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21-Hydroxylase Deficiency

If the patient has an XX karyotype and ambiguous genitalia, the most likely diagnosis is congenital adrenal hyperplasia owing to 21-hydroxylase deficiency 21 hydroxylase deficiency, dificiency, hydroxolase. This condition results in increased ACTH secretion, which, in turn, results in hyperpigmentation of the genital skin. An infant with both ambiguous genitalia and hyperpigmented genital skin has impaired adrenocortical function until proven otherwise 21 hydroxylase deficiency, dificiency, hydroxolase. The milder forms are

On the basis of data collected during neonatal screening, the incidence of 21-hydroxylase deficiency is 1 in 14,500. Only affected females have ambiguous genitalia, which is caused by the ACTH-stimulated hypersecretion of adrenal androgens. Development of the ovaries and internal female reproductive organs is unaffected. Because enzyme activity is reduced to practically zero in the salt-wasting form and to approximately 1% in the simple virilizing form, the conversion of 17alpha-hydroxyprogesterone to 11-deoxycortisol and of corticosterone to desoxycorticosterone is impaired. Three quarters of affected infants have the severe salt-losing form, which is associated with vomiting and, from about 7 days after birth, signs of hyponatremic dehydration and hyperkalemia. Without prompt and appropriate treatment (intravenous rehydration and replacement of electrolytes, hydrocortisone, and mineralocorticoid), the condition is fatal. The gene for 21 hydroylase is termed CYP 21 and is located on chromosome 6 adjacent to the gene for HLA; many mutations have 

The combination of ambiguous genitalia and hyperpigmented genital skin is seen with several other steroidogenic defects including 11beta-hydroxylase deficiency, lipoid adrenal hyperplasia, and 3beta-hydroxysteroid dehydrogenase deficiency. These are all rare. In the last two disorders, the karyotype may be either

This defect impairs the conversion of androstenedione to testosterone in the testis. Sixty cases have been reported from one inbred community in the Gaza Strip. Inheritance is autosomal recessive. Most XY cases have either ambiguous or female genitalia. In that group, at least 14 mutations in the 17beta-hydroxysteroid reductase 3 gene have been detected. In infancy and childhood, the diagnosis of partial androgen insensitivity may be incorrectly made unless a human chorionic gonadotropin (hCG) stimulation test is performed. This test would reveal an abnormally high ratio of androstenedione to testosterone in the serum. At puberty, testosterone levels rise as a result of conversion from androstenedione by other unaffected isoenzymes of

In androgen target tissues, particularly those of the external genitalia and male beard area, testosterone undergoes intracellular conversion to the more potent androgen, 5alpha-dihydrotestosterone (DHT) before binding to the AR. Deficiency of the converting enzyme 5alpha-reductase 2 results in a condition once called "pseudovaginal perineal hypospadias." In this rare condition, affected XY subjects are born with ambiguous genitalia and at least one palpable testis, and are usually identified as female in childhood but undergo striking virilization at puberty. Nevertheless, the penis of adult patients is rarely greater than 6 cm in length. The natural history has been extensively documented from an anthropologic point of view in the 

Placental Aromatase Deficiency.

Placental aromatase converts C19 androgens of fetal adrenal origin into estrogens. A deficiency in this enzyme exposes the mother and the female fetus to these androgens, and both become virilized. Development of the uterus and ovaries is unaffected. Missense mutations in the gene encoding aromatase (P450 arom) have been identified. Endocrine abnormalities persist beyond birth and are characterized by high FSH and low estriol during infancy in affected females and by high FSH and LH with

Partial Androgen Insensitivity Syndrome

Partial androgen insensitivity syndrome has the same phenotype as 17beta-hydroxysteroid dehydrogenase deficiency, but the hCG-stimulated ratio of androstenedione to testosterone is normal, and the levels of testosterone reached are normal or high. Serum LH may be normal or elevated. Usually, at least one gonad is palpable. The degree of virilization varies considerably within families (Reifenstein syndrome). There is no uterus. Left in situ, the testes visibly enlarge at puberty, and the patient undergoes considerable virilization but inevitably experiences gynecomastia. AR-binding studies in cultured genital skin fibroblasts give low or normal results. AR gene mutations (mostly in exons encoding the steroid-binding domain) have been found, but the proportion of cases with no mutation detected remains disconcertingly high. Therefore, PAIS frequently is a

Luteinizing Hormone Receptor Gene Mutation

Leydig cell hypoplasia or agenesis occurs in a familial form. In several cases, an inactivating mutation in the gene encoding LH receptor has been demonstrated. The phenotype in XY subjects is similar to that in XY gonadal dysgenesis; the external genital genitalia are either female or ambiguous, gonads are usually not palpable, the serum gonadotropin levels are elevated, and

Phenotype 4: The 46,XY Male with Persistent Mullerian Structures

Patients with the persistent mullerian duct syndrome have normal male genitalia, and the testes are usually undescended. The presence of mullerian structures (uterus and fallopian tubes) is often discovered by the surgeon at operation. The testes secrete normal amounts of testosterone and should therefore never be removed. The cause of the condition in 50% of cases is a 

Phenotype 5: The 46,XX Female with Mullerian Agenesis

One of the causes of primary amenorrhea is mullerian agenesis. In some cases the entire mullerian tract is absent, whereas in others the agenesis affects only certain parts of the tract (such as the vagina and body of the uterus). The alternative name, Meyer-Rokitansky-Kuster-Hauser syndrome, is widely used. The etiology remains unknown. One group has hypothesized that


When an infant is born with ambiguous genitalia, the immediate problem for staff in the delivery room is what to tell the parents. The next challenge is to make a diagnosis of the underlying cause to plan management of the condition. In a very real sense, the