Sex Chromosome Diseases
• They are diseases related to number and shape anomalies of sex chromosomes. Since sex chromosomes do not affect embryological development as much as autosomal chromosomes, they generally do not cause severe physical disorders but lead to gonadal dysgenesis.
Two intact X chromosomes are required for a functional ovary.
Turner Syndrome (Monosomy X) (45, X0)
Its incidence is 1:2.500 in all live births.
• Classical karyotype is 45, XO and Barr body is absent.
• Gonads are bilateral streak gonads; Due to the absence of the second intact X chromosome in Turner syndrome, gonadogenesis is adversely affected and there is an accelerated atresia with rapid loss of oocytes. Because cases have gonadal dysgenesis.
• Internal genitals are female. Since there is no gonadal antimullerian hormone (AMH) and testosterone secretion, the internal genitalia differentiate in the female direction.
• External genitals are female. Since there is no gonadal testosterone secretion, the urogenital sinus and genital tubercle differentiate in the female direction.
• Secondary sex characters are infantile. Since the gonads are dysfunctional, estrogen is not released and secondary sexual characteristics do not develop. There is no breast development, but there may be mild pubic and axillary hair growth due to adrenal hormones.
• Primary is amenorrhoeic (hypergonadotropic) but uterine bleeding occurs when exogenous hormone is given.
• Intelligence development is normal. However, some cognitive functions and object perception may be retarded.
• Stigmas of Turner syndrome: Short stature, broad chest, flail neck, low hairline, short 4-5. metacarpals, hyperconvex nails, ptosis, droopy ears, micrognathia, multiple pigmented nevi, cubitus valgus , arched palate, lymphedema, cystic hygroma, intrauterine growth retardation
• The average maximum height to be reached in girls with Turner's who are not given growth hormone treatment is 143-147 cm. The main reason for the short neck encountered in Turner syndrome is the absence of the SHOX gene. This gene is located on the short arm of the X chromosome.
Diseases accompanying Turner syndrome:
► Cardiac anomalies (most common bicuspid aorta)
► Large vessel diseases ( most common aortic coarctation)
► Renal anomalies (most common horseshoe kidney)
► Essential hypertension
► Autoimmune diseases
- 0 Thyroid diseases (most common autoimmune thyroiditis)
- 0 diabetes mellitus
Pure Gonadal Dysgenesis
• 46,XX or 46,XY patients are phenotypically female.
• Patients typically present with sexual infantilism, streak gonads, and primary amenorrhea (hypergonadotropic). Unlike Turner syndrome, their height is normal and there are no accompanying stigmas.
46,XX Pure Gonadal Dysgenesis
► Karyotype is 46,XX.
► Gonads are bilaterally line {streak} gonads; It is caused by a defect of the second X chromosome (often a deletion of the long arm).
► Internal genitals are female; Since there is no gonadal antimullerian hormone (AMH) and testosterone secretion, the internal genitalia differentiate in the female direction.
► The external genitalia is female; Since there is no gonadal testosterone secretion, the urogenital sinus and genital tubercle differentiate in the female direction.
► Secondary sex characters are infantile; Since the gonads are dysfunctional, there is no estrogen release and no secondary sex characteristics {no breast development}.
► Primary amenorrheic (hypergonadotropic}; however, uterine bleeding occurs when exogenous hormone is given.
► Their size is normal.
Perrault Syndrome; neurosensory deafness + ptosis + 46, XX pure gonadal dysgenesis
46, XY Pure Gonadal Dysgenesis (Swyer Syndrome)
► Karyotype is 46, XY.
► It can be sporadic or X-linked recessive.
► Gonads are bilaterally line {streak} gonads; It is most commonly seen due to a mutation in the SRY gene (Ypll) on the short arm of the Y chromosome.
► Internal genitals are female; Since there is no gonadal AMH and testosterone secretion, the internal genitalia differentiate in the female direction.
► The external genitalia is female; Since there is no gonadal testosterone secretion, the urogenital sinus and genital tubercle differentiate in the female direction.
► Secondary sex characters are infantile; gonads are dysfunctional (no breast development).
► Primary amenorrheic (hypergonadotropic) but uterine bleeding occurs when exogenous hormone is given
► Their size is normal.
► Gonadectomy should be performed as soon as the diagnosis is made; The risk of germ cell tumors increases due to the presence of the Y chromosome.
Tumors arising from dysgenetic gonad background
- The most common gonadal tumor➔ Gonadoblastoma (benign)
- The most common malignant gonadal tumor➔ is dysgerminoma
Klinefelter Syndrome (47, XXY / 48, XXXY)
• It is the most common sex chromosome disease and its incidence is 1: 2,000 in all live births. It is a type of primary testicular failure. Although the internal and external genitalia show male type, Barr body is positive.
• Klinefelter findings: Female type body structure, domed palate, gynecomastia at puberty (25%), female type hair growth, extremely small testicles, infertility (main finding in diagnosis), mental retardation (25%)
Normal Chromosome Sexual Disorders (Hermaphroditism)
• The presence of bisexual development in the external genitalia. Initial evaluation of the newborn is very important in detecting suspicious genitalia.
