Technological Advances Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
Imaging, Endoscopy and Diagnostic Surgery Lutz Wünsch a · Michael Buchholz b
a
b
Klinik für Kinderchirurgie and Michael Buchholz Klinik für Radiologie und Nuklearmedizin, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany
Abstract
In this chapter imaging techniques and endoscopy are presented as parts of a comprehensive diagnostic approach by a multidisciplinary team. This is uncommon because the techniques are applied by different medical specialties, but they have the common aim of defining the deep phenotype and conferring a meaning to these findings. Imaging and endoscopy techniques contribute to the medical diagnosis by describing the anatomic details of the deep phenotype and allocating these findings to the spectrum of anatomic normality or pathology. Imaging and endoscopy thus produce a visible representation of hidden details and propose an interpretation based on our current medical knowledge. This distinction should be kept in mind because in the case of disorder of sex development (DSD) the concept of normality is currently challenged and is likely to be significantly broadened in the near future. Good-quality counselling is the cornerstone of informed consent and essential for empowerment of the families, which is particularly relevant to DSD with its multiple facets and complex issues. Detailed knowledge of the deep phenotype is important for the discussion within the multidisciplinary team and helps the involved individuals to understand their condition.
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Imaging of the inner genitalia and the gonads is part of the diagnostic work-up and is essential for an individualized approach to the disorder of sex development individual. Ultrasound is used as a first-line modality to detect the presence of a uterus and gonads. Magnetic resonance imaging can reveal the sex duct anatomy and details of prostate and pelvic muscle anatomy. Laparoscopy is an invasive surgical procedure that adds valuable information in gonadal dysgenesis and situations of © 2014 S. Karger AG, Basel diagnostic uncertainty.
When a newborn presents with ambiguous genitalia, imaging is an essential part of the diagnostic work-up [1]. Later, during childhood and adolescence, imaging procedures are needed to monitor the physiologic development and for screening of individuals with an increased tumor risk through the adult age.
Ultrasound is the most commonly available imaging technique and is used as the firstline imaging modality. It offers a high resolution of small details, is not invasive, avoids radiation exposure and is relatively inexpensive. However, the lack of standardization makes the comparison of images and findings difficult and inter-observer variability is a well-known problem. At a basic level, magnetic resonance imaging (MRI) has emerged as a powerful technique to image the abdomen and pelvis. It is most appropriate for cooperative children, adolescents and adults. In infants, the need for sedation in order to avoid movement artifacts limits its use. Intra-abdominal gonads of the size of a normal testicle are well defined by MRI, but smaller dysgenetic gonads are usually not detected. Ectopic testes and noncystic immature ovaries have intermediate signal intensity on T1-weighted images and high signal intensity with an intermediate intensity outer rim on T2-weighted images. High signal intensity foci in dysgenetic gonads may indicate neoplastic transformation [1, 2]. Genitography has been used frequently in the past, but is now replaced by cystoscopy/genitoscopy under most circumstances [3]. Cystoscopy and laparoscopy are both invasive and require anesthesia. Cystoscopy, or genitoscopy if combined with examination of the inner genitalia, shows the mucosal surfaces and inner orifices. In particular, the posterior urethra and Müllerian structures can be examined. Laparoscopy is the only reliable technique to detect small dysgenetic gonads. It is also valuable for detecting the Fallopian tubes and the intra-abdominal vas deferens. Though the operative risk is very low, both procedures should be used only if the diagnostic information cannot be obtained by other means. High-quality documentation must be assured and the need for biopsies or other procedures should be considered in advance. All findings should be documented in a standardized manner – a proposal for cystoscopic findings in DSD has recently been published [4]. For the purpose of this text, the authors assume that finding a correct medical diagnosis is in the best interest of the affected person. Imaging and surgical endoscopy can contribute to this process. Many aspects of classification and the need and benefit of interventions are under discussion. This discussion, however, cannot proceed with a clear referral to well-established diagnostic categories. Currently, only about 50% of individuals with 46,XY DSD receive a well-defined diagnosis [5]. The following suggestions for imaging and endoscopy aim at a diagnostic work-up of the best possible quality in order to improve future counselling and treatment.
Imaging, Endoscopy and Diagnostic Surgery Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Techniques
Ambiguous genitalia Ultrasound Uterus Ovaries
No ovaries No uterus
No ovaries Uterus
CAH
17 β Hydroxylase deficiency
Partial androgen insensivity Partial/mixed gonadal dysgenesis
Fig. 1. Ultrasound evaluation of a child with ambiguous genitalia. Only the most frequently encountered disorders are indicated.
