Parenting Children with Disorders of Sex Development (DSD): A Developmental Perspective Beyond Gender.

Advances in therapeutics for specific conditions have contributed to a categorical psychological approach to chronic diseases that affect children. Consensus statements and clinical guidelines recognize stress associated with disorders of sex development (DSD) for patients and their caregivers - yet much remains to be learned concerning the social adjustment, mental health, and quality of life of affected children and their families. We present preliminary data on the psychosocial comorbidities of caregivers of children with DSD, including stigma, isolation, stress, anxiety, and depressive symptomatology. Evidence is offered in support of individualized psychological approaches for families according to such variables as: 1) gender of the caregiver, 2) gender of the affected child and 3) presence of genital ambiguity at birth. Development of feasible, targeted interventions to ameliorate psychosocial comorbidities among caregivers is needed to optimize social adjustment, mental health, and health-related quality of life (HRQoL) for children with DSD.

Disorders of Sex Development (DSD): Networking and Standardization Considerations.

Syndromes resulting in Disorders of Sex Development (DSD) are individually rare. Historically, this fact has hindered both clinical research and the delivery of evidence-based care. Recognizing the need for advancement, members of European and North American medical societies produced policy statements, notably the Consensus Statement on Management of Intersex Disorders, which recognize that optimal healthcare in DSD requires multidisciplinary teams in conjunction with networking of treatment centers and continued development of patient registries. This paper summarizes efforts in Europe and the U.S. toward creating networks focused on expanding discovery and improving healthcare and quality of life outcomes in DSD. The objectives and function of registry-based networks (EuroDSD/I-DSD), learning collaboratives (DSD-net), clinical outcomes research (DSD-Life), and networking hybrids (DSD-TRN) are reviewed. Opportunities for, and barriers to standardization in research and care are highlighted in light of practical considerations, for example, limitations in reliably classifying anatomic phenotypes and gaps in behavioral health staffing resources. The role of patient-reported outcomes is considered, with emphasis on integrating patient perspectives, given findings of limited agreement in outcome ratings by healthcare providers and patients. Finally, the characteristics of clinical centers likely to deliver the highest quality outcomes are discussed.

Preliminary report: Surgical outcomes following genitoplasty in children with moderate to severe genital atypia.

INTRODUCTION: Prior studies of outcomes following genitoplasty have reported high rates of surgical complications among children with atypical genitalia. Few studies have prospectively assessed outcomes after contemporary surgical approaches. OBJECTIVE: The current study reported the occurrence of early postoperative complications and of cosmetic outcomes (as rated by surgeons and parents) at 12 months following contemporary genitoplasty procedures in children born with atypical genitalia. STUDY DESIGN: This 11-site, prospective study included children aged ≤2 years, with Prader 3-5 or Quigley 3-6 external genitalia, with no prior genitoplasty and non-urogenital malformations at the time of enrollment. Genital appearance was rated on a 4-point Likert scale. Paired t-tests evaluated differences in cosmesis ratings. RESULTS: Out of 27 children, 10 were 46,XY patients with the following diagnoses: gonadal dysgenesis, PAIS or testosterone biosynthetic defect, severe hypospadias and microphallus, who were reared male. Sixteen 46,XX congenital adrenal hyperplasia patients were reared female and one child with sex chromosome mosaicism was reared male. Eleven children had masculinizing genitoplasty for penoscrotal or perineal hypospadias (one-stage, three; two-stage, eight). Among one-stage surgeries, one child had meatal stenosis (minor) and one developed both urinary retention (minor) and urethrocutaneous fistula (major) (Summary Figure). Among two-stage surgeries, three children developed a major complication: penoscrotal fistula, glans dehiscence or urethral dehiscence. Among 16 children who had feminizing genitoplasty, vaginoplasty was performed in all, clitoroplasty in nine, external genitoplasty in 13, urethroplasty in four, perineoplasty in five, and total urogenital sinus mobilization in two. Two children had minor complications: one had a UTI, and one had both a mucosal skin tag and vaginal mucosal polyp. Two additional children developed a major complication: vaginal stenosis. Cosmesis scores revealed sustained improvements from 6 months post-genitoplasty, as previously reported, with all scores reported as good or satisfied. DISCUSSION: In these preliminary data from a multi-site, observational study, parents and surgeons were equally satisfied with the cosmetic outcomes 12 months after genitoplasty. A small number of patients had major complications in both feminizing and masculinizing surgeries; two-stage hypospadias repair had the most major complications. Long-term follow-up of patients at post-puberty will provide a better assessment of outcomes in this population. CONCLUSION: In this cohort of children with moderate to severe atypical genitalia, preliminary data on both surgical and cosmetic outcomes were presented. Findings from this study, and from following these children in long-term studies, will help guide practitioners in their discussions with families about surgical management.

