AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Ovotestis refers to the histology of a gonad that contains both ovarian follicles and testicular tubular elements. Such gonads are found exclusively in people with true hermaphroditism. The diagnosis of true hermaphroditism is based solely on the presence of ovarian and testicular tissue in the gonad and not on the characteristics of the internal and external genitalia, even if ambiguous. Ovotestes are usually compartmentalized, with connective tissue separating the ovarian components from the testicular components. However, on rare occasions, an intermixture of these elements may occur.

Pathophysiology

People with true hermaphroditism are individuals who have both ovarian and testicular tissue. This diagnostic nomenclature is applied regardless of the peripheral karyotype. The gonads may be ovotestis, or they may be separate, with an ovary on one side and a testis or ovotestis on the other. Additionally, testicular and ovarian tissue may develop on the same side of the pelvis as a separate ovary and testis.

Ovotestes are the most frequent gonad present in true hermaphroditism (60%), followed by the ovary and then the testis. The ovotestis tends to be anatomically located in an ovarian position, in the labioscrotal fold, in the inguinal canal, or at the internal inguinal ring. Ovaries, when found in true hermaphroditism, can occupy the normal abdominal position, although they may occasionally be found at the internal inguinal ring. Interestingly, ovaries occur more commonly on the left side than the right. The reason for this predilection is unknown. Testes are usually found in the scrotum, although they can be found at any level along the path of embryonic descent from abdomen to scrotum, frequently presenting as inguinal hernias.

Many patients with true hermaphroditism have a uterus and internal duct development usually corresponds to the adjacent gonad. Wolffian duct structures tend to be observed on the gonad side(s) containing functioning testicular tissue. Otherwise, müllerian duct structures are observed on the gonad side not containing testicular tissue.

Ovaries and ovarian portions of ovotestes appear normal and demonstrate follicular growth with estradiol production. Approximately 50% of ovotestes show evidence of ovulation. The presence of estradiol in developing ovarian follicles usually inhibits spermatogonia development in adjacent or contralateral seminiferous tubules. Degeneration and hyalinization of the seminiferous tubules with poor germ cell development is frequently observed. Leydig cell hyperplasia may also occur. Spermatogenesis in testis and ovotestis is rare.

People with true hermaphroditism have ambiguous genitalia at birth. The majority of affected individuals are reared as males due to the size of the phallus. Most have varying degrees of labioscrotal fusion and/or hypospadias. However, because of functioning normal ovarian tissue, most people with true hermaphroditism experience breast development at puberty, and approximately two-thirds of those with a 46,XX peripheral karyotype menstruate.

Frequency

International

True hermaphroditism is a rare condition and makes up less than 10% of all intersex cases. More than 400 cases have been reported worldwide.

Mortality/Morbidity

Aside from the physical and emotional consequences associated with genital ambiguity, patients with true hermaphroditism usually do not possess other developmental malformations. These individuals usually possess average intelligence and in general have a normal life expectancy.

• Neoplasia: Gonadal tumors with malignant potential occur in 2.6% of all cases of true hermaphroditism. Because the testis or testicular component of an ovotestis is likely to be dysgenetic, dysgerminomas, seminomas, gonadoblastomas, and yolk sac carcinomas have been reported. Benign tumors, including mucinous cystadenomas, benign teratomas, and Brenner tumors, have also been reported. If a testis is located in the scrotum, maintaining rigorous follow-up with sonography and/or pelvic MRI is prudent, and a biopsy after puberty is indicated to detect early premalignant or malignant transformation. One case report of a 47-year-old 46,XX/46,XY woman with a malignant phyllodes tumor in the right breast and an invasive lobular carcinoma in the left breast suggests a modified breast cancer risk similar to that observed in Klinefelter syndrome. Another case reported an invasive squamous cell carcinoma of the vagina, serving as a reminder that malignant changes can occur in residual müllerian tissue.
• Obstructed genital tract: Cryptomenorrhea, hematometra, and lower abdominal pain associated with endometriosis may occur in individuals with cervical atresia or other forms of müllerian duct anomalies.
• Hernias and cryptorchism: Because of malposition of the gonads, gonadal torsion, and associated duct structures, a variety of organs have been encountered within the inguinal canal, and inguinal hernias are a common occurrence. Complications associated with undescended or partial testicular descent also may be encountered.