There are three main goals in imaging: evaluation of the gonads, definition of the bladder, urethra and inner genitalia, and assessment of the deeper structures of the external genitalia. Today, most imaging is based on ultrasound and MRI. Fluoroscopy is rarely employed but may add valuable information [2]. When ambiguous genitalia are observed, imaging is required immediately to detect salt-wasting congenital adrenal hyperplasia (CAH) as early as possible. A diagnostic algorithm is outlined in figure 1. Imaging can be required at different time points during the care of a person with DSD. Recommendations for imaging are summarized in table 1.
Imaging of the gonads is relevant for the diagnosis of DSD. Intra-abdominal gonads in a newborn are best examined by ultrasound, by which ovaries, testes or ovotestes can be found. A gonad with multiple cysts in a newborn is an ovary. In CAH, ultrasound will identify typical ovaries. Testes have a typical ‘coffee bean’ appearance because of the higher echogenicity of the rete testis. When complete androgen insensitivity syndrome (CAIS) is suspected, imaging at diagnosis points at the confirmation of the typical deep phenotype (fig. 2). This includes a blind-ending vagina, absent uterus and gonads with testis-like features [6]. The gonads are localized intra-abdominally or in the inguinal canal, and a hernia is sometimes present. Testis-like features include size and shape, a homogenous low echogenicity, a typical vascular architecture, as well as the presence of a rete testis. Ultrasound is the imaging method of choice in newborns and children, whilst cooperative patients should undergo MRI. Cystoscopy and laparoscopy are not required to establish the diagnosis. Preservation of the gonads in CAIS is recommended at least until puberty to maintain the endocrine function and because the tumor risk is low. After puberty, the tu-
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Wünsch · Buchholz Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Imaging of the Gonads
Table 1. Recommendations for structured examination in DSD Disorder
Clinical setting
Imaging modality
Report details, expected findings
CAH
At diagnosis
Ultrasound
– Uterus – Ovaries – Adrenal hyperplasia
Before surgery
MRI Genitoscopy
– Distance between bladder neck and vagina – Length of urogenital sinus
At diagnosis
Ultrasound
– – – –
during follow-up
Ultrasound MRI
– gonads (size, location, tissue homogeneity, shape) – cysts
Gonad not visualized
Laparoscopy
– Gonads (size, shape, location) – Consider fixation of gonads to the abdominal wall
Suspected tumor
Laparoscopy
– Tumor biopsy/removal – Size, location and shape of contralateral gonad if preservation desired – Staging laparoscopy
At diagnosis
Ultrasound
– Uterus – Testicles (volume, echogenicity, calcifications)
Control of testicles
Ultrasound
– – – –
5α-Reductase deficiency
At diagnosis
Ultrasound
– Absent uterus – Testicles (echogenicity, calcifications shape, homogeneity)
17β-Hydroxylase deficiency
Control of testicles
Ultrasound
– – – –
Echogenicity Calcifications Shape Homogeneity
Complete gonadal dysgenesis
At diagnosis
ultrasound
– – – –
Absent gonads Uterus Possible hernia Tumor
At follow-up
Ultrasound MRI
– Tumor
At diagnosis
Ultrasound
– – – –
PAIS
Partial/mixed gonadal dysgenesis
Gonads (size/volume, location) Absent uterus Blind ending vagina behind bladder Possible hernia
Echogenicity Calcifications Shape Homogeneity
Testicles Uterus Phallus Distance between bladder neck and vagina
Imaging, Endoscopy and Diagnostic Surgery Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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CAIS
a
b
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Wünsch · Buchholz Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Fig. 2. Complete androgen insensitivity. a Ultrasound of intra-abdominal testes in CAIS. The testicle lies under the abdominal wall on the iliopsoas muscle. b MRI of a 23-year-old woman with CAIS. The upper left image is a coronal plane T1-weighted image showing low signal gonads on both sides (white arrows). The upper right image is a coronal plane image of a so-called TIRM sequence with a T2 contrast and fat saturation, showing an intermediate signal with asymmetrical intensity (white arrows) and a peripheral cyst on the right side, meaning dysgenetic gonads on both sides. The sagittal plane TIRM image again in the midline shows a vaginal cavity (arrows) without a uterus.
