Novel mutation among two sisters with 17ß hydroxysteroid dehydrogenase type 3 deficiency.

The clinical presentations of 17ß hydroxysteroid dehydrogenase type 3 (17ß-HSD3) deficiency, 5α-reductase type 2 deficiency, and complete androgen insensitivity syndrome can be similar. However, those with 17ß-HSD3 deficiency and 5α-reductase type 2 deficiency will develop virilization and should undergo gonadectomy after genetic testing before the age of puberty if reared in the female sex. Two sisters were initially diagnosed with complete androgen insensitivity syndrome as young children after testes were discovered during hernia surgery. Virilization occurred in both sisters during puberty, and a diagnosis of 17ß-HSD3 deficiency was suspected. Confirmatory diagnosis through gene sequencing identified a heterozygous mutation for both a known splicing mutation and a previously unreported amplification mutation of the HSD17B3 gene.

Review and management of 46,XY disorders of sex development.

Disorders of sex development (DSD) among 46,XY individuals are rare and challenging conditions. Abnormalities of karyotype, gonadal formation, androgen synthesis, and androgen action are responsible for the multiple disorders that result in undervirilization during development. Phenotypic appearance and timing of presentation are quite variable. The focus of treatment has shifted from early gender assignment and corrective surgery to careful diagnosis, proper education of patients and their families, and individualized treatment by a multi-disciplinary team. The modern management of these patients is difficult and controversial. Conflicting data on long-term outcomes of these individuals have been reported in the literature. The various etiologies of 46,XY DSD, current approaches to diagnosis and treatment, and reported long-term results are reviewed.

Absence of prostatic growth in large cohort of adult female patients with congenital adrenal hyperplasia.

PURPOSE: In girls with congenital adrenal hyperplasia the degree to which excess androgen exposure leads to the development of prostatic tissue is largely uncharacterized, except in rare case reports of prostatic growth and adenocarcinoma. Such growth yields concern for future malignant degeneration. MATERIALS AND METHODS: Chart review identified 43 adult women with congenital adrenal hyperplasia who had been longitudinally followed from birth, of whom 11 were available for history and physical examination, laboratory testing for androgen metabolites, and pelvic magnetic resonance imaging. RESULTS: Periurethral thickening was noted on digital rectal examination in 1 patient with increased 17-hydroxyprogesterone and tissue analogous to prostatic tissue was impalpable in the remaining 10. Prostate specific antigen was 0.2 ng/ml in another patient with notably increased testosterone, androstenedione, dihydrotestosterone and 17-hydroxyprogesterone, and was less than 0.1 ng/ml in the remaining patients. Magnetic resonance imaging revealed an absence of definitive prostatic tissue in all 11 patients despite evidence of genitourinary masculinization in all. Of the 11 women 7 had marked androgen excess. CONCLUSIONS: Despite androgen excess and genitourinary masculinization in patients with congenital adrenal hyperplasia, as well as case reports citing evidence of prostatic tissue and adenocarcinoma in these women, our study successfully documents the absence of notable prostatic growth in these patients. A better understanding of the timing and factors involved in prostatic growth would aid in identifying the degree to which adult women with congenital adrenal hyperplasia are at risk for adverse sequelae of Skene gland growth.

