Gender Development Disorders

Sometimes babies are born without clearly resembling either a boy or a girl, making it impossible to determine their sex at first glance. In other cases, although the baby's external genitalia appear typical, their genetic makeup (chromosome analysis) does not match their external genital appearance. These conditions are referred to as disorders of sex development (ambiguous genitalia). It is also referred to as hermaphroditism.

Hermaphroditism, named after the son of the Greek gods Hermes and Aphrodite, who was born from their forbidden relationship, refers to the combination of both male and female sex characteristics in the same body, i.e., dual sex. It is a very rare, congenital genetic disorder of sexual development.

How is gender determined?

In the first weeks of the baby's development in the womb, the gonads (ovaries or testicles) had not yet differentiated into male or female. Under the influence of chromosomes and hormones, the ovaries in females and the testes in males undergo transformation. Of the 46 chromosomes or 23 pairs of chromosomes found in humans, the 23rd pair are the sex-determining chromosomes. Girls typically have two X chromosomes, while boys have one X and one Y chromosome. The chromosome composition is written as 46XX for females and 46XY for males.

A gene on the Y chromosome (SRY gene) secretes the Testis Determination Factor (TDF) and causes the gonad to develop into a testis. The testosterone hormone secreted by the testis causes the penis, scrotum (testicles), and urethra (the external urinary tract) to develop.

If the SRY gene is absent, the ovaries differentiate into ovaries. The uterus and fallopian tubes form. The structures that would have developed into the male genital system regress and disappear. This stage is the first stage of sex determination. Later, sex is fully determined by hormonal, psychological, and social influences. If there are disruptions at these stages, sex development disorders (sex ambiguity) may occur.

 

Which Children Should Be Screened for Gender Development Anomalies?

• If there is ambiguous genitalia (genital uncertainty)
• Girls with clitoral hypertrophy
• Boys with severe hypospadias, especially if they also have undescended testicles
• Boys with micro (small) penises
• Boys with testicles that cannot be felt during a bilateral manual examination
• Girls with bilateral inguinal hernias

 

How is Gender Development Disorder Diagnosed in Infants or Children?

Infants and children with the above-mentioned findings undergo a detailed medical and family history interview conducted by physicians specializing in this field, followed by a detailed physical examination. Subsequently, certain tests and procedures are performed to establish a definitive diagnosis, including:

• Chromosome and genetic analyses
• Hormone and other blood tests
• Ultrasound/magnetic resonance imaging to evaluate internal organs
• Contrast-enhanced imaging to evaluate vaginal and urethral anatomy
• Diagnostic laparoscopy
• Combination examinations consisting of tests including gonadal biopsy.

How Are Gender Development Anomalies Treated?

The treatment of gender ambiguity varies depending on the type of gender development disorder. Corrective surgery, removal or creation of certain organs is planned according to the gender decided upon. Hormone treatments are planned. Treatment is planned for each patient according to their characteristics and in consultation with the family and the patient.

In determining the gender of these patients, a scientific council decision is usually required. The council includes a pediatric endocrinologist, pediatric surgeon, child psychiatrist, geneticist, religious advisor, family, and, if the child is older, the child themselves. Psychological and social support for the family may also often require the assistance of a family counselor and social development specialist.

What are the types of sexual development disorders?

A- Female Pseudohermaphroditism:

1. Congenital Adrenal Hyperplasia (CAH)
2. Mother's Use of Androgenic Drugs
3. Aromatase Deficiency

What is Congenital Adrenal Hyperplasia?

It accounts for 70% of gender development anomalies. It occurs in approximately 1 in 15,000 live births. 75% of cases are of the salt-losing type, while 25% are of the salt-retaining type. In the salt-losing type, aldosterone synthesis is inhibited, so in these patients, Na+ (sodium) excretion from the kidneys increases while K+ (potassium) retention increases. As a result, Na+ levels in the blood decrease and K+ levels increase. With appropriate medical and surgical treatment, normal sexual function and fertility can be achieved in CAH patients.

Newborns with congenital adrenal hyperplasia have 46 XX chromosomes. They have been exposed to increased androgens in the womb. This syndrome is characterized by a deficiency of one of the enzymes 21-hydroxylase, 11-hydroxylase, or 3-beta-hydroxysteroid dehydrogenase. Deficiency of any of these enzymes results in excessive formation of androgenic intermediates, leading to masculinization (male) development of the XX fetus. The phenotypic (external) appearance can vary from moderate clitoral enlargement to complete masculinization of the urethra with a normal-appearing male penis.

The most common type of Congenital Adrenal Hyperplasia is 21-hydroxylase enzyme deficiency. In this condition, both cortisol (stress hormone) and aldosterone (water and salt-retaining hormone) production are impaired, while there is a significant increase in androgen (male hormone) production.

