Editing Disorders of Sexual Differentiation (section)

=== Disorders of Gonadal Differentiation and Development ===

* '''Includes (6):'''
*# '''Klinefelter Syndrome'''
*# '''46XX Males'''
*# '''Turner Syndrome'''
*# '''46XX Pure Gonadal Dysgenesis'''
*# '''Mixed Gonadal Dysgenesis'''
*# '''46XY Partial Gonadal Dysgenesis'''

==== Klinefelter syndrome ====
* '''<span style="color:#ff0000">Karyotype: characterized by 1 Y chromosome and ≥ 2 X chromosomes</span>'''
** '''<span style="color:#ff0000">Most common karyotype will be 47,XXY'''
* '''Epidemiology'''
** Incidence: 1 in 600 live-born males
*** '''<span style="color:#ff0000">Most common major abnormality of sexual differentiation'''
* '''<span style="color:#ff0000">Clinical characteristics (7):</span>'''
*# '''<span style="color:#ff0000">Primary hypogonadism</span>'''
*#* '''Leydig cells are present, but testosterone production is abnormally low, with elevated gonadotropins and estradiol'''
*#* '''The decreased androgen production may impair normal secondary sexual development'''.
*#** '''Muscle development may be poor, and the fat distribution is more female than male'''
*#* '''Facial hair is sparse'''
*#'''<span style="color:#ff0000">Small, firm testes</span>'''
*#* Seminiferous tubules undergo replacement with hyaline after pubertal development
*#* '''Predisposed to developing extra-gonadal (e.g. mediastinal) germ cell tumours as well as non-germ cell tumours (Leydig and Sertoli cell tumors [not gonadoblastoma])'''
*#** Routine surveillance scrotal ultrasonography has been advocated for post-pubertal patients
*# '''<span style="color:#ff0000">Gynecomastia</span>'''
*#* Common development during puberty
*#* Result of an increased ratio of estradiol to testosterone
*#* Can be quite marked
*#* '''8x the risk for development of breast carcinoma, requiring lifelong surveillance after puberty'''
*# '''<span style="color:#ff0000">Infertility</span>'''
*#* '''<span style="color:#ff0000">Most commonly identified genetic cause of male infertility</span>'''
*#*'''<span style="color:#ff0000">Vast majority are azoospermic</span>'''
*#** '''Presence of sperm suggests 46,XY/47,XXY mosaicism'''
*#* '''<span style="color:#ff0000">Fertility is possible with the use of testicular sperm extraction (TESE)</span>'''
*#** Some advocate combining intracytoplasmic sperm injection (ICSI) with pre-implantation diagnosis, given the lower (54%) rate of normal embryos from Klinefelter syndrome patients
*# '''Autoimmune disorders'''
*# '''Above average height''', mainly because of the disproportionate length of their legs
*# '''Neurophysiologic and cognitive deficits'''
*#* Decreased verbal skills, frontal executive function and cognitive skills
* '''Management'''
** '''Exogenous testosterone to treat signs and symptoms associated with low testosterone'''
** Reduction mammoplasty, if necessary
** '''Surveillance for testicular tumor and breast carcinoma'''

==== 46,XX Males ====
* '''Karyotype: 46XX'''
* '''Characterized by testicular development in subjects who have two X chromosomes and lack a normal Y chromosome'''
* '''Two categories of patients with XX maleness have been identified:'''
** '''SRY positive (90% of cases)'''
*** '''The most common mechanism to explain sex reversal is translocation of Y-chromosomal material, including SRY, to the X chromosome.'''
*** '''Rarely have genital abnormalities, but they have phenotypic features of Klinefelter syndrome, including hypogonadism, gynecomastia, azoospermia'''. These patients differ from those with Klinefelter syndrome in that they are shorter and have normal skeletal proportions
** '''SRY negative'''
*** More commonly have genital ambiguity
* '''Clinical characteristics:'''
** '''Most of these subjects have normal male external genitalia''', but 10% have hypospadias
** '''All are infertile'''
* Management
** Similar to Klinefelter syndrome
** Androgen replacement benefits selected patients, and reduction mammoplasty may be beneficial.
** Likely that these patients will also be at increased risk for breast carcinoma and testis tumor.
** '''Unable to have biological children because of their lack of germ cell elements'''
*** Those classic patients with infertility would not benefit from testicular biopsy for potential intracytoplasmic sperm injection

