Ultrasound of retained gonads in children and young women with androgen insensitivity syndrome.

INTRODUCTION: Gonadal management in androgen insensitivity syndrome (AIS) patients has been controversial due to low risk of testicular cancer. Our study evaluated the role of ultrasound (US) in screening for malignancy in retained gonads in AIS patients. METHODS: This was a retrospective study (2001-2020) of gonadal US in patients with AIS. Demographics and clinical information were retrieved from the medical records. US studies were reviewed for nodule presence, size, echotexture, and change on follow-up studies. When available, pathology correlation was performed. Two-tailed t-test was used to compare age and development of nodules clinically or on US examination. RESULTS: 13 patients were included with a median age was 9.9 years (range 3.8-18.4 years). In 11 patients, gonads were in the inguinal canals on either initial or follow-up US. No nodules were palpable on physical examination, but nodules were detected in ten testicles by US in five of 13 patients (41.7%). Presence of nodules was significantly (p = 0.0038) associated with older age. The largest nodule size varied from 0.4 to 2.2 cm (average 0.9 ± 0.5 cm) and most (7/10, 70%) were hypoechoic. Finding testicular nodules on US led to change in management in three patients; bilateral gonadectomies, unilateral gonadectomy, and gonadal excisional biopsies (Figure). Pathology demonstrated Sertoli hamartoma in these patients, and in an additional two patients who underwent post-puberty gonadectomy. No malignancy was found in any specimen. DISCUSSION: Preservation of the gonads in children with AIS is associated with low risk for malignant transformation. The role of US surveillance of the gonads is unknown. In our series on 13 patients, most of the visualized 24 gonads (22/24, 91.7%) were localized in the groins in either the first or follow-up US studies. Nodules were detected in ten gonads in five of 13 patients (41.7%). Most of these gonads (8/10) had numerous nodules, most (7/10) were hypoechoic with average diameter of the largest nodule of 0.9 ± 0.5 cm. Pathology in 5 patients demonstrated Sertoli hamartomas in all of the gonads. No malignancy was found. In our series, gonadal nodules led to either gonadectomies or excisional biopsies in three patients. Our study has several limitations, related to the retrospective nature of the study and the small size of our series. CONCLUSION: Multiple testicular nodules were commonly detected by US in AIS patients and were not associated with malignancy. Therefore, we are concerned that US screening can lead to unnecessary excisional biopsies and orchiectomies.

Detección del síndrome de Morris con técnica imagenológica híbrida: reporte de casos / Detection of the Morris syndrome with a hybrid imaging technique: case report

El síndrome de Morris es un trastorno genético recesivo ligado al cromosoma X. Se caracteriza por fenotipo femenino y cariotipo 46 XY. Las gónadas pueden estar localizadas en los labios mayores, el canal inguinal o intraabdominal. En los casos en los que la localización está en el conducto inguinal o labios mayores, las gónadas son confundidas con hernias y son extirpadas en la infancia; cuando son intraabdominales aproximadamente el 30 % tienen el riesgo de desarrollar tumores gonadales en la edad adulta, por lo que es necesario su extirpación quirúrgica. La localización de estas se realizan con ecografía, tomografía o resonancia magnética, pero en ocasiones no es posible identificar estas estructuras, es allí donde nosotros proponemos la tomografía por emisión de positrones con 18-Fluordesoxiglucosa como herramienta diagnostica para localizar el tejido gonadal, aprovechando la captación fisiológica de este radiotrazador en el tejido testicular.

Morris Syndrome is a recessive genetic disorder linked to the X chromosome. It is characterized by a feminine phenotype and 46 XY karyotype. Gonads can be localized at the upper lips and the inguinal or intra-abdominal canal. In cases where the localization can be at the inguinal conduct or upper lips, gonads are mistaken for hernias and they are removed in childhood; when they are intra-abdominal, approximately 30% has risks of developing gonadal tumors at adulthood, so is necessary its surgical removal. Their localization can be made by ultrasound scans, tomography or magnetic resonance, but sometimes is not possible to identify these structures, so this is where we propose 18-Fluorodeoxyglucose positron emission tomography as a diagnostic tool to localize the gonadal tissue, exploiting the physiological capture of this radiotracer at the testicular tissue.

Distinct clinical picture of Cushing's syndrome in a patient with Morris' syndrome - first literature report.

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Severe forms of complete androgen insensitivity syndrome caused by a p.Q65X novel mutation in androgen receptor: Clinical manifestations, imaging findings and molecular genetics.

