Extensive Literature Review of 46,XX Newborns with Congenital Adrenal Hyperplasia and Severe Genital Masculinization: Should They Be Assigned and Reared Male?

46,XX individuals born with severely masculinized genitals due to congenital adrenal hyperplasia (CAH) who have been assigned male at birth and reared male can successfully establish a male gender identity/role, find employment, marry, function sexually with a female partner, and develop positive mental health status. While there were a few individuals who reportedly did not fare well or who changed gender to female, the majority of those identifying as males appear to have an overall good quality of life. Parental/family support, along with the support of others, appears essential to a positive outcome as a male, or as a female. This paper suggests that serious consideration should be given to male gender assignment and rearing and, in certain situations, is justified. Disorders of sex differentiation teams should inform parents about the option for male assignment and rearing in 46,XX CAH infants with severe genital masculinization, which is a rare condition. To provide this option is concordant with the principles of ethics, transparency and with the Endocrine Society Guidelines and the American Academy of Pediatrics' policy of fully informed consent.

DSD/intersex: historical context and current perspectives.

Intersex/Disorders/Differences of sex development conditions have been recognized for millennia. An organized approach was adopted in the 1960-70s using the philosophy that gender identity was fluid and malleable. Consequences of this approach were the lack of disclosure, stigmatization, and excessive surgery to "normalize" the genitalia. Often this led to quality of life issues for those patients. There have been many modifications in approach since then to avoid the problems noted. There is consensus on many of these changes (e.g. disclosure) but continued controversy on others (e.g. the benefits of early surgery). This review summarizes the historical context and the current areas of consensus and controversy.

The Long Path to Our Current Understanding Regarding Care of Children with Differences/Disorders of Sexual Development.

Testes were associated with maleness from antiquity, and ancient societies had fanciful myths about the origins of the sexes and about fetal sexual development. 17th century anatomists developed the concept that mammals developed from eggs and discovered sperm in semen; in 1878, Hertwig observed sperm entering eggs (of sea urchins), establishing the cellular basis of sex development. Individuals with atypical genitalia were known clinically in the 17th century, with much debate about their origins, but by the late 19th century it was generally accepted that gonads determined sex, and that sex determined gender role. Testosterone was isolated in 1935, and Alfred Jost showed that both circulating testosterone and diffusible anti-Mullerian hormone were needed for male development. Patients with apparent androgen insensitivity were reported in 1937 and shown to be unresponsive to exogenous androgen by Lawson Wilkins in 1957; androgen receptor mutations were reported in 1989. Steroidogenic errors were associated with differences in sex development (DSDs) starting in the 1940s, and finding mutations in the responsible enzymes explained many forms of hyper- and hypo-androgenism in both sexes. Sex chromosomes were identified in the early 20th century; Y was associated with maleness, and the responsible SRY gene was identified in 1991. Early efforts to manage patients with DSDs were confounded by philosophical perspectives on the relative roles of prenatal biology versus postnatal environment. Approaches to natal sex assignment evolved in the later 20th century and now emphasize a team approach based on data, not guessing, parental involvement, cultural considerations, and the acknowledgement of uncertainty.

Tetrahedron beam imaging with a multi-pixel thermionic emission X-ray source and a photon-counting detector: A benchtop experimental study.

PURPOSE: A tetrahedron beam (TB) X-ray system with a linear X-ray source array and a linear detector array positioned orthogonal to each other may overcome the X-ray scattering problem of traditional cone-beam X-ray systems. We developed a TB imaging benchtop system using a linear array X-ray source to demonstrate the principle and benefits of TB imaging. METHODS: A multi-pixel thermionic emission X-ray (MPTEX) source with 48 focal spots in 4-mm spacing was developed in-house. The X-ray beams are collimated to a stack of fan beams that are converged to a 6-mm wide multi-row photon-counting detector (PCD). The data collected with a sequential scan of the sources at a fixed view angle were synthesized to a 2D radiography image by a shift-and-add algorithm. The data collected with a full rotation of the system were reconstructed into 3D TB CT (TBCT) images using an Feldkamp, Davis, and Kress (FDK)-based computed tomography (CT) algorithm modified for the TB geometry. RESULTS: With an 18.8-cm long source array and a 35-cm long detector array, the TB benchtop system provides a 25-cm cross-sectional and 8-cm axial field of view (FOV). The scatter-to-primary ratio (SPR) was approximately 17% for TB, as compared with 120% for cone beam geometry. The TBCT system enables reconstructions in two-dimensional radiography and three-dimensional volumetric CT. The TBCT images were free of "cupping" artifacts and have similar image quality as diagnostic helical CT. CONCLUSIONS: A TB imaging benchtop imaging system was successfully developed with MPTEX source and PCD. Phantom and animal cadaver imaging demonstrated that the TB system can produce satisfactory radiographic X-ray images and 3D CT images with image quality comparable to diagnostic helical CTs.

