Understanding the Various Dimensions of a XX Male

Introduction

XX Male syndrome, also known as de la Chapelle syndrome, is an autosomal dominant sexual development disorder characterized by the growth of male genitalia in an individual who is genetically female. Sometimes the external and internal sexual characteristics are very ambiguous for the individual to be categorized into either male or female and are often termed as hermaphrodites.

What Are the Causes of XX Male Syndrome?

XX male syndrome is caused due to a translocation mutation in the Y chromosome. The sex-determining proteins or testes' determining factors are encoded by the SRY gene present on the Y chromosome. The mutation results in the displacement of the gene into another chromosome and after fertilization of a 44, X ovum with 44, X sperm which was supposed to be a female offspring turns into a male due to activation of the SRY gene proteins.

What Are the Types of XX Male Syndrome?

Since the condition is determined primarily by the SRY gene, the syndrome is categorized on the basis of that gene.

SRY-positive: SRY gene is translocated from the Y chromosome to the X chromosome or any of the autosomes.

SRY-negative: There is no SRY gene. The syndrome is caused by the copy-number variation of certain genes encoding the sex-determining factors.

Who Are Susceptible to XX Male Syndrome?

XX male syndrome is a very rare genetic disorder occurring in about 1 in 20,000 to 30,000 individuals with a male phenotype. An estimated 3,000 to 30,000 individuals in the U.S. may be carrying this genetic abnormality. XX male syndrome has two variants based on SRY gene presence; the SRY variant accounts for nearly 80 to 90 % of the cases reported and SRY absent cases account for the remaining 10 to 20 %.

What Is the Pathophysiology of XX Male Syndrome?

Females have a genetic formula of 44, XX, and males have 44, XY. The sex-determining genes of the males are responsible for the formation of external and internal male genitalia, also known as the testis determining factor. After gametogenesis, the ovum contains the normal alleles which are 22 autosomal alleles and an X chromosome; and the sperm cell contains 22 autosomal alleles along with a Y chromosome.

During anaphase in meiosis I of spermatogenesis, a recombination process occurs during which a translocation mutation to the SRY gene results in the gene being misplaced from the Y chromosome into either the X chromosome or any other autosome.

During fertilization, if the Y chromosome minus the SRY gene pairs with a normal maternal X-chromosome, the resultant offspring will be an XY female (Swyer syndrome).

If the X chromosome with the SRY gene pairs with the normal maternal X chromosome or the fertilization results in the pairing of the SRY gene carrying autosome with its maternal allele, the condition will result in an SRY-positive XX male.

In about 20 % of the cases, there is no SRY gene translocation when a normal maternal and paternal X chromosome combine to form the zygote.

There are certain genes that are responsible for the formation of the female or male phenotype:

• SOX9 Gene: It plays an important role in testis differentiation.

• DAX1 Gene: It suppresses masculinization.

• SF1 Gene: The steroid hormone production and the production of müllerian-inhibiting substance (MIS)

• WNT4 Gene: It plays an important role in the formation of the female reproductive system.

Some mutations can lead to the activation of the SOX9 gene or the inactivation of DAX1, SF1, and/or WNT4 genes. The presence of such mutations in one or more of the genes can produce male phenotypic characteristics in a genetically female individual. This condition is referred to as an SRY-negative XX male.

In a normal XX female, one copy of the X chromosome is inactivated or silenced. In an SRY-positive XX male, one of the X chromosomes is hypothesized to be silenced similarly. The inactivation of the SRY-positive X chromosome is present in about 10 % of the cases resulting in incomplete masculinization. The majority, 90 % of the cases, have an activated SRY-positive X-chromosome that results in complete masculinization.

How to Diagnose XX Male Syndrome?

A very small number of actual cases are diagnosed with the condition. The diagnosis is based on clinical features and diagnostic screening. Patients with external and internal male genitalia are often diagnosed during fertility and endocrine testing.

The hormonal assay shows hypogonadotropic hypogonadism and cytogenetic or molecular testing (SNP array) can confirm the presence of an XX genome in the male phenotypic individual. Fluorescence hybridization (FISH) or polymerase chain reaction (PCR) techniques may detect the presence of the SRY gene either on the X-chromosome or on the autosomes.

SNP array can diagnose the SRY-negative XX males while FISH and PCR techniques can just identify the SRY-positive males. Both FISH and PCR might show results similar to that of a genetically normal female.

Non-invasive prenatal testing (NIPT) has proven to be a great tool to diagnose any genetic disorder in the fetus. A sample of the mother’s peripheral blood is taken from which free-cell fetal DNA is isolated and analyzed for any major genetic abnormality.

Invasive methods such as chorionic villus (taking a sample from the placenta) and amniocentesis (taking a sample from the amniotic fluid) during the gestational period and analyzing the genetic material can detect the presence of any genetic disorder.

A peripheral blood sample or inner cheek swab of the patient is sufficient to karyotype an individual which shows the absolute nature or presence of any abnormality.