c
mor risk increases. For women who retain their gonads, surveillance is recommended as both benign and malignant tumors have been described [5]. Because more women are deciding to preserve their gonads, screening protocols must be developed. Both ultrasound and MRI have been employed for screening of the gonads [1, 2]. For ultrasound examination, a full bladder is helpful to lift the gonads out of the pelvis. Cystic dilatation of the epididymis is frequently observed. Imaging should define the size and structure of the gonad. At present, no evidence-based screening protocols exist. If no gonads are found at imaging, laparoscopy is needed for a detailed assessment of the gonads. The presence of an epididymis or a Fallopian tube can also be detected. If a tumor is suspected, the gonad should be removed. A gonadal biopsy may detect the presence of in situ neoplasia and allow for a better estimation of the tumor risk. Fixation of the gonad to the abdominal wall is an option to make the retrieval and serial examinations of the gonad easier. In partial androgen insensitivity, large phenotypic variation is found, depending on the residual activity of the androgen receptor. In most individuals, a male sex of rearing is appropriate and laparoscopic mobilization of the gonad orchidopexy may be needed. During adolescence, testicular growth can be followed by ultrasound. In 5α-reductase deficiency, a female phenotype is present at birth. If the diagnosis is suspected, ultrasound reveals the absence of a uterus and gonads with testis-like features in the abdomen or inguinal canal. The findings are similar in 17β-hydroxysteroid dehydrogenase deficiency, but the gonads are less developed and may be difficult to find (fig. 3). If male gender is chosen, laparoscopy is often needed for orchidolysis and orchidopexy of abdominal testes. MRI is helpful in older patients.
Imaging, Endoscopy and Diagnostic Surgery Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Fig. 2. Complete androgen insensitivity. c Intra-abdominal testes in CAIS. Note the cystic dilatation on the right side representing an epididymis, similar to the representation of the MRI.
a
b
Fig. 3. 17β-hydroxysteroid dehydrogenase deficiency. a An axial T2-weighted MRI image showing small dysplastic gonads on both sides in the inguinal canal (white arrows) and no uterus behind the bladder (black arrows). b Dysgenetic gonad in the inguinal canal in 17β-hydroxysteroid dehydrogenase deficiency. The gonad is small and is retracted from the inguinal canal.
In partial and mixed gonadal dysgenesis (fig. 4), the gonads and the uterus can frequently be seen by ultrasound, and MRI in the newborn rarely adds useful information. Laparoscopy allows for a morphologic evaluation. The risk for germ cell tumors for this category is significant. Scrotal placement or gonadectomy have to be considered in this situation. During-follow up, ultrasound is a useful addition to clinical examination of preserved gonads. The gonads in complete gonadal dysgenesis (fig. 5) are of small size and mobile. They are located in the abdomen and they are not detected by any available imaging technique. Laparoscopic gonadectomy is recommended once the diagnosis is established. Because not all patients develop a tumor, future research should point to reliable prognostic criteria.
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Wünsch · Buchholz Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Fig. 4. Dysgenetic gonad in partial gonadal dysgenesis.
a
b
Fig. 5. Dysgenetic gonad in complete gonadal dysgenesis. a Dysgenetic gonad in 46,XY gonadal dysgenesis containing gonadoblastoma. b Dysgerminoma in a girl with complete gonadal dysgenesis.
*
a
*
b
Fig. 6. a, b Perineal ultrasound in CAH: inverted view of the perineum. The bladder is seen (asterisk), and the urethra and the bulbospongiosus muscle are hypoechogenic. The arrow indicates the junction between the vagina and the urethra.
In CAH, the urethra and vagina open through a common channel of variable length. The assessment of these structures is required for counselling and if surgery is planned. Perineal ultrasound (fig. 6) is able to define the level at which the vagina enters the urethra, and is being increasingly used. Genitography is no longer required for diagnosis, but can represent these structures equally well. Most girls with CAH will undergo surgery to open the vaginal introitus. To guide the surgical approach, preoperative genitoscopy and cystoscopy is helpful [7].
Imaging, Endoscopy and Diagnostic Surgery Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Imaging of the Sex Ducts and the Vagina
a
b
Fig. 7. Gonadal dysgenesis. a Genitography mixed gonadal dysgenesis: the bladder and a large vaginal cavity are filled with contrast media [1, 5]. b Cystoscopy/genitoscopy of the same patient – cystoscopic view of the posterior urethra in a boy with mixed gonadal dysgenesis. The opening in the floor (arrow) represents a large utricular cyst, the colliculus seminalis is absent.
