Disorders of Sexual Differentiation

Pseudohermaphroditism

Male or female karyotype but ambiguous genitalia.

Caused by excess/deficient androgen:

Female Pseudohermaphroditism

Is due to excessive and inappropriate exposure to androgenic steroids during early gestation (e.g, congenital adrenal hyperplasia or exogenous administration of androgens during pregnancy).

Male Pseudohermaphroditism

Is most commonly caused by androgen insensitivity syndrome (testicular feminization).

Androgen Insensitivity Syndrome

Formerly testicular feminization.

Is due to impaired androgen receptors.

At birth:

Puberty:

Methods for diagnosis:

Orchidectomy is recommended in patients to reduce the risk of malignancy.

5-a reductase deficiency

An autosomal recessive disorder resulting in an inability to convert testosterone to dihydrotestosterone (DHT).

At birth:

During puberty:

Internal genitalia are normal: presence of the SRY gene on the Y chromosome encodes Leydig cells which produce normal levels of testosterone that stimulate development of Wolffian structures. They also encode for Sertoli cells, which produce AMH/MIF that leads to normal regression of the Mullerian duct structures.

Lab findings:

Diagnosis is done by:

Treatment includes two phases:

Aromatase Deficiency

The inability to synthesize estrogens from androgens.

Masculinization of female (46, XX) infants produces ambiguous genitalia

True Hermaphroditism

Previously known as True Hermaphroditism.

Defined by the presence of both testicular and ovarian tissues in a single individual. This affects the development of external and internal genitalia in a variable manner.

Various genes have been implicate, including:

A 46, XX karyotype is most commonly seen. The 47, XXY karyotype can also be seen, but it is less common..

Patients are born with ambiguous genitalia. Most patients will undergo breast development during puberty. Physical exam findings include:

Diagnosis:

Definitive diagnosis can be made with gonadal biopsy.

Treatment options involves:

Sex Chromosome Disorder

Klinefelter’s syndrome

47, XXY males is a sex chromosome disorder caused by meiotic non-disjunction (most commonly in meiosis I).

The manifestations are the result of the following hormonal abnormalities:

The primary reason for hypogonadism and feminization is that testosterone does not have a normal interaction with androgen receptors, which along with increased conversion into estradiol, causes hypogonadism and feminization.

The clinical presentation is variable, but includes:

Diagnosis is confirmed with a karyotype showing 47, XXY.

Patients often have complications including:

Can be managed with the following:

Turner

45, XO females, is the most common genetic cause of primary amenorrhea.

Can be caused by:

The clinical presentation includes the following:

cystic hygroma: lymphatic systems not completely developed swollen areas, neck

Hormonal testing would reveal:

Complications associated include:

Pharmacological treatment includes:

Although rare, pregnancy is possible in some patients with Turner Syndrome. In those cases, they must become pregnant via in vitro fertilization using donor oocytes, exogenous estradiol-17beta and progesterone. It is important to remember that although these patients do not have working ovaries, in most cases they do have a normal uterus with an endometrium that responds normally estrogen; thus making pregnancy possible..

Double Y

47, XYY is found in 1:1000 males and is often undetected.

Is caused by a random event of paternal nondisjunction during anaphase II of meiosis II..

patients will be phenotypically normal, but will present with tall stature and severe acne.

Fragile X

The second most common genetic cause of intellectual disability (Down syndrome is the most common).

Is caused by expanded trinucleotide CGG repeats in the promoter segment of the FMR1 gene. The expanded promoter segment enhances methylation leading to silencing of the FMR1 gene.

Is more common in males and presents with:

Kallmann syndrome

A form of hypogonadotropic hypogonadism, which results in a failure to complete puberty.

It is associated with anosmia.

Is also known as hypogonadotropic hypogonadism with anosmia.

Is caused by failed migration of GnRH neurons from the olfactory placode to the hypothalamus, which results in improper development of the olfactory bulb (explains the anosmia).

Without GnRH neurons, the hypothalamus synthesizes and secretes decreased amounts of GnRH leading to decreased LH, FSH, and testosterone/estrogen (which accounts for hypogonadism).

Presents with the following symptoms:

Is treated with sex hormone replacement therapy in order to achieve normal adult sexual development in patients. Puberty can be induced with the administration of LH and FSH..

Backlinks