Disorders of Sexual Development

doi:10.1016/j.ogc.2009.02.001

Obstetrics and Gynecology Clinics of North America

Volume 36, Issue 1, March 2009, Pages 25-45

https://doi.org/10.1016/j.ogc.2009.02.001 Get rights and content

Disorders of sex development are medical conditions in which the development of chromosomal, gonadal, or anatomic sex varies from normal and may be incongruent with each other. This article primarily addresses the medical conditions where infants may be born with ambiguous genitalia leading to decisions with regard to gender assignment. The approach to investigations and diagnosis in the newborn period will be stressed within an interprofessional team. Policies with regard to surgery have developed, with techniques evolving and data emerging from long-term outcome studies. Current medical and surgical management are reviewed. Finally, a developmental approach to disclosure is presented.

Section snippets

Disorders of sex development classification and etiologies

Disorders of sex development may result from a heterogeneous group of etiologies. The DSD nomenclature divides these etiologies into categories of 46XX DSD, 46XY DSD, Sex Chromosome DSD, Ovotesticular DSD, and 46XX Testicular DSD. Within each category specific diagnoses are made when possible (Table 1).

Approach to diagnosis

In the newborn period, in particular, when an infant is born with ambiguous genitalia reflecting a possible diagnosis of a DSD, there is felt a sense of urgency to provide the family with not only the specific diagnosis but in conjunction a gender assignment. This urgency arises from the cultural pressures that necessitate the usual announcement of “It's a boy” or “It's a girl” to friends, family, and colleagues. However, the complexities of diagnosis and gender assignment require time; it is

Management: gender assignment

Before discussing assignment of gender, one must understand the three components of psychosexual development. Gender identity refers to the intrinsic sense of oneself as female or male. Gender role refers to the set of behaviors typical of one gender or another, these will vary with context such as the surrounding culture. Sexual orientation refers to an individual's erotic responsiveness, that is the gender or genders to whom one is attracted (homosexual, heterosexual, bisexual). Gender

Surgery

When undertaken, feminizing genital surgery includes some or all of the following: clitoral surgery for clitoral hypertrophy, urogenital sinus mobilization if present, labioplasty, neovaginal construction, and possible gonadectomy in XY containing karyotypes.

Clitoral surgery has evolved considerably. Originally surgery to reduce the size of the clitoris involved clitoral resection, owing to its obvious severe impact on sexuality, clitoral recession replaced resection in the 1980s.29, 30

Gonadectomy

Gonadectomy is required in some 46XY DSD conditions for two main reasons: risk of malignancy and risk of ongoing virilization with continued androgen exposure (with female gender assignment).

Dysgenetic gonads or intra-abdominal testes carry a varying risk of malignancy. DSD patients are at increased risk of developing seminomas of the testes and dysgerminomas in dysgenetic gonads.³⁹ Gonadoblastomas may occur in the dysgenetic gonads of children.⁴⁰ Less frequent gonadal malignancies include

Medical

The discussion of the steroid management of the most common cause of ambiguous genitalia, congenital adrenal hyperplasia, is beyond the scope of this article. Principles of hormone replacement therapy will be presented for DSD diagnoses with female gender. The goals of hormone replacement therapy are not only to initiate and maintain secondary sexual characteristic development (including uterine growth) but also to allow for psychosexual development. Bone health will benefit from sex steroid

Outcomes

The ideal information to guide policies on the management of individuals with DSD is long-term outcome data covering all aspects of quality of life, sexuality, fertility, and psychosocial functioning. There are challenges with regard to interpreting the information that is beginning to become available. The most marked is that management has evolved; surgical techniques have changed; and interprofessional teams recognizing the importance of psychological support, family-centered care,

Gender identity

Gender dysphoria is present in 46XY DSD conditions with normal gonadal function and less commonly in 46XX DSD medical conditions including CAH and in other DSD conditions. Gender dysphoria is more common with female gender assignment than male gender assignment, although dissatisfaction with male sex of rearing can be seen.20, 21, 22

Several studies have assessed the degree of gender dysphoria and gender change in adolescent and adult women with CAH.20, 22, 53 This group of individuals would

Surgical outcomes

In the past several years, an increasing number of international clinics and DSD teams have published on the outcomes of childhood surgery for the women they care for. Recognition exists that the cosmesis of external genitalia may not reflect the function of the genitalia. Studies that look at interim results, with only short-term follow-up into childhood may not reflect or correlate with longer term results but at the present time are the only measures available for assessing newer surgical