In newborns with CAIS, the length of the vagina can be estimated by ultrasound. A longitudinal section through the bladder is appropriate. In adolescent girls and in women this information is obtained by MRI or vaginal examination. In 5α-reductase deficiency, the vagina is a blind-ending pit. In 17β-hydroxysteroid dehydrogenase deficiency, a more variable phenotype occurs. In the newborn, ultrasound may reveal the absence of gonads and a uterus. Laparoscopy may sometimes be necessary to detect the presence of a vas deferens and the gonads, if no mutation is detected. Urethral construction will be considered for patients with XY DSD assigned to male gender. A hypoplastic vagina or a uterus may exist. These structures can be visualized by genitography, but perineal ultrasound is also effective. Anomalies of the prostatic urethra and colliculus are frequent and a vaginal anlage may enter the urethra at a variable level. If surgery is planned, a cystoscopy/genitoscopy is needed (fig. 7).
CAH is frequently associated with a visible enlargement of the clitoris. Imaging of the clitoral hypertrophy can be done by ultrasound and MRI, but is rarely helpful. It reveals the difference from a penis, because the bulbospongiosus muscle is poorly de-
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Wünsch · Buchholz Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Imaging of the Genitalia
veloped or absent. MRI studies have also shown that the perineal muscles and the puborectalis muscle are placed in a posterior location [1, 2, 8]. There is an ongoing debate on the presence of prostatic tissue in CAH, and further research should clarify this issue.
Very Rare Disorders of Sex Development
Several very rare DSDs exist. As a rule, ultrasound is the first examination. In children able to understand and cooperate, MRI is indicated. Laparoscopy is particularly helpful for detecting the features of an ovotestis in 46,XX/46,XY DSD. The direct examination of small gonads and sex ducts is the last step of the diagnostic process.
Concluding Remarks
Imaging, Endoscopy and Diagnostic Surgery Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Imaging of a DSD is special in several regards. The need for imaging must be critically appraised in view of the individual attitude of the DSD individual and family. Some may consider DSD to be more a difference in sexual development than a medical condition. Reporting and communicating the findings may be challenging because the names of organs may be discordant with the selected gender. A respectful communication should include a terminology that is acceptable to the patient. For example, in a young woman it may be more appropriate to talk about gonads than testes. It is of utmost importance that the examiner is sensitive in this regard. This is particularly true for the ultrasound examinations with their typically long duration and intimate contact. The results of imaging should be explained to all members of the DSD team. As long as the diagnosis is unclear, the team discussion should precede the communication of imaging results to the patient to avoid bias and confusion. The role of ultrasound and MRI is likely to increase in the future because most differences of sex development will be managed expectantly. The most relevant clinical problem is the control of the germ cell tumor risk. To that purpose, ultrasound examinations should be standardized. Vaginal ultrasound and MRI based on fast sequence acquisition may add useful information in the future. The detailed description of the deep phenotype remains a challenge, but it is also an essential part of a comprehensive diagnostic process. A precise diagnosis remains a fundamental requirement to improve the care and outcome in DSD.
References 5 Hughes IA, Houk C, Ahmed F, et al: Consensus statement on management of intersex disorders. Arch Dis Child 2006;91:554–563. 6 Nakhal RS, Hall-Craggs M, Freeman A, Kirkham A, Conway GS, Arora R, Woodhouse CRJ, Wood DN, Creighton SM: Evaluation of retained testes in adolescent girls and women with complete androgen insensitivity syndrome. Radiology 2013;268:153–160. 7 Schuster W, Färber D: Kinderradiologie: Bildgebende Diagnostik, ed 2. Berlin, Springer, 1996, pp 674–707. 8 Lapointe SP, Wei DC, Hricak H, Varghese SL, Kogan BA, Baskin LS: Magnetic resonance imaging in the evaluation of congenital anomalies of the external genitalia. Urology 2001;58:452–456.
Lutz Wünsch, MD, Professor of Paediatric Surgery Klinik für Kinderchirurgie, Campus Lübeck, Universitätsklinikum Schleswig-Holstein Ratzeburger Allee 160 DE–23538 Lübeck (Germany) E-Mail [email protected]
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1 Chavhan GB, Parra DA, Oudjhane K, Miller SF, Babyn PS, Pippi Salle JL: Imaging of ambiguous genitalia: classification and diagnostic approach. Radiographics 2008;28:1891–1904. 2 Carty H, Brunelle F, Stringer DA, Kao SCS (eds): Imaging Children, ed. 2. London, Churchill Livingstone, 2005, pp 943–953. 3 Ahmed SF, Achermann JC, Arlt W, et al: UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development. Clin Endocrinology 2011;75:12–26. 4 Wünsch L: Checklist for the structural description of the deep phenotype in disorders of sexual development. Int J Endocrinol 2012;2012:816365.
