sequencing may be important for undervirilized males who receive no molecular diagnosis despite extensive testing. We anticipate that a higher diagnosis rate can be achieved in DSDs using all currently available genetic tools. There may remain novel genetic epigenetic causes for DSD that will be identifiable using emerging tests.

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