Androgen insensitivity syndrome (AIS), a rare X-linked recessive genetic disorder with a normal 46, XY karyotype, is caused by defect of androgen receptor gene (AR) leading to resistance of the target tissues to androgenic hormones. There is a wide spectrum of clinical presentations of AIS, ranging from male infertility, hypospadias to completely normal female external genitalia. Here, we describe a 15-year old, phenotypically female individual, who visited our clinic for primary amenorrhea. The physical examination revealed normal female external genitalia, normal breast development, as well as sparse pubic hair and absence of axillary hair. A short blind vagina pouch was noticed in gynecological examination apart from the absence of cervix and uterus. Serum testosterone measured a considerable high level, and the karyotype was indicative of a normal male (46, XY). Transabdominal ultrasound (US) and magnetic resonance imaging (MRI) confirmed the absence of uterus, ovaries and fallopian tubes, only with a small blind-ending vagina observed. The clinical, laboratory, imaging, and genetic findings strongly suggest the diagnosis of complete androgen insensitivity syndrome (CAIS). Mutational analysis of the AR gene revealed a novel small insertion mutation c.192_193insTAGCAG(Q65X) in exon 1, which gives rise to a truncated nonfunctional protein, resulting in the loss of the remaining 856 C-terminus amino acid residues. This study indicates that US and MRI are two useful and noninvasive imaging methods for the diagnosis and evaluation of CAIS, and identification of this novel mutation expands the database of AR gene mutations. Furthermore, with the availability of the identification technology for this mutation, prenatal diagnosis could be offered for future pregnancies.

Role of testosterone and Y chromosome genes for the masculinization of the human brain.

Women with complete androgen insensitivity syndrome (CAIS) have a male (46,XY) karyotype but no functional androgen receptors. Their condition, therefore, offers a unique model for studying testosterone effects on cerebral sex dimorphism. We present MRI data from 16 women with CAIS and 32 male (46,XY) and 32 female (46,XX) controls. METHODS: FreeSurfer software was employed to measure cortical thickness and subcortical structural volumes. Axonal connections, indexed by fractional anisotropy, (FA) were measured with diffusion tensor imaging, and functional connectivity with resting state fMRI. RESULTS: Compared to men, CAIS women displayed a "female" pattern by having thicker parietal and occipital cortices, lower FA values in the right corticospinal, superior and inferior longitudinal tracts, and corpus callosum. Their functional connectivity from the amygdala to the medial prefrontal cortex, was stronger and amygdala-connections to the motor cortex weaker than in control men. CAIS and control women also showed stronger posterior cingulate and precuneus connections in the default mode network. Thickness of the motor cortex, the caudate volume, and the FA in the callosal body followed, however, a "male" pattern. CONCLUSION: Altogether, these data suggest that testosterone modulates the microstructure of somatosensory and visual cortices and their axonal connections to the frontal cortex. Testosterone also influenced functional connections from the amygdala, whereas the motor cortex could, in agreement with our previous reports, be moderated by processes linked to X-chromosome gene dosage. These data raise the question about other genetic factors masculinizing the human brain than the SRY gene and testosterone. Hum Brain Mapp 38:1801-1814, 2017. © 2017 Wiley Periodicals, Inc.

Imaging characteristics of androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS), also known as testicular feminization, is a genetic disorder which leads to lack of response to androgens caused by a defect in the androgen receptor. It is relatively uncommon and is usually diagnosed through clinical symptoms, laboratory findings, physical exam, radiological imaging, and genetic analysis. Our case is a middle-aged woman with complete AIS and demonstrates the importance of the various imaging modalities that are implemented in initially diagnosing and assisting in surgical management.

The effect of hormone therapy on biochemical and ultrasound parameters associated with atherosclerosis in 46,XY DSD individuals with female phenotype.

