Multi-stakeholder opinion statement on the care of individuals born with differences of sex development: common ground and opportunities for improvement.

BACKGROUND: In the last 15 years, the care provided for individuals born with differences of sex development (DSD) has evolved, with a strong emphasis on interdisciplinary approaches. However, these developments have not convinced some stakeholders to embrace the current model of care. This care model has also paid insufficient attention to socio-cultural differences and global inequalities. SUMMARY: This article is an opinion statement, resulting from in-depth discussions and reflection among clinicians, patients, and family support organizations based in the US and Europe, where we seek areas of common ground and try to identify opportunities to further develop resources. The product of these conversations is summarized in 10 panels. The corresponding sections provide additional discussion on some of the panel items. KEY MESSAGES: Participants identified areas of agreement and gained a deeper understanding of the reasons behind disagreements on certain matters and identified the necessary steps to foster future consensus. We offer preliminary recommendations for guiding clinical management and resource allocation. By promoting a broader consensus, we aim to enhance the quality of care and well-being for individuals of all ages who have a DSD.

Endocrine outcome and seminal parameters in young adult men born with hypospadias: A cross-sectional cohort study.

BACKGROUND: Hypospadias affects around 1/200 newborn males. Intrauterine testicular dysfunction may underlie a subset of cases. The long-term endocrine and reproductive outcomes in these men remain largely unknown. METHODS: Cross-sectional study in Ghent and Vienna University Hospitals to assess the endocrine and seminal parameters of young adult men (16-21 years) born with non-syndromic hypospadias (NSH) (n = 193) compared to healthy typical males (n = 50). Assessments included physical exam, semen analysis, hormone assays and exome-based gene panel analysis (474 genes). FINDINGS: All participants had experienced a spontaneous puberty, in spite of higher LH and INSL3 levels than typical males. Oligo- or azoospermia was observed in 32/172 (18·6%; 99%-CI: 12·2-27·4%) of NSH men; but in 5/16 (31·3%; 99%-CI: 11·1;62·4%) of complex NSH men and in 13/22 (59·1%; 99%-CI: 33·2-80·7%) of those born small for gestational age (SGA). No (likely) pathogenic coding variants were found in the investigated genes. Suboptimal statural growth affected 8/23 (34·8%; 99%-CI: 15·4-61·0%) of men born SGA with NSH. INTERPRETATION: Spermatogenesis is significantly compromised in NSH men, especially in those born SGA or those with complex NSH. Long-term andrological follow-up is recommended, including end-pubertal semen analysis. No clear monogenic causes could be demonstrated in our cohort even in proximal or complex NSH. Being born SGA with NSH is frequently associated with poor catch-up growth, requiring growth hormone therapy in some. FUNDING: Research grants from the European Society of Paediatric Endocrinology, the Belgian Society of Pediatrics, the Belgian Society of Pediatric Endocrinology and Diabetology and the Research Foundation Flanders (FWO).

Cohort profile: 'Biomarkers of Personalised Medicine' (BioPersMed): a single-centre prospective observational cohort study in Graz/Austria to evaluate novel biomarkers in cardiovascular and metabolic diseases.

PURPOSE: Accumulating evidence points towards a close relationship between cardiovascular, endocrine and metabolic diseases. The BioPersMed Study (Biomarkers of Personalised Medicine) is a single-centre prospective observational cohort study with repetitive examination of participants in 2-year intervals. The aim is to evaluate the predictive impact of various traditional and novel biomarkers of cardiovascular, endocrine and metabolic pathways in asymptomatic individuals at risk for cardiovascular and/or metabolic disease. PARTICIPANTS: Between 2010 and 2016, we recruited 1022 regional individuals into the study. Subjects aged 45 years or older presenting with at least one traditional cardiovascular risk factor or manifest type 2 diabetes mellitus (T2DM) were enrolled. The mean age of the participants was 57±8 years, 55% were female, 18% had T2DM, 33% suffered from arterial hypertension, 15% were smokers, 42% had hyperlipidaemia, and only 26% were at low cardiovascular risk according to the Framingham 'Systematic COronary Risk Evaluation'. FINDINGS TO DATE: Study procedures during screening and follow-up visits included a physical examination and comprehensive cardiovascular, endocrine, metabolic, ocular and laboratory workup with biobanking of blood and urine samples. The variety of assessed biomarkers allows a full phenotyping of individuals at cardiovascular and metabolic risk. Preliminary data from the cohort and relevant biomarker analyses were already used as control population for genomic studies in local and international research cooperation. FUTURE PLANS: Participants will undergo comprehensive cardiovascular, endocrine and metabolic examinations for the next decades and clinical outcomes will be adjudicated prospectively.

