Sexual anomalies

The symptoms of Klinefelter's syndrome in a human male.

DSDs caused by chromosomal variation generally do not present with genital ambiguity. This includes sex chromosome DSDs such as Klinefelter syndrome, Turner syndrome and 45,X or 46,XY gonadal dysgenesis.[10]

Males with Klinefelter syndrome usually have a karyotype of 47,XXY as a result of having two or more X chromosomes.[11] Affected patients generally have normal genital development, yet are infertile and have small, poor functioning testes, breast growth and delayed puberty.[11] The incidence for 47,XXY is 1 in 500 males, but severe and rare cases of Klinefelter syndrome presents as three or more X chromosomes.[11]

Turner syndrome is classified as aneuploidy or structural rearrangement of the X chromosome. Signs and symptoms of affected females vary among them, such as low birth weight, low-set ears, short stature, short neck and delayed puberty.[12] The incidence is 1 in 2500 live-born females, while most patients do not survive for more than one year after birth.[10]

Gonadal development disorders form a wide spectrum, classified by their cytogenetic and histopathological features. However, unsolved diagnosis and malignancy still represent difficulties in the sex determination of these patients.[13] Such disorders include partial or complete gonadal dysgenesis, ovotesticular DSD, testicular DSD and sex reversal.[3]

Genital abnormality can occur in the penis, scrotum or testes in males; and vagina and labia in females.[3] Sometimes, ambiguous genitalia could occur, where the clear distinction of external genitalia is absent in both male and female. Hence, examination (typically at birth) is carried out where the sex of the patient will be determined through imaging and blood tests.[3] Abnormal genital development includes disorders of fetal origin, disorders in androgen synthesis or action, disorders in anti-Müllerian hormone synthesis or action.[3]

In addition to the aforementioned sexual anomalies, there are other unclassified sexual anomalies. In males, this includes severe early-onset intrauterine growth restriction, isolated hypospadias, congenital hypogonadotropic hypogonadism, hypogonadism and cryptorchidism. In females, this includes Malformation syndromes, Müllerian agenesis/hypoplasia, uterine anomalies, vaginal atresia and labial adhesions.[3]

• Symptoms such as infertility, early menopause, amenorrhea or sudden infant death syndrome (SIDS) could be a sign. Hence, an early check-up should be conducted.[3]

• Peripheral blood is collected for karyotyping. This helps classify the patient in one of the three main categories of DSD: chromosomal variation, gonadal development disorders and abnormal genital development.[3]

• The presence of gonads, uterus and vagina should be monitored. This can be done through abdominal ultrasounds. However, the absence of these sex organs will lead to difficulties in gender identification.[3]

1. Inspection of the genitalia with care and palpation must be conducted with the following points in mind.[3]
   • Determining the degree of virilization or masculinisation:
     • In a female fetus, the Prader scale should be used to assess the extent of the virilisation if the karyotyping results are not out yet.[3]
     • In males, the external masculinization score should be used.[3]
2. Palpation of gonads from the labioscrotal fold to the abdomen (inguinal canal).[3]
3. Hydration and blood pressure assessment should be conducted.[3]
4. Additional dysmorphic features should be ruled out because genitalia malformations would occur if the patient has multiple malformation syndromes.[3]

• 17-Hydroxyprogesterone can be used to screen for congenital adrenal hyperplasia (CAH). This is commonly found in patients with 46, XX DSD.[3][17]
• Dehydroepiandrosterone (DHEA) in addition to progesterone allows for the diagnosis of more uncommon forms of CAH and other inherited disorders.[3]
• Base testosterone, follicle stimulating hormone (FSH) and luteinising hormone (LH) levels are precursors in individuals with 46,XX DSD. These tests are conducted within the timeframe of thirty hours post-birth to anywhere between fifteen and ninety days post-birth. This data collected within time frame can be used to gauge the growth of the fetus when it reaches six months of age.[3][17]
• Basal cortisol levels and adrenocorticotropic hormone (ACTH) is essential in diagnosing panhypopituitarism and enzymatic disorders affecting adrenal steroidogenesis.[3]
• The anti-Müllerian hormone is used for evaluating the function of Sertoli cells.[3]
• A urinary steroid profile shows the ratio of precursor metabolites within measured urine concentrations and the resultant products produced indicates the enzyme is the cause of a sexual defect. This is a more specific procedure in the detection of the defect in comparison to analysing blood.[3]

Gender affirmation plays a critical role in the management of sexual anomaly cases. Ultimately, the parents and a multidisciplinary team are responsible for assigning the sex that is affirmative the gender of the concerned person. The current guidelines of gender affirmation include the psychosocial effects in adults with etiological diagnosis, the potential for fertility, surgical opportunities and hormone replacement therapy in the course of puberty.[18][5]

There are other factors considered during this process. This may include cultural and religious factors as well as the implications it has on the individual in later life. It is regulated by reference centers with groups specialised in managing cases of sexual anomalies.[5]

Hormonal treatment is an accepted and standardised approach to treat different congenital sexual anomalies. Patients that are deficient in hormones produced by the adrenal glands require immediate medical attention. They are given a hormone called hydrocortisone, a form of hormone replacement therapy, with the objective to induce puberty.[5]

Utilizing sex steroids as hormonal therapy is deemed controversial with concerns of its duration of initiation, dosage and regimen.[5] However, it is agreed amongst most clinicians that low doses of hormonal treatment should begin around the age of 11 to 12 years old and should be increased progressively.[5]

Surgical procedures are an alternative to hormonal treatment available for patients to address genital anomalies and improve the body's sexual functions. However, a common dilemma in these procedures is that they are often derived from the patient's expectation of 'normal' genitals from an aesthetic and functional standpoint. Oftentimes, this leads to extensive surgical interventions.[19]

In most cases, surgical procedures result in permanent changes to the appearance and function of the patient's body. Therefore, the decision to proceed with this arrangement must be a joint agreement between the family and the multidisciplinary team. The most ideal situation would be to include the patient as part of the decision-making process. However, cases where surgical treatments were performed at an early age are recognised as mutilation of the body. Subsequently, it has become increasingly common to defer surgical treatments until the patient is of appropriate age to be involved in the decision-making process.[5]