The aim of this study was to evaluate the effect of hormone therapy (HT) in the endothelial function of 46,XY disorders of sexual development (DSD) patients with female phenotype. Biochemical and ultrasound measurements were performed in 20 patients at initiation of oral 2 mg 17ß-estradiol/1 mg norethisterone acetate, and after 6 months of therapy. Lipid profile, including total cholesterol (TC), LDL, HDL, triglycerides (TG) and Atherogenic Index of Plasma (AIP), as well as levels of VE-Cadherin, E-Selectin, Thrombomodulin and vWf were determined. Ultrasonographic examinations included evaluation of flow-mediated dilatation (FMD) and measurement of Carotid and Femoral Intima Media Thickness (IMT). HT raised HDL (35.4 mg/dl versus 40.1 mg/dl, p = 0.019) while lowering TG (166 mg/dl versus 109 mg/dl, p = 0.026) and AIP (0.24 versus 0.04, p = 0.007). No changes were noted in TC and LDL (215.7 mg/dl versus 192.25 mg/dl and 87.46 mg/dl versus 76.35 mg/dl, respectively). There was significant reduction of VE-Cadherin (4.05 ng/ml versus 2.20 ng/ml, p = 0.002) and E-selectin (73.98 ng/ml versus 56.73 ng/ml, p = 0.004). No change was observed in Thrombomodulin and vWf (11.76 ng/ml versus 13.90 ng/ml and 80.75% versus 79.55%, respectively). FMD improved significantly (5.4% versus 8.15%, p = 0.003), while only carotid bulb IMT decreased significantly (0.65 mm versus 0.60 mm, p = 0.018). Overall, HT was found to improve biochemical and ultrasound markers of endothelial function in 46,XY DSD patients with female phenotype.

Testicular feminization: complete androgen insensitivity syndrome. Discussions based on a case report.

INTRODUCTION AND OBJECTIVES: Testicular feminization is the syndrome when a male, genetically XY, because of various abnormalities of the X chromosome, is resistant to the actions of the androgen hormones, which in turn stops the forming of the male genitalia and gives a female phenotype. The androgen insensitivity syndrome occurs in one out of 20,000 births and can be incomplete (various sexual ambiguities) or complete (the person appears to be a woman). The aim of this paper is to present the diagnosis and treatment of a case of testicular feminization. PATIENT AND METHODS: A 22-year-old patient is admitted at Gynecology for primary amenorrhea. The clinical examination shows a female phenotype: the breasts are normally developed, but there is no hair in the groins and axillary areas, the labia are small and hypoplastic, the urinary meatus is normally inserted, and the vulva is unpigmented. The gynecological exam reveals that the hymen is present, the vagina has 1.5 cm in length, while the uterus is absent. At Endocrinology, the levels of gonadotropins were measured and found normal (FSH 3.18 mU/mL, LH 15 mU/mL), the progesterone was 5.79 nmol/L, estradiol was 82.39 pmol/L and the testosterone was 4.27 nmol/L. The karyotype was mapped in order to differentiate the androgen insensitivity syndrome from other genetic abnormalities, like the Klinefelter syndrome (46XXY), Turner syndrome (45XO), mixed gonadal dyssynergia (45XO/46XY) or tetragametic chimerism (46XX/46XY). These tests confirmed the suspected diagnosis - testicular feminization (46XY). The pelvic CT scan revealed the lack of uterus and ovaries, hypoplastic vagina, and intra-abdominal prepsoic testes. The testes were removed in order to avoid the malignant risk. We performed laparoscopic bilateral orchiectomy. RESULTS: Surgically, the patient had a simple evolution, being discharged in the second day postoperatory, and estrogen therapy was started from that moment on. Mentally, the patient kept thinking she was a woman, so the decision of telling her the truth was left to the parents. CONCLUSIONS: Testicular feminization is a rare disease that must be diagnosed and treated through close work between gynecologists, endocrinologists, geneticians, urologists, and psychiatrists. Bilateral laparoscopic orchiectomy is the best procedure to remove the intra-abdominal testes, in order to avoid their malignant transformation.

[Application of scintigraphy for preoperative localization of testis in a patient with Morris syndrome].

The paper presents the successful application for the first time in Bulgaria of the new hybrid imaging technique--tomographic scintigraphy combined with computed tomography--SPECT/CT for visualization and localization of the testis by injection of 99mTc-pertechnetate with activity of 185 MBq. The study was performed on a girl with 46XY karyotype and lack of sensitivity to androgens, known in gynecology as "testicular feminization syndrome" or Morris syndrome. Until now testicular scintigraphy has been used mainly as a very accurate technique for rapid diagnosis in cases of testicular torsion, acute epididymitis or after trauma. We found no published data in the literature concerning the use of hybrid SPECT-CT for testicular localization in Morris syndrome. Our experience is this case allows us to recommend SPECT/CT as a fast, accurate, noninvasive method with potential to be used for localization, visualization and perfusion of testicular tissue before performing surgery in cases of Morris syndrome.