Normal sex differences in prenatal growth and abnormal prenatal growth retardation associated with 46,XY disorders of sex development are absent in newborns with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is the most common presentation of a disorder of sex development (DSD) in genetic females. A report of prenatal growth retardation in cases of 46,XY DSD, coupled with observations of below-optimal final height in both males and females with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, prompted us to investigate prenatal growth in the latter group. Additionally, because girls with congenital adrenal hyperplasia are exposed to increased levels of androgens in the absence of a male sex-chromosome complement, the presence or absence of typical sex differences in growth of newborns would support or refute a hormonal explanation for these differences. METHODS: In total, 105 newborns with congenital adrenal hyperplasia were identified in our database. Gestational age (weeks), birth weight (kg), birth length (cm) and parental heights (cm) were obtained. Mid-parental height was considered in the analyses. RESULTS: Mean birth weight percentile for congenital adrenal hyperplasia was 49.26%, indicating no evidence of a difference in birth weight from the expected standard population median of 50th percentile (P > 0.05). The expected sex difference in favor of heavier males was not seen (P > 0.05). Of the 105 subjects, 44 (27%; 34 females, 10 males) had birth length and gestational age recorded in their medical chart. Mean birth length for this subgroup was 50.90 cm (63rd percentile), which differed from the expected standard population median of 50th percentile (P = 0.0082). The expected sex difference in favor of longer males was also not seen (P > 0.05). CONCLUSION: The prenatal growth retardation patterns reported in cases of 46,XY disorders of sex development do not generalize to people with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Sex differences in body weight and length typically seen in young infants were not seen in the subjects who participated in this study. We speculate that these differences were ameliorated in this study because of increased levels of prenatal androgens experienced by the females infants.

Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia: Guidance from the CARES Foundation Initiative.

Patients with rare and complex diseases such as congenital adrenal hyperplasia (CAH) often receive fragmented and inadequate care unless efforts are coordinated among providers. Translating the concepts of the medical home and comprehensive health care for individuals with CAH offers many benefits for the affected individuals and their families. This manuscript represents the recommendations of a 1.5 day meeting held in September 2009 to discuss the ideal goals for comprehensive care centers for newborns, infants, children, adolescents, and adults with CAH. Participants included pediatric endocrinologists, internal medicine and reproductive endocrinologists, pediatric urologists, pediatric surgeons, psychologists, and pediatric endocrine nurse educators. One unique aspect of this meeting was the active participation of individuals personally affected by CAH as patients or parents of patients. Representatives of Health Research and Services Administration (HRSA), New York-Mid-Atlantic Consortium for Genetics and Newborn Screening Services (NYMAC), and National Newborn Screening and Genetics Resource Center (NNSGRC) also participated. Thus, this document should serve as a "roadmap" for the development phases of comprehensive care centers (CCC) for individuals and families affected by CAH.

Clinical, genetic, and enzymatic characterization of P450 oxidoreductase deficiency in four patients.

CONTEXT: P450 oxidoreductase (POR) deficiency causes disordered steroidogenesis; severe mutations cause genital ambiguity in both sexes plus the Antley-Bixler skeletal malformation syndrome, whereas mild mutations can cause adult infertility. OBJECTIVE: We describe four patients with POR deficiency and identify and characterize the activities of their mutations. A 46,XY male with micropenis and two 46,XX female infants with genital ambiguity presented with skeletal malformations, and a 46,XX adolescent presented with primary amenorrhea, elevated 17alpha-hydroxyprogesterone, and low sex steroids. METHODS: The coding regions of the POR gene were sequenced, and the identified mutations were recreated in human POR cDNA expression vectors lacking 27 N-terminal residues. POR and human P450c17 were expressed in bacteria. POR activity was measured by four assays: reduction of cytochrome c, oxidation of reduced nicotinamide adenine dinucleotide phosphate, and support of the 17alpha-hydroxylase and 17,20 lyase activities of P450c17. RESULTS: All four patients were compound heterozygotes for POR mutations, including five novel mutations: L577R, N185K, delE217, and frameshift mutations 1363delC and 697-698insGAAC. N185K and delE217 lacked measurable activity in the assays based on P450c17 but retained partial activity in the assays based on cytochrome c. As assessed by V(max)/Km, L577R supported 46% of 17alpha-hydroxylase activity but only 27% of 17,20 lyase activity. Computational modeling of these novel mutants revealed the structural basis for their reduced or absent activities. CONCLUSION: These patients illustrate the broad clinical spectrum of POR deficiency, including amenorrhea and infertility as the sole manifestation. POR assays based on P450c17 correlate well with hormonal and clinical phenotypes.

Gender role across development in adults with 46,XY disorders of sex development including perineoscrotal hypospadias and small phallus raised male or female.

