MORRIS SYNDROME: SYMPTOMS, CAUSES, TREATMENTS - GEOGRAFÍA - 2024

The syndrome Morris, also called syndrome androgen insensitivity (AIS) or testicular feminization, it is a genetic condition that affects sexual development. The individuals that suffer from it genetically are male, that is, they have an X and a Y chromosome in each cell. However, the body shape does not match that of said sex.

For a male phenotype to develop, not only must certain levels of male hormones (testosterone) exist in the blood; the androgen receptors that capture them also need to work properly.

What happens in this syndrome is that there is a deficit in these receptors and therefore the body's tissues do not absorb enough testosterone to develop a male form.

Thus, these individuals are born with apparent female genitalia and are usually raised as girls. When they reach puberty, secondary female characteristics develop (enlarged hips, high voice, increased fat) and breasts. However, they realize that menstruation does not appear, since they do not have a uterus. In addition, they have a shortage of hair in the armpits and on the pubis (or is absent).

Discovery

The masculinization of the male genitalia is dependent on testosterone and dihydrotestosterone. Source: Jonathan Marcus / Gilbert SF. Developmental Biology, Sixth Edition. Sunderland, MA: Sinauer Associates, 2000. CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) via Wikimedia Commons)

Morris syndrome was discovered in 1953 by scientist and gynecologist John McLean Morris (hence its name). After observing 82 cases (two were his own patients), he described the “testicular feminization syndrome”.

Morris thought that it was because the testicles of these patients produced a hormone that had a feminizing effect, however, it is now known that it is due to the lack of action of androgens in the body.

When the necessary testosterone is not absorbed, the body tends to develop into feminine characters. No matter that testosterone levels are increased, the problem lies in the body not capturing it. That is why the term "androgen resistance" is used more today.

We can also find Morris syndrome conceptualized as male pseudohermaphroditism.

Morris syndrome prevalence

According to Borrego López, Varona Sánchez, Areces Delgado and Formoso Martín (2012); Morris syndrome is estimated to occur in one in 20,000 to 64,000 male newborns. The figure could even be higher if the cases not yet diagnosed or that do not request medical assistance are counted.

Morris syndrome is considered the third cause of amenorrhea after gonadal dysgenesis and absence of the vagina at birth.

Types

There is no single degree of androgen insensitivity, but the characteristics of the syndrome depend on the level of androgen receptor deficiency.

Thus, there may be fewer dihydrotestosterone receptors than usual and receive less testosterone than necessary, or there may be cases in which the receptor deficiency is total.

The three classic types of androgen insensitivity (AIS) are:

- Mild androgen insensitivity syndrome: male external genitalia.

- Partial androgen insensitivity syndrome: partially masculinized genitalia.

- Complete androgen insensitivity syndrome: female genitalia.

Morris syndrome falls within the latter, as there is complete androgen resistance in which patients are born with female external genitalia.

In incomplete forms, different levels of male and female traits may appear such as clitoromegaly (larger than normal clitoris), or partial closure of the external vagina.

Characteristics and symptoms

Source: wikipedia-org.

Individuals with Morris syndrome will not manifest symptoms in childhood. In fact, most receive the diagnosis when they go to the specialist with the reason that menstruation does not appear.

Women with Androgen Insensitivity Syndrome. Source: Ksaviano. CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) via Wikimedia Commons)

The characteristics that usually present are the following:

- 46 XY karyotype, which is associated with the male sex.

- The external genitalia have a feminine appearance, although with hypoplasia of the labia majora and minora. That means that the lips are not fully developed, being smaller.

- Despite having normal external genitalia, the vagina is shallow and ends in a blind cul-de-sac. That is, it is not connected to the uterus because most often it has not been formed.

- Sometimes they do not have ovaries or they are atrophied.

- They usually have undescended testicles that are in the inguinal region, in the abdomen or labia majora. Sometimes the testicles are inside an inguinal hernia that can be felt on physical exam.

These testes are normal before puberty, but after puberty the seminiferous tubules are smaller and spermatogenesis does not occur.

- At puberty, normal secondary female sexual characteristics develop, reaching the total appearance of a woman. This is due to the action of estradiol, a female sex hormone that is produced in various parts of the body.

A distinctive feature of the syndrome is that they do not have hair in the armpits or pubis, or it is very little.

- Absence of menarche (the first menstruation).

- Testosterone levels in the blood are typical for men, but since there is no proper function of androgen receptors, male hormones cannot do their job.

- Of course, this disease causes infertility.

- If it is not intervened, difficulties in sexual relations are frequent, such as problems to carry out penetration and dyspareunia (pain).

- A decrease in bone density has been found in these patients, which may be due to the influence of androgens.

- If the testicles are not removed, there is an increased risk of malignant germ cell tumors with increasing age. In one study, the risk has been estimated at 3.6% at 25 years, and 33% at 50 years (Manuel, Katayama & Jones, 1976).

Causes

Location and structure of the human androgen receptor. Above, the AR gene is on the proximal long arm of the X chromosome. In the middle, the eight exons are separated by introns. Below, illustration of the AR protein, with labeled primary functional domains. Source: Jonathan Marcus / Quigley CA, De Bellis A, Marschke KB, El-Awady MK, Wilson EM, French FS. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev. 1995. CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) via Wikimedia Commons)

Morris syndrome is an inherited condition, with a recessive pattern linked to the X chromosome. This means that the mutated gene that causes the syndrome is located on the X chromosome.

It occurs more often in men than in women, since women require mutations on both chromosomes (XX) to present the disorder. Instead, men can develop it with a mutation on their X chromosome (they only have one).