It is more common in babies whose mothers used hormones during pregnancy (for IVF), took birth control pills, or consumed soy products during pregnancy. Hirsutism and a “Cushing's syndrome” appearance may be observed in the mother. If there is a discrepancy between the external genitalia observed in prenatal ultrasounds and the fetal karyotype, careful monitoring is required postpartum.

In these patients, aldosterone deficiency, hyponatremia, hyperkalemia, dehydration, shock, increased ACTH, hyperpigmentation, advanced bone age, and short adult height may occur.

The average adult height is short. The average adult height is 149.5 cm in females and 154 cm in males.

How is Congenital Adrenal Hyperplasia Diagnosed?

Early diagnosis and prompt gender determination are important in terms of sexual function and fertility. Prenatal diagnosis and treatment are important for preventing crises.

The first and most important thing in diagnosis is to consider the disease. Then, a detailed medical history is taken and a thorough physical examination is performed.

During the physical examination, the external labia majora resemble the scrotum in males, while the clitoris enlarges and takes on the appearance of a penis, leading to these children being mistakenly identified as male. Some are brought to the doctor with complaints of undescended testicles.

The following examinations are then performed:

• Chromosome and genetic analyses
• Hormone and other blood tests
• Ultrasound/Magnetic Resonance Imaging (MRI) for evaluation of internal organs
• Diagnostic laparoscopy if necessary

Can Congenital Adrenal Hyperplasia Be Detected in the Womb?

If there is a possibility that the family has a baby with congenital adrenal hyperplasia, blood samples can be taken from the baby and parents, or tissue or amniotic fluid samples can be taken from the unborn baby to determine whether the baby is male or female and whether it has congenital adrenal hyperplasia.

Can Congenital Adrenal Hyperplasia Be Treated If Detected in the Womb?

Certain hormone treatments can be administered. This facilitates postnatal follow-up and treatment.

What are the treatment methods for congenital adrenal hyperplasia?

The priority in treatment is to replace the missing hormones, i.e., drug therapy. These drugs are determined individually for each patient;

• Glucocorticoid therapy; Hydrocortisone
• Mineralocorticoid therapy (for the group with salt loss); Fludrocortisone (Astonin)
• Dehydration, hyponatremia, hyperkalemia, and hypoglycemia are detected and treated.
• Surgical treatment (should be performed in centers with experience in early single-stage surgery),

Is steroid (cortisone) treatment harmful?

In congenital adrenal hyperplasia, steroid treatment is vital for normal growth and development in children. When used at the appropriate dose, there are no side effects because the treatment only replaces the missing hormone. However, when high-dose steroid therapy is administered, growth slows down, and when administered at low doses, excessive growth and, in the early stages, the effects of increased male hormones lead to the development of sexual characteristics.

What is the required dose for treatment? Which test determines this?

The appropriate dose of steroid treatment varies from patient to patient. The dose of hydrocortisone or equivalent steroids increases as the child grows and gains weight. During puberty, when growth accelerates, the steroid dose is gradually increased by the doctor. In congenital adrenal hyperplasia, blood pressure, growth rate, bone maturation, blood and urine tests are used to adjust the corticosteroid and hydrocortisone dose.

How Often Should the Child Be Taken for a Check-Up?

Children with congenital adrenal hyperplasia should initially be seen by a doctor 3-4 times a year, the steroid dose should be increased as needed by the doctor, blood pressure should be measured at each check-up, and hand X-rays should be taken once or twice a year to determine bone age. After treatment is established, the child should be taken for check-ups 1-2 times a year, depending on their age and clinical condition.

Can the child grow normally and reach adult height?

When treated carefully, children with congenital adrenal hyperplasia have adequate growth rates and can reach normal adult height within appropriate limits. However, even with the best treatment, growth may not always be perfect, and in such cases, some may remain short in stature as adults.

How is Treatment Administered in Emergency Situations?

Hydrocortisone is a very important hormone that combats stress. Normally, cortisol, which is produced in greater quantities in individuals when they are ill, undergoing surgical stress, and in similar situations, is even more important in patients with congenital adrenal hyperplasia because the mechanism does not work and therefore it is not produced. Accordingly;

1. In a child with congenital adrenal hyperplasia who has a mild illness (such as a cold), there is no increase in the need for hydrocortisone.
2. If a child with congenital adrenal hyperplasia who is ill (e.g., respiratory tract infection, gastrointestinal infection) is unable to perform their normal daily activities, even if the child is receiving treatment for the infection, it is appropriate to double the daily hydrocortisone dose. When the child recovers after 2-3 days, the hydrocortisone dose to be used is usually the same as the dose used before the illness. If there is any doubt about this, it is advisable to consult the doctor again.
3. In cases of serious illness, especially when diarrhea or vomiting is present, the absorption of the medication through the oral route may not be adequate. In such cases, the required dose of hydrocortisone should be administered by injection without delay, or the child should be taken to the relevant hospital immediately. If the child appears very ill, especially if they look pale, are sweating profusely, and their normal communication with you is impaired, the injection should be administered urgently at home by the parents. Spending time contacting the hospital or doctor before administration can cause a delay that may lead to serious consequences. Sometimes parents delay administering the injection even though they know their child is ill, thinking it may cause an excessive reaction. Even if there is doubt, the injection should always be administered first, followed by contacting the hospital or doctor. It should be remembered that there is no harm in administering an unnecessary hydrocortisone injection.
4. If minor surgical procedures requiring general anesthesia are to be performed (e.g., tooth extraction), hospital conditions should be prepared, and a hydrocortisone injection should be administered to the child before anesthesia. If the tooth extraction is to be performed under local anesthesia, there is generally no need for special precautions; however, the dentist must be informed about the child's condition before the procedure.
5. To avoid adverse outcomes, it is advisable for children with congenital adrenal hyperplasia to wear a necklace or bracelet indicating their condition and the need for steroid treatment, in case of emergencies requiring urgent treatment, even though such situations are rare.

