Educational article
Review and management of 46,XY Disorders of Sex Development

https://doi.org/10.1016/j.jpurol.2012.12.002Get rights and content

Abstract

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.

Introduction

The Jost paradigm states that four steps must occur during sexual differentiation: establishment of chromosomal sex at fertilization, formation of undifferentiated gonads, gonadal differentiation into testes or ovaries, and development of the internal and external genitalia [1]. Disorders of Sex Development (DSD) may result from defects in any of these stages. In 2006, the European Society for Paediatric Endocrinology (ESPE) and the Lawson Wilkins Pediatric Endocrine Society (LWPES) devised the current classification and nomenclature of DSD. DSD can be categorized into the following groups: 46,XX Ovarian DSD, 46,XY DSD, Ovotesticular DSD, 46,XX Testicular DSD, and 46,XY Complete Gonadal Dysgenesis (CGD) [2].

Individuals with DSD have variable phenotypes ranging from completely female external genitalia to male-appearing genitalia with hypospadias, bifid scrotum, and descended gonads. The degree of virilization is determined by the levels of androgens and the responsiveness of the target organs to androgen [3]. Diagnosis of DSD may be established at birth in individuals born with ambiguous genitalia, while others go undiagnosed until around puberty. The management of these patients may be complicated by many factors including, but not limited to, medical, sexual, psychological, and social concerns. This review will focus on the etiology, management, and outcomes of 46,XY DSD, which are summarized in Table 1.

In the past, gender assignment among patients with ambiguous genitalia was established quickly so that corrective surgery could be used to establish the chosen gender. Individuals born with a small phallus and perineoscrotal hypospadias represent the most challenging group to treat. In cases of severely undervirilized males, female gender assignment was considered optimal by physicians and considered to be more successful from a surgical standpoint. In recent years, this practice has been challenged for medical and ethical concerns. There is much controversy in the current literature associated with the timing of corrective surgery, with the primary goal to establish the best management plan for the individual while considering the choice of the patient. Gender assignment should be a careful decision made by knowledgeable parents and caregivers only after they have been thoroughly educated about their child's diagnosis and all available medical and surgical treatment options [4], [5], [6].

Section snippets

Etiology and pathogenesis

The pathogenesis of 46,XY DSD may or may not be related to endocrine dysfunction. Non-endocrine disorders result from the abnormal development of the urogenital primordia (i.e. cloacal malformations, isolated hypospadias, etc.). Endocrine causes can be further categorized into impaired or absent androgen production or specific androgen receptor or post-receptor dysfunction in target organs [3]. Fetal androgen production, as well as functioning receptors, is necessary for normal development of

Evaluation and management

Individuals born with DSD represent a possible medical emergency due to potentially life-threatening consequences of CAH and should be managed appropriately by a multidisciplinary team of neonatologists, pediatric urologists, endocrinologists, psychologists, and social workers [20]. After an infant has been stabilized and is determined to have ambiguous genitalia, evaluation should begin with thorough history (including family history and maternal exposure history) and physical examination.

Outcomes

Only 30% of children evaluated for DSD are found to have 46,XY genotype [45]. Given the rarity of these disorders, good long-term follow-up data is lacking. A few groups have published reports on these individuals regarding gender identity and reassignment, physical appearance, and sexual function.

Conclusion

The diagnosis of 46,XY DSD carries many challenges for patients, caregivers, and medical providers. Making the correct diagnosis at an early age will, in most cases, provide the patient and family with a better understanding of the condition and leads to improved satisfaction with treatment. Unfortunately, early diagnosis is not always possible, and conditions may go missed until adulthood. Regardless of when a person is diagnosed with DSD, a multidisciplinary approach may improve our ability

Conflict of interest statement

There are no disclosures or financial conflicts associated with any author or this study.

Funding

No funding was received in the preparation of this educational review article.

Ethical approval

Approval from our institution's internal review board was not required for this manuscript.

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