Psychosexual outcomes/quality of life measures

Quality of life for women includes aspects of intimacy with partners, arousal and sexual function, as well as self-esteem, social functioning, and mental health. Recently, quality-of-life studies are being reported on women with DSD diagnoses compared with either illness controls or population controls. Women with DSD may report delayed sexual milestones, fewer partnerships and sexual experiences, and a lower level of arousal.53, 54, 62 Overall lower quality of life, higher anxiety, higher

Disclosure

Disclosure begins with the family at the time of the diagnosis and assessment of their newborn with a DSD and should be considered a lifelong ongoing process that evolves along a developmental time line. The diagnosis of DSD is both challenging to understand and challenging to explain; however, the health care team should consider themselves as having a role in preparing the family and the child/adolescent to receive this diagnosis when they are cognitively and psychologically prepared. In

Summary and future direction

Patients with DSD are infrequently encountered with an incidence 1:5500.² Their complex management must address medical, surgical, and psychosexual needs of the individual patient. Evolving information suggests that thoughtful, flexible, family-centered care by specialized interprofessional teams may provide the optimal environment for care. The awareness that current management cannot eliminate all adverse outcomes (eg, gender dysphoria, surgical complications) should drive ongoing research

Acknowledgment

I acknowledge the dedicated team of health care professionals who make up the Multidisciplinary Urogenital Clinic at The Hospital for Sick Children from whom I have learned so much: Riyanna Babul-Hirji, MS, Darius Bagli, MD, Susan Bradley, MD, David Chitayat, MD, Walid Farhat, MD, Genevieve Kilman, BA, CCLS, Armando Lorenzo, MD, Barb Neilson, MSW RSW, J.L. Pippi Salle, MD, PhD, Dianne Wherret, MD, and Ken Zukker, PhD. A special thank you to Barb Neilson for her comments on the article.