Race

Geographic variation has been noted, with the highest incidence occurring in the black population of southern Africa.

Age

Despite the fact that most people with true hermaphroditism present with genital ambiguity, less than 20% are diagnosed before age 5 years. Seventy-five percent are diagnosed by age 20 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

The presence of both testicular and ovarian tissue within one individual gives rise to varying degrees of ambisexual development.

• The most common presenting symptom is abnormal appearing external genitalia.
• Although some cases of true hermaphroditism are diagnosed in the newborn period, only 20% are diagnosed prior to age 5 years.
• Most people with true hermaphroditism are given a male sex assignment at birth but develop breasts at puberty or later.
• Approximately 60% of those individuals with a 46,XX peripheral karyotype menstruate or present signs of obstructed genital outflow tract at puberty.

Physical

A thorough physical examination is mandatory.

• Newborn period: When faced with the delivery of an infant with genital ambiguity, the physician must determine if the newborn is a virilized female, an undermasculinized male, or a rare person with true hermaphroditism. Physical examination should focus on the following considerations:
• • Genetic stigmata: A general assessment of the infant's body habitus should be made, giving special attention to the presence of any genetic stigmata.
  • Skin pigmentation: Skin pigmentation pattern should be noted as areolar, and scrotal hyperpigmentation may be a manifestation of high serum adrenocorticotropic hormone (ACTH) levels associated with congenital adrenal hyperplasia (CAH). Skin mottling and heterochromia of the iris may be present in the rare person with chimeric hermaphroditism.
  • Genital examination: Determine the penile length and the location of the urethral opening, inspect the frenulum, determine the labioscrotal condition, document the number and location of perineal orifices, and identify the position of the gonads. One important clinical finding that may be present is a palpable gonad in one of the labioscrotal folds. If the newborn has true hermaphroditism, the palpated gonad is most likely an ovotestis or testis and usually is located on the right side. Discerning a difference between the ovarian (firmer) and testicular (softer) components of an ovotestis by palpation may be possible.
• Pubertal period: Most cases of true hermaphroditism are diagnosed in the pubertal period when the young male begins to experience feminization. Cyclic hematuria from an occult müllerian tract and late breast development are not uncommon. By puberty, most of the life-threatening conditions associated with genital ambiguity have been diagnosed previously, such as salt wasting adrenogenital syndrome in virilized females and pituitary insufficiency in undermasculinized males. Aside from the physical examination findings discussed in the newborn section, pay special attention to the following:
• • Sexual hair distribution: Adrenarche is a normal part of both male and female puberty. The absence of pubic and axillary hair suggests androgen insensitivity. Alternatively, a feminine sexual hair pattern in a pubescent male should trigger further investigation.
  • Uterus: In true hermaphroditism, the presence or absence of a uterus is variable. Anomalies are common when the uterus is present. Uterine hypoplasia and cervical atresia are the most frequent uterine anomalies noted.
  • Vagina: The vagina, when present, is normal in only 9% of cases of true hermaphroditism. The vagina generally shares the urogenital sinus with the urethra as the common external orifice.
  • Phallus: The phallus, if present, is almost always in chordee. Phallic length varies greatly. The urethra most commonly opens as a urogenital sinus. Hypospadias, often associated with bifid scrotal folds, is the most common anomaly of the external genitalia encountered in true hermaphroditism.
  • Labia/scrotum: The presence or absence of labioscrotal fusion is variable. In one review, 7% of people with true hermaphroditism had normal labia majora, 13% had hemiscrotum, 17% had a normal scrotum, and 63% had labioscrotal folds. Gonads were found frequently on the right side of the labioscrotal folds.
  • Breast development: Thelarche occurs in over 90% of people with true hermaphroditism.