==== Turner syndrome ====
* '''Karyotype: 45X'''
** '''Presence of only one normally functioning X chromosome; the other sex chromosome may be absent or abnormal, or mosaicism may be present'''
* '''Clinical characteristics:'''
** '''Female phenotype'''
** '''Short stature'''
** '''Lymphedema'''
*** Majority of the associated congenital anomalies can be explained by the presence of lymphedema at critical points in development, leading to an imbalance in growth forces
** '''Broad chest, webbed neck''', widespread nipples, cubitus valgus (increased carrying angle at the elbows), peripheral edema at birth, short fourth metacarpal, hypoplastic nails, multiple pigmented nevi
** '''Primary amenorrhea'''
*** '''Common cause of primary amenorrhea, and the diagnosis is frequently made because pubertal development never occurs'''
** '''Lack of secondary sexual characteristics'''
*** Pubic and axillary hair fails to develop in normal abundance, and the well-differentiated external genitalia, vagina, müllerian derivatives, and breasts remain small
** '''Gonadal dysgenesis'''
*** '''Ovaries become streaks and are located in the broad ligament'''
**** Histologically, the hypoplastic streak possesses interlacing waves of dense fibrous stroma that is devoid of oocytes but is otherwise indistinguishable from normal ovarian stroma.
*** '''Both estrogen and androgen are decreased, and levels of FSH and LH are increased'''
** '''Coarctation of the aorta, bicuspid aortic valve, and renal anomalies'''
*** 33-60% have structural or positional abnormalities of the kidney such as '''horseshoe kidney,''' duplication or renal agenesis, and malrotation
** Neurophysiologic and cognitive deficits
*** Differences in parietal and temporal lobe anatomy and posterior fossa morphology
* Diagnosis and Evaluation
** May be diagnosed prenatally on the basis of a variety of ultrasound findings (increased nuchal translucency, lymphedema, cystic hygroma, coarctation of the aorta, renal anomalies) or by abnormal results of fetal karyotyping.
* '''Management'''
** '''Must identify possible Y-chromosomal material or 45X/46XY mosaicism'''
*** Occult Y-chromosomal material in the neonate is evaluated with fluorescence in situ hybridization (FISH) or PCR
*** '''Risk of gonadoblastoma (in situ germ cell cancer of low malignant potential) with occult Y-chromosomal material: 12%'''
**** '''Gonadoblastoma is associated with dysgerminoma or other germ cell neoplasms'''
*** '''Because the age of occurrence of gonadoblastoma is variable and has been reported as early as age 10 months, timely prophylactic excision of the streak gonads in the Y mosaic Turner syndrome patient is advised'''
*** '''Streak gonads in confirmed 45,XO patients (without any Y-chromosome material) do not need to be removed'''
** Ultrasound screening for renal and cardiac abnormalities
** Human growth hormone has successfully been used in children to achieve increased adult height.
** At an appropriate age, typically 12-15 years, exogenous hormonal therapy to induce puberty and then to maintain a normal female endocrine status is begun.
*** '''A spectrum of potential gonadal function has been noted in large series of patients with Turner syndrome. In 2-5% of Turner patients, spontaneous menses will occur with a potential to achieve pregnancy independently, although spontaneous fertility is rare.'''
** Because of a high likelihood of premature ovarian failure, early oocyte preservation may be useful for long-term fertility preservation.
** Turner syndrome patients are at increased risk of bladder and urethral cancer