Self-rated degree of femininity and masculinity across development were evaluated for 40 adults affected by 46,XY disorders of sex development (DSDs) who presented at birth with a small phallus and perineoscrotal hypospadias, raised either male (n = 22) or female (n = 18). Most participants were confirmed or presumed to be affected by partial androgen insensitivity syndrome (n = 14), partial gonadal dysgenesis (n = 11), or were considered to have a poorly defined case of 46,XY DSD including ambiguous external genitalia (n = 15). Participants retrospectively evaluated their degree of masculinity and femininity during their childhood, adolescence, adulthood, and in the past 12 months of filling out a questionnaire pertaining to their psychosexual development. Participants raised male reported more masculinity than those raised female due to an increase in masculinization during adolescence and adulthood. Participants raised male also reported less femininity than those raised female throughout development. Participants raised female reported more femininity than those raised male due to an increase in feminization during adolescence and adulthood. Participants raised female also reported less masculinity than those raised male throughout development. These data support the proposition that some aspects of gender role (GR), such as masculinity and femininity, are capable of proceeding along female- or male-typic patterns depending on sex of rearing among individuals affected by specific types of 46,XY DSD. Furthermore, regardless of male or female rearing, GR increasingly corresponds with assigned sex as individuals proceed through sexual maturity and into adulthood. These results are consistent with the idea that socialization/learning contributes to GR development in humans in addition to data from others demonstrating endocrine influences.

Prostate screening in patients with 46,XY disorders of sex development--is it necessary?

PURPOSE: We used current methods of screening for prostate cancer, digital rectal examination and serum prostate specific antigen as an initial assessment of risk in a young group of adult 46,XY patients affected by disorders of sex development. MATERIALS AND METHODS: Adult intersex patients older than 21 years, under long-term followup at the Pediatric Endocrinology Clinic of the Johns Hopkins Hospital, with a diagnosis of male psuedohermaphroditism and raised as male or female were included in analysis. After written consent all participants underwent digital rectal examination and blood sampling for prostate specific antigen and testosterone measurements. RESULTS: Prostate specific antigen values were available for analysis in 26 patients. Diagnoses included micropenis (8), complete androgen insensitivity syndrome (3), partial androgen insensitivity syndrome (9) and mixed gonadal dysgenesis (6). Of the 26 patients 9 had been raised as female (complete androgen insensitivity syndrome in 3, partial androgen insensitivity syndrome in 3, micropenis in 2 and mixed gonadal dysgenesis in 1). Mean patient age was 38 years (range 24 to 57). Serum prostate specific antigen was less than 0.1 ng/ml in 18 patients including the 9 reared as female. The remaining 8 patients had a prostate specific antigen of 0.1 to 0.9 ng/ml, were reared as male and had a mean age of 39.6 years (range 33 to 44). The diagnoses in this group consisted of micropenis (4), partial androgen insensitivity syndrome (2) and mixed gonadal dysgenesis (2). All patients had a palpable, small prostate gland with no abnormalities noted on digital rectal examination. CONCLUSIONS: This study found measurable prostate specific antigen in a subset of male intersex patients that were comparable to controls matched for age and race. We recommend that patients with 46,XY disorder of sex development, reared as male, be screened for prostate cancer in a manner similar to men not affected by disorder of sex development.

Medical and psychosexual outcome in women affected by complete gonadal dysgenesis.

BACKGROUND: Prenatal exposure to testicular hormones influences the development of brain structures and behavior in many non-human mammalian species. Less understood is the role of possessing a Y chromosome, independent of testicular hormones, on psychosexual differentiation. HYPOTHESIS: Phenotypic women affected by complete gonadal dysgenesis possess a 46,XY chromosome complement and streak gonads. This population is suitable to test the influence of an absence of androgens and Müllerian inhibiting substance on psychosexual development in genetic males. PATIENTS: Three 46,XY women diagnosed with complete gonadal dysgenesis participated. METHODS: Psychosexual development, medical outcome and knowledge of medical condition were assessed with a written questionnaire and a physical examination. RESULTS: All participants were healthy, compliant with their hormone therapy, and exhibited female-typical psychosexual development. However, participants were poorly informed about their condition and the fertility treatment options available to them. CONCLUSIONS: These data indicate no obvious role for genes on the Y chromosome, outside of its pseudoautosomal region and SRY, on psychosexual differentiation in genetic males who do not produce testicular hormones. Greater efforts need to be made to educate affected women about their pregnancy options.

Cognitive outcome in adult women affected by congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND: Some research suggests that girls with congenital adrenal hyperplasia (CAH), who are exposed to higher than normal levels of prenatal androgens, perform better on spatial tasks, worse on verbal tasks and have a greater incidence of left-handedness than unaffected controls, all of which suggests the development of a more male-typical cognitive pattern. However, research in all three areas has produced inconsistent findings. OBJECTIVES: To determine if prenatal androgen exposure has an organizing effect on female cognitive development and to what extent. METHODS: 24 women, 21-71 years, with either the salt-losing (SL) or simple virilizing (SV) forms of CAH due to 21-hydroxylase deficiency, and 18 controls, 21-73 years, who were unaffected female relatives or women with polycystic ovary syndrome, were assessed with IQ, handedness, executive function, verbal learning and memory, non-verbal learning and memory, perceptual speed, visuospatial processing and visuomotor ability measures. The battery included tests known to elicit sex differences and control measures. RESULTS: The findings did not support the hypothesis that women with CAH develop a more male-typical cognitive pattern. CONCLUSION: This study differs from others in the older age of its participants, grouping by SL/SV diagnosis and assessment of medical treatment and compliance as determined through hormone assays. Our findings provide additional support for the conclusion that, in adult women with CAH, previous prenatal androgen exposure does not enhance spatial abilities, impair verbal abilities nor alter hand preferences in a long-lasting way.

Long-term corticosteroid replacement and bone mineral density in adult women with classical congenital adrenal hyperplasia.

CONTEXT: Concern has been raised regarding the potential impact of chronic glucocorticoid therapy on the bone mineral density (BMD) of patients with congenital adrenal hyperplasia (CAH). OBJECTIVE: The purpose of this investigation was to assess the impact of chronic glucocorticoid replacement in adult women with classical CAH. PATIENTS AND DESIGN: We used dual energy x-ray absorptiometry to evaluate lumbar spine and whole body BMD in 11 women with salt-losing (SL) CAH and 15 with the simple virilizing form. Physical characteristics and serum hormone concentrations were also measured. Results were compared with those of unaffected sisters of CAH patients (n = 9). MAIN OUTCOME MEASURE: BMD was the main outcome measure. RESULTS: Osteopenia was noted in 45% of SL CAH patients, 13% of patients with the simple virilizing form, and 11% of controls. Lumbar spine and whole body BMDs of CAH subjects were lower than those of controls (P < 0.05). Compared with CAH subjects with normal BMD, those with osteopenia had reduced serum levels of dehydroepiandrosterone sulfate and dehydroepiandrosterone. Adrenal androgen levels were particularly suppressed among postmenopausal women receiving glucocorticoid replacement. CONCLUSIONS: Adult women with classical CAH treated with long-term glucocorticoids are at risk for decreased BMD, especially those with the SL form. Oversuppression of adrenal androgens is associated with increased risk for bone loss in this population.