Imaging, Endoscopy and Diagnostic Surgery Lutz Wünsch a · Michael Buchholz b
a
b
Klinik für Kinderchirurgie and Michael Buchholz Klinik für Radiologie und Nuklearmedizin, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany
Abstract
In this chapter imaging techniques and endoscopy are presented as parts of a comprehensive diagnostic approach by a multidisciplinary team. This is uncommon because the techniques are applied by different medical specialties, but they have the common aim of defining the deep phenotype and conferring a meaning to these findings. Imaging and endoscopy techniques contribute to the medical diagnosis by describing the anatomic details of the deep phenotype and allocating these findings to the spectrum of anatomic normality or pathology. Imaging and endoscopy thus produce a visible representation of hidden details and propose an interpretation based on our current medical knowledge. This distinction should be kept in mind because in the case of disorder of sex development (DSD) the concept of normality is currently challenged and is likely to be significantly broadened in the near future. Good-quality counselling is the cornerstone of informed consent and essential for empowerment of the families, which is particularly relevant to DSD with its multiple facets and complex issues. Detailed knowledge of the deep phenotype is important for the discussion within the multidisciplinary team and helps the involved individuals to understand their condition.
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/1/2015 6:40:24 PM
Imaging of the inner genitalia and the gonads is part of the diagnostic work-up and is essential for an individualized approach to the disorder of sex development individual. Ultrasound is used as a first-line modality to detect the presence of a uterus and gonads. Magnetic resonance imaging can reveal the sex duct anatomy and details of prostate and pelvic muscle anatomy. Laparoscopy is an invasive surgical procedure that adds valuable information in gonadal dysgenesis and situations of © 2014 S. Karger AG, Basel diagnostic uncertainty.
When a newborn presents with ambiguous genitalia, imaging is an essential part of the diagnostic work-up [1]. Later, during childhood and adolescence, imaging procedures are needed to monitor the physiologic development and for screening of individuals with an increased tumor risk through the adult age.
Ultrasound is the most commonly available imaging technique and is used as the firstline imaging modality. It offers a high resolution of small details, is not invasive, avoids radiation exposure and is relatively inexpensive. However, the lack of standardization makes the comparison of images and findings difficult and inter-observer variability is a well-known problem. At a basic level, magnetic resonance imaging (MRI) has emerged as a powerful technique to image the abdomen and pelvis. It is most appropriate for cooperative children, adolescents and adults. In infants, the need for sedation in order to avoid movement artifacts limits its use. Intra-abdominal gonads of the size of a normal testicle are well defined by MRI, but smaller dysgenetic gonads are usually not detected. Ectopic testes and noncystic immature ovaries have intermediate signal intensity on T1-weighted images and high signal intensity with an intermediate intensity outer rim on T2-weighted images. High signal intensity foci in dysgenetic gonads may indicate neoplastic transformation [1, 2]. Genitography has been used frequently in the past, but is now replaced by cystoscopy/genitoscopy under most circumstances [3]. Cystoscopy and laparoscopy are both invasive and require anesthesia. Cystoscopy, or genitoscopy if combined with examination of the inner genitalia, shows the mucosal surfaces and inner orifices. In particular, the posterior urethra and Müllerian structures can be examined. Laparoscopy is the only reliable technique to detect small dysgenetic gonads. It is also valuable for detecting the Fallopian tubes and the intra-abdominal vas deferens. Though the operative risk is very low, both procedures should be used only if the diagnostic information cannot be obtained by other means. High-quality documentation must be assured and the need for biopsies or other procedures should be considered in advance. All findings should be documented in a standardized manner – a proposal for cystoscopic findings in DSD has recently been published [4]. For the purpose of this text, the authors assume that finding a correct medical diagnosis is in the best interest of the affected person. Imaging and surgical endoscopy can contribute to this process. Many aspects of classification and the need and benefit of interventions are under discussion. This discussion, however, cannot proceed with a clear referral to well-established diagnostic categories. Currently, only about 50% of individuals with 46,XY DSD receive a well-defined diagnosis [5]. The following suggestions for imaging and endoscopy aim at a diagnostic work-up of the best possible quality in order to improve future counselling and treatment.
Imaging, Endoscopy and Diagnostic Surgery Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Techniques
Ambiguous genitalia Ultrasound Uterus Ovaries
No ovaries No uterus
No ovaries Uterus
CAH
17 β Hydroxylase deficiency
Partial androgen insensivity Partial/mixed gonadal dysgenesis
Fig. 1. Ultrasound evaluation of a child with ambiguous genitalia. Only the most frequently encountered disorders are indicated.