==== 46,XX “Pure” Gonadal Dysgenesis ====
* '''Karyotype: 46XX'''
* '''Condition entails gonadal dysgenesis only; these patients exhibit none of the somatic stigmata associated with Turner syndrome'''
* '''Clinical characteristics:'''
** '''Bilateral streak gonads'''
** '''Sexual infantilism'''
** '''Normal female external genitalia'''
** '''Normal müllerian ducts with absence of wolffian duct structures'''
** '''Normal height'''
** '''The streak gonads result in elevated serum gonadotropins'''
* '''Management'''
** Proper cyclic hormone replacement with estrogen and progesterone.
** In contrast to Turner syndrome, growth is not abnormal with this condition, and therefore growth hormone should not be required.
** '''Because, by definition, these patients have no Y-chromosomal material, gonadectomy is not required.'''

==== Mixed Gonadal Dysgenesis (MGD) ====
* '''Karyotype: most 45,XO/46,XY'''
* '''Clinical characteristics (4):'''
*# '''Unilateral dysgenetic testis, which is often intra-abdominal'''
*# '''Contralateral streak gonad'''
*# '''Persistent contralateral müllerian structures'''
*# '''Varying degrees of inadequate masculinization'''
* The phenotypic spectrum of patients with XO/XY mosaicism ranges from phenotypic females with Turner syndrome, to those with ambiguous genitalia, to those with normal male genitalia.
** '''MGD is the 2nd most common cause of ambiguous genitalia (after CAH) in the neonatal period and must be in the differential diagnosis.'''
** '''The majority of these patients have varying degrees of phallic development, a urogenital sinus with labioscrotal fusion, and an undescended testis.'''
* '''The dysgenetic or streak gonad is associated with ipsilateral müllerian derivatives (uterus, fallopian tube)'''
** '''In virtually all patients, a uterus, vagina, and fallopian tube are present.'''
* '''The dysgenetic testis'''
** '''Is capable of responding to gonadotropins and secreting testosterone in normal quantities at puberty'''
** '''Lacks germinal elements, so infertility is the rule'''
* '''Increased risk of developing'''
** '''A gonadal tumor (gonadoblastoma, dysgerminoma)'''
*** '''Gonadoblastoma is the most common'''
** '''Wilms tumor'''
* '''Management'''
** '''Gender assignment'''
** '''Appropriate gonadectomy'''
** '''Proper screening for Wilms tumor'''

==== Partial Gonadal Dysgenesis ====
* '''Karyotype: typically 45,X/46,XY or 46,XY'''
* '''Characterized by two dysgenetic testes'''
** Closely related to mixed gonadal dysgenesis (one dysgenetic testis and a streak gonad)
* '''Clinical characteristics:'''
** '''Spectrum of external genital abnormalities'''
*** '''Depends on the capability of the dysgenetic gonads to produce testosterone'''
** '''Persistent müllerian structures'''
*** '''Typically present, but to varying degrees depending on MIS secretion by the dysgenetic gonads'''
* '''Increased risk for gonadal (gonadoblastoma, dysgerminoma) malignancy'''
* Management
** Similar to mixed gonadal dysgenesis

==== 46,XY Complete (“Pure”) Gonadal Dysgenesis (Swyer Syndrome) ====
* '''Karyotype: may be due to an abnormality of the SRY gene'''
** '''Mutations in the SRY gene are the cause in 10-15% of cases'''
* '''Characterized by:'''
** '''[Female phenotype] normal female genitalia, well-developed müllerian structures'''
** '''Bilateral streak gonads'''
** '''Non-mosaic karyotype'''
* '''Because there is complete absence of testicular determination in this condition, ambiguity of genitalia is not an issue, but sexual infantilism is the primary clinical problem'''
* '''Majority present in their teens with delayed puberty and amenorrhea'''
* '''Increased risk for germ cell tumors'''
** '''Gonadoblastoma is most common, and it is frequently bilateral'''
* Management:
** Removal of both streak gonads and proper cyclic hormone replacement with estrogen and progesterone.