testicular feminization syndrome

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ALIGN="bottom" HSPACE="0" VSPACE="0">Testicular</B><B> </B><B>feminization</B><B> </B><B>syndrome</B><B> is characterized by female external genitalia which may be incompletely developed. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The affected individuals are genetically male, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Because of a defect in the androgen receptor, target tissues are unresponsive to androgens. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The inheritance is X-linked recessive.</B><B> </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">genetic form of male pseudohermaphroditism (patient who is genetically 46 XY but has deficient masculinization of external genitalia) caused by complete or partial resistance of end organs to the peripheral effects of androgens. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">This androgenic insensitivity is caused by a mutation of the gene for androgenic receptor inherited as an X-linked recessive trait.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> In the complete form the external genitalia appear to be female with a rudimentary vagina, absent uterus and ovaries.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The infant may present with inguinal hernias that at surgery may contain testes. Axillary/pubic hair is sparse and primary amenorrhea is present. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The incomplete form may represent undervirilized infertile men. </B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Evaluation should include: </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">karyotype,</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> hormonal assays, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">pelvic ultrasound,</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> urethrovaginogram, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">gonadal biopsy </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">and labial skin bx for androgen receptor assay.</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> This patients will </B><FONT SIZE="3" COLOR="#66FFFF" FACE="Arial" ><B><U>never menstruate or bear children</U></B></FONT><B>. </B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Malignant degeneration</B><FONT SIZE="3" COLOR="#00FFFF" FACE="Arial" ><B><U> (germ cell tumors) </U></B></FONT><B>of the gonads is increased (22-33%).</B></div> <bR> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ffff0000.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Early gonadectomy is advised to: decrease the possible development of malignancy,</U></B><FONT SIZE="3" COLOR="#FFFF00" FACE="Arial" ><B> avoid the latter psychological trauma to the older child, and eliminate risk of losing the pt during follow-up. </B></FONT></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000ffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Vaginal reconstruction is planned when the patient wishes to be sexually active.</B></div> <bR> <bR> <bR> <div> <B><U>Testicular</U></B><B><U> </U></B><B><U>feminization</U></B><B><U> </U></B><B><U>syndrome</U></B><B><U> (androgen insensitivity </U></B><B><U>syndrome</U></B><B><U>)</U></B></div> <bR> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Androgen insensitivity </B><B>syndrome</B><B> is the most studied of the disorders of sexual differentiation </B><B>testicular</B><B> </B><B>feminization</B><B> </B><B>syndrome</B><B>, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">androgen insensitivity </B><B>syndrome</B><B>. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Women with complete androgen insensitivity </B><B>syndrome</B><B> (CAIS) have a </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc0000ff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">normal Y chromosome </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc0000ff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">and fully functioning testes.</B><FONT SIZE="2" COLOR="#FFFF00" FACE="Arial" ><B> </B></FONT></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The androgen receptor in this condition is either absent or unable to bind androgen or transduce the androgenic signal to target genes. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">XY women with</B><B><U> androgen insensitivity </U></B><B><U>syndrome</U></B><B><U> are phenotypically female</U></B><B>, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc0000ff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">with female external genitalia, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc0000ff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">a short blind-ending vagina</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The diagnosis frequently is made in infancy or childhood because most girls with CAIS have </B><B><U>bilateral inguinal hernias containing testes.</U></B><B> </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Alternatively, the girl may </B><B><U>seek help in adolescence when menstruation does not occur despite normal breast development</U></B><B>. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Pubic hair is either completely absent or very sparse. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The vagina is usually about 6 cm in length (two-thirds of normal) but Women with CAIS may </B><B><U>be relatively tall</U></B><B>. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc0000ff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">In adult patients,</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc0000ff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">serum testosterone levels are in the male range or higher, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc0000ff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">serum LH is normal or elevated, </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc0000ff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">and serum estradiol levels are between the normal male and female ranges</B><FONT SIZE="2" COLOR="#FFFF00" FACE="Arial" ><B>. </B></FONT></div> <bR> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">In 80% of cases, </B><B><U>assays of androgen binding show this to be absent or very low</U></B><B> (these patients are called </B><B><U>"receptor-negative"</U></B><B>).