Incidental detection of Sertoli-Leydig cell tumor by FDG PET/CT imaging in a patient with androgen insensitivity syndrome.

A 29-year-old female patient who was being followed up for differentiated papillary thyroid carcinoma was referred to us for exploration of any possible metastasis since her serum thyroglobulin levels were high. The patient underwent an F-18 fluorodeoxyglucose positron emission tomography study, and a pathologically increased FDG uptake at the left lower abdomen was detected corresponding to a solid, cystic lesion on CT images. The patient had a history of primary amenorrhea and, together with the magnetic resonance imaging findings of absent uterus, short and blind end vagina, a diagnosis of androgen insensitivity syndrome was made. The patient underwent laparoscopic left pelvic mass resection, and the histopathology of the lesion revealed Sertoli-Leydig cell tumor.

Androgen insensitivity syndrome after preimplantation genetic diagnosis for sex selection: a case report.

OBJECTIVE: To report the first case of androgen insensitivity syndrome after preimplantation genetic diagnosis (PGD) for sex selection. DESIGN: Case report. SETTING: The Farah Hospital (a private tertiary referral fertility center). PATIENT(S): A healthy woman with three daughters underwent PGD for sex selection, seeking a male baby. INTERVENTION(S): PGD was done and the woman became pregnant. Ultrasound examination showed female phenotype. Amniocentesis was performed and culture of cells confirmed XY karyotype. RESULT(S): Karyotyping confirmed the diagnosis of XY genotype and pregnancy was terminated. CONCLUSION(S): Although androgen insensitivity syndrome is very rare, it can occur in cases of PGD for sex selection.

Root growth in the teeth of 46,XY females.

The subjects of this study are women with a male sex chromosome complement or 46,XY females who show the complete form of the testicular feminization syndrome (CTF). The basic endocrine defect is end organ insensitivity to androgens. They are on average tall individuals and also show an increase in head and face dimensions relative to normal females. A size increase is likewise evident in permanent tooth crowns and here we report permanent tooth root lengths in eight 46,XY females, their five female relatives and population control females and males. Measurements were made from panoramic radiographs by a digital calliper according to established procedures on both sides of the jaws. The results show increased root lengths of 46,XY females relative to control females with values similar to those in population control males. The root and crown findings point to evident irreversible growth excesses in 46,XY females beginning 3 years after birth up to the age of 14 years expressing an effect which apparently is influencing in a continuous way. Excess root growth conceivably would develop independently of the possible androgen influence, and it is suggested that the increase results from the direct effect of the genes on the Y chromosome. It is possible that these genes on the Y chromosome are the same that promote tooth crown growth.

[Complete androgen insensitivity syndrome in 16-year-old girl with female phenotype]. / Zespól calkowitej niewrazliwosci na androgeny u 16-letniej fenotypowej dziewczynki.

We present a case of a 16-year-old girl who attended Endocrinology Clinic in Kraków. Her main complains were amenorrhea and lack of pubic and axillary hair development. Breast development was normal. Based on those features, male karyotype (46, XY) as well as high levels of blood testosterone and lack of uterus on ultrasound examination allowed for establishing the diagnosis of complete androgen insensitivity syndrome. The authors emphasize the possibility of diagnosing severe disorders of sex differentiation, such as sex reversal, not earlier than in teenage patients with delayed puberty. In such cases the diagnosis can be established based on physical examination with evaluation of sexual development, basic blood hormonal tests and karyotype results. Reliable knowledge of male sex differentiation physiology is needed for their correct interpretation.

Antenatal diagnosis and early laparoscopic treatment of a rare variation of androgen-insensitivity syndrome.

Androgen-insensitivity syndrome (AIS) (Testicular feminisation or Morris syndrome) is characterised by external female genitalia and bilateral testes with a normal male karyotype. This kind of syndrome is transmitted recessively. Presence of hypoplastic and short "pseudo-vagina" is one of the characteristics of this syndrome. We report here a case of AIS in which there was a well-formed vagina (6 cm). The case was diagnosed antenatally and managed laparoscopically.

Testicular feminization: radiologic considerations in a unique form of cryptorchidism.

A case report of complete testicular feminization is presented. The medical and radiological characteristics of this condition which distinguish it from male cryptorchidism and other disorders of sexual differentiation are discussed. To our knowledge, only three previous case reports have been published in the radiology literature. Our report is the first to describe MRI findings.