Prospective assessment of cosmesis before and after genital surgery.

INTRODUCTION: Little data exist about the surgical interventions taking place for children with disorders of sex development (DSD). Most studies that have evaluated cosmetic outcomes after genitoplasty have included retrospective ratings by a physician at a single center. OBJECTIVE: The present study aimed to: 1) describe frequency of sex assignment, and types of surgery performed in a cohort of patients with moderate-to-severe genital ambiguity; and 2) prospectively determine cosmesis ratings by parents and surgeons before and after genital surgery. STUDY DESIGN: This prospective, observational study included children aged <2 years of age, with no prior genitoplasty at the time of enrollment, moderate-to-severe genital atypia, and being treated at one of 11 children's hospitals in the United States of America (USA). Clinical information was collected, including type of surgery performed. Parents and the local pediatric urologist rated the cosmetic appearance of the child's genitalia prior to and 6 months after genitoplasty. RESULTS: Of the 37 children meeting eligibility criteria, 20 (54%) had a 46,XX karyotype, 15 (40%) had a 46,XY karyotype, and two (5%) had sex chromosome mosaicism. The most common diagnosis overall was congenital adrenal hyperplasia (54%). Thirty-five children had surgery; 21 received feminizing genitoplasty, and 14 had masculinizing genitoplasty. Two families decided against surgery. At baseline, 22 mothers (63%), 14 fathers (48%), and 35 surgeons (100%) stated that they were dissatisfied or very dissatisfied with the appearance of the child's genitalia. Surgeons rated the appearance of the genitalia significantly worse than mothers (P < 0.001) and fathers (P ≤ 0.001) at baseline. At the 6-month postoperative visit, cosmesis ratings improved significantly for all groups (P < 0.001 for all groups). Thirty-two mothers (94%), 26 fathers (92%), and 31 surgeons (88%) reported either a good outcome, or they were satisfied (see Summary Figure); there were no significant between-group differences in ratings. DISCUSSION: This multicenter, observational study showed surgical interventions being performed at DSD centers in the USA. While parent and surgeon ratings were discordant pre-operatively, they were generally concordant postoperatively. Satisfaction with postoperative cosmesis does not necessarily equate with satisfaction with the functional outcome later in life. CONCLUSION: In this cohort of children with genital atypia, the majority had surgery. Parents and surgeons all rated the appearance of the genitalia unfavorably before surgery, with surgeons giving worse ratings than parents. Cosmesis ratings improved significantly after surgery, with no between-group differences.

Assessment of colon and bladder crosstalk in an experimental colitis model using contrast-enhanced magnetic resonance imaging.

BACKGROUND: Inflammatory bowel disease (IBD) consists of two chronic remitting-relapsing inflammatory disorders in the colon referred to as ulcerative colitis and Crohn's disease (CD). Inflammatory bowel disease affects about 1.4 million Americans. 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis is a widely used model of experimental intestinal inflammation with characteristic transmural and segmental lesions that are similar to CD. METHODS: Here, we report on the use of contrast-enhanced magnetic resonance imaging (CE-MRI) to monitor in vivo bladder permeability changes resulting from bladder crosstalk following colon TNBS exposure, and TNBS-induced colitis. Changes in MRI signal intensities and histology were evaluated for both colon and bladder regions. KEY RESULTS: Uptake of contrast agent in the colon demonstrated a significant increase in signal intensity (SI) for TNBS-exposed rats (p < 0.01) compared to controls. In addition, a significant increase in bladder SI for colon TNBS-exposed rats (p < 0.001) was observed compared to saline controls. Histological damage within the colon was observed, however, bladder histology indicated a normal urothelium in rats with TNBS-induced colitis, despite increased permeability seen by CE-MRI. CONCLUSIONS & INFERENCES: Contrast-enhanced MRI was able to quantitatively measure inflammation associated with TNBS-induced colitis, and assess bladder crosstalk measured as an increase in urothelial permeability. Although CE-MRI is routinely used to assess inflammation with IBD, currently there is no diagnostic test to assess bladder crosstalk with this disease, and our developed method may be useful in providing crosstalk information between organ and tissue systems in IBD patients, in addition to colitis.

Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome.

Controversy concerning the most appropriate treatment guidelines for intersex children currently exists. This is due to a lack of long-term information regarding medical, surgical, and psychosexual outcome in affected adults. We have assessed by questionnaire and medical examination the physical and psychosexual status of 14 women with documented complete androgen insensitivity syndrome (CAIS). We have also determined participant knowledge of CAIS as well as opinion of medical and surgical treatment. As a whole, secondary sexual development of these women was satisfactory, as judged by both participants and physicians. In general, most women were satisfied with their psychosexual development and sexual function. Factors reported to contribute to dissatisfaction were sexual abuse in one case and marked obesity in another. All of the women who participated were satisfied with having been raised as females, and none desired a gender reassignment. Although not perfect, the medical, surgical, and psychosexual outcomes for women with CAIS were satisfactory; however, specific ways for improving long-term treatment of this population were identified.

Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Growth, development, and therapeutic considerations.

In the absence of long-term results of experimental therapies, a common sense approach toward dealing with the growth of patients who have CAH is desirable. First, an effort can be made to decrease the replacement cortisol dose during the first year of life. Doubling, rather than tripling, the basal dose at times of stress could be helpful. The use of adjunctive therapy for infections could result in fewer fevers. After 1 year of age, mean parental height could be used to establish at which centile the child should theoretically grow. The dose of cortisol could be adjusted to maintain the bone age between +/- 1 SD. Plasma androstenedione levels should not rise above 50 ng/dL, and 17-hydroxyprogesterone should not be totally suppressed but be maintained between 500 and 1000 ng/dL. Compliance with therapy should be encouraged, particularly for adolescent patients. In the final analysis, a realistic expectation for patients would be a height between the 50th and third percentile of the normal growth curve and, in some cases, slightly below the third percentile when the genetic potential is slight.

Sexually-dimorphic patterns of cortical asymmetry, and the role for sex steroid hormones in determining cortical patterns of lateralization.

Cortical asymmetry varies in degree and direction. Sex differences exist for both dimensions of asymmetry: males tend to exhibit more accentuated asymmetries and stronger right hemisphere dominance compared with females, while females typically exhibit more diffuse lateralization patterns and greater left hemisphere bias compared with males. The following review considers the effects of sex steroid hormones on the sexual dimorphism of cortical lateralization patterns in human and nonhuman animals. Several excellent papers exist which consider sexual dimorphism in cortical asymmetries for morphological, physiological or functional asymmetries alone. This paper attempts to consider influences of sex steroid hormones on cortical lateralization in a framework that includes morphology, physiology and function. Converging evidence from studies that incorporate varying methodologies and theoretical backgrounds indicates that sex steroid hormones are important for influencing cortical asymmetry. Although a mechanism has not yet been identified, testosterone is the most likely candidate to influence cortical dominance.

Auditory scene analysis by songbirds: stream segregation of birdsong by European starlings (Sturnus vulgaris).

Three experiments examined the capacity of European starlings to segregate perceptually 2 superimposed, intermixed auditory stimuli. The stimuli were 10-s song samples from 2 of 4 songbird species: European starling, brown thrasher, mockingbird, and nightingale. The birds first learned a discrimination between the intermixed song pairs. Then, they maintained the discrimination with novel song exemplars in the mixtures and when song stimuli for each species were presented alone. Performance fell, but remained above chance, when song pairs were mixed with the dawn chorus of bird song. The results show that starlings were identifying the songs of individual species within the baseline superimposed song pairs, a process of auditory stream segregation and scene analysis (A. S. Bregman, 1990).

Lateral asymmetries in infant melody perception.

Two experiments investigated lateral asymmetries in infants' perception of contour-altered and contour-preserved melody changes. In the first study, 40 infants (8.5 months old) of right-handed parents were trained to respond to binaural melody changes with a head turn toward mechanized toy reinforcers. The subsequent test phase included monaural left-ear and right-ear presentations of the familiar melody and of a changed melody. Infants who heard a contour-altered change showed a left-ear advantage, whereas infants who heard a contour-preserved change showed a right-ear advantage. These effects were replicated with a different set of melodies in the second study. The pattern of lateralization for detection of melody changes in infants of right-handed parents resembles that previously found in right-handed adults and may reflect more general hemispheric processing differences in the early organization of auditory information processing.

