31.7Management of Patients with DSD

•The management of patients with DSD depends on the underlying cause.

•Supplemental hormone therapy may be given if gonadal function is compromised.

•In a virilized female, the surgical management is feminizing genitoplasty and this includes vaginoplasty and clitoroplasty.

•Undervirilized males typically have hypospadias and this is corrected with urethroplasty.

•Gender reassignment may be considered in patients with 46XY males and inadequate external genitalia.

•Sex assignment and therapy:

–There are several factors which must be considered during sex assignment, including:

1.The phenotype

2.The appearance of the genitals

3.The surgical options

4.The need for future hormonal replacement therapy

5.The potential for future fertility

6.The culture and preferences of the family

7. The effect of high levels of testosterone exposure on the brain development

•Sex assignment also depends on the type of DSD (46XX DSD, 46XY DSD or chromosomal DSD)

•46 xx chromosomes:

–Congenital adrenal hyperplasia:

•These patients are usually assigned a female sex.

•Their fertility is preserved.

•These patients are given hydrocortisone to replace cortisol, and, if there is associated salt wasting, fludrocortisone is given to replace aldosterone.

•Surgical treatment is required to correct the external genitalia. This should be done early and includes:

–Clitoroplasty.

–Vaginoplasty

•46 XY chromosomes:

–Testosterone biosynthesis defects

•These patients are assigned a male sex.

•Fertility is preserved.

•Some of these patients have deficiencies of glucocorticoids and/or mineralocorticoids and these are treated with glucocorticoids and/or mineralocorticoids.

•Patients with hypospadias require urethroplasty.

•Testosterone replacement may be required at puberty, particularly if testosterone levels remain low.

–5-alpha-reductase deficiency

•These patients are assigned a male sex.

•Fertility is preserved.

•Patients with hypospadias require urethroplasty.

•These patients do not typically require hormonal replacement and the rise in testosterone levels at the onset of puberty is sufficient to induce development of secondary sexual characteristics.

–Partial androgen resistance

•Most of these patients are raised as males and fertility is preserved.

•Some patients with severe partial androgen resistance may be raised as females, as adequate virilization at puberty may not be possible.

•If the patient is raised as a male, early surgical correction of hypospadias is recommended.

•Testosterone replacement may be required at puberty, particularly if testosterone levels remain low.

•If the patient is raised as a female:

–Early vaginoplasty is recommended.

–Clitoroplasty in those with severe virilization.

–These patients require gonadectomy before puberty to prevent virilization at puberty and also malignant transformation.

–Estrogen supplements are required at puberty to allow development of secondary sexual development.

–Gonadal dysgenesis

•The sex assignment in these patients depends on several factors including:

–The likelihood of fertility.

–The genital appearance.

•In a virilized female, the surgical procedure is termed feminizing genitoplasty and includes vaginoplasty and clitoroplasty. The optimal timing of feminizing genitoplasty is still controversial.

•The American Academy of Pediatrics guidelines on the timing of genital surgery recommend feminizing genitoplasty between 2 and 6 months of age and many pediatric urologists also recommend early feminizing genitoplasty.

•Feminizing genitoplasty for the infants who are to be raised as females includes:

–Removing the corporal bodies

–Creating a normal-looking introitus and labia minora and majora

–Vaginoplasty to provide an adequate vaginal opening

•Masculine reconstruction may include:

–Orchidopexy

–Repair of hypospadias

–Excision of retained Müllerian duct structures when present

•Clitroplasty:

–Clitoroplasty should be considered only in cases of severe virilization.

–It should be performed combined with repair of the common urogenital sinus.

–Until the 1960s, the principal surgical procedure for clitoromegaly was clitoridectomy.

–Clitoridectomy results in a near normal looking female perineum but it will affect the orgasmic function and erectile sensation.

–Clitoridectomy is currently contraindicated.

–The preferred procedure is clitoral reduction. This spares the neurovascular bundle which is important for the preservations of intact orgasmic function and erectile sensation.

•Vaginoplasty:

–Some authors prefer to correct the external genitalia in a single-stage procedure in the newborn period to take advantage of all native genital tissue and to avoid subsequent scarring.

–This is also advantageous to the parents.

–Others advocate delaying vaginal reconstruction until puberty when vaginal

dilatations are more feasible to prevent vaginal stenosis. To prevent stenosis, vaginal dilatation can begin 2 weeks after the operation.

–Labioplasty is performed at the time of the vaginoplasty and gives the external genitalia a normal female appearance.

–During clitoroplasty, the remnant skin from the clitoris shaft could be used to make the labia minora and majora.

•Phaloplasty:

–Currently, there is no tissue available to increase the size of an underdeveloped phallus.

–In patients with DSD associated with hypospadias, the complexity of this procedure must be discussed with the parents during the initial counseling.

