Rev Mex Urol 2014;74(2):117-122

ÓRGANO OFICIAL DE DIFUSIÓN DE LA SOCIEDAD MEXICANA DE UROLOGÍA

www.elsevier.es/uromx

Clinical case

Complete androgen insensitivity syndrome: a case report and surgical management illustration J. D. Farias-Cortésa,*, F. Minakata-Ochoaa and I. Sedano-Portillob a

Urology Service, Hospital Regional “Valentín Gómez Farías”, ISSSTE, Zapopan, Jal., Mexico

b

Urology Service, Centro Médico Nacional de Occidente, IMSS, Guadalajara, Jal., Mexico

KEYWORDS Disorders of sexual differentiation; Gonadal agenesis; Vaginoplasty; Morris syndrome; Mexico.

Abstract  The term “disorders of sexual differentiation” (DSD) encompasses a group of abnormalities in the development of the genitourinary tract. Atypical development occurs at one or more chromosomal, gonadal, or anatomic levels. 46 XY genetic males may present with external genitals that are phenotypically female or ambiguous. Androgen insensitivity syndrome could be considered a disease caused by resistance to androgenic action due to the Xq11-12 mutation that affects the androgenic receptors. Clinical presentation depends on the degree of insensitivity: mild (infertile male), partial, or complete, as with our patient. Psychologic and psychiatric follow-up is required for both the patient and family members so there can be adequate psychosexual development before and after definitive surgical treatment. The aim of this article was to conduct a systematic review of published reports in the MEDLINE database to identify the epidemiology and incidence of complete androgen insensitivity syndrome and to examine the approach, treatment, and follow-up of these cases. We present herein a 23-year-old patient, with an unremarkable pathologic history, who began to be studied by the Gynecology Service at 17 years of age due to amenorrhea and lack of secondary sexual development. Imaging studies failed to show Müllerian structures. Diagnostic laparoscopy was performed on 2 occasions in which female sexual organs or vestiges of testes were unable to be identified. Hormonal study revealed obviously low levels of estrogens and testosterone, and follicle-stimulating hormone (FSH), luteinizing hormone (LH), and gonadotropin-releasing hormone were within normal parameters; 46XY karyotype was reported. Psychiatric support was then offered. It was decided that the patient would continue to be raised and treated as a female and therefore she was given breast implants. Our service was subsequently consulted for performing vaginoplasty using an intestinal segment as the vaginal canal.

* Corresponding author at: Av. Soledad Orozco N° 203, Colonia el Capullo, C.P. 45150, Zapopan, Jal., México. Telephone: (33) 1080 6462. Email: [email protected] (J. D. Farias-Cortés).

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Palabras clave Desórdenes en la diferenciación sexual; Agenesia gonadal; Vaginoplastía; Síndrome de Morris; México.

J. D. Farias-Cortés et al

Síndrome de insensibilidad completa a los andrógenos: reporte de un caso, ilustración del manejo quirúrgico Resumen El término “desorden en la diferenciación sexual” (DDS) representa un grupo de anormalidades en el desarrollo del tracto genitourinario, en el cual ocurre un desarrollo atípico en uno o más niveles: cromosómico, gonadal o anatómico. Los genéticamente varones 46XY pueden presentarse con genitales externos fenotípicamente femeninos o ambiguos. El síndrome de insensibilidad a los andrógenos se podría considerar una enfermedad causada por la resistencia a la acción androgénica, causada por la mutación Xq11-12, que afecta los receptores androgénicos; la presentación clínica dependerá del grado de insensibilidad, leve (masculino infértil), moderada o completa como en nuestro caso. Requiere seguimiento por psicólogo y psiquíatra para familiares y paciente, para un desarrollo psicosexual adecuado, antes y después del tratamiento quirúrgico definitivo. El objetivo del presente artículo es realizar una revisión sistemática de los artículos publicados en la base de datos de Medline, para identificar la epidemiología e incidencia del síndrome de insensibilidad completa a los andrógenos, así como reconocer su abordaje, tratamiento y seguimiento de estos casos. Se presenta paciente de 23 años de edad, sin antecedentes patológicos de importancia, la cual inicia su estudio a los 17 años de edad por el Servicio de Ginecología, por presentar amenorrea y falta de desarrollo en caracteres sexuales secundarios, tiene estudios de imagen sin evidenciar estructuras Müllerianas; se realiza laparoscopía diagnóstica en 2 ocasiones sin poder identificar órganos sexuales femeninos o vestigios de testículos; estudio hormonal con niveles de estrógenos y testosterona evidentemente bajos con hormona folículo estimulante (FSH), hormona luteinizante (LH) y hormona liberadora de gonadotropinas dentro de parámetros normales; el cariotipo reporta 46XY. En ese momento se ofrece apoyo psiquiátrico, se decide continuar con educación femenina, por lo que se resuelve colocación de prótesis mamaria. Finalmente, se nos interconsulta para la realización de vaginoplastía con uso de segmento intestinal como canal vaginal. 0185-4542 © 2014. Revista Mexicana de Urología. Publicado por Elsevier México. Todos los derechos reservados.