Ischemic Priapism in a 12 Year Old Patient Associated With Coronavirus Disease 2019 (COVID-19): A Case Report.

Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been associated with changes in blood coagulation resulting in increased incidence of venous thromboembolic events and coagulopathy. Moreover, single cases of ischemic priapism have been reported in adult patients with SARS-CoV-2 infection. In this report, we describe the case of ischemic priapism in a 12-year-old child with recent SARS- CoV-2 infection.

Growth, puberty and testicular function in boys born small for gestational age with a nonspecific disorder of sex development.

OBJECTIVE: Being born small for gestational age (SGA) is frequently associated with unexplained disorders of sex development (nonspecific DSD) in boys. Little is known about their future growth, puberty and testicular function. Our objective is to determine the long-term endocrine outcome of boys born SGA who have a nonspecific DSD. DESIGN: Boys with a nonspecific DSD born SGA and appropriate for GA (AGA) were retrieved through the International Disorders of Sex Development registry and retrospective data collected, based on a spreadsheet containing 102 items. PATIENTS AND MEASUREMENTS: In total, 179 boys were included, of which 115 were born SGA and 64 were born AGA. Their growth and pubertal development were compared. Serum LH, FSH, testosterone, AMH and inhibin B levels in infancy and puberty were analysed to assess testicular function. RESULTS: At 2 years of age, 30% of SGA boys had incomplete or absent catch-up growth. Boys born SGA also had higher LH during minipuberty and lower testosterone in stimulation tests (p = 0.037 and 0.040, respectively), as compared to boys born AGA. No differences were observed in timing or course of puberty or end-pubertal hormone levels. CONCLUSIONS: Almost one out of three SGA boys with a nonspecific DSD experiences insufficient catch-up growth. In addition, our data suggest dysfunction of infantile Leydig cells or altered regulation of the hypothalamic-pituitary-gonadal axis in SGA boys during childhood. Sex steroid production during puberty seems unaffected.

A prospective observational study on the feasibility of subumbilical laparoscopic procedures under epidural anesthesia in sedated spontaneously breathing infants with a natural airway.

BACKGROUND: Laparoscopic procedures are usually performed under general anesthesia with a secured airway including endotracheal intubation or supraglottic airways. AIMS: This is a prospective study of the feasibility of subumbilical laparoscopic procedures under epidural anesthesia in sedated, spontaneous breathing infants with a natural airway. METHODS: We consecutively enrolled 20 children <3 years old with nonpalpable testes scheduled for diagnostic laparoscopy with or without an ensuing orchidopexy, inguinal revision, or Fowler-Stephens maneuver. Inhalational induction for venous access was followed by sedation with propofol and ultrasound-guided single-shot epidural anesthesia via the caudal or thoracolumbar approach using 1.0 or 0.5 ml kg-1 ropivacaine 0.38%, respectively. The primary outcome measure was block success, defined as no increase in heart rate by >15% or other indicators of pain upon skin incision. RESULTS: Of the 20 children (median age: 10 months; IQR: 8.3-12), 17 (85%) were anesthetized through a caudal and 3 (15%) through a direct thoracolumbar epidural, 18 (90%) underwent a surgical procedure and 2 (10%) diagnostic laparoscopy only. Five patients (25%) received block augmentation using an intravenous bolus of fentanyl (median dose: 0.9 µg kg-1 ; IQR: 0.8-0.95) after the initial prick test and before skin incision. There was no additional need for systemic pain therapy in the operating theater or recovery room. No events of respiratory failure or aspiration were observed. CONCLUSIONS: In experienced hands, given our success rate of 100%, epidural anesthesia performed in sedated spontaneously breathing infants with a natural airway can be an alternative strategy for subumbilical laparoscopic procedures.