Individualized care for patients with intersex (differences of sex development): part 4/5.Considering the Ifs, Whens, and Whats regarding sexual-reproductive system surgery.

Issues and concerns regarding surgery of the sexual-reproductive anatomy during infancy and early childhood are discussed using four actual examples. A case of a 46, XX infant with 21 hydroxylase deficiency congenital adrenal hyperplasia (CAH) with atypical (ambiguous) genitalia is discussed regarding timing and potential harms and benefits of surgery. We present the perspective of balancing the child's rights to bodily autonomy and right to an open future versus parents' decision making authority regarding what they perceive as their child's future best interests. The second case is a newborn with complete androgen insensitivity syndrome and we discuss the harms, benefits and timing of gonadectomy. The third case examines the physical and psychological impact of penile shaft hypospadias, raising the question of whether surgery is justified to prevent what may or may not be considered a permanent disability. The fourth case involves an adult woman with classic CAH, born with a urogenital sinus and clitoromegaly, who never had genital surgery and is now requesting vaginoplasty, but not clitoral reduction. The primary message of this article, as the previous articles in this series, is to encourage patient-family centered care that individualizes treatment guided by shared decision making.

Individualized care for patients with intersex (disorders/differences of sex development): part I.

The care of individuals with disorders/differences of sex development aims to enable affected individuals and their families to have the best quality of life, particularly those born with severe genital ambiguity. Two of the biggest concerns for parents and health professionals are: (1) making a gender assignment and (2) the decisions of whether or not surgery is indicated, and if so, when is best for the patient and parents. These decisions, which can be overwhelming to families, are almost always made in the face of uncertainties. Such decisions must involve the parents, include multidisciplinary contributions, have an underlying principle of full disclosure, and respect familial, philosophical, and cultural values. Assignment as male or female is made with the realization that gender identity cannot be predicted with certainty. Because of the variability among those with the same diagnosis and complexity of phenotype-genotype correlation, the use of algorithms is inappropriate. The goal of this article is to emphasize the need for individualized care to make the best possible decisions for each patient's unique situation.

Growth Hormone Deficiency Causing Micropenis: Lessons Learned From a Well-Adjusted Adult.

This report of a 46,XY patient born with a micropenis consistent with etiology from isolated congenital growth hormone deficiency is used to (1) raise the question regarding what degree testicular testosterone exposure to the central nervous system during fetal life and early infancy has on the development of male gender identity, regardless of gender of rearing; (2) suggest the obligatory nature of timely full disclosure of medical history; (3) emphasize that virtually all 46,XY infants with functional testes and a micropenis should be initially boys except some with partial androgen insensitivity syndrome; and (4) highlight the sustaining value of a positive long-term relationship with a trusted physician (R.M.B.). When this infant presented, it was commonly considered inappropriate to gender assign an infant male whose penis was so small that an adult size was expected to be inadequate, even if the karyotype was 46,XY, and testes were functional. Concomitantly, female gender assignment was considered the appropriate decision, believing that parental rearing in the assigned gender was considered the major factor determining established adult gender identity. Full disclosure of medical information was considered inappropriate. Progress in appreciating the complexities of gender identity development, which is not yet completely understood, and sexuality, coping ability, and outcome data has resulted in a change of practice in initial gender assignment. A 46,XY individual with functional testes and verified androgen responsiveness should be assigned and reared as male, regardless of penis size. Without androgen responsiveness, the multiple factors must be carefully considered and disclosed.