Introduction

Case presentation

The recently coined term “disorders of sexual differentiation” (DSD), previously known as “intersex condition, hermaphroditism, and pseudohermaphroditism”, has now been adopted, since experts worldwide prefer this nomenclature; 1,2 it is a class of abnormalities in the development of the genitourinary tract and refers to a group of congenital conditions in which there is atypical development at one or more levels (chromosomal, gonadal, or anatomic). Genetic males with DSD (46XY) can present with phenotypically female, male, or ambiguous external genitalia, such as in the case of micropenis (length < 2.5 times shorter in relation to chronological age). 3 These conditions can be caused by chromosomal and endocrine aberrations that are reflected in the sexual phenotype of the individual. DSD incidence may vary according to ethnic group; for example, one out of every 5,000 live births in Germany vs. one out of every 3,000 in Egypt; this is due to a higher consanguinity rate.4 Congenital adrenal hyperplasia and mixed gonadal dysgenesis are the most common causes of ambiguous genitalia in 50% of the cases, with a worldwide incidence of 1:15,000 and 1:10,000, respectively. However, this can vary considerably among different populations.5

A 23-year-old patient, single, with no past history of remarkable hereditary, familial, or personal pathologies related to this case, began to be studied at 17 years of age by the Gynecology Service for presenting with amenorrhea and lack of development of secondary sexual characteristics. Imaging studies revealed no evidence of Müllerian structures or renal alterations and so the patient underwent diagnostic laparoscopy on 2 occasions in which internal sexual organs were looked for. No female sexual organs or remnants of testes were found and an immediate hormone study showed a total estrogen level of 15 pg/dL. These studies were repeated various times with no significant differences; follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were within normal low parameters and testosterone was always very low (the last value was 1.07 ng/dL). The genetics team was called in and they carried out the karyotype study that reported 46XY (fig. 1). Genetic counseling as well as psychiatric support was then offered to the patient and family and they decided to continue raising her as a female, as had been done all her life, given that she was phenotypically female since birth. The case was presented to the Hospital Ethics Committee and with the consent of the patient and her family she underwent breast implantation at the Plastic Surgery

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Figure 1  Characteristic of the karyotype of the patient, 46XY.

Service. Finally, we were consulted to perform a vaginoplasty using intestinal segment for the vaginal canal. Initially, patient preparation was a liquid diet one day before surgery and enemas. With the patient under general anesthesia and in the lithotomy position, a midline infraumbilical incision was made. Dissection up to the abdominal cavity was done by layers, and detailed exploration revealed the absence of Müllerian structures and testicular remnants, a normal capacity bladder, and no bimanually palpable prostate. The opening of the dome in the urogenital diaphragm was begun (figs. 2 and 3). Twelve centimeters of the sigmoid colon were then selected, due to its extensive vasculature and redundant mesentery. An end-to-end anastomosis was performed. The resected segment was taken to the new vaginal canal and anastomosed and closed in 2 layers (figs. 4-6). Because the patient progressed adequately, she was promptly released from the hospital. Follow-up included 20-minute dilations with a Hegar dilator at home, 3 times a week, with a gradual increase in measurements from 8 to 22 mm at the end of 10 months. At the 6-month follow-up, the patient presented with a mild discharge of mucus twice a week, due to the colon segment. She continues to undergo both psychologic and psychiatric treatment and has a satisfactory sex life with her current partner, as well as a normal work life.

Discussion The androgen insensitivity syndrome can be considered a disease caused by resistance to androgen action that influences 2 things: the morphogenesis and differentiation of body structures and systems that these hormones have an effect on. It depends on an X mutation in the androgen receptor gene in which a variety of phenotypes can be expressed; from infertile males to normal external female genitals. 6 John Morris 7 was the first to describe this syndrome, but it was not until 1989 that the exact location

Figure 2  Abdominal surgical exploration revealing the absence of Müllerian structures and of testicular remnants.