Causes

Normal sexual differentiation is based on genetic sex (XX or XY), which is established at conception. Determinants controlled by the established genetic sex promote development of the undifferentiated gonad to move toward becoming either a testis or an ovary. Once differentiated, the testis directs internal and external male genital development. Female internal and external genital development occurs in the absence of a normal embryonic testis.

Testicular differentiation requires a highly regulated expression of a series of genes. To better define the role of specific genes in testicular development, investigators have used several techniques, including gene cloning, mutation analysis, transgenic mice experiments, and gene deletion studies.

Differentiation of the indifferent gonad into a testis is dependent on a 35-kilobase (kb) gene determinant located on the distal short arm of the Y chromosome. This region is known as SRY (sex determining region of the Y chromosome) and is highly conserved in a wide range of mammals. SRY codes for a transcription factor that acts in the somatic cells of the genital ridge. The transient expression of this gene triggers a cascade of events that leads to the development of testicular Sertoli and Leydig cells. SRY expression directs testicular morphogenesis, characterized by the production of MIS (müllerian inhibiting substance), and testosterone.

Surprisingly, most people with XX true hermaphroditism lack SRY despite the presence of testicular differentiation. This suggests that this gene codes for a product that reacts with other genes on Y, X, and/or autosomes to complete testicular differentiation. Recently, an inactivating mutation in an autosomal gene, SRY-related high mobility box 9 gene (SOX9), was shown to be associated with autosomal sex reversal and camptomelic dysplasia.

The DAZ (deleted in azoospermia) gene family consists of a cluster of genes on the Y chromosome, which give rise to proteins that influence male germ cell differentiation. In humans, deletion of any 1 of 3 DAZ regions (ie, AZFa, AZFb, AZFc) disrupts spermatogenesis. Today, deletion of the AZFc region of the Y chromosome is the most frequent molecularly defined cause of spermatogenic failure.

Ovarian differentiation appears to rely on a mechanism that is triggered in the absence of the testicular determinant. In humans, a complete 46,XX chromosomal complement is necessary for normal ovarian differentiation. Autosomal genes appear to be involved in ovarian maintenance. Properties of the X-linked gene DAX1 (DSS-AHC critical region on X chromosome, gene 1) suggest that this gene is important in ovarian determination. Investigators have postulated that the DAX1 gene product may actually be antagonistic to the action of SRY.

In humans, genetic sex has traditionally been evaluated through establishing the karyotype of peripheral lymphocytes. However, the peripheral karyotypes of true hermaphroditism show marked variation. Approximately 60% of people with true hermaphroditism are 46,XX; 15% are 46,XY; and 25% show various forms of mosaicism. Less than 1% show 46,XX/46,XY chimerism or the existence of 2 or more cell lines, each of which has a different genetic origin.

True hermaphroditism, therefore, is a genetically heterogeneous condition. Phenotypic, gonadal, and molecular studies have led to several causation theories:

• Genetic chimerism: Less than 1% of people with true hermaphroditism have 46,XX/46,XY chimerism or the existence of 2 or more cell lines, each of which has a different genetic origin. Chimerism can result from several events. Dispermic chimerism (double fertilization) can arise from fertilization of the secondary oocyte and first polar body, fertilization of the ovum and the first polar body, or fertilization of the ovum and the second polar body. Chimerism also can arise as an exchange of cells between dizygous twins of different sex (ie, fusion of 2 embryos).
• Nondisjunction: Postzygotic mitotic errors arising from anaphase lag may occur in 45,X/46,XY or 45,X/46,XY/47,XYY mosaicism. Note, however, that most 45,X/46,XY individuals have mixed gonadal dysgenesis as opposed to true hermaphroditism.
• X-Y translocation: Paternal meiotic exchange between the pseudoautosomal regions of chromosomes X and Y could provide a mechanism for the translocation Y-chromosomal sequences, including SRY onto an X chromosome in some forms of 46,XX testicular differentiation.
• Mutation: A mutation of a gene on the X chromosome or alternatively on an autosome that allows testis determination without the SRY gene could explain some forms of 46,XX testicular differentiation. In addition, some 46,XX true hermaphrodites have been observed to have a translocation of SRY onto the X chromosome. However, most individuals with 46,XX true hermaphroditism are SRY negative.
• Occult mosaicism: Although most people with true hermaphroditism have a 46,XX peripheral karyotype, recent case reports have documented the detection of occult mosaicism in the gonads of some of these individuals through molecular techniques. Polymerase chain reaction (PCR) has identified SRY-positive tissue in gonads from several, but not all, people with 46,XX true hermaphroditism.
• Mutation of downstream autosomal genes involved with testicular differentiation and mutation/duplication or deletion of an X-linked locus may explain SRY-negative true hermaphroditism.