Interdisciplinary care in disorders/differences of sex development (DSD): The psychosocial component of the DSD-Translational research network.

Scientific discovery and clinical management strategies for Disorders/Differences of Sex Development (DSD) have advanced in recent years. The 2006 Consensus Statement on Management of Intersex Disorders stated that a mental health component to care is integral to promote positive adaptation, yet the parameters of this element have not been described. The objective of this paper is threefold: to describe the psychosocial screening protocol adopted by the clinical centers of the DSD-Translational Research Network; to summarize psychosocial data collected at 1 of the 10 network sites; and to suggest how systematic behavioral health screenings can be employed to tailor care in DSD that results in better health and quality of life outcomes. Steps taken in developing the largely "noncategorical" screening protocol are described. These preliminary findings suggest that DSD, as one category of pediatric chronic conditions, is not associated with marked disturbances of psychosocial adaptation, either for the family or the child; however, screening frequently uncovered "risk factors" for individual families or patients that can potentially be addressed in the context of ongoing clinical care. Administration of the DSD-TRN psychosocial screening protocol was demonstrated to be feasible in the context of interdisciplinary team care and was acceptable to families on a longitudinal basis. The ultimate value of systematic screening will be demonstrated through a tailoring of psychosocial, medical and surgical services, based on this information that enhances the quality of patient and family-centered care and subsequent outcomes.

Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care.

The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk.

Degree of external genital malformation at birth in children with a disorder of sex development and subsequent caregiver distress.

PURPOSE: We determined whether the degree of genital malformation at birth in children with a disorder of sex development is related to subsequent caregiver distress, specifically symptoms of depression and anxiety. MATERIALS AND METHODS: A total of 66 caregivers of children with disorders of sex development were recruited from 3 centers that specialize in disorders of sex development medicine. The caregivers completed the Beck Depression Inventory, 2nd Edition and the Beck Anxiety Inventory. The child's Prader score at birth was determined by the child's treating pediatric endocrinologist and/or pediatric urologist at each institution. RESULTS: Results from the current study revealed that for caregivers of male children, under masculinization of the child's genitals at birth was significantly related to higher levels of subsequent caregiver depression. In contrast, over masculinization of the genitals of female children at birth was unrelated to caregiver depression or anxiety. CONCLUSIONS: These findings suggest that caregivers of male children with disorders of sex development may be at increased risk for psychological distress and could benefit from family based psychosocial interventions.

Disorders of sex development: management of gender assignment in a preterm infant with intrauterine growth restriction.

We describe how a gender specialist team managed the case of a disorder of sex development in a preterm infant where definitive diagnosis and gender assignment were delayed due to complications of prematurity, anemia, and severe intrauterine growth restriction.

Parenting characteristics of female caregivers of children affected by chronic endocrine conditions: a comparison between disorders of sex development and type 1 diabetes mellitus.

Rearing a child with a chronic illness is stressful and can potentially affect parenting style, which may result in poorer outcomes for children. The purpose of this study was to compare parenting characteristics of female caregivers rearing children with a disorder of sex development (DSD) to female caregivers rearing children with type 1 diabetes mellitus (T1DM). Caregivers of both groups were matched according to age and compared on measures of stress and parenting practices. Both groups demonstrated significant levels of stress and negative parenting practices. Children with T1DM and male children with non-life-threatening DSD were perceived as more vulnerable by their caregivers. Better understanding of parenting experiences of female caregivers rearing children with DSD, particularly male children, will facilitate the development of individualized interventions to ameliorate negative parenting practices and stress, with the long-term goal of improved health outcomes for their children.

Disorders of sex development-when and how to tell the patient.

Physicians and other providers are often confronted with difficult decisions in the area of disclosure. This article examines a hypothetical situation relevant to the practice of pediatric endocrinology. The parents of a child with a disorder of sex development (DSD) wish the physician to treat their child, but without revealing key medical information to the child. Herein, we will explore the legal and ethical responsibilities of a provider to disclose information to an under-age DSD patient and to provide insight on when and how to tell the patient.

Primary caregivers of children affected by disorders of sex development: mental health and caregiver characteristics in the context of genital ambiguity and genitoplasty.