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Metzincin metalloproteases in PGC migration and gonadal sex conversion
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Citation Excerpt :
At same time, their extracellular matrix (ECM) must also go through dramatic remodeling and differentiation for proper gonad development (Marty et al., 2003; Beckman and Feuston, 2003; Maack and Segner, 2003; King et al., 1968; Hirsh et al., 1976; McLaren, 1991; Yildirim et al., 2020). Disruption of these complex processes via genetic or environmental causes typically leads to disorders of sexual development (DSDs) and infertility in humans (Allen, 2009; Öçal, 2011; Juul et al., 2014; Abrao et al., 2013; Roupa et al., 2009; Ferlin et al., 2006; Ferlin et al., 2006; Galani et al., 2008; Zuccarello et al., 2007) but can result in sex reversal in other animal species including fish (Baroiller and D’Cotta, 2020; Carter et al., 2019; Dranow et al., 2013; Dranow et al., 2016; Sakae et al., 2020). Most studies in gonad development and sex determination were focused on the roles of transcription factors and restricted to early sex determination and differentiation (Mamsen et al., 2017; Nagahama, 2005; Hayes, 1998; Devlin and Nagahama, 2002; Nagahama et al., 2021; Wilhelm et al., 2007).
Development of a functional gonad includes migration of primordial germ cells (PGCs), differentiations of somatic and germ cells, formation of primary follicles or spermatogenic cysts with somatic gonadal cells, development and maturation of gametes, and subsequent releasing of mature germ cells. These processes require extensive cellular and tissue remodeling, as well as broad alterations of the surrounding extracellular matrix (ECM). Metalloproteases, including MMPs (matrix metalloproteases), ADAMs (a disintegrin and metalloproteinases), and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), are suggested to have critical roles in the remodeling of the ECM during gonad development. However, few research articles and reviews are available on the functions and mechanisms of metalloproteases in remodeling gonadal ECM, gonadal development, or gonadal differentiation. Moreover, most studies focused on the roles of transcription and growth factors in early gonad development and primary sex determination, leaving a significant knowledge gap on how differentially expressed metalloproteases exert effects on the ECM, cell migration, development, and survival of germ cells during the development and differentiation of ovaries or testes. We will review gonad development with focus on the evidence of metalloprotease involvements, and with an emphasis on zebrafish as a model for studying gonadal sex differentiation and metalloprotease functions.
Patients with disorders of sex development undergoing surgical treatment: A psychosocial evaluation in adolescence
2021, Archives de Pediatrie
Citation Excerpt :
Disorders of sex development (DSD) include congenital conditions in which the development of gonadal, chromosomal, or anatomic sex is different from normal, with these differences potentially incompatible with each other. These disorders are mostly apparent at birth, displaying as ambiguous genitalia of the infant [1]. Worldwide it is estimated to occur in one of every 4500–5000 births [2].
The surgical outcomes of disorders on sex development (DSD) are comparatively well studied in the literature, whereas studies investigating its impacts on mental health are scarce. In this study, we aimed to evaluate psychiatric diagnoses, sex roles, quality of life, and adolescents who were surgically treated because of DSD as well as parental attitudes in their parents. The study group consisted of 19 patients diagnosed with DSD and the control group consisted of 20 age- and gender-matched healthy peers. The Kiddie-Schedule for Affective Disorders and Schizophrenia was performed by a child and adolescent psychiatrist to assess the psychiatric diagnoses. To evaluate quality of life (QoL) and sex roles, The Pediatric Quality of Life Inventory (PedsQL), and the Bem Sex Role Inventory were used, respectively. Mothers completed the PedsQL-Parent Form and the Parental Attitude Research Instrument (PARI). Of 19 children in the patient group, 14 (73.7%) had a past or current history of at least one psychiatric disorder. The most common psychiatric disorder was major depression. There was no significant difference between the two groups in terms of sex roles. A statistically significant difference was found between the study and control groups in four factor scores of the PARI. While there was no significant difference between the groups in terms of the children's QoL scores, parent-proxy reports of psychosocial health scores and total QoL scores of the study group were significantly lower than the controls. This finding shows that parents perceived the QoL of their children with DSD as worse than their healthy peers, probably due to their concerns for the future. In conclusion, it is important to identify and treat the psychiatric disorders concomitant in patients with DSD.
Congenital abnormalities of the female reproductive tract: Anomalies of the Vagina, Cervix, Uterus, and Adnexa
2021, Comprehensive Gynecology
Disorders of sex development
2019, Clinical Molecular Medicine: Principles and Practice
The birth of a baby with disorder of sex development (DSD) is a clinical challenge that requires the involvement of a multidisciplinary group of specialists including pediatric endocrinologists, geneticists, urologists, gynecologists, social workers, and psychologists/psychiatrist with an expert in this field. The findings, plan for investigation, gender assignment, and treatment should be discussed among the group members prior to meeting the parents. Once a consensus is being reached, the information should be presented to the parents to easily understand fashion, and their questions should be answered, so that they can make an informed decision regarding gender assignment and surgical and hormone treatment. Potential for sexual relationship and fertility preservation should be discussed.
DSD can be categorized into isolated and nonisolated and further classified into chromosomal, gonadal, and anatomic internal and external abnormalities. Investigation should be directed by the findings and genetic tools including microarray analyses and DNA analysis using DSD panels and, when need, whole exome/whole genome sequencing should be performed.
Frequency and distribution of primary site among gender minority cancer patients: An analysis of U.S. national surveillance data
2018, Cancer Epidemiology
Citation Excerpt :
In addition, transgender people who undergo gender affirmation treatment may receive high doses of sex steroid hormones for extended periods of time; the carcinogenicity of hormone therapy in this context is also unclear [8,9]. The term DSD refers to a heterogeneous group of conditions affecting the development of sex chromosomes, gonads, or anatomic sex [10,11]. DSD can be identified at birth by the presence of atypical genitalia, during adolescence by the absence of or contra-sexual pubertal development, or in adulthood following discovery of fertility problems.
Transgender people and persons with disorders of sex development (DSD) are two separate categories of gender minorities, each characterized by unique cancer risk factors. Although cancer registry data typically include only two categories of sex, registrars have the option of indicating that a patient is transgender or has a DSD.
Data for primary cancer cases in 46 states and the District of Columbia were obtained from the North American Association of Central Cancer Registries (NAACCR) database for the period 1995–2013. The distributions of primary sites and categories of cancers with shared risk factors were examined separately for transgender and DSD patients and compared to the corresponding distributions in male and female cancer patients. Proportional incidence ratios were calculated by dividing the number of observed cases by the number of expected cases. Expected cases were calculated based on the age- and year of diagnosis-specific proportions of cases in each cancer category observed among male and female patients.
Transgender patients have significantly elevated proportional incidence ratios (95% confidence intervals) for viral infection induced cancers compared to either males (2.3; 2.0–2.7) or females (3.3; 2.8–3.7). Adult DSD cancer patients have a similar distribution of primary sites compared to male or female patients but DSD children with cancer have ten times more cases of testicular malignancies than expected (95% confidence interval: 4.7–20).
The proportions of certain primary sites and categories of malignancies among transgender and DSD cancer patients are different from the proportions observed for male or female patients.
Intersexuality in aquatic invertebrates: Prevalence and causes
2017, Science of the Total Environment
Citation Excerpt :
At present OT-DSD is considered an intersex condition in which an individual is born with ovarian and testicular tissue. Due to advances in scientific knowledge, the term hermaphroditism is no longer confused with intersex, as the former refers only to a specific phenotypic characteristic of sex organs whilst the latter to a more complex mixture of phenotypic and genotypic displaying, often involving genital ambiguity, and even combinations of chromosomal genotype and sexual phenotype other than XY-male and XX-female (Allen, 2009). Most of the Earth's flowering plants are hermaphrodite (94%), however it is a rare condition among animals, excluding insects.
This review is the first assembling information on intersexuality in aquatic invertebrates, from freshwater to estuarine and marine environments. Intersex is a condition whereby an individual of a gonochorist (separate sexes) species has oocytes or distinct stages of spermatogonia, at varying degrees of development, within the normal gonad of the opposite gender (i.e. spermatocytes in the ovary or oocytes in the testis), often involving alterations in the gonadal structure, reproductive tract or external genitalia. By the end of 2016 we found approximately 340 records of aquatic invertebrate species evidencing signs of intersexuality (or imposex), all comprised within the Phyla Mollusca and Arthropoda. Gastropod molluscs are by far the group with more examples documented (256 species), followed by crustaceans, i.e., decapods, copepods and amphipods. To our knowledge no further cases of intersexuality were known concerning other invertebrate taxa. Despite some reports suggesting that a baseline level of intersexuality may occur naturally in some populations, the causes are multifaceted and mostly linked with environmental contamination by estrogenic and organotin endocrine disrupting chemicals (EDCs), parasitism, and genetic/environmental sex determination abnormalities. A more comprehensive discussion about the origin of intersexuality, prevalence and causes, knowledge gaps and future research directions in the light of new omics scientific advances (genomics, proteomics and transcriptomics) is also provided. The lack of studies linking molecular responses of invertebrate intersex individuals to multiple stressors represents a true challenge to be further investigated in the future.