–The standard surgical repair include:

•Increase penile size and length with topical or injectable testosterone.

•Chordee correction

•Repair of hypospadias

•Gonadectomy:

–There is controversy regarding the timing of gonadectomy.

–It is recommended that gonadectomy should be performed soon after diagnosis because estrogen-replacement therapy could be started.

–Others prefer delayed gonadectomy.

–The advantages of late gonadectomy include breast development and avoidance of poor adolescent compliance with estrogen-replacement therapy.

–Germ cell malignancy only occurs in patients with DSD who have Y-chromosomal material (GBY region).

–Testes in patients with 46,XY gonadal dysgenesis who are raised as a female should be removed to prevent testicular malignancy.

–In patients with androgen biosynthetic defects raised who are raised as females, gonadectomy should be performed before puberty.

–A scrotal testis in patients with gonadal dysgenesis is at risk for malignancy. The

•Because of the andrenocorticotropic hormone drive there is hyperpigmentation of the external genitalia and nipples.

•These patients are raised as females especially those with mild to moderate virilization.

•Fertility is normally expected in these patients.

•A prenatal diagnosis of CAH in high-risk families is possible via:

–Determination of an elevated 17-hydroxyprogesterone in amniotic fluid

–Human leukocyte antigen genotyping of chorionic villus samples

•However, the diagnosis cannot be confirmed before the initial development of the external genitalia.

•Medical treatment with life-long cortisone replacement after birth is mandatory.

•Mineralocorticoteroids are indicated in those with salt wasting CAH.

•The incidence of CAH to be 1 case per 15,000 live births.

•Frequency was highest in neonates of European Jewish, Hispanic, Slavic, or Italian descent.

•Male infants with this syndrome may be phenotypically normal, and the diagnosis may be missed.

•CAH may result from several metabolic defects, one of which is 21-hydroxylase deficiency.

•In 90 % of patients with CAH, the block is at the 21-hydroxylation enzyme. This leads to a mineralocorticoid deficiency and a buildup of androgenic byproducts, which causes masculinization of a female fetus.

•The result is a female infant with varying degrees of virilization.

•Biochemically, 75 % of patients have saltwasting nephropathy. Before this condition was commonly recognized, as many as one third of patients presented with evidence of vascular collapse.

•The 21-hydroxylase defect is inherited as an autosomal recessive trait closely linked to the human leukocyte antigen (HLA) locus on chromosome 6. The transmitted trait may have two varieties, which helps account for the clinical heterogenicity seen in patients with salt-wasting nephropathy.

•Diagnosis is confirmed by an elevated serum level of 17-OHP.

–Reference range newborn cord blood levels of 17-OHP can be as high as 900–5,000 ng/ dL, but the serum level rapidly decreases by the second or third day of life.

–A repeat elevated serum value exceeding 500 ng/dL at this point makes the diagnosis highly likely.

–It should be kept in mind that 17-OHP levels may be markedly elevated in the 11-hydroxylase form of CAH, as well as in therarechildwiththe3-beta-hydroxysteroid dehydrogenase form.

•CAH presents a spectrum of abnormalities, including (Figs. 31.15, 31.16, 31.17, and 31.18):

–The degree of phallic enlargement

–The extent of urethral folds fusion

–The size and level of entry of the vagina into the urogenital sinus

•The level of entry of the vaginal opening into the urogenital sinus is divided into two types (Figs. 31.19, 31.20, 31.21, and 31.22):

Figs. 31.17 and 3.18

Figs. 31.19 and 3.20 Genitograms showing the level of entry of the vaginal opening into the urogenital sinus. This shows a low level of insertion

Clinical photographs of a patient with CAH showing virilization of external genitalia

URINARY BLADDER

VAGINA

URINARY BLADDER

VAGINA

UROGENITAL SINUS

Fig. 31.21 Diagrammatic representation of urogenital sinus showing high insertion of the vaginal opening into the urogenital sinus. Note the point of entry above the sphincter

Fig. 31.22 Diagrammatic representation of urogenital sinus showing low insertion of the vaginal opening into the urogenital sinus. Note the point of entry below the sphincter

UTERUS

URINARY

BLADDER

SPHINCTER

URINARY

BLADDER

SPHINCTER

VAGINA

RECTUM

UTERUS

VAGINA

RECTUM

–Below the urethral sphincter

–Above the urethral sphincter

•The internal Müllerian structures are well developed in these patients and females with this condition are usually fertile with the ability to become pregnant and give birth.

•There is a salt-losing variety of CAH and this is fatal in infants if left untreated as it causes hypotension which can cause vascular collapse and death.

•Causes of CAH:

–CAH is commonly caused by enzyme deficiencies in the sex hormones pathway as follows:

•21-Hydroxylase deficiency

•11-Hydroxylase deficiency

•3-Beta-hydroxysteroid dehydrogenase deficiency

–Rarely, CAH is caused by maternal androgens

–21-Hydroxylase deficiency:

•This is the commonest cause seen in 90 % of patients with CAH.

