Prenatal detection and evaluation of differences of sex development.

INTRODUCTION: Differences/disorders of sex development (DSD) can be detected at different ages, including prenatally. The recent implementation of prenatal genetic testing (including cell-free DNA) may affect the frequency and impact of prenatal diagnosis of DSD. Our aims were to (1) describe prenatal detection and evaluation of differences of sex development presenting to a multidisciplinary DSD clinic and (2) explore possible parental distress accompanying this evaluation. MATERIALS AND METHODS: A retrospective chart review of mothers presenting prenatally, and patients presenting during infancy, to a multidisciplinary DSD clinic from 2013 to 2017 was conducted. Data extracted included demographics, final diagnoses, prenatal screening, prenatal evaluation, postnatal endocrine, genetic and radiologic testing, and clinician's notes on parent/patient distress. RESULTS: Sixty-seven patients were identified; ten (15%) had prenatal detection of a suspected DSD. Of those, 4/10 were detected prenatally in the last study year alone. Within the prenatal group, 6/10 had cell-free DNA results discordant with ultrasound, 2/10 were detected by atypical genitalia on ultrasound, and 2/10 were detected through karyotyping performed for other indications. After birth, 3/10 patients were found to not have a DSD. Final diagnoses for the full study cohort are shown in the Summary Table, comparing prenatal versus postnatal presentation to our DSD clinic. Clinicians noted distress for most parents during the prenatal evaluation of a possible DSD, including one mother who reported suicidal thoughts. DISCUSSION AND CONCLUSIONS: Prenatal suspicion of DSD can occur through discordant prenatal testing and has been observed at our clinic in recent years, in line with other recent studies. Contributing factors to these prenatal presentations could be increased referrals to the clinic, and increased use of non-invasive prenatal testing, which can lead to inaccurate or discordant sex identification. The prenatal suspicion of a potential DSD can be associated with parental distress, underscoring the need for adequate counseling for tests that determine fetal sex, including cell-free DNA.

Gonadal Tissue Cryopreservation for Children with Differences of Sex Development.

INTRODUCTION: Infertility is common for individuals with differences of sex development (DSD) and is a significant concern to these individuals. Fertility potential in many DSD conditions is poorly understood. Gonadal tissue cryopreservation (GTC) for fertility preservation (FP) is offered to children with cancer undergoing gonadotoxic therapy. Our team sought to expand the field of FP by offering and evaluating the success of GTC for individuals with DSD. MATERIALS AND METHODS: GTC was offered to patients with DSD undergoing prophylactic gonadectomy, after extensive multidisciplinary counseling. For those who elected to attempt GTC, data were retrospectively abstracted, including: DSD diagnosis, age at gonadectomy, indication for gonadectomy, pathology results, and final decision about long-term gonadal tissue storage. RESULTS: Ten patients were enrolled to attempt GTC, with a mean age of 11.5 years (range 1-18). Five of the 10 patients had germ cells (GCs) present. Diagnoses (age at gonadectomy) for patients with GCs included ovotesticular DSD (13 months), mixed gonadal dysgenesis (17 months), partial gonadal dysgenesis (3 years), partial androgen insensitivity syndrome (11 years), and mixed gonadal dysgenesis (12 years). Four of the 5 subjects with GCs elected for GTC. One opted against GTC, citing immature gametes that did not match gender identity. CONCLUSION: GTC at the time of gonadectomy for patients with DSD is feasible. In many patients, GCs are present. While questions remain about the timing of gonadectomy, quality of GCs, and future success for use of the tissue based on technological advancement, GTC represents a novel approach to experimental FP for individuals with DSD.

Gonadal Tissue Cryopreservation for a Girl With Partial Androgen Insensitivity Syndrome.

Individuals with differences/disorders of sex development (DSD) have increased rates of infertility. For children and youth undergoing prophylactic gonadectomy for malignancy risk, our institution offers gonadal tissue cryopreservation, an experimental technique to preserve fertility cryopotential. An 11-year-old girl with partial androgen insensitivity syndrome presented for evaluation for fertility preservation in the setting of a planned bilateral gonadectomy at an outside institution. At presentation, the patient had begun puberty with an elevated serum androgen level and was experiencing undesired virilization. She expressed a strong female gender identity, an understanding of the various treatment options, and a preference for gonadectomy to prevent further virilization. After thorough counseling with the patient and family in our institution's multidisciplinary DSD clinic, she underwent bilateral gonadectomy with gonadal tissue cryopreservation. Her gonadal pathologic examination demonstrated well-developed peripubertal testes, with present, albeit decreased, numbers of spermatogonial germ cells, decreased Leydig cells, and nonspecific degenerative changes. The patient and her family chose to maintain the cryopreserved tissue for the patient's potential future use. To the best of our knowledge, the present case is the first reported case of gonadal tissue cryopreservation in a patient with partial androgen insensitivity syndrome. Storage of gonadal tissue is a feasible method of germ cell preservation in patients with DSD undergoing gonadectomy, although further research advances are required to facilitate development of this tissue into mature gametes capable of biological fertility.