Congenital adrenal hyperplasia (CAH, adrenogenital syndrome) should be the first disorder that should be considered when gender discrimination in newborns cannot be made.
True Hermaphroditism
• These rare cases have gonads of both sexes (over-testis or ovotestis). 70% of the cases are 46 XX.
• Internal genitals are shaped according to the gonad it is adjacent to (ipsilateral).
• The appearance of the external genitalia is usually ambigious, but closer to the male.
• All patients have a uterus. There is often breast development. Menstruation occurs in 2/3 of patients; however, no ancestry has been reported in XY individuals. Although some patients ovulate, spermatogenesis is very rare.
False Hermaphroditism
• The majority of hermaphrodites are in this group. External genitalia are the opposite of what chromosomal sex indicates. There are 2 types, male and female. The nomenclature is determined by the chromosomal structure.
Female False Hermaphroditism
► Karyotype is 46,XX; however, the external genitalia was virilized (androgenic activity).
Causes of female pseudohermaphroditism
1. Congenital adrenal hyperplasia (adrenogenital syndrome) (most common)
2. Androgen exposure during pregnancy
3. Androgen-secreting tumors
4. Placental aromatase deficiency
Congenital Adrenal Hyperplasia (Adrenogenital syndrome)
0 It is a picture that is characterized by masculinization of external genital organs in female fetus and results from adrenal enzyme defects inherited with autosomal recessive inheritance (N-00). The most common 21 hydroxylase enzyme defect is seen.
0 These lead to impaired cortisol secretion, resulting in over-secretion of ACTH and ultimately adrenal cortex hyperplasia. Excessive production of ACTH also causes high levels of androgens from the zona reticularis.
0 Karyotype is 46,XX.
0 Gonad is ovary.
0 Internal genitalia are female; Since there is no gonadal antimullerian hormone (AMH) and testosterone secretion, the internal genitalia differentiate in the female direction.
0 External genitalia virilized; It develops due to excess adrenal androgens. Various degrees of labioscrotal fusion and clitoromegaly occur in relation to the time, amount, and duration of increased androgens exposure in intrauterine life.
0 Heterosexual puberty is the most common cause of precocious; It develops in untreated girls with classic CAD. Hirsutism and virilization begin at an early age. Pubic and axillary hair growth develops at an early stage, while breast development and menarche do not occur among other findings of puberty.
0 Patients are hypogonadotropic, primary amenorrheic, because sex steroids with increased adrenal production suppress pituitary gonadotropins.
0 Uterine bleeding occurs when exogenous hormone is given.
0 They are short in stature. If left untreated, adrenarche and rapid growth occur at 2-4 years of age. However, at the age of 10, the epiphysis closes and their stature remains short.
Congenital adrenal hyperplasia (CAH); Normal pregnancy and childbearing are the only inherited sexual disorders that are possible with appropriate treatment.
► There are three subtypes:
21 Hydroxylase deficiency: 90% of CADs. The conversion of 17a-OHP to 11-deoxycortisol and progesterone to deoxycorticosterone is impaired. While cortisol and deoxycortisol decrease in serum, 17a-OHP, progesterone, androstenedione and testosterone levels increase. The diagnosis is made by the elevation of 17a-OHP in the serum and the increased excretion of pregnanetriol in the urine.
11 Beta -Hydroxylase deficiency: It is the second most common enzyme defect in CAD. 11-deoxycortisol cannot be converted to cortisol, the diagnosis is made by the presence of increased 11-deoxycorticosterone and 11-deoxycortisol in the serum.
0 313-hydroxysteroid dehydrogenase deficiency: No steroid can be synthesized (mineralocorticoid, glucocorticoid, sex steroids) in this enzyme defect, which is the third most common enzyme defect. Therefore, it is mortal.
► Diagnosis: 17a-hydroxy progesterone level in the blood; Since ACTH has a diurnal rhythm in adults, it should be measured in the morning and in the follicular phase. If the 17a-hydroxy progesterone level is > 10,000 ng/dl, it makes the diagnosis of CAD.
Maternal androgen exposure during pregnancy
Androgens and Progesterones That Can Cause ambiguous genitalia
The effects are certain
Testosterone enanthate
Testosterone propionate
• Methyl androstenediol
• 6a-methyltestosterone
• Ethisterone
· Norethindron
· Danazol
no influence
• Progesterone
• 17a-OH-progesterone
Medroxyprogesterone acetate
Norethinodrel
Androgen-secreting tumors
Tumors that can lead to virilization in pregnancy
1. Pregnancy luteoma (most common)
2. Krukenberg tumors
3. Mucinous cystadenomas
4. Brenner tumors
5. Serous cystadenomas
6. Endodermal sinus tumor
7. Dermoid cyst
Male False Hermaphroditism
► Karyotype is 46,XY. In cases, external genitalia are insufficiently virilized.
Etiology of Male False Hermaphroditism
1. Male pseudohermaphroditism due to CNS defect
a. Abnormal pituitary gonadotropin release
b. Absence of gonadotropin release
2. Male pseudohermaphroditism due to primary gonadal defect
a. Defect in testosterone biosynthesis
1- Congenital lipoid adrenal hyperplasia (StAR defect)
2- 3a-Hydroxysteroid dehydrogenase deficiency
3- 17 a- Hydroxylase (P450c17) deficiency
4- 17a- Hydroxysteroid dehydrogenase deficiency
b. familial gonadal destruction
c. Leydig cell agenesis
D. Bilateral testicular dysgenesis
3. Male pseudohermaphroditism due to peripheral end organ defect
a. Androgen insensitivity syndrome (testicular feminization)
b. 5 alpha reductase deficiency
4. Anti-Müllerian hormone deficiency
Complete Androgen Insensitivity (Testicular Feminization)
0 Incidence is 1:2.000. Maternal X-linked recessive inheritance. There is a defect in the gene encoding the androgen receptor on the long arm of the X chromosome.
0 Karyotype is 46,XY.
0 Gonad is testis; Due to the defect of androgen receptors on the gubernaculum, the testis is in the inguinal canal or in the abdomen in 50% of cases ,
0 Internal genitalia not developed (NULL); There is no Wolff channel development due to androgen receptor defect. In addition, there is no Müllerian duct development due to the release of AMH .
0 External genitalia are female; Since it is an androgen receptor defect, the urogenital sinus and genital tubercle differentiate in the female direction. However, since only the lower 1:3 part of the vagina develops from the urogenital sinus, the blind vagina available.
0 Secondary sex character development is asynchronous; There is breast development by peripheral aromatization of androgens . There is no pubic and axillary hair due to androgen receptor defect.
0 They are eunicoid (long arms, big hands and feet) and they are tall.
0 Primary amenorrheic (normogonadotropic); Because the pituitary androgen receptors are defective, androgens cannot create a negative feedback on LH and LH rises. Testosterone level is also at normal male level.
0 Uterine bleeding does not occur with the use of exogenous hormones .
Gonadectomy should be performed when pubertal development is complete.
Reifenstein syndrome, Luns syndrome; Partial (incomplete) androgen insensitivity is seen in 10% of the complete form.
5a-Reductase Enzyme Defect
0 It is an autosomal recessive enzyme defect.
0 Karyotype is 46,XY
0 Gonad is testis.
0 Internal genitalia are male; Since gonadal AMH and testosterone are released, the internal genitalia differentiate in the male direction.
0 External genitalia are female; Depending on the degree of enzyme defect, an external genital development can be seen between the full female external genitalia and hypospadias.
0 Secondary sex character development is virilized.
- There is no breast development.
- Pubic and axillary hairs are present.
0 Primary amenorrhoeic (hypogonadotropic); LH is suppressed when testosterone, which cannot convert to DHT and whose level rises, creates a negative feedback on LH.
0 Uterine bleeding does not occur with the use of exogenous hormones. Increased T/DHT ratio is used for diagnosis.
0 If the patient wants to continue his life as a woman, gonadectomy should be done as soon as the diagnosis is made; to prevent the risk of tumor development and possible virilization.
|
Comparison
of sexual development disorders |
||||||
|
|
Turner
Syndrome |
46 XX
Pure Gonadal Dysgenesis |
Swyer
Syndrome |
Complete
Androgen Insensitivity |
5-u
reductase enzyme defect |
RKMH
Syndrome |
|
karyotype |
45, xo |
46, XX |
46, XY |
46, XY |
46, XY |
46, XX |
|
Phenotype |
Female |
Female |
Female |
Female |
Female |
Female |
|
Genetic |
|
|
Sporadic/
X-linked recessive |
bound
to X |
autosomal
recessive |
recessive
sporadic |
|
gonadotropin |
Hyper |
Hyper |
Hyper |
normal |
Hypo |
normal |
|
ductal
development |
Muller |
Muller |
Muller |
none |
Wolff |
none |
|
breast
development |
none |
none |
none |
There
is |
none |
There
is |
|
Pubic /
Axillary Hair |
none |
none |
none |
none |
there
is |
there
is |
|
stature |
short |
normal |
normal |
normal |
normal |
normal |
|
gonadectomy |
|
|
directly |
at the
end of puberty |
directly |
|
|
Hormonal
therapy in sexual development disorders |
|
|
Bleeding with hormone
therapy |
Those who do not bleed
with hormone therapy |
|
gonadal dysgenesis |
male pseudohermaphrodites |
|
Turner
syndrome |
Complete
androgen insensitivity |
|
Swyer
syndrome |
5a reductase
enzyme deficiency |
|
46.XX pure
gonadal dysgenesis |
|
|
female
pseudohermaphrodites |
|
|
CAH
(congenital adrenal hyperplasia) |
|