•This leads to a mineralocorticosteroid deficiency.

•As a result of this, there is accumulation of androgenic byproducts, which causes masculinization of a female external genitalia.

•The end result is a female infant with varying degrees of virilization.

•A large number of these patients (75 % of patients) have also salt-wasting. This is a serious condition which must be recognized and treated to avoid vascular collapse.

•The 21-hydroxylase deficiency is hereditary inherited as an autosomal recessive trait.

•The transmitted trait may have two varieties, which explains the clinical heterogenecity seen in patients with salt-wasting nephropathy.

•CAH can be diagnosed prenatally by demonstrating an elevated amniotic fluid level of 17-hydroxyprogesterone (17-OHP) during the second trimester or by HLA typing of amniotic cells.

•CAH is commonly diagnosed in newborns during evaluation of a 46XX newborn with ambiguous genitalia and the diagnosis is confirmed by demonstrating an elevated serum level of 17-hydroxyprogesterone.

•17-Hydroxyprogesterone levels may be elevated also in the 11-hydroxylase deficiency form of CAH, as well as in the rare type seen in those with the 3-beta- hydroxysteroid dehydrogenase deficiency.

–11-Hydroxylase deficiency:

•Another cause of CAH is 11-hydroxylase deficiency.

•Patients who have CAH with 11-hydroxylase block accumulate deoxycorticosterone (DOC) and 11-deoxycortisol.

•This form of the syndrome exhibits salt retention and hypertension because DOC is a potent mineralocorticoid.

•The diagnosis can be confirmed by a steroid screen of the serum.

•CAH secondary to 11-hydroxylase deficiency leads to accumulation deoxycorticosterone (DOC) and 11-deoxycortisol.

•CAH secondary to 11-hydroxylase deficiency should be suspected in a 46XX child with ambiguous genitalia in whom:

–The 17-Hydroxyprogesterone level is mildly elevated.

–There is accumulation of deoxycorticosterone and 11-deoxycortisol.

–3-Beta-hydroxysteroid dehydrogenase deficiency:

•A less frequently seen version of CAH is caused by 3-beta-hydroxysteroid dehydrogenase deficiency.

•This version causes less severe virilization of a female infant than the virilization caused by 21-hydroxylase or 11-hydroxylase deficiency.

•The buildup of pregneninolone, which is subject to hepatic conversion into testosterone, produces the virilization.

•These patients can present with a saltlosing crisis caused by deficient mineralocorticoid production, similar to that occurring with 21-hydroxylase deficiency.

•The diagnosis can be confirmed by identifying an elevated serum level of dehydroepiandrosterone or its sulfate metabolite.

•It should be kept in mind that 3-beta- hydroxysteroid dehydrogenase deficiency is the only common form of CAH that can also cause ambiguity in the genetic male. This ambiguity occurs because the enzyme defect is present in both the adrenal glands and the testes, leading to inadequate production of testosterone in utero.

•3-beta-hydroxysteroid dehydrogenase deficiency is the only common form of CAH that can also cause ambiguous genitalia in the genetic male.

•This ambiguous genitalia occurs because this enzyme defect is present in both the adrenal glands and the testes, leading to inadequate production of testosterone in utero.

–Maternal androgens:

•Although rare, 46,XX DSDs may be drug-induced.

•Virilization of a female fetus may occur if progestational agents or androgens are used during the first trimester of pregnancy.

–After the first trimester, these drugs cause only phallic enlargement without labioscrotal fusion.

–The incriminated drugs were formerly administered to avoid spontaneous miscarriages in patients who had a history of habitual abortion.

•Endocrine abnormality in the mother as a source of virilizing hormones is even rarer because these abnormalities, if initially present, usually prevent development of a pregnancy.

•Extremely rare, various functional ovarian tumors have caused virilization of a female fetus.

•These tumors include:

–Arrhenoblastomas

–Krukenberg tumors

–Luteomas

–Lipoid tumors of the ovary

–Stromal cell tumors of the ovary

Causes of Congenital Adrenal Hyperplasia

•Enzyme deficiency:

–21-Hydroxylase deficiency

–11-Hydroxylase deficiency

–3-Beta-hydroxysteroid dehydrogenase deficiency

•Maternal androgens:

–Drug-induced (Progestational agents or Androgens)

–Functional ovarian tumors

•Arrhenoblastomas

•Krukenberg tumors

•Luteomas

•Lipoid tumors of the ovary

•Stromal cell tumors of the ovary

•Management:

–These patients are treated early.

–They should receive hormone replacement with corticosteroids.

–Those with salt-losing CAH must be recognized and treated with replacement therapy including corticosteroids and minerlocorticoids.

–The surgical management is variable depending on the extent of virilization and include: