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SPECIAL ARTICLE |
a Department of Pediatrics, Backus Children’s Hospital, Mercer University School of Medicine, Savannah, Georgia
b Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom
c Co-chairs
d Department of Child Health, Royal Hospital for Sick Children, Glasgow, Scotland, United Kingdom
e Department of Pediatrics, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania
Key Words: intersex • sexual differentiation • ambiguous genitalia • genital surgery
Abbreviations: DSD—disorder(s) of sex development • AE—androgen exposure • CAH—congenital adrenal hyperplasia • 5
-RD2—5-reductase deficiency • CAIS—complete androgen insensitivity syndrome
Advances in understanding of genetic control of sexual determination and differentiation, improvements in diagnostic testing and surgical genital repair, and the persistent controversies inherent to clinical management were all compelling factors that led to the organization of an international consensus conference. The goals were to acknowledge and discuss the more controversial issues in intersex management, provide management guidelines for intersex patients, and identify and prioritize questions that need additional investigation. This is a summary statement.
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NOMENCLATURE AND DEFINITIONS |
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 TOP NOMENCLATURE AND DEFINITIONS BACKGROUND INFORMATIONEVALUATIONMANAGEMENTINTERNATIONAL INTERSEX CONSENSUS...REFERENCES |
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Additional rationale for new classification is the need for modern categorization to integrate the modern molecular genetic aspects, to maximize precision when applying definitions and diagnostic labels,3 and to meet the need for psychologically sensitive yet descriptive medical terminology. Nomenclature should be flexible enough to incorporate new information, robust enough to maintain a consistent framework, use descriptive terms, reflect genetic etiology, accommodate phenotypic variation spectrum, and be useful for clinicians, scientists, patients, and families. Hence, we propose a new classification (see "Consensus Statement on Management of Intersex Disorders"4 in this month's issue of Pediatrics Electronic Edition).
Three traditionally conceptualized domains of psychosexual development are gender identity (one's self-representation [ie, male or female]), gender role (sexually dimorphic behaviors within the general population, such as toy preferences, aggression, and spatial ability), and sexual orientation (direction[s] of erotic interest). Gender dissatisfaction denotes unhappiness with assigned sex and may result in gender self-reassignment. Psychosexual developmental factors relate to parental psychopathology, parent-child attachment, or parenting practices (eg, not discouraging cross-sex behavior). Dissatisfaction occurs more frequently in individuals with DSD than the general population, is not predictable by karyotype, androgen exposure (AE), degree of genital virilization, or assigned sex,5 and has not been well studied with regard to social, personal, or biological factors.
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BACKGROUND INFORMATION |
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TOPNOMENCLATURE AND DEFINITIONSBACKGROUND INFORMATIONEVALUATIONMANAGEMENTINTERNATIONAL INTERSEX CONSENSUS...REFERENCES |
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-reductase deficiency [5-RD2]). Emerging evidence suggests direct effects of sex-chromosome genes on brain and behavior,8 but behavioral roles for Y-chromosome genes have not been identified.9 A Y-chromosome and male-typical prenatal AE does not unequivocally entrain adult male gender identity.10
Sex differences in brain structures have been identified across species.11 Human postmortem and neuroimaging studies have found that male brains are 8% to 10% larger than female brains. Sexual dimorphism in specific neural subcomponents persists after adjustment for brain size. The limbic system and hypothalamus are important because of roles in reproduction; specific nuclei show sexual dimorphism on postmortem studies (bed nucleus of the stria terminalis, suprachiasmatic nucleus, and the interstitial nucleus of the anterior hypothalamus 3), although it is unknown when these differences emerge. Relationships between structural brain differences and psychosexual development are unclear.
DSD may carry stigma. Environmental and cultural factors influence gender role (gender-change frequency differences in 5-RD2 deficiency in different counties). Religious, philosophical, fatalism, or guilt viewpoints influence parents' actions. In some societies, female infertility precludes marriage, employment prospects, and economic independence. Poverty impairs access to health care.12
Standard-of-care concepts for best clinical management of DSD13 include a gender assignment for all; avoiding gender assignment before expert evaluation in newborns; open communication; multidisciplinary-team evaluation and management; family/patient participation in decision-making; respect and attention to patient/family concerns; and strict confidentiality.
Key points to address during the crucial initial parental contact include: children with DSD have the potential to become well-adjusted persons; DSD is not shameful, but privacy is respected; and although the best course of action may not be obvious, caregivers with parents arrive at the best possible decisions.