Gender role across development in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

This study evaluated the degree of femininity and masculinity at different developmental stages in a group of adult women, some of whom were exposed to elevated prenatal adrenal androgens as a result of congenital adrenal hyperplasia (CAH) due to 21 hydroxylase (21-OH) deficiency. Women who had presented to the Johns Hopkins Hospital Pediatric Endocrine Clinic for treatment of CAH due to 21-OH deficiency were included. The control group consisted of sisters of CAH participants and women referred for evaluation of polycystic ovary syndrome. Study participants were given a questionnaire asking them to indicate their degree of masculinity and femininity during childhood, adolescence, and adulthood. In addition, participants were asked questions related to their play behavior during childhood, including playmate preferences, toy preferences, and admiration of male or female characters during fantasy play. Across participant groups, self-reported femininity decreased in a dose response manner, according to prenatal androgen exposure. For all groups, femininity increased through developmental stages. Women with salt-losing CAH remained less feminine than controls into adulthood. Conversely, self-reported masculinity increased in a dose-response manner, according to prenatal androgen exposure, across participant groups. Women with CAH showed a decrease in masculinity across developmental stages, such that by adulthood, there were no significant differences in masculinity between controls and the women with CAH. Women with salt-losing CAH were more likely to recall preferences for boy playmates, male-typical toys, and admiration for male characters during childhood than other study participants. Our data support the effect of both prenatal androgen exposure and socialization on gender role behavior in adult women with CAH due to 21-OH deficiency.

Psychosexual outcome in women affected by congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

PURPOSE: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in increased adrenal androgen secretion. When the deficiency is severe, the result is the salt losing (SL) form, and when the deficiency is partial, the result is the simple virilizing (SV) form of CAH. We documented long-term satisfaction with gender, cosmetic appearance and function of the genitalia, and surgical management practices in a group of women with CAH due to 21-hydroxylase deficiency. MATERIALS AND METHODS: Psychosexual and surgical outcome were assessed in 41 women with CAH using an interview, a written questionnaire and a physical examination. When appropriate, outcome measures were compared to those in unaffected control women. RESULTS: Women in the SL group were more likely to question their female gender and report sexual concerns, and less likely to have sexual relations with a partner than those with the SV form or control women. Overall women with CAH were moderately satisfied with the cosmetic appearance of the genitalia but the SL group reported worse genital function than the SV group. Physician rated appearance of the genitalia was better than ratings provided by patients and women with the SL form were judged to have a worse cosmetic outcome of genital reconstruction than women with the SV form. The most common response concerning the optimal timing for genital reconstruction was during infancy and early childhood, although a number of women favored waiting until later for these procedures or did not respond to this question. CONCLUSIONS: Women with the SV form reported greater satisfaction and fewer concerns regarding their psychosexual and surgical outcome than women with the SL form.

Human sex differentiation and its abnormalities.

The purpose of this chapter is to review the presentation and management of patients affected by conditions of abnormal sex differentiation. First, the processes of normal sex differentiation are covered, followed by an overview of the various syndromes of abnormal sex differentiation, or intersex conditions, that can occur. These disorders are presented according to the following categories: patients who possess a 46,XX chromosome complement, those who possess a 46,XY chromosome complement, and individuals who present with an atypical sex chromosome complement (i.e. 45,XO or 45,X0/46,XY mosaicism). A description of the medical, surgical and psychological treatment options for people affected by various intersex conditions and reared as females are included. Practice points, based on research studies when available, are dispersed throughout the chapter. Additionally, information pertaining to relevant Internet websites and patient support groups are provided, so that medical staff can educate their patients about the availability of these resources.

Long-term perspectives for 46,XY patients affected by complete androgen insensitivity syndrome or congenital micropenis.

Controversy concerning optimal treatment for individuals affected by syndromes of abnormal sex differentiation can best be resolved with knowledge about long-term medical, surgical, and psychosexual outcomes of patients. Follow-up information has recently been gathered on older cohorts of the following patient groups: (1) those affected by complete androgen insensitivity syndrome (CAIS) raised female and (2) those affected by congenital micropenis raised male or female. As a group, women with CAIS were satisfied with their female gender and sexual function. However, a need for better patient education was identified for this specific population. Most patients with congenital micropenis, whether raised male or female, were satisfied with their gender. Regardless of sex of rearing, dissatisfaction with the appearance and function of the genitalia as judged by both physicians and subjects was evident. For patients with congenital micropenis, male sex of rearing was concluded to be optimal because genital reconstructive surgery is not required with this choice.