Surgical Practice in Girls with Congenital Adrenal Hyperplasia: An International Registry Study.

In this article international trends in surgical practice in girls with congenital adrenal hyperplasia (CAH) are evaluated. All cases that had been classified in the I-CAH/I-DSD registry as 46,XX CAH and who were born prior to 2017 were identified. Centers were approached to obtain information on surgical decision making. Of the 330 included participants, 208 (63.0%) presented within the first month of life, and 326 (98.8%) cases were assigned female. Genital surgery had been performed in 250 (75.8%). A total of 64.3, 89.2, and 96.8% of cases residing in Europe, South America and Asia, respectively, had at least one surgery. In a logistic regression model for the probability of surgery before the second birthday (early surgery) over time an increase of probability for early vaginal surgery could be identified, but not for clitoral surgery or both surgeries combined. Genitoplasty in girls with CAH remains controversial. This large international study provides a snapshot of current practice and reveals geographical and temporal differences. Fewer surgeries were reported for Europe, and there seems to be a significant trend towards aiming for vaginal surgery within the first 2 years of life.

Adolescent and Young Adult Urogenital Outcome following Childhood Hypospadias Repair: Perfection Revisited.

PURPOSE: We assessed the long-term surgical, functional urinary and sexual outcomes of adolescent and young adult men who underwent childhood hypospadias repair. MATERIALS AND METHODS: Men born with nonsyndromic hypospadias and healthy male controls aged 16-21 years old were recruited, and their surgical, urinary, sexual functional and aesthetic outcomes assessed. Good outcome was defined as a patent and orthotopic meatus without fistulas, and straight erections (<30 degree curvature) without erectile or ejaculatory problems. Statistics included regression analyses, chi-square/Fisher exact tests and Student's t/Mann-Whitney U and Kruskal-Wallis tests. RESULTS: A total of 193 patients and 50 controls participated 16.4 years (range 8.2-21.2) after initial repair. At least 1 reintervention was performed in 39.2%. The highest reintervention rate was found in those younger than 12 months at initial repair, even when excluding proximal hypospadias cases. A disturbed urinary and/or suboptimal sexual functional outcome was seen in 52.9% of cases. Suboptimal voiding was found in 22.1%, although few had relevant residual urine. More reinterventions and proximal hypospadias cases were associated with suboptimal urinary outcome, and the latter also with impaired sexual function. Poor inter-observer agreements were found between physician and patient genital appraisal. CONCLUSIONS: In 52.9% of cases, at least 1 concern was identified that required long-term followup. Hypospadias repair below 12 months was associated with more reinterventions. Adopting a restrictive attitude toward aesthetic refinement, unless on the patient's own request, could improve urinary outcomes.

Psychosexual Outcome, Sexual Function, and Long-Term Satisfaction of Adolescent and Young Adult Men After Childhood Hypospadias Repair.

