Case Report
Embryonic Testicular Regression Syndrome Presenting as Primary Amenorrhea: A Case Report and Review of Disorders of Sexual Development

https://doi.org/10.1016/j.jpag.2016.03.006Get rights and content

Abstract

Background

Sex development depends on the synchronous interaction of complicated genetic and hormonal events. Sex differentiation begins with sex determination, which is the assignment of the embryonic bipotential gonads as either testes or ovaries on the basis of transcriptional regulation. Hormonal regulation then directs the development of the male or female phenotype. Disruptions of this intricate cascade of events result in disorders of sexual development.

Case

A 16-year-old female adolescent presented with primary amenorrhea. Evaluation revealed female external genitalia, XY karyotype, absent gonadal tissue, and rudimentary Müllerian structures. On the basis of her constellation of findings, the most logical diagnosis was the rare embryonic testicular regression syndrome.

Summary and Conclusion

A careful understanding of embryonic sexual development is critical to the evaluation of patients with disorders of sexual development.

Introduction

Disorders of sexual development (DSD) result from a disruption in the complex cascade of events required for fetal sex determination and reproductive system development. DSD occur in approximately 1 in 4000 infants, and this broad diagnostic term encompasses a number of chromosomal, genetic, gonadal, hormonal, and anatomical abnormalities.1 Therefore, a thorough understanding of the embryology of the urogenital system is essential to proper diagnosis and management of patients with DSD.

Sexual development begins with sex determination of the bipotential embryonic gonad, as either an ovary or testis, and this process is regulated by the chromosomal complement. Ovarian differentiation is the default pathway unless a Y chromosome with a normal sex-determining region on the Y (SRY) gene encodes a threshold level of transcription factor to trigger testis development (Figure 1A).1 After male sex determination, Sertoli and Leydig cells are evident by the seventh and eighth weeks of gestation, respectively.1 Before gonadal sex determination, male and female embryos have 2 pairs of genital ducts (Müllerian [paramesonephric] ducts and Wolffian [mesonephric] ducts) that are destined to become internal genital structures. In the 46,XY fetus, secretion of anti-Müllerian hormone (AMH) by Sertoli cells results in Müllerian duct regression, while testosterone secretion by Leydig cells stabilizes Wolffian ducts and induces their differentiation into epididymides, vas deferens, and seminal vesicles.2 In the 46,XX fetus, Müllerian ducts persist and Wolffian ducts regress as a result of the absence of AMH and testosterone.

External genital differentiation in the 46,XY fetus begins with the development of the phallus and genital swellings during the ninth week of gestation. Virilization of male structures is dependent on the presence of dihydrotestosterone (DHT), which is essential for fusion of urethral folds and labioscrotal swellings.2 Therefore, female fetuses develop labia minora and majora in the absence of DHT.

Undervirilization of the 46,XY fetus can result from a number of abnormalities occurring at various critical periods in reproductive development (Figure 1B).3 Diagnostic considerations include complete gonadal dysgenesis, testicular regression syndrome (TRS), defects in testosterone biosynthesis, 5-α reductase deficiency, and androgen insensitivity syndrome (AIS). Understanding of the timing of errors in embryonic reproductive development and their corresponding phenotypic findings allows for the proper diagnosis of these cases.

Complete gonadal dysgenesis, or Swyer syndrome, might occur as a result of a mutation in several genes and proteins including SRY, steroidogenic factor 1, mitogen-activated protein 3 kinase 1,4 and others essential to gonadal development. The abnormal, streak gonads do not produce adequate testosterone (for the formation of male internal genital structures from Wolffian ducts) or AMH, which results in persistence of the Müllerian-derived uterus and fallopian tubes as well as undervirilized external genitalia.5 Undervirilization of external genitalia might also occur if testosterone is unable to be converted to DHT, as in the case of 5-α reductase deficiency. These individuals exhibit normal male internal structures (owing to normal testosterone and AMH production by the testes) but undervirilized external genitalia in the absence of DHT.2 Those individuals with testosterone biosynthesis defect or AIS also have male internal genital structures because AMH production from testis is not affected, external genitalia is undervirilized to varying degrees depending on the severity of the enzymatic defect or androgen insensitivity.

One of the most rare etiologies for undervirilization of the 46,XY fetus is TRS (or vanishing testes). This term is used commonly to describe testicular absence in men with undescended unilateral, or more infrequently, bilateral testes but otherwise normal external genitalia; however, the phenotype varies greatly according to the timing of testicular function loss. If testicular regression occurs very early in fetal sex development (before or soon after Leydig cells begin testosterone production at approximately 8 weeks' gestation), then men will have undervirilization or, rarely, no virilization of external genitalia (Figure 1B). Similarly, the timing of testicular regression determines the way internal genitalia differentiate, resulting in the presence of only female internal genital structures, both male and female genital structures, or most commonly male internal genital structures. Testicular loss is usually sporadic and attributed commonly to antenatal vascular accident or testicular torsion on the basis of histological findings1; however, familial cases have been described.6 In a review of the literature very few reports of early embryonic testicular regression resulting in phenotypic female appearance of the external genitalia were found. There is only one other report of a patient with female external genitalia and absent gonadal, Müllerian and Wolffian structures on laparotomy to date.7 Josso and Briard reported a pair of siblings with embryonic testicular regression. Both siblings had absence of gonadal tissue but one was a male phenotype with a micropenis and the other was a female phenotype with slight fusion of the genital folds and absent Müllerian ducts.6 In a case series, Marcantonio et al reported four patients with TRS with ambiguous genitalia and one patient with microphallus,5 and in a case series Latrech et al8 reported six patients with TRS with male phenotypes ranging from normal to microphallus.

In this report we describe a rare case of early embryonic TRS. Careful consideration of the patient's clinical findings illustrate the complexity of fetal sexual differentiation and the importance of timing of critical events in reproductive system development.

Section snippets

Case

A 16-year-old Hispanic female adolescent presented to the pediatric endocrinology clinic with primary amenorrhea and delayed puberty. She had normal stature (163 cm, at the 32nd percentile for height), and no dysmorphic features. She had minimal breast development and sparse pubic hair. She had normal external female genitalia without clitoromegaly or labioscrotal fusion (Figure 2).

Her laboratory evaluation was significant for elevated ultrasensitive gonadotropins and low ultrasensitive

Summary and Conclusion

This phenotypically female patient presented with primary amenorrhea and a near absence of internal genitalia. She was subsequently found to have a 46,XY karyotype. Complete AIS might be considered in the differential diagnosis; however, the patient's absence of gonads and, therefore, lack of significant testosterone production, and breast development, and, although sparse, the presence of pubic hair, are inconsistent with complete AIS. Complete gonadal dysgenesis is also a diagnostic

References (8)

There are more references available in the full text version of this article.

Cited by (0)

The authors indicate no conflicts of interest.

View full text