Human sex differentiation: from transcription factors to gender.

Over the past decade, knowledge of the genetic control of human sex differentiation has greatly expanded our understanding of the developmental processes needed to form a male or female. The purpose of this review is to discuss how transcription factors are relevant to such processes. Additionally, an attempt is made to relate current knowledge of these factors with gender development of subjects with intersex conditions. Finally, we discuss how information about the genetic control of sex differentiation may contribute to decisions about medical treatment of individuals with conditions of abnormal sex differentiation.

Seasonal variation in human functional cerebral lateralization and free testosterone concentrations.

Men have previously been reported to exhibit seasonal fluctuations on specific types of cognitive performance. It has been speculated that this performance variability is a result of changes in cerebral asymmetry due to lowered testosterone concentrations in the spring relative to the fall. In the present study, functional cerebral lateralization was measured in a group of men and women in the spring and fall. Free testosterone concentrations were assessed for participants to determine what associations might exist between seasonal variability in lateralization and seasonal fluctuations in testosterone exposure. Men and women tested in the spring exhibited exaggerated patterns of asymmetry compared to participants tested in the fall. Lower testosterone concentrations were observed in the spring compared to the fall in women, but not men. No direct associations between testosterone and lateralization were detected for either sex at either season. These results illustrate that seasonal fluctuations in testosterone exposure do not directly influence seasonal changes in functional lateralization patterns.

Sexual differentiation: from genes to gender.

A person's sex can be considered across various levels. To illustrate, genes, hormones, and genitalia can all be considered physical markers of a person's sex. In addition to physical markers, behaviors such as gender role, gender identity and sexual orientation can be perceived as stereotypically male or female. The purpose of this review is to summarize current knowledge of sexual differentiation which emphasizes genetic and hormonal mechanisms that result in male and female development of gonads and genitalia. Finally, consideration is given to associations between genetic sex, gonadal sex, and hormonal sex with gender.

Attitudes of adult 46, XY intersex persons to clinical management policies.

PURPOSE: We surveyed a clinic sample of adult 46,XY intersex patients regarding attitudes to clinical management policies. MATERIALS AND METHODS: All adult former patients of 1 pediatric endocrine clinic in the eastern United States whose addresses could be obtained and who consented to participation were surveyed by a comprehensive written followup questionnaire. Three questions on attitudes concerning the desirability of a third gender category and the age at which genital surgery should be done were presented in the context of ratings of satisfaction with gender, genital status and sexual functioning. RESULTS: A total of 72 English speaking patients with 46,XY, including 32 men and 40 women 18 to 60 years old, completed the questionnaire. The majority of respondents stated that they were mainly satisfied with being the assigned gender, did not have a time in life when they felt unsure about gender, did not agree to a third gender policy, did not think that the genitals looked unusual (although the majority of men rated their penis as too small), were somewhat or mainly satisfied with sexual functioning, did not agree that corrective genital surgery should be postponed to adulthood and stated that their genital surgeries should have been performed before adulthood, although there were some significant and important differences among subgroups. CONCLUSIONS: The majority of adult patients with intersexuality appeared to be satisfied with gender and genital status, and did not support major changes in the prevailing policy. However, a significant minority was dissatisfied and endorsed policy changes.

Congenital micropenis: long-term medical, surgical and psychosexual follow-up of individuals raised male or female.

OBJECTIVES: To document long-term medical, surgical and psychosexual outcome of individuals with congenital micropenis (13 males, 5 females). METHODS: Physical measurements from childhood were collected retrospectively from medical records and at adulthood by physical examination. An adult psychosexual assessment was conducted with a written questionnaire and oral discussion. RESULTS: Adult penile length was below the normal mean in all men. Three women had vaginoplasty resulting in normal length. All men reported good or fair erections but 50% were dissatisfied with their genitalia. Dissatisfaction with body image resulted from having a small penis (66%), inadequate body hair (50%), gynecomastia (33%) and youthful appearance (33%). Ten men were heterosexual, 1 homosexual and 2 bisexual. Among women, 4 (80%) were dissatisfied with their genitalia. Three women reported average libido with orgasm and were also heterosexual. Two women had no sexual interest or experience. Finally, males were masculine and females feminine in their gender-role identity, and both groups were satisfied with their sex of rearing. CONCLUSIONS: Regarding choice of gender, male sex of rearing can result in satisfactory genito-sexual function. Female gender can also result in success, however it requires extensive feminizing surgery.