BACKGROUND: The psychosexual outcome in adolescents and young adults (AYA) men born with hypospadias is precarious. However, the factors responsible for impaired outcome in some AYA men have been understudied. AIM: To explore the outcome after hypospadias repair in childhood of AYA men aged 16-21 years and examine their opinion and their parents' opinion about this type of surgery. METHODS: Cross-sectional assessment of 193 AYA men born with hypospadias and 50 male controls was performed. Questionnaires such as the Decision Regret Scale, Pediatric Penile Perception Score, Sexual Quality of Life-Male, International Index of Erectile Function, and a custom-made questionnaire were used. The Decision Regret Scale and a custom-made questionnaire were also completed by the participants' parents. Physical examination including Hypospadias Objective Penile Evaluation and measuring stretched penile length was performed. OUTCOMES: This study reports the psychosexual functioning (ie, social, relational, and sexual), erectile and sexual function after childhood hypospadias repair, using ad hoc measures. In addition, the opinion about hypospadias repair of patients and their parents is represented. RESULTS: The number of surgeries and satisfaction regarding penile appearance were the most important factors associated with the opinion on hypospadias repair and the psychosexual outcome. Most AYA men were more satisfied with their penile appearance than the physician. 80% of men were satisfied with having had a childhood hypospadias repair, even though they had not been able to consent to surgery themselves. Erectile and ejaculation problems were mild and seen in approximately 10% of the population. CLINICAL IMPLICATIONS: Based on our data, deferring hypospadias repair until the patient can decide himself is not warranted. However, physicians who accept a suboptimal esthetic outcome and withdraw from repeated surgery may contribute importantly to the patient's well-being, especially in proximal forms of hypospadias. STRENGTHS & LIMITATIONS: This is one of the rare studies addressing the AYA's psychosexual outcome after childhood hypospadias repair. Strengths include the combination of clinical and psychosexual data from a very large cohort of men and their parents to provide a more holistic view. By entering this study, participants might have a different comfort level regarding their sexuality or have a different body image than the overall population of young men. CONCLUSION: Uncomplicated hypospadias surgery results in equal psychosexual outcome as controls and in high satisfaction rates; multiple surgeries are a risk factor for poorer outcomes. 80% of men are satisfied with childhood hypospadias repair. Tack LJW, Springer A, Riedl S, et al. Psychosexual Outcome, Sexual Function, and Long-Term Satisfaction of Adolescent and Young Adult Men After Childhood Hypospadias Repair. J Sex Med 2020;17:1665-1675.

The External Genitalia Score (EGS): A European Multicenter Validation Study.

CONTEXT: Standardized description of external genitalia is needed in the assessment of children with atypical genitalia. OBJECTIVES: To validate the External Genitalia Score (EGS), to present reference values for preterm and term babies up to 24 months and correlate obtained scores with anogenital distances (AGDs). DESIGN, SETTING: A European multicenter (n = 8) validation study was conducted from July 2016 to July 2018. PATIENTS AND METHODS: EGS is based on the external masculinization score but uses a gradual scale from female to male (range, 0-12) and terminology appropriate for both sexes. The reliability of EGS and AGDs was determined by the interclass correlation coefficient (ICC). Cross-sectional data were obtained in 686 term babies (0-24 months) and 181 preterm babies, and 111 babies with atypical genitalia. RESULTS: The ICC of EGS in typical and atypical genitalia is excellent and good, respectively. Median EGS (10th to 90th centile) in males < 28 weeks gestation is 10 (8.6-11.5); in males 28-32 weeks 11.5 (9.2-12); in males 33-36 weeks 11.5 (10.5-12) and in full-term males 12 (10.5-12). In all female babies, EGS is 0 (0-0). The mean (SD) lower/upper AGD ratio (AGDl/u) is 0.45 (0.1), with significant difference between AGDl/u in males 0.49 (0.1) and females 0.39 (0.1) and intermediate values in differences of sex development (DSDs) 0.43 (0.1). The AGDl/u correlates with EGS in males with typical genitalia and in atypical genitalia. CONCLUSIONS: EGS is a reliable and valid tool to describe external genitalia in premature and term babies up to 24 months. EGS correlates with AGDl/u in males. It facilitates standardized assessment, clinical decision-making and multicenter research.

A Systematic Review of Core Outcomes for Hypospadias Surgery.