DIFFERENTIALS

Section 4 of 10  

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• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
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• References

Other Problems to be Considered

Adrenogenital syndrome
Androgen insensitivity
Enzymatic defects in testosterone synthesis
Gonadotropin deficiency
Maternal exposure to high levels of androgen
Multiple congenital anomalies
Structural testicular abnormalities

WORKUP

Section 5 of 10  

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• References

Lab Studies

• Cytogenetic investigation
• • 46,XX peripheral karyotype: Diagnostic possibilities include adrenogenital syndrome (ie, CAH), maternal androgen ingestion, excess maternal androgen production (eg, from maternal adrenocortical tumor), multiple congenital anomalies, and true hermaphroditism.
  • 46,XY peripheral karyotype: Diagnostic possibilities include enzymatic defects in testosterone synthesis, such as 5-alpha reductase deficiency, complete or partial androgen insensitivity syndrome, gonadotropin deficiency, structural testicular abnormalities such as gonadal dysgenesis, and true hermaphroditism.
  • 46,XX/46,XY peripheral karyotype: Diagnostic possibilities include true hermaphroditism in a chimeric individual.
  • 45,X/46,XY, other mosaic patterns in peripheral karyotype: Diagnostic possibilities include mixed gonadal dysgenesis or true hermaphroditism.
  • Molecular studies: Fluorescent in situ hybridization for occult Y-DNA is used clinically today to enhance cytogenetic results. Probing for evidence of the Y-centromere (Y97 probe) and SRY is currently used on an investigational basis. Both peripheral lymphocytes and gonadal tissue samples can be studied. Several cases have been published showing discordance between the peripheral karyotype and the gonadal tissue.
• Hormonal evaluation
• • Serum 17-hydroxyprogesterone: CAH must be ruled out with the use of serum 17-hydroxyprogesterone measurements. Individuals with true hermaphroditism have levels of this hormone that are within the reference range. If the patient is a newborn, supportive management must be provided for suspected salt-wasting forms of CAH and pituitary insufficiency until these potentially life-threatening conditions have been ruled out.
  • Basal and stimulated serum androgens: The presence of functional testicular tissue can be determined with the use of a human chorionic gonadotropin (HCG) stimulation test. In this test, basal levels of testosterone, dehydroepiandrosterone sulfate, androstenedione, and dihydrotestosterone (DHT) should be obtained. HCG (3000-5000 IU/m²/d IM) is administered for 5 days after the basal hormone levels. On the sixth day, the hormone level tests are repeated. A rise in serum testosterone demonstrates the presence of functioning Leydig cells. Elevated testosterone precursors may suggest a specific defect of testosterone synthesis. Failure of testosterone to reduce to DHT may suggest a 5-alpha hydroxylase deficiency.
  • Basal and stimulated estrogen levels: The presence of functional ovarian tissue can be determined with the use of gonadotropin or clomiphene citrate administration. An estradiol response to gonadotropin stimulation is a reliable test to differentiate true hermaphroditism from other disorders of sexual differentiation.
• Study of androgen target cells: Defects in peripheral sensitivity to androgens may be responsible for genital ambiguity in male individuals with partial androgen insensitivity. Androgen receptor activity can be determined in fibroblasts grown from a genital skin biopsy sample; 5-alpha reductase activity also may be determined by this method.