What Are the Signs and Symptoms of XX Male Syndrome?

The signs and symptoms of XX Male syndrome vary according to the degree of masculinization which in turn is dependent on the inactivation of the relevant X chromosome and the degree of mutation in the genes involved in the SRY-negative variant.

Phenotypically the XX males can be categorized into one of the three variants:

1. Having normal internal and external genitalia.

2. Having external genital ambiguities.

3. True hermaphrodites (with both internal and external genital ambiguities).

The symptoms exhibited by an XX male are:

• Genital ambiguity.

• Micropenis.

• Clitoromegaly (enlarged clitoris)

• Hypoplastic testes (underdeveloped testes).

• Hypospadias.

• Cryptorchidism (undescended testes).

• Gynecomastia (breast in males).

• Male hypogonadism.

• Polycystic ovaries.

• Infertility.

• Azoospermia.

• Endocrinopathies.

• Decreased libido.

• Short stature.

• Insufficient testosterone or sperm.

• Müllerian hypoplasia (underdeveloped internal female genitalia, when present).

• Renal agenesis (absence of one or both kidneys).

• Cervicothoracic somite abnormalities (spine abnormalities).

• Hypergonadotropic hypogonadism.

• Bilateral hydrocele.

• Clinodactyly of fifth fingers (crooked pinky finger).

• Bilateral/partial deafness.

• Pseudotruncus arteriosus (heart disorder).

• Microcephaly.

• Enophthalmos (an eye disorder).

• Obesity.

• Psychasthenia (a psychological disorder)

• Low IQ (intelligence quotient).

• Decreased facial hair.

• Adrenal insufficiency.

• Elevated gonadotropin excretion in urine.

What Is the Histopathology of XX Male Syndrome?

Histopathology of the testes shows:

• Absence of spermatogonia.

• Diminished diameter of the tubules.

• Hyalinization of tubules.

• Obliteration of tubules.

• Peritubular fibrosis.

• Hyperplasia of Leydig cells.

• Polymorphism of Leydig cells.

• Immature spermatogonia cells (occasionally).

How to Treat or Manage XX Male Syndrome?

XX male syndrome is a congenital genetic condition that cannot be treated but the symptoms can be fairly managed. Early diagnosis and implementing a management protocol can greatly improve the patients’ lives.

Some treatment options include

• Hormone replacement.

• Therapy.

• Surgery.

Hormone Replacement

The patients have very low levels of testosterone in the blood due to which many of the secondary sexual characteristics and behaviors are greatly suppressed. Synthetic testosterone replacements can be prescribed for the patient that will result in increased body hair, increased libido, deepening of the voice, and muscular growth.

Therapy

To counteract the emotional and psychiatric shortcomings, specialists should be included in the management regime. Emotional, behavioral, and family therapists can be consulted to improve the patient's social well-being.

Surgical Intervention

Even after hormonal replacement, some amount of breast tissue persists. To incite confidence and mental strength in the patient’s psyche mastectomy can be done to remove the vestigial mammary tissues. Individuals with both male and female genitalia (external and or internal) can undergo radicular surgeries to remove the genitalia according to their sexual preference.

Additionally, regular interdisciplinary monitoring is required to take care of other symptoms. Cardiopulmonologists, endocrinologists, and fertility experts can be regularly consulted to avoid any complications. Patients may opt for in-vitro fertilization or intracytoplasmic sperm injection to father offspring.

What Is the Differential Diagnosis of XX Male Syndrome?

• 45, X/46, XY mixed gonadal dysgenesis.

• 47, XXY XX Klinefelter syndrome.

• 46, XX ovotesticular DSD (differences in sex development).

• Sex chromosome mosaicisms.

• 46,XX testicular or ovotesticular DSD.

• Palmoplantar keratoderma-XX sex reversal.

• SERKAL syndrome (sex reversion and underdevelopment of kidneys, adrenal glands, and lungs)

• MIDAS syndrome (a triad of microphthalmia, dermal aplasia, and sclerocornea).

What Is the Prognosis of XX Male Syndrome?

With hormonal replacement, therapy, surgery and multidisciplinary follow up the prognosis of XX male syndrome is good. The patients can live a fairly normal life but like all disorders, they require a strong social support system, in the presence of which the quality of life is greatly improved.

What Are the Complications of XX Male Syndrome?

• Erectile dysfunction.

• Osteopenia.

• Depression.

• Ovarian cancer.

• Testicular cancer.

• Breast cancer.

Conclusion:

XX male syndrome is autosomal dominant hereditary in inheritance so the fathers need to be vigilant to avoid the development of the condition. Pre-natal genetic screening, semen analysis, testicular ultrasound, and bloodwork can be great tools to determine the possibility of any genetic abnormality. With early diagnosis and interdepartmental care, there will be no difference between the lives of a normal person and an aberrant chromosomal patient.