There are three main goals in imaging: evaluation of the gonads, definition of the bladder, urethra and inner genitalia, and assessment of the deeper structures of the external genitalia. Today, most imaging is based on ultrasound and MRI. Fluoroscopy is rarely employed but may add valuable information [2]. When ambiguous genitalia are observed, imaging is required immediately to detect salt-wasting congenital adrenal hyperplasia (CAH) as early as possible. A diagnostic algorithm is outlined in figure 1. Imaging can be required at different time points during the care of a person with DSD. Recommendations for imaging are summarized in table 1.
Imaging of the gonads is relevant for the diagnosis of DSD. Intra-abdominal gonads in a newborn are best examined by ultrasound, by which ovaries, testes or ovotestes can be found. A gonad with multiple cysts in a newborn is an ovary. In CAH, ultrasound will identify typical ovaries. Testes have a typical ‘coffee bean’ appearance because of the higher echogenicity of the rete testis. When complete androgen insensitivity syndrome (CAIS) is suspected, imaging at diagnosis points at the confirmation of the typical deep phenotype (fig. 2). This includes a blind-ending vagina, absent uterus and gonads with testis-like features [6]. The gonads are localized intra-abdominally or in the inguinal canal, and a hernia is sometimes present. Testis-like features include size and shape, a homogenous low echogenicity, a typical vascular architecture, as well as the presence of a rete testis. Ultrasound is the imaging method of choice in newborns and children, whilst cooperative patients should undergo MRI. Cystoscopy and laparoscopy are not required to establish the diagnosis. Preservation of the gonads in CAIS is recommended at least until puberty to maintain the endocrine function and because the tumor risk is low. After puberty, the tu-
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Wünsch · Buchholz Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Imaging of the Gonads
Table 1. Recommendations for structured examination in DSD Disorder
Clinical setting
Imaging modality
Report details, expected findings
CAH
At diagnosis
Ultrasound
– Uterus – Ovaries – Adrenal hyperplasia
Before surgery
MRI Genitoscopy
– Distance between bladder neck and vagina – Length of urogenital sinus
At diagnosis
Ultrasound
– – – –
during follow-up
Ultrasound MRI
– gonads (size, location, tissue homogeneity, shape) – cysts
Gonad not visualized
Laparoscopy
– Gonads (size, shape, location) – Consider fixation of gonads to the abdominal wall
Suspected tumor
Laparoscopy
– Tumor biopsy/removal – Size, location and shape of contralateral gonad if preservation desired – Staging laparoscopy
At diagnosis
Ultrasound
– Uterus – Testicles (volume, echogenicity, calcifications)
Control of testicles
Ultrasound
– – – –
5α-Reductase deficiency
At diagnosis
Ultrasound
– Absent uterus – Testicles (echogenicity, calcifications shape, homogeneity)
17β-Hydroxylase deficiency
Control of testicles
Ultrasound
– – – –
Echogenicity Calcifications Shape Homogeneity
Complete gonadal dysgenesis
At diagnosis
ultrasound
– – – –
Absent gonads Uterus Possible hernia Tumor
At follow-up
Ultrasound MRI
– Tumor
At diagnosis
Ultrasound
– – – –
PAIS
Partial/mixed gonadal dysgenesis
Gonads (size/volume, location) Absent uterus Blind ending vagina behind bladder Possible hernia
Echogenicity Calcifications Shape Homogeneity
Testicles Uterus Phallus Distance between bladder neck and vagina
Imaging, Endoscopy and Diagnostic Surgery Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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CAIS
a
b
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Wünsch · Buchholz Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Fig. 2. Complete androgen insensitivity. a Ultrasound of intra-abdominal testes in CAIS. The testicle lies under the abdominal wall on the iliopsoas muscle. b MRI of a 23-year-old woman with CAIS. The upper left image is a coronal plane T1-weighted image showing low signal gonads on both sides (white arrows). The upper right image is a coronal plane image of a so-called TIRM sequence with a T2 contrast and fat saturation, showing an intermediate signal with asymmetrical intensity (white arrows) and a peripheral cyst on the right side, meaning dysgenetic gonads on both sides. The sagittal plane TIRM image again in the midline shows a vaginal cavity (arrows) without a uterus.