Imaging Studies

• Ultrasonography, genitogram, and intravenous pyelogram studies have traditionally been used prior to definitive surgery.
• Today pelvic or abdominal ultrasonography, CT scan, or MRI may aid in the identification of gonads and duct structures.
• A scrotal ultrasonography may be used to detect occult gonads.
• A genitogram is used to evaluate the structure of the urethra and to confirm the presence of a vagina.
• An intravenous pyelogram is important to rule out any associated urinary tract anomalies.

Other Tests

The diagnosis of true hermaphroditism can sometimes be made prenatally. An amniocentesis following prenatal ultrasonography showing ambiguous genitalia may reveal a 46,XX, 46,XX/46,XY or 46,XX/47,XXY karyotype, providing a hint to the diagnosis.

Procedures

• Laparoscopy or laparotomy with gonadal biopsy/gonadectomy allows for histologic confirmation of both ovarian and testicular tissue. Conservative gonadal surgery is the procedure of choice for individuals with true hermaphroditism. This approach entails partial resection of ovotestes guided by intraoperative histologic examination, preservation of gonadal tissue concordant with sex of rearing, and removal of all tissue discordant with sex of rearing.
• Cystoscopy may be used to determine the position of entry of the vagina into the urethra or urogenital sinus.
• Prophylactic gonadectomy should be considered in those who manifest signs of virilization.

Histologic Findings

Ovotestis, ovary and/or testis, and associated duct structures may be recovered on surgical exploration.

Ovotestes contain both ovarian follicles and testicular tubular elements. They usually are compartmentalized, with connective tissue separating the ovarian from the testicular components. However, on rare occasions, an intermixture of these elements may occur.

Ovaries and ovarian portions of ovotestes appear normal and demonstrate follicular growth capable of estradiol production.

In true hermaphroditism, testicular elements show degeneration and hyalinization of the seminiferous tubules with poor germ cell development. Leydig cell hyperplasia also may occur. Spermatogenesis in the testes is rare.

Internal duct development usually corresponds to the adjacent gonad so that wolffian duct structures are observed on the gonad side(s) containing functioning testicular tissue. Müllerian duct structures are observed on the gonad side not containing testicular tissue.

TREATMENT

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Medical Care

Sex hormone replacement might be required for those with pubertal delay.

Surgical Care

With the exception of 46,XX individuals with CAH or documented maternal androgen excess, most patients with genital ambiguity require surgical exploration for diagnostic confirmation and removal of contradictory gonadal tissue. This should be performed to allow for maximal gender-specific development and to increase fertility potential. True hermaphroditism only can be confirmed using gonadal biopsy results.

Indications for surgery include biopsy of the gonads for histologic confirmation, removal of intra-abdominal testis or streak gonads with Y chromosome-DNA (because of their increased malignant potential), removal of wolffian structures and testicular tissue if the patient has been given a female gender assignment, removal of müllerian structures and ovarian tissue if the patient has been given a male gender assignment, and orchiopexy to reposition a maldescended testis in a patient with male gender assignment.

Ovotestes frequently can be separated into ovarian and testicular components using frozen sections to define clear margins. Conservative gonadal surgery is the procedure of choice for individuals with true hermaphroditism. This approach entails partial resection of ovotestes guided by intraoperative histologic examination, preservation of gonadal tissue concordant with sex of rearing, and removal of all tissue discordant with sex of rearing.The ovarian segment can be preserved in people with true hermaphroditism who are given a female sex assignment. Frequently, these segments demonstrate normal ovarian function and confer potential for reproduction. All 46,XY individuals with genital ambiguity and a palpable gonad should have a gonadal biopsy to rule out ovotestis.