Although the outcome of hypospadias surgery requires careful scrutiny, there is little consensus on what clinical outcome parameters should be considered essential as part of routine clinical practice. To understand the extent of variation in reported outcome measures, Pubmed was searched to identify outcomes in boys with hypospadias published in the English language from 2008 to 2017. Eligibility criteria were met in 268 publications. Outcomes were inconsistently reported and only 9 (13%) were reported in more than 25% of papers. Outcome studies describing younger boys were overrepresented. Urethrocutaneous fistula was reported in about 90% of publications that included boys aged <16 years. Among younger boys meatal stenosis, dehiscence, and urethral strictures were next most frequent. In the older age groups, an increasing frequency of cosmesis, meatal shape/location, and genital skin changes was described. Outcomes reflecting sexual health, erection, and relationship status including paternity were reported in those aged >16 years. The current study identifies the range of parameters that are measured to assess outcome after hypospadias surgery. The results can be used to promote the development of an age-specific core outcome set that can be applied as a standardized assessment tool in future routine clinical settings.

Standardised data collection for clinical follow-up and assessment of outcomes in differences of sex development (DSD): recommendations from the COST action DSDnet.

The treatment and care of individuals who have a difference of sex development (DSD) have been revised over the past two decades and new guidelines have been published. In order to study the impact of treatments and new forms of management in these rare and heterogeneous conditions, standardised assessment procedures across centres are needed. Diagnostic work-up and detailed genital phenotyping are crucial at first assessment. DSDs may affect general health, have associated features or lead to comorbidities which may only be observed through lifelong follow-up. The impact of medical treatments and surgical (non-) interventions warrants special attention in the context of critical review of current and future care. It is equally important to explore gender development early and refer to specialised services if needed. DSDs and the medical, psychological, cultural and familial ways of dealing with it may affect self-perception, self-esteem, and psychosexual function. Therefore, psychosocial support has become one of the cornerstones in the multidisciplinary management of DSD, but its impact remains to be assessed. Careful clinical evaluation and pooled data reporting in a global DSD registry will allow linking genetic, metabolomic, phenotypic and psychological data. For this purpose, our group of clinical experts and patient and parent representatives designed a template for structured longitudinal follow-up. In this paper, we explain the rationale behind the selection of the dataset. This tool provides guidance to professionals caring for individuals with a DSD and their families. At the same time, it collects the data needed for answering unsolved questions of patients, clinicians, and researchers. Ultimately, outcomes for defined subgroups of rare DSD conditions should be studied through large collaborative endeavours using a common protocol.

Addressing gaps in care of people with conditions affecting sex development and maturation.

Differences of sex development are conditions with discrepancies between chromosomal, gonadal and phenotypic sex. In congenital hypogonadotropic hypogonadism, a lack of gonadotropin activity results primarily in the absence of pubertal development with prenatal sex development being (almost) unaffected in most patients. To expedite progress in the care of people affected by differences of sex development and congenital hypogonadotropic hypogonadism, the European Union has funded a number of scientific networks. Two Actions of the Cooperation of Science and Technology (COST) programmes - DSDnet (BM1303) and GnRH Network (BM1105) - provided the framework for ground-breaking research and allowed the development of position papers on diagnostic procedures and special laboratory analyses as well as clinical management. Both Actions developed educational programmes to increase expertise and promote interest in this area of science and medicine. In this Perspective article, we discuss the success of the COST Actions DSDnet and GnRH Network and the European Reference Network for Rare Endocrine Conditions (Endo-ERN), and provide recommendations for future research.

Midline Incision of a Graft in Staged Hypospadias Repair-Feasible and Durable?