c
mor risk increases. For women who retain their gonads, surveillance is recommended as both benign and malignant tumors have been described [5]. Because more women are deciding to preserve their gonads, screening protocols must be developed. Both ultrasound and MRI have been employed for screening of the gonads [1, 2]. For ultrasound examination, a full bladder is helpful to lift the gonads out of the pelvis. Cystic dilatation of the epididymis is frequently observed. Imaging should define the size and structure of the gonad. At present, no evidence-based screening protocols exist. If no gonads are found at imaging, laparoscopy is needed for a detailed assessment of the gonads. The presence of an epididymis or a Fallopian tube can also be detected. If a tumor is suspected, the gonad should be removed. A gonadal biopsy may detect the presence of in situ neoplasia and allow for a better estimation of the tumor risk. Fixation of the gonad to the abdominal wall is an option to make the retrieval and serial examinations of the gonad easier. In partial androgen insensitivity, large phenotypic variation is found, depending on the residual activity of the androgen receptor. In most individuals, a male sex of rearing is appropriate and laparoscopic mobilization of the gonad orchidopexy may be needed. During adolescence, testicular growth can be followed by ultrasound. In 5α-reductase deficiency, a female phenotype is present at birth. If the diagnosis is suspected, ultrasound reveals the absence of a uterus and gonads with testis-like features in the abdomen or inguinal canal. The findings are similar in 17β-hydroxysteroid dehydrogenase deficiency, but the gonads are less developed and may be difficult to find (fig. 3). If male gender is chosen, laparoscopy is often needed for orchidolysis and orchidopexy of abdominal testes. MRI is helpful in older patients.
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Fig. 2. Complete androgen insensitivity. c Intra-abdominal testes in CAIS. Note the cystic dilatation on the right side representing an epididymis, similar to the representation of the MRI.
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Fig. 3. 17β-hydroxysteroid dehydrogenase deficiency. a An axial T2-weighted MRI image showing small dysplastic gonads on both sides in the inguinal canal (white arrows) and no uterus behind the bladder (black arrows). b Dysgenetic gonad in the inguinal canal in 17β-hydroxysteroid dehydrogenase deficiency. The gonad is small and is retracted from the inguinal canal.
In partial and mixed gonadal dysgenesis (fig. 4), the gonads and the uterus can frequently be seen by ultrasound, and MRI in the newborn rarely adds useful information. Laparoscopy allows for a morphologic evaluation. The risk for germ cell tumors for this category is significant. Scrotal placement or gonadectomy have to be considered in this situation. During-follow up, ultrasound is a useful addition to clinical examination of preserved gonads. The gonads in complete gonadal dysgenesis (fig. 5) are of small size and mobile. They are located in the abdomen and they are not detected by any available imaging technique. Laparoscopic gonadectomy is recommended once the diagnosis is established. Because not all patients develop a tumor, future research should point to reliable prognostic criteria.
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Fig. 4. Dysgenetic gonad in partial gonadal dysgenesis.
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Fig. 5. Dysgenetic gonad in complete gonadal dysgenesis. a Dysgenetic gonad in 46,XY gonadal dysgenesis containing gonadoblastoma. b Dysgerminoma in a girl with complete gonadal dysgenesis.
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Fig. 6. a, b Perineal ultrasound in CAH: inverted view of the perineum. The bladder is seen (asterisk), and the urethra and the bulbospongiosus muscle are hypoechogenic. The arrow indicates the junction between the vagina and the urethra.
In CAH, the urethra and vagina open through a common channel of variable length. The assessment of these structures is required for counselling and if surgery is planned. Perineal ultrasound (fig. 6) is able to define the level at which the vagina enters the urethra, and is being increasingly used. Genitography is no longer required for diagnosis, but can represent these structures equally well. Most girls with CAH will undergo surgery to open the vaginal introitus. To guide the surgical approach, preoperative genitoscopy and cystoscopy is helpful [7].
Imaging, Endoscopy and Diagnostic Surgery Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Imaging of the Sex Ducts and the Vagina
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Fig. 7. Gonadal dysgenesis. a Genitography mixed gonadal dysgenesis: the bladder and a large vaginal cavity are filled with contrast media [1, 5]. b Cystoscopy/genitoscopy of the same patient – cystoscopic view of the posterior urethra in a boy with mixed gonadal dysgenesis. The opening in the floor (arrow) represents a large utricular cyst, the colliculus seminalis is absent.