Clitoral recession, vaginoplasty, and labioscrotal reduction are necessary for people with true hermaphroditism who are given a female sex assignment. Ideally, this should occur at age 3-6 months. For feminizing procedures, clitoral reduction and perineoplasty should be performed as early as possible as a 1-stage procedure. Follow-up procedures, such as reconstruction of the clitoral hood, repositioning of the urethral meatus, and widening of the vagina with vaginal dilators, are common and are often performed after puberty. Masculinizing genitoplasty consists of correction of the penile curvature and repositioning of the urethral meatus, also in a 1-stage procedure. Follow-up surgery may be required if fistulas form or if grafts are used.

Consultations

Because of the complexities surrounding gender assignment/reassignment, use of an experienced team is the best approach. The decision of when and if to perform surgery is controversial. Many patients have expressed the sentiment that decisions concerning surgery on the external genitalia should not be made without the understanding and consent of the affected person. Because of the complexity and ramifications of this decision, the clinician must approach the issue in concert with the family in a compassionate and thoughtful manner.

Members should represent expertise in gynecologic and urologic surgery, reproductive endocrinology, pediatrics, and psychiatry. All should be comfortable with the gender assignment decision, which depends on the diagnostic evaluation results. Gender assignment in the newborn period should be based on the individual's potential for normal sexual function and the potential for future reproductive function. Because most cases of true hermaphroditism are diagnosed during the adolescent period, gender is usually not reassigned. Rather, surgery is performed to conform to the patient's preestablished gender. Most maintain a male sexual assignment, although male reproductive potential in these individuals is rare. Identity and self-esteem issues in this age group make psychological support of utmost importance.

FOLLOW-UP

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Complications

• Traditionally, complications from the surgical treatment of true hermaphroditism and other intersex disorders were related to stenosis after vaginal reconstruction procedures and urinary tract problems associated with correction of severe hypospadias.
• Today, patients are diagnosed and operated on earlier and tend to have fewer complications.
• Gender assignment should be made prior to age 18 months, when children develop gender identity, so as to minimize psychosocial trauma.

Prognosis

• Aside from the physical and emotional consequences associated with genital ambiguity, patients with true hermaphroditism usually do not possess other developmental malformations.
• These individuals generally are of average intelligence and have a normal life expectancy.
• Fertility potential does exist in people with true hermaphroditism who are given a female sexual assignment. Ovulation can occur, and several pregnancies have been reported in this group. One report describes a 46,XX/46,XY infertile chimeric male who fathered a child with sperm obtained from his testicular tissue through intracytoplasmic sperm injection.
• People with true hermaphroditism who are given a male sex assignment rarely reproduce. Spermatogenesis has been reported in only 12% of these cases, and tubular atrophy with hypoplastic testicular tissue is the norm. Only 3 cases of males with hermaphroditism fathering children have been reported.
• Patients with true hermaphroditism should be counseled that infertility is common despite excision of discordant tissue and genital reconstruction.
• Patients with true hermaphroditism remain sexually active with a small portion being sexually dissatisfied. Those raised as males may complain of an inability to have and/or maintain erections, while females may complain of vaginal stenosis, recurrent cystitis, and hot flushes.

Patient Education

• Once the diagnosis of genital ambiguity is made, ongoing psychological support for the patient, parents, and other family members is critical.
• Psychological counseling is perhaps even more important for patients with a diagnosis delayed until puberty or adult life.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Although gender assignment in the newborn period should be based on the individual's potential for normal sexual function and the potential for future reproductive function, most cases of true hermaphroditism are diagnosed during the adolescent period, so gender usually is not reassigned. Rather, surgery is performed to conform to the patient's preestablished gender. Identity and self esteem issues in this age group make psychological support of utmost importance.
• Genital ambiguity in the newborn period should be viewed as a medical emergency until salt wasting adrenogenital syndrome (ie, CAH) and pituitary insufficiency have been ruled out. Supportive management must be provided for suspected salt-wasting forms of CAH and pituitary insufficiency until these potentially life-threatening conditions have been ruled out.

MULTIMEDIA

Section 9 of 10  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  This histologic section of an ovotestis demonstrates both seminiferous tubules and ovarian follicles.
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Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
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• Clinical
• Differentials
• Workup
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• Miscellaneous
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• References

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Article Last Updated: May 5, 2008