Can children with congenital adrenal hyperplasia receive routine vaccinations?

Yes, they can. The steroid dose used in congenital adrenal hyperplasia is not related to different treatments, including vaccinations.

When should children with congenital adrenal hyperplasia undergo surgical correction?

The treatment plan is tailored to the patient, but the general approach should be planned as follows.

First 6 months;

• Gonadectomy
• Clitoral reduction
• Vaginoplasty

6 months to 1 year;

• Orchidopexy
• Hypospadias

Pre-puberty

• Vaginal surgery
• Testicle prosthesis

2- Mixed Gonadal Dysgenesis

This is a syndrome associated with Müllerian duct remnants and dysgenetic gonads. Patients are usually 46XO or 46XY.

In mixed gonadal dysgenesis, patients have both testes and streak gonads. The testes cannot produce sperm, and since the Müllerian Inhibiting Factor is not produced by the streak gonads, the ipsilateral fallopian tube and unicornuate uterus are present. The phenotype (external appearance) includes a short hypospadias penis, gynecomastia, and virilization at puberty.

There is a high risk of malignancy (50%) in dysgenetic gonads. Gonadoblastoma is the most common tumor. In normal gonads, seminoma and dysgerminoma frequently develop.

Due to the high risk of malignancy, bilateral gonadectomy should be performed in all patients during the first decade of life.

As in congenital adrenal hyperplasia, reconstructive surgery may be performed to correct the external genitalia in these patients. A council decision is required to determine gender.

If the penis is adequate and responsive to testosterone, male-oriented correction is performed, and hypospadias surgery is performed. If the penis is small, female-oriented correction is performed, and feminizing genitoplasty is performed.

B- Male pseudohermaphroditism:

1- Testicular Feminization Syndrome

Male pseudohermaphroditic newborns have an XY karyotype. Male pseudohermaphroditism often occurs due to the following causes:

1. Inadequate testosterone production due to a deficiency of enzymes necessary for biosynthesis
2. Inability of testosterone to convert to dihydrotestosterone due to 5-alpha-reductase deficiency
3. Deficiency in androgen receptors.

The most common and well-known cause of testicular feminization syndrome is androgen receptor deficiency. It is X-linked recessive.

These patients are often raised as girls. In some female-pheno children, the diagnosis is made incidentally during routine inguinal herniorrhaphy when the testes are found. There is a high risk of malignancy in intra-abdominal gonads. Suspicion should be raised in patients with bilateral inguinal hernias and gonads palpable within the hernia sac, and the necessary tests should be performed.

Generally, patients present with amenorrhea after puberty.

The testes may also cause masculinization during puberty. Additionally, these patients have short vaginas and should be treated with vaginal dilation.

Gender is determined by a gender council decision. Surgical corrections are planned according to the determined gender and tailored to the individual.

2- True hermaphroditism

True hermaphroditism is a rare form of ambiguous genitalia. These patients have both female and male gonadal tissue (ovaries, testes, ovotestis).

Eighty percent of patients have a 46XY karyotype.

Most patients have an inappropriate phallus and are raised as girls. The testes and the testicular portion of the ovotestis in these patients should be removed. Reconstructive surgery may be performed, as in congenital adrenal hyperplasia and mixed gonadal dysgenesis. Gender is determined by a gender council decision, and surgical correction is planned on an individual basis.

3-Pure Gonadal Dysgenesis

Bilateral streak gonads are present. The chromosomes are 46 XX or 46 XY. These patients have hypoplastic Müllerian anatomical structures, but no Wolffian structures. If the genetic structure is XX, the patients have sexual infantilism and amenorrhea, and if it is XY, they have clitoral hypertrophy.

The risk of gonadal cancer in later years should not be overlooked, and treatment planning should be done accordingly.

*** The information provided here is intended to inform visitors, particularly families, about the content of the website. No information should be considered as advice by visitors and should not lead to any decisions or actions. Families concerned about this issue should consult a pediatric surgeon and a pediatric endocrinologist, discuss the matter with them, and make decisions based on their individual advice.