of the androgen receptor gene was discovered to be on Xq11-12, where it was demonstrated that the mutation can present and the disease develop.8 The androgen receptors are expressed from gestation week 8, and the testes of the male embryo begin to secrete testosterone at week 9, with 2 peaks at weeks 11 and 18. The epididymis, vas deferens, and seminal vesicles simultaneously differentiate from the Wolffian ducts. A more potent androgen, dihydrotestosterone, originates from testosterone through the action of type 2 5-alpha-reductase and stimulates the differentiation of the male genital primordium.9 The clinical phenotypes of androgen insensitivity syndrome may vary depending on the severity of resistance and they are classified into 3 grades: complete, partial, and mild.10 Complete resistance, in particular, is characterized by a short vagina ending in a blind sac, absence of the Wolffian products such as the epididymis, vas deferens, seminal vesicles, or prostate. Clinical presentation from birth is a totally female phenotype, making its early diagnosis difficult.11 An important pattern helping establish clinical suspicion is that in puberty there is generally slow or small mammary growth in relation to chronologic age, with very little or no axillary and pubic hair. 12 Other clinical characteristics that can be found are mono or bilateral inguinal hernia, even though the differences with apparently female patients are minimal, making an earlier diagnosis difficult to suspect. This syndrome is the cause of 10% of all cases of primary amenorrhea.5 With respect to endocrine presentation in these patients, we can find: normal or increased LH and testosterone slightly above normal in the first month of life. After that, LH and testosterone levels are normal until puberty13, due

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Figure 4  12 cm of the sigmoid colon were taken due to its extensive vasculature and mesentery.

Figure 3  The surgical exploration revealed a normal capacity bladder and no bimanually palpable prostate; the dome in the urogenital diaphragm was opened.

to androgen insensitivity and the lack of negative feedback of the sex hormones in the hypothalamus and hypophysis. Testosterone is aromatized and converted into estrogens at a later time through enzyme action. This is why patients with complete insensitivity have higher estrogen levels than normal males and develop mammary growth. In addition, they can have normal anti-Müllerian hormone levels,

explaining the absence of internal female sexual characteristics.9

Differential diagnoses in 46XY patients Among the other diagnoses that should be contemplated when evaluating an individual with DSD are: Swyer syndrome, in which the lack of testicular development in the early stages of the embryonic period leads to the formation of female sexual characteristics such as the uterus and Fallopian tubes; paramesonephric duct participation and the lack of testosterone and anti-Müllerian hormone sent by the testes results in rudimentary female sexual development with no ovaries. Among other differential syndromes are: testicular feminization that consists of well differentiated female sexual characteristics, with a short undeveloped vagina, and bilateral cryptorchidism, but with no uterus,14,15 and ovoteste, also known as “true hermaphrodite” syndrome, which presents with ovaries with seminiferous tubes,16 as listed in table 1.

Follow-up

Figure 5  An end-to-end anastomosis of the proximal and distal segment was performed.

It is currently recommended to raise the awareness of the patient’s relatives in regard to the surgical management, emphasizing its risks, benefits, and potential outcomes so that they can participate more actively in the care of their child. Psychosocial management is the basis of promoting a positive adaptation. These patients require professional follow-up to help them manage the sexual dysfunction and gender dysmorphia as they become present. Group therapy is also recommended because support is necessary up to the adult age so these patients can develop a healthy psychosexual life.5 The risk for acquiring malignant disease in this type of patient exists, especially for presenting germ cell tumors such as gonadoblastoma, dysgerminoma, or seminoma,

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Table 1  Differential diagnoses in the medical conditions of disorders of sex differentiation. Differential diagnoses

Clinical characteristics

Swyer syndrome

Presence of a uterus and rudimentary tubes

Testicular feminization

Female secondary sexual characteristics, but bilateral cryptorchidism

Ovotestis

Presence of seminiferous tubes in ovaries

Conflict of interest Figure 6  The resected segment was taken to the new vaginal canal and was anastomosed and closed in 2 layers.

given that they all belong to the same type of cancer16 and arise from undifferentiated gonadal tissue.17 Therefore they should be intentionally looked for and dysmorphic gonads should be extracted at an early age.18 Today an international database, called I-DSD, is accessible that includes cases recognized by researchers from specialized centers, as well as isolated case reports from private medical practices. This information is available to patients, their families, and doctors so they can know where to find the specialized research centers and information on the disease, treatment, and follow-up.19

Conclusions Complete androgen insensitivity is included in the term DSD, and can include patients ranging from infertile men to those individuals presenting with complete female phenotype with no internal sexual organs, as was the case with our patient. It is a rare entity that has a psychologic impact on family members, as well as a psychosexual impact on the patient. Thus, counseling is required from the time of diagnosis, so that doubts can be cleared up and there can be support during the sexual adaptation. These patients require lifetime maintenance from their psychotherapist, as well as their urologist, who will monitor lower urinary symptoms and carry out periodic hormone function tests. A database is currently at the disposition of patients, relatives, and attending physicians where they can become familiar with the clinical characteristics of the disease and connect with support groups. During surgical treatment it is important to provide extensive counseling on the expectations of both the patient and family members in relation to the procedure, clearly explaining its likely complications. The surgeon should also intentionally look for hypofunctioning dysmorphic gonads and remove them, in order to prevent the aforementioned probability of malignant transformation.

The authors declare that there is no conflict of interest.

Financial disclosure No financial support was received in relation to this article.

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