A core team ideally includes pediatric endocrinologists, surgeons, urologists or gynecologists, psychologists/psychiatrists, geneticists, neonatologists, social workers, nurses, and medical ethicists14 with communication with the primary care physician.15 Consensus regarding diagnosis, gender assignment, and treatment options must be reached before making recommendations, with one team member primarily interacting with the family.16 The surgeon's role involves outlining surgical sequences and consequences of aligning genitalia for assigned gender, establishing functional genital anatomy, and, if indicated, timely gonadectomy. Support groups can play a positive role.17
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EVALUATION |
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DSD in older individuals may include unrecognized genital ambiguity, inguinal hernia in a female, delayed/incomplete puberty, virilization in a female, primary amenorrhea, male breast development, and gross hematuria in a male.
Clinical evaluation includes family and prenatal history and physical examination with an accurate and objective assessment of genitalia and any dysmorphic features. To minimize psychological distress, the patient/family should be informed exactly what will be done and why. Medical photography requires sensitivity and consent.18
A specific molecular diagnosis is identified in only 
20% of gonadal differentiation defects.19 Most virilized 46,XX infants have CAH; only 50% of undervirilized 46,XY patients receive a definitive diagnosis.20,21 Given the spectrum of findings and diagnoses, no specific single evaluation protocol can be used. Plasma hormone concentrations must be interpreted using normal ranges for gestational and chronological age for the assay used.
In newborns, first-line testing includes karyotyping with SRY detection (even when prenatal karyotype is available), imaging (abdominopelvic ultrasound), and measurement of 17-hydroxyprogesterone, testosterone, gonadotropins, anti-Mullerian hormone, and electrolytes. Usually, results that are sufficient for diagnosis should be available within 48 hours. Although cases must be individualized, practical decision-making algorithms are available22 to guide additional investigation. Although mutations in established genes may be readily identified by clinical laboratories, current molecular diagnosis is limited by cost, accessibility, quality control, and inadequate functional interpretation.23
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MANAGEMENT |
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-RD2 who were initially assigned female sex who virilize at puberty, and all who were assigned male, live as males. Gender-role changes are reported for approximately half of the 17ß-hydroxysteroid dehydrogenase-3-deficient patients who are raised as girls. The recommendations are to raise infants with 46,XY CAIS and 46,XX CAH as females, whereas for infants diagnosed with 5-RD2 or 17ß-hydroxysteroid dehydrogenase-3 deficiency, a male assignment should be considered.24
Sexual functioning, psychosocial adjustment, mental health, quality of life, and social participation are understudied. Attention has been toward dissatisfaction with assigned sex or gender self-reassignment. Dissatisfaction is found in 25% of 46,XY patients with partial virilization regardless of assigned gender.25 Data support male rearing in most XY infants with significant phallic tissue and all with micropenis.26 Assignment for patients with ovotesticular DSD must consider fertility potential assuming consistent genitalia. In the child with mixed gonadal dysgenesis, AE, phallic size, gonadal function, and location are considered. Outcome data for 46,XY child with cloacal exstrophy are conflicting precluding clear assignment recommendations. Hence, decisions should be made with the families' full input and consent after they know the potential risks and benefits and potential impact of options. Available evidence-based data concerning fertility potential and surgical procedures must be provided.
Assignment should be made as quickly as thorough diagnostic evaluation permits. Influencing factors include diagnosis, genital appearance, therapeutic options, fertility potential, cultural practices and pressures, and parental views. Individual DSD outcome data regarding gender identity, quality of life, avoidance of unnecessary surgery, hormone replacement, and fertility preservation must be considered. Fertility-potential considerations include expected fertility in virilized females with a well-developed uterus and ovaries, unlikely fertility in undermasculinized males without assisted-reproduction techniques, and fertility in some patients with ovotesticular DSD. Appearance-altering surgery is not urgent. Somatosexual and psychosexual differentiation information and treatment options are needed. Balanced, technologically sound, Web-based information may be helpful.27 Ample time should be provided for discussion, repeating information, and reassessment of understanding. To assist parents in coping, information to be shared with siblings and others should be discussed.
Surgery
Rationale for early reconstruction28 includes beneficial effects of estrogen on infant tissues, avoiding complications from anatomic anomalies, satisfactory outcomes,29 minimizing family concern and distress,30 and mitigating the risks of stigmatization and gender-identity confusion of atypical genital appearance. Adverse outcomes have led to recommendations to delay unnecessary genital surgery to an age of patient informed consent, although relative risks and benefits are unknown. Age-specific preparatory procedures including coping-skill training and behavior-therapy techniques are psychologically beneficial.31 The goals of genital surgery are to maximize anatomy to enhance sexual function and romantic partnering.