Purpose. To determine the relationship between having a child with a DSD including ambiguous external genitalia, as well as the decision of whether or not to have early genitoplasty for that child, on the mental health and parenting characteristics of caregivers. Materials and Methods. Caregivers were recruited from centers that specialize in DSD medicine and completed the Beck Depression Inventory 2nd Edition (BDI-2), Beck Anxiety Index (BAI), Parent Protection Scale (PPS), Child Vulnerability Scale (CVS) and Parenting Stress Index/Short Form (PSI/SF). Results and Conclusions. Sixty-eight caregivers provided informed consent and completed the study. Among female caregivers whose children never received genitoplasty, greater parenting stress was reported (F(1, 40) = 5.08, p = .03). For male caregivers, those whose children received genitoplasty within the first year of life reported more overprotective parenting and parenting stress than those whose children received genitoplasty later than 12 months of age (F(1, 13) = 6.16, p = 0.28); F(1, 15) = 6.70, p = .021), respectively).

46,XY DSD with Female or Ambiguous External Genitalia at Birth due to Androgen Insensitivity Syndrome, 5alpha-Reductase-2 Deficiency, or 17beta-Hydroxysteroid Dehydrogenase Deficiency: A Review of Quality of Life Outcomes.

Disorders of sex development refer to a collection of congenital conditions in which atypical development of chromosomal, gonadal, or anatomic sex occurs. Studies of 46,XY DSD have focused largely on gender identity, gender role, and sexual orientation. Few studies have focused on other domains, such as physical and mental health, that may contribute to a person's quality of life. The current review focuses on information published since 1955 pertaining to psychological well-being, cognition, general health, fertility, and sexual function in people affected by androgen insensitivity syndromes, 5-alpha reductase-2 deficiency, or 17beta-hydroxysteroid dehydrogenase-3 deficiency-reared male or female. The complete form of androgen insensitivity syndrome has been the focus of the largest number of investigations in domains other than gender. Despite this, all of the conditions included in the current review are under-studied. Realms identified for further study include psychological well-being, cognitive abilities, general health, fertility, and sexual function. Such investigations would not only improve the quality of life for those affected by DSD but may also provide information for improving physical and mental health in the general population.

Gender dysphoria and gender change in androgen insensitivity or micropenis.

This review article answers three questions relevant to the medical management and care of individuals born with complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), or a micropenis: (1) Do any of these individuals reassign themselves from their initial gender assignment? (2) Do more reassign than the ones who do not? (3) Is there evidence of gender dysphoria in those who do not self-initiate reassignment? Reviewed were all articles on CAIS, PAIS, and micropenis cited in K. J. Zucker (1999) plus articles published through 2004. There were no documented cases of gender change in individuals with CAIS (N= 156 females) or micropenis (N= 89: 79 males, 10 females). Nine (9.1%) out of 99 individuals with PAIS changed gender. Thus, self-initiated gender reassignment was rare. Gender dysphoria also appears to be a rare occurrence. The best predictor of adult gender identity in CAIS, PAIS, and micropenis is initial gender assignment.

Male pseudohermaphroditism: long-term quality of life outcome in five 46,XY individuals reared female.

We assessed the adult quality of life of five medical chart-selected genetic males (ages 29-34 years) assigned and reared as females due to ambiguity of the external genitalia. All five were treated following the traditional method proposed by John Money and colleagues in 1955, commonly referred to as the "optimal gender policy". The adult follow-up assessment included physical and endocrinological evaluation, completion of self-report questionnaires, and a semi-structured interview assessing gender identity, sexual experience and orientation. Quality of life domains assessed by questionnaire included health-related issues, satisfaction with health-care management, emotional distress, and relationship satisfaction. Vaginoplasty in four out of five patients was initially unsuccessful. Four patients had periodic lapses in adherence to hormone replacement therapy. Gender role behavior across development was masculine relative to norms for women. All participants reported a female gender identity without a history of gender dysphoria. The majority of participants (four of five) reported being sexually active and in long-term relationships (three heterosexual, one homosexual). Current emotional adaptation and health-related quality of life are within the normal range for four participants. Sex assignment of 46,XY individuals with ambiguous genitalia as females is compatible with a positive quality of life.