Proximal Hypospadias-Isolated Genital Condition or Marker of More?

PURPOSE: The prevalence of endocrine/genetic anomalies in boys with proximal hypospadias is unknown. We describe an endocrine/genetic evaluation for boys with proximal hypospadias to determine who may have a difference/disorder of sex development and/or benefit from additional testing. MATERIALS AND METHODS: We retrospectively reviewed boys with hypospadias seen at our hospital between January 2013 and October 2018. Those with proximal (penoscrotal, scrotal, perineal) hypospadias who presented before age 6 months and underwent endocrine/genetic testing were included. Demographics, test results, testicular examination at presentation, comorbidities and diagnoses were abstracted. RESULTS: A total of 1,789 boys with hypospadias were identified. Of 131 boys with proximal hypospadias all 60 who underwent endocrine/genetic evaluation were included. Most of these patients had bilateral palpable testes (52, 86%) that were fully descended (41, 68%). Associated anatomical anomalies were found in 53% of patients. All boys underwent endocrine testing, which was completely typical for a male infant in most (41, 68%). Common genetic tests included karyotyping (100%), microarray (38%) and multigene panel (13%). Genetic anomalies were found in 17 boys (28%), including 7 of 41 (17%) with bilateral descended testes and 10 of 19 (53%) with 1 or more undescended testes (p=0.01). Six of 8 boys with at least 1 nonpalpable testis had a genetic anomaly vs 11 of 52 with bilateral palpable testes (p=0.005). Differences/disorders of sex development were found in 9 patients (15%). CONCLUSIONS: Of 60 boys with proximal hypospadias 53% had nongenital anomalies, 28% had genetic anomalies and 15% had a difference/disorder of sex development. Although endocrine testing was clinically useful, genetic testing was most diagnostically revealing. Endocrine/genetic evaluation should be considered for boys with proximal hypospadias.

Impact of cell-free DNA screening on parental knowledge of fetal sex and disorders of sex development.

OBJECTIVE: Discrepancies between cfDNA and ultrasound predicted fetal sex occur, possibly indicating disorders/differences of sex development (DSDs). Among expectant/recent parents, this study assessed cfDNA knowledge/use, fetal sex determination attitudes/behaviors, general knowledge of DSD, and possible psychological impact of discrepancy between fetal sex on cfDNA and ultrasound. METHOD: Parents were surveyed about fetal sex determination methods, knowledge of cfDNA and DSD, distress related to possible cfDNA inaccuracy. RESULTS: Of 916 respondents, 44% were aware of possible discrepancy between cfDNA and ultrasound, 22% were aware of DSD. 78% and 75% would be upset and worried, respectively, with results showing fetal sex discrepancy. Most (67%) revealed predicted fetal sex before delivery. 38% were offered cfDNA. Of those revealing fetal sex, 24% used cfDNA results, 71% ultrasound, and 7% both. cfDNA users were more frequently aware of possible discrepancy between cfDNA and ultrasound (76% vs 41%, P < .0001), but not of DSD (29% vs 23%, P = .29). CONCLUSION: Fetal sex determination is favored, and cfDNA is frequently used for predicting fetal chromosomal sex. Many parents are unaware of possible discrepancies between cfDNA and ultrasound, and potential for DSD. Most would be distressed by discordant results. Accurate counseling regarding limitations cfDNA for fetal sex determination is needed.

Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis-Practice Resource of the National Society of Genetic Counselors.

The goal of this practice resource is to provide genetic counselors and other healthcare professionals with a resource to reference when providing genetic counseling services to individuals and families undergoing evaluation for neurofibromatosis (NF) or who have received a diagnosis of NF, including NF1, NF2, and schwannomatosis. This resource represents the opinions of a multi-center working group of Certified Genetic Counselors with experience in the care of individuals with NF, providing topics to be considered for the incorporation into a clinical genetic counseling session.

Reproductive Endocrinologists' Utilization of Genetic Counselors for Oncofertility and Preimplantation Genetic Diagnosis (PGD) Treatment of BRCA1/2 Mutation Carriers.

Genetic counselors believe fertility preservation and preimplantation genetic diagnosis (PGD) discussions to be a part of their role when counseling BRCA1/2 mutation-positive patients. This study is the first to explore reproductive endocrinologists' (REI) practices and attitudes regarding involvement of genetic counselors in the care of BRCA1/2 mutation carriers seeking fertility preservation and PGD. A survey was mailed to 1000 REIs from Reproductive Endocrinology & Infertility (SREI), an American Society for Reproductive Medicine (ASRM) affiliate group. A 14.5 % response rate was achieved; data was analyzed using SPSS software. The majority of participating REIs were found to recommend genetic counseling to cancer patients considering fertility preservation (82 %) and consult with a genetic counselor regarding PGD for hereditary cancer syndromes (92 %). Additionally, REIs consult genetic counselors regarding PGD patient counseling (88 %), genetic testing (78 %), and general genetics questions (66 %). Two areas genetic counselors may further aid REIs are: elicitation of family history, which is useful to determine fertility preservation and PGD intervention timing (32 % of REIs utilize a cancer family history to determine intervention timing); and, interpretation of variants of uncertain significance (VOUS) as cancer panel genetic testing becomes more common (36 % of REIs are unfamiliar with VOUS). Given our findings, the Oncofertility Consortium® created an online resource for genetic counselors focused on fertility preservation education and communication strategies.

Turner Syndrome with Y Chromosome: Spontaneous Thelarche, Menarche, and Risk of Malignancy.

STUDY OBJECTIVE: Girls with Turner syndrome with Y-chromosome material (TS + Y) are assumed to have nonfunctional gonads with increased tumor risk, therefore prophylactic gonadectomy is recommended at diagnosis. In this study we aimed to determine rates of spontaneous thelarche (ST) and spontaneous menarche (SM), and prevalence of gonadal tumor and malignancy in girls with TS + Y, to further inform discussions about gonadectomy. DESIGN: Retrospective review of clinical and pathology data. SETTING: Multicenter study involving 4 United States children's hospitals. PARTICIPANTS: Patients included those with a genetically proven diagnosis of TS + Y and phenotypically female genitourinary exam. INTERVENTIONS: Demographic characteristics, pubertal development, and gonadal pathology data were abstracted from clinical records. Data for ST were analyzed for patients aged 13 years and older and SM for patients older than 15 years. MAIN OUTCOME MEASURES: ST, SM, prevalence of gonadal tumor, and malignancy. RESULTS: Forty-four patients met inclusion criteria. Nineteen patients were 13 years or older; 8/19 (42%) had ST and reached Tanner stages 2-4 and 2 (11%) had normal ovarian pathology. Nineteen patients were 15 years or older; 2/19 (11%) had SM. Thirty-seven patients underwent gonadectomy; 35 had available pathology results. Gonadoblastoma was identified in 35/7 patients (19%), 1 in situ germ cell neoplasia, and 1 dysgerminoma (3%). One patient with bilateral gonadoblastoma had ST and SM. CONCLUSION: In this multicenter cohort, 42% of girls with TS + Y entered puberty spontaneously and 11% had SM, supportive of gonadal function. Risk of tumor was similar to previous reports. To achieve informed decision-making, discussions about gonadectomy should incorporate potential for gonadal function and tumor risk.