Feminizing genital surgery involves external genitalia reconstruction and vaginal exteriorization, with early separation of the vagina and urethra.32 Clitoral reduction is considered with severe virilization and performed in conjunction with common urogenital sinus repair. Vaginal dilatation should not be performed during childhood. Refinement is generally necessary at puberty.33 Procedures should emphasize functional cosmetic appearance and be designed to preserve erectile function and enervation. Vaginoplasty should be performed in the teenage years; each of the techniques (self-dilatation, skin or bowel substitution) has specific advantages and disadvantages,34 and all carry potential for scarring that would require modification before sexual function.35
Masculinizing genital surgery involves more surgical procedures and urologic difficulties than feminizing genitoplasty. Standard surgical repair involving hypospadias includes chordee correction, urethral reconstruction, and judicious testosterone supplementation.36 If needed, adult-sized testicular prostheses should be inserted after sufficient pubertal scrotal development. The enormity of the undertaking and complexity of phalloplasty must be considered during the initial counseling period.37 Care should be taken to avoid unrealistic expectations about penile reconstruction.
Germ cell malignancy only occurs in patients with DSD who have Y-chromosomal material (GBY region). The highest risk (up to 60%) is found in patients with DSD with GBY-positive gonadal dysgenesis and partial androgen insensitivity syndrome with intraabdominal gonads. The lowest risk (<5%) is found in ovotestis38 and genetically confirmed CAIS. Intraabdominal gonads of high-risk patients (gonadal dysgenesis plus GBY and partial androgen insensitivity syndrome) should be removed at diagnosis. Gonadectomy of streak gonads should be performed in childhood in mixed gonadal dysgenesis and in females with gonadal dysgenesis and Y-chromosome material. Patients with DSD, raised as males with scrotal gonads, should have a gonadal biopsy at puberty.39
Gender Reassignment
Gender reassignment, which should always be initiated by the patient, should be approached very cautiously. Because childhood gender dissatisfaction may remit, the key challenge is to identify multiple determinants of gender identity, additional biological factors, social factors (especially parent characteristics, family functioning, peer relationships), and personal characteristics. Discordant gender-role behavior, which is more common in children with DSD, should not be considered an indication for gender reassignment, because sex-typical behavior, sexual orientation, and gender identity should be considered separately. Homosexual orientation (relative to sex of rearing) or strong cross-sex interest in an individual with DSD is not an indication of incorrect sex assignment. In patients with DSD who have significant gender dysphoria, a comprehensive psychological evaluation40 and extensive parental discussion is required. A patient with persistent desire for gender change should be referred to a skilled specialist.
If needed, timing of the pubertal induction should be individualized. Hormone effects, reproduction, sexuality, and the patient's expectations should be discussed. Sex-steroid replacement induces pubertal changes, growth, and bone mineralization and provides for psychosocial and psychosexual maturation.41 Androgens for males include testosterone esters (oral [testosterone undecanoate] and transdermal preparations). Females with hypogonadism require estrogen supplementation followed by progestin breakthrough bleeding (unneeded if the uterus is absent).
Data on fertility are limited for most DSD. Females with an adequately formed uterus and males with evidence of functional seminiferous tubules may have fertility potential with assisted-reproduction techniques.
Psychosocial management with a practitioner who has expertise in sexuality is integral for patients with DSD to promote positive adaptation. Specialized psychosocial assessment can guide team decisions about gender assignment/reassignment, timing of surgery, and sex-hormone replacement. Coping should be evaluated in the context of overall vulnerability (developmental history, temperamental characteristics, cognitive level, family and social environment).42 Psychological issues to be addressed include sexuality, fertility, culture, and social circumstances. The most frequent sexual problems in patients with DSD are avoidance of intimacy, sexual aversion, and lack of arousability, often misinterpreted as low libido.43 The process of relationship-building includes informing a partner about one's condition, addressing fears of rejection, and focusing on relationships rather than solely on sexual function and activity.
Disclosure of salient and sensitive aspects of the patient's condition (karyotype, gonadal status, fertility) are integral parts of patient care and a flexible individual-based approach. Disclosure should be planned with parents for ongoing dialogue.44 Generally, disclosure is associated with enhanced psychosocial adaptation,45 but it may not always be helpful.
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INTERNATIONAL INTERSEX CONSENSUS CONFERENCE PARTICIPANTS |
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FOOTNOTES |
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Address correspondence to Peter A. Lee, MD, PhD, Department of Pediatrics, MC-H085, Penn State College of Medicine, Milton S. Hershey Medical Center, Box 850, 500 University Dr, Hershey, PA 17033-0850. E-mail: plee{at}psu.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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A. T. Maciel-Guerra, M. P. de Mello, F. B. Coeli, M. L. Ribeiro, M. L. Miranda, A. P. Marques-de-Faria, M. T. M. Baptista, S. G. Moraes, and G. Guerra-Junior XX Maleness and XX True Hermaphroditism in SRY-Negative Monozygotic Twins: Additional Evidence for a Common Origin J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 339 - 343. [Abstract] [Full Text] [PDF]
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