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Disorders of Sexual Development

Section snippets

Disorders of sex development classification and etiologies

Approach to diagnosis

Management: gender assignment

Surgery

Gonadectomy

Medical

Outcomes

Gender identity

Surgical outcomes

Psychosexual outcomes/quality of life measures

Disclosure

Summary and future direction

Acknowledgment

Genet Med

J Pediatr

J Pediatr

Horm Behav

J Pediatr

Brain Res Mol Brain Res

J Pediatr Surg

J Urol

Lancet

J Pediatr Surg

Best Pract Res Clin Endocrinol Metab

Am J Obstet Gynecol

Gynecol Oncol

J Pediatr Surg

Horm Behav

J Pediatr Adolesc Gynecol

J Urol

J Pediatr Surg

J Urol

Lancet

J Pediatr Surg

Consensus statement on management of intersex disorders. International Consensus Conference on Intersex

Pediatrics

How common is intersex? A response to Anne Fausto-Sterling

J Sex Res

Prenatal gender determination and the diagnosis of genital anomalies

BJU Int

Evaluation of the newborn with developmental anomalies of the external genitalia. American Academy of Pediatrics. Committee on Genetics

Pediatrics

Predictive value of anatomical findings and karyotype analysis in the diagnosis of patients with disorders of sexual development

Sex Dev

Should the definition of micropenis vary according to ethnicity?

Horm Res

Clitoral size in full-term infants

Am J Perinatol

Early assessment of ambiguous genitalia

Arch Dis Child

Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Pediatrics

Epidemiology and initial management of ambiguous genitalia at birth in Germany

Horm Res