In newborns with CAIS, the length of the vagina can be estimated by ultrasound. A longitudinal section through the bladder is appropriate. In adolescent girls and in women this information is obtained by MRI or vaginal examination. In 5α-reductase deficiency, the vagina is a blind-ending pit. In 17β-hydroxysteroid dehydrogenase deficiency, a more variable phenotype occurs. In the newborn, ultrasound may reveal the absence of gonads and a uterus. Laparoscopy may sometimes be necessary to detect the presence of a vas deferens and the gonads, if no mutation is detected. Urethral construction will be considered for patients with XY DSD assigned to male gender. A hypoplastic vagina or a uterus may exist. These structures can be visualized by genitography, but perineal ultrasound is also effective. Anomalies of the prostatic urethra and colliculus are frequent and a vaginal anlage may enter the urethra at a variable level. If surgery is planned, a cystoscopy/genitoscopy is needed (fig. 7).
CAH is frequently associated with a visible enlargement of the clitoris. Imaging of the clitoral hypertrophy can be done by ultrasound and MRI, but is rarely helpful. It reveals the difference from a penis, because the bulbospongiosus muscle is poorly de-
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Imaging of the Genitalia
veloped or absent. MRI studies have also shown that the perineal muscles and the puborectalis muscle are placed in a posterior location [1, 2, 8]. There is an ongoing debate on the presence of prostatic tissue in CAH, and further research should clarify this issue.
Very Rare Disorders of Sex Development
Several very rare DSDs exist. As a rule, ultrasound is the first examination. In children able to understand and cooperate, MRI is indicated. Laparoscopy is particularly helpful for detecting the features of an ovotestis in 46,XX/46,XY DSD. The direct examination of small gonads and sex ducts is the last step of the diagnostic process.
Concluding Remarks
Imaging, Endoscopy and Diagnostic Surgery Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 76–86 (DOI: 10.1159/000363632)
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Imaging of a DSD is special in several regards. The need for imaging must be critically appraised in view of the individual attitude of the DSD individual and family. Some may consider DSD to be more a difference in sexual development than a medical condition. Reporting and communicating the findings may be challenging because the names of organs may be discordant with the selected gender. A respectful communication should include a terminology that is acceptable to the patient. For example, in a young woman it may be more appropriate to talk about gonads than testes. It is of utmost importance that the examiner is sensitive in this regard. This is particularly true for the ultrasound examinations with their typically long duration and intimate contact. The results of imaging should be explained to all members of the DSD team. As long as the diagnosis is unclear, the team discussion should precede the communication of imaging results to the patient to avoid bias and confusion. The role of ultrasound and MRI is likely to increase in the future because most differences of sex development will be managed expectantly. The most relevant clinical problem is the control of the germ cell tumor risk. To that purpose, ultrasound examinations should be standardized. Vaginal ultrasound and MRI based on fast sequence acquisition may add useful information in the future. The detailed description of the deep phenotype remains a challenge, but it is also an essential part of a comprehensive diagnostic process. A precise diagnosis remains a fundamental requirement to improve the care and outcome in DSD.
References 5 Hughes IA, Houk C, Ahmed F, et al: Consensus statement on management of intersex disorders. Arch Dis Child 2006;91:554–563. 6 Nakhal RS, Hall-Craggs M, Freeman A, Kirkham A, Conway GS, Arora R, Woodhouse CRJ, Wood DN, Creighton SM: Evaluation of retained testes in adolescent girls and women with complete androgen insensitivity syndrome. Radiology 2013;268:153–160. 7 Schuster W, Färber D: Kinderradiologie: Bildgebende Diagnostik, ed 2. Berlin, Springer, 1996, pp 674–707. 8 Lapointe SP, Wei DC, Hricak H, Varghese SL, Kogan BA, Baskin LS: Magnetic resonance imaging in the evaluation of congenital anomalies of the external genitalia. Urology 2001;58:452–456.
Lutz Wünsch, MD, Professor of Paediatric Surgery Klinik für Kinderchirurgie, Campus Lübeck, Universitätsklinikum Schleswig-Holstein Ratzeburger Allee 160 DE–23538 Lübeck (Germany) E-Mail [email protected]
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1 Chavhan GB, Parra DA, Oudjhane K, Miller SF, Babyn PS, Pippi Salle JL: Imaging of ambiguous genitalia: classification and diagnostic approach. Radiographics 2008;28:1891–1904. 2 Carty H, Brunelle F, Stringer DA, Kao SCS (eds): Imaging Children, ed. 2. London, Churchill Livingstone, 2005, pp 943–953. 3 Ahmed SF, Achermann JC, Arlt W, et al: UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development. Clin Endocrinology 2011;75:12–26. 4 Wünsch L: Checklist for the structural description of the deep phenotype in disorders of sexual development. Int J Endocrinol 2012;2012:816365.