Purpose: In severe hypospadias staged repair is commonly used and it is regarded as feasible, safe, and durable. In this article we want to describe the results of a modification of the staged repair: a midline incision of the graft during the second stage. Materials and Methods: This is a consecutive single team (2 surgeons) retrospective series. Between 2014 and 2017, 250 patients underwent hypospadias repair, among them 35 patients that had primary staged hypospadias surgery with completed first and second stage repair. 24 (68.6%) cases received a preputial skin graft and 11 (31.4%) buccal mucosa graft. Median age at first stage was 1.5 (0.5-22.1) years, mean time between first and second stage operation was 0.72 (0.4-1.76) years. Follow up rate was 100%, mean follow up period was 1.50 (0.4-3.8) years. Results: The total complication rate was 22.9%. In buccal mucosa repair the complication rate was 36.4% and in preputial graft repair the complication rate was 16.7%, respectively. In 23 patients (65.7%) during second stage urethroplasty a midline incision was performed (8 glandular graft, 15 penile graft, 6 at level of urethral opening). Complication rate in non-incised urethroplasty was 8.3%, in incision at glandular level 37.5%, in incision at penile level 13.3% and in incision at urethral opening 16.7%, respectively. Conclusions: Two stage repair is the method of choice in the correction of severe hypospadias. In selected cases a midline incision of the graft is feasible and can be applied if needed. Randomized studies will be needed to evaluate the true benefit of incising the graft.

Optimal Management of Undescended Testis in Boys with Cerebral Palsy. A Debate.

Cerebral palsy is a rare condition following injury of the developing brain and including nonprogressive neurological disorders, spasticity, intellectual impairment and others. Boys with cerebral palsy have a high incidence of undescended testis. Although the motives for treatment (infertility, cancer prevention, psychological aspects, testicular torsion) are not different in boys without neurological impairment, the decision-making process in boys with cerebral palsy is very difficult. Besides medical and surgical arguments the discussion involves challenging ethical issues.

Bladder augmentation in children: current problems and experimental strategies for reconstruction.

Bladder augmentation is a demanding surgical procedure and exclusively offered for selected children and has only a small spectrum of indications. Paediatric bladder voiding dysfunction occurs either on a basis of neurological dysfunction caused by congenital neural tube defects or on a basis of rare congenital anatomic malformations. Neurogenic bladder dysfunction often responds well to a combination of specific drugs and/or intermittent self-catheterization. However, selected patients with spinal dysraphism and children with congenital malformations like bladder exstrophy and resulting small bladder capacity might require bladder augmentation. Ileocystoplasty is the preferred method of bladder augmentation to date. Because of the substantial long-and short-term morbidity of augmentation cystoplasty, recent studies have tried to incorporate new techniques and technologies, such as the use of biomaterials to overcome or reduce the adverse effects. In this regard, homografts and allografts have been implemented in bladder augmentation with varying results, but recent studies have shown promising data in terms of proliferation of urothelium and muscle cells by using biological silk grafts.

Long-term outcome of pediatric renal transplantation in boys with posterior urethral valves.

PURPOSE: To determine whether there is a difference in the outcome of renal transplantation (RT) in patients with posterior urethral valves (PUV) and children with non-uropathy related end stage renal disease. METHODS: Data were acquired retrospectively. We analyzed possible factors that influence the function of renal allografts and graft survival. Between 1995 and 2016 there were 149 RT. Out of them, there were 27 boys with PUV, who received 29 kidneys. Thirty patients, who received a total of 31 renal grafts due to a non-uropathic (NU) diagnosis, served as control group. Mean follow-up was 7.4 to 10.2 years. RESULTS: There was no difference in estimated graft survival between patients with PUV and NU patients. Graft failure occurred in 23.1% of PUV patients and 34.5% patients of the NU group. There was no statistically significant disparity in graft function between the two groups. Age at transplantation and donor age were the only factors that had a significant impact on renal function. There was a higher incidence of UTI in the PUV group (96%) than in the NU group (67%). Vesicostomy was the favourable intervention in regards of graft function. CONCLUSIONS: RT in PUV patients is successful with the same outcome as in NU patients. Bladder dysfunction may not have a major impact on graft function and graft survival. It seems that the type of pre-transplant surgical procedures may influence outcome. Therefore, these interventions -if necessary- should be limited to a minimum. TYPE OF STUDY: Retrospective Comparative Study LEVEL OF EVIDENCE: Level III.