Thus, women can be carriers of the mutated gene, but not have the syndrome. In fact, it appears that approximately two-thirds of all cases of androgen resistance are inherited from mothers who possess an altered copy of the gene on one of their two X chromosomes.

The other cases are due to a new mutation that appears to occur in the maternal ovum at the time of conception or during the development of the fetus (Genetics Home Reference, 2016).

The mutations of this syndrome are located in the AR gene, which is responsible for sending instructions for the development of AR (Androgen Receptor) proteins. These are the ones that mediate the effects of androgens in the body.

The receptors take up male sex hormones such as testosterone, sending them to the various cells for normal male development to occur.

When this gene is altered, as in Morris syndrome, both quantitative (number of receptors) and qualitative (abnormal or malfunctioning receptors) deficits of androgen receptors can occur.

In this way, the cells do not respond to androgens, that is, the male hormones do not take effect. Therefore, the development of the penis and other typical characteristics of the male is impeded, and a female development is given way.

Specifically, the testosterone that exists in these individuals is aromatized (transformed by the aromatase enzyme) into estrogen, a sex hormone that is the cause of the female appearance in Morris syndrome.

Some male traits develop because they are not androgen dependent. For example, the testes are formed due to the SRY gene present on the Y chromosome.

Diagnosis

3-D model of the human androgen receptor protein. Source: Prof. JH Wu McGill University Lady Davis Institute. CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) via Wikimedia Commons)

The diagnosis of Morris syndrome is usually made after puberty, as these patients do not usually notice any symptoms before it. However, it is a difficult syndrome to diagnose, since the appearance is totally feminine and until a scan of the pelvic area or a chromosomal study is performed, the problem is not detected.

If Morris syndrome is suspected, the specialist will make a diagnosis based on:

- Complete clinical history of the patient, being important that he has not presented menstruation.

- Physical examination that may be based on the Tanner Scale, which is one that reflects the level of sexual maturation. In this syndrome, it should be normal in the breasts, but less in the genitals and hair in the armpits and pubis.

The Quigley Scale, which measures the degree of masculinity or femininity of the genitalia, can also be used. Thanks to this index it is also possible to distinguish between the different types of insensitivity to androgens.

- Gynecological ultrasound: images of the internal genitalia are obtained through sound waves. Uterus or ovaries are often not observed, but testicles may be present in a nearby area. The vagina is usually shorter than normal in length.

- Hormonal studies: through a blood test it is convenient to explore testosterone levels (in Morris syndrome they are high and similar to male levels), Follicle Stimulating Hormones (FSH), luteinizing hormones (LH) or estradiol (E2).

- Chromosome study: they can be done through a blood sample, skin biopsy or any other tissue sample. In this syndrome the result should be a 46 XY karyotype.

In history there have been conflicts when deciding when and how to reveal a diagnosis of Morris Syndrome to the affected person. In ancient times it was hidden by doctors and relatives, but obviously this has an even more negative impact on the person.

Despite the dilemma that it generates, we must try to ensure that the patient receives the information in an empathic and relaxed environment, responding to all their concerns.

Treatment

There is currently no method to correct the androgen receptor deficiency present in Morris syndrome. But there are other interventions that can be done:

Dilation therapy

Before considering surgery, an attempt is made to increase the size of the vagina using dilation methods. This is recommended to be done after puberty.

As the vagina is elastic, this therapy consists of the introduction and rotation of a phallic-shaped object several times a week for a few minutes, this being progressive.

Gonadectomy

The testes need to be removed in patients with Morris syndrome, as they tend to develop malignant tumors (carcinomas) if they are not removed. It is essential for a good prognosis that they are extracted as soon as possible.

Psychological assistance

It is essential in these patients that they receive psychological treatment, since this syndrome can cause significant dissatisfaction with the body itself. Through this type of intervention, the person will be able to accept their situation and lead a life as satisfactory as possible, avoiding social isolation.

You can even work on family ties, so that the family supports and contributes to the well-being of the patient.

Supplements

For the decrease in bone density typical of these patients, calcium and vitamin D supplements are advised. Exercise can be very beneficial as well.

In more severe cases, the use of bisphosphonates, drugs that inhibit bone resorption, may be recommended.

Vaginal construction surgery

If dilation methods have not been effective, rebuilding a functional vagina may be an alternative. The procedure is called neovaginoplasty, and the reconstruction uses skin grafts from the intestine or buccal mucosa.

After surgery, dilation methods will also be necessary.

Hormone replacement

Attempts have been made to administer estrogen to these patients to alleviate the lack of bone density, but this does not appear to have the desired effect on everyone.

On the other hand, androgens have been administered after the removal of the testicles (since there is a significant drop in their level). Androgens appear to maintain a feeling of well-being in patients.

References

1. Borrego López, JA, Varona Sánchez, JA, Areces Delgado, G., & Formoso Martín, LE (2012). Morris syndrome. Cuban Journal of Obstetrics and Gynecology, 38 (3), 415-423. Retrieved on October 14, 2016.
2. Quigley CA, De Bellis A., Marschke KB, el-Awady MK, Wilson EM, French FS (1995). Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr. Rev. 16 (3): 271–321.
3. Manuel M., Katayama PK, & Jones HW (1976). The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am. J. Obstet. Gynecol. 124 (3): 293–300.
4. Hughes IA, Deeb A. (2006). Androgen resistance. Best Pract. Res. Clin. Endocrinol. Metab. 20 (4): 577-98.
5. Gottlieb B., Beitel LK, Trifiro MA (1999). Androgen Insensitivity Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., Editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2016.
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9. Androgen insensitivity syndrome. (October 11, 2016). Obtained from Genetics Home Reference.
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