</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> These assays are </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Because of the fact that the androgen receptor is on the X chromosome, CAIS is an X-linked disorder. In most cases, a mutation in the coding region of the gene for the AR can be demonstrated, and extensive structure-function studies have been carried out. Similar to all steroid receptors, the AR is a ligand-dependent transcription factor. Mutations in the gene encoding AR may consist of complete absence, large deletions, or point mutations introducing premature stop codons that cause complete disruption of the protein sequence. Point mutations affecting hormone binding, DNA binding, and dimerization of the receptor have enabled the construction of a detailed map of the functional domains present in</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">In this rare condition, the phenotype resembles Klinefelter's </B><B>syndrome</B><B> (XXY) in that the testes are small (pealike) and dysgenetic, such that infertility is inevitable. Patients can be normal males or somewhat eunuchoid with gynecomastia. Mullerian structures are absent. The hypothesis that testes develop because of a small Y-to-X translocation bearing the testis-determining gene is borne out in 90% of cases. Y chromosome-derived DNA is apparently absent in the remaining 10% (although DNA of gonadal origin has not always been studied). It remains possible that, in some cases, testis determination can occur in the</B><B> </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">If an infant has a phallus that is intermediate in size between a normal penis and a normal clitoris, an aberrantly located urethral opening, and at least one impalpable gonad, the term </B><B>ambiguous genitalia</B><B> may be</B><B> </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The two most likely diagnoses are congenital adrenal hyperplasia (21-hydroxylase deficiency) and gonadal dysgenesis (including true hermaphroditism). Partial androgen insensitivity </B><B>syndrome</B><B> (PAIS) and 17beta-hydroxysteroid dehydrogenase deficiency (a defect in testosterone biosynthesis) are next in order of prevalence, followed by a group of very rare conditions (11beta-hydroxylase deficiency, 3beta-hydroxysteroid dehydrogenase deficiency, 5alpha-reductase deficiency, 17alpha-hydroxylase deficiency, placental aromatase deficiency, and LH receptor mutations). In at least one third of cases, even the most thorough investigation fails to reveal the underlying cause. There is no clear distinction between what one clinician might call "a disorder of sexual differentiation" and what another might refer to as "perineal hypospadias." In patients with hypospadias, the following additional features should prompt further investigation: a family history of hypospadias, height below the third percentile, associated dysmorphic features, one or more impalpable testes, any evidence of retained mullerian structures, and </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc00ffff00.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Questions that should be asked on history taking are as follows: Was the mother taking any medications during pregnancy that could affect fetal genital development? Does she have any symptoms or signs of a virilizing disorder? Is there a family history of ambiguous genitalia or of perinatal death? Because genital appearances in such cases are highly variable, a staging system is extremely useful . According to the Prader classification, external genital appearances are given one of six grades from O (female) to V (male) according to the relative size of the phallus, the number of orifices, and the degree of midline fusion. Having defined the Prader grade by inspection of the genitalia, the examiner looks for other clues to the diagnosis. Careful inspection under daylight or a white light source may reveal a brownish-yellow hyperpigmentation of the genital skin if ACTH secretion is increased (e.g., an infant with congenital adrenal hyperplasia). Asymmetry of the labioscrotal folds is seen more often in cases of mixed gonadal dysgenesis and true hermaphroditism than in partial androgen insensitivity or testosterone biosynthetic defects. On a more general inspection, the infant may be found to</B><B> </B></div> <bR> <bR> <bR> <div> <B> <TABLE BORDER="2" CELLPADDING="2" CELLSPACING="1" WIDTH="1357" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=TOP HEIGHT= 6496 WIDTH="1345"><div> <B>Disease characteristics. </B><B>The androgen insensitivity </B><B>syndrome</B><B> (AIS) typically includes </B><B>feminization</B><B> or undermasculinization of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility.</B></div> <bR> <div> <B>Diagnosis/testing. </B><B>The diagnosis of AIS is established in individuals with the clinical findings of undermasculinization of the external genitalia, impaired spermatogenesis with otherwise normal testes, absent or rudimentary müllerian structures, 46,XY karyotype, evidence of normal or elevated synthesis of testosterone and its normal conversion to dihydrotestosterone, normal or elevated pituitary LH, and deficient or defective androgen-binding activity in genital skin fibroblasts. Molecular diagnosis based on identification of mutations of the </B><B>AR</B><B> gene (chromosomal locus Xq11-q12) is available on a research basis only.</B></div> <bR> <div> <B>Genetic counseling. </B><B>AIS is inherited in an X-linked recessive manner. Affected 46,XY individuals are infertile. Carrier women have a 50% chance of transmitting the </B><B>AR</B><B> gene mutation in each pregnancy. Prenatal testing by mutation analysis or linkage analysis is not available.</B></div> <bR> <bR> <div> <B> <A NAME="diagnosis"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B></div> <div> <B>Diagnosis </B></div> <div> <B>The diagnosis of androgen insensitivity </B><B>syndrome</B><B> (AIS) is based on clinical findings, endocrine evaluation, and, whenever possible, family history. Mutation analysis of the androgen receptor (</B><B>AR</B><B>) gene (chromosomal locus Xq11-q12) is available on a research basis only. </B></div> <div> <B>Clinical Diagnosis </B></div> <div> <B>AIS can be subdivided into three phenotypes: complete androgen insensitivity </B><B>syndrome</B><B> (CAIS), partial androgen insensitivity </B><B>syndrome</B><B> (PAIS), and mild androgen insensitivity </B><B>syndrome</B><B> (MAIS). The clinical diagnosis of CAIS is usually made on clinical findings and laboratory evaluations alone. The diagnosis of PAIS and MAIS may also require a family history consistent with X-linked inheritance.</B></div> <bR> <div> <B>The </B><B>clinical findings</B><B> that permit a presumptive diagnosis of AIS include the following:</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Absence of extragenital abnormalities </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Two nondysplastic testes </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Absent or rudimentary müllerian structures (i.e., no fallopian tubes, uterus, or cervix) and presence of a short vagina </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Undermasculinization of the external genitalia at birth </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Impaired spermatogenesis and/or somatic virilization at puberty (Table 1)</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > <A NAME="table_1"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></FONT><B> </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Table 1. Classification of AIS Phenotypes </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> <TABLE BORDER="2" CELLPADDING="1" CELLSPACING="1" WIDTH="638" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 58 ><NOBR><div> <B>Type </B></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="120"><div> <B>External Genitalia (Synonyms) </B></div> </tD> <tD VALIGN=CENTER WIDTH="478"><div> <B>Findings </B></div> </tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 58 ><NOBR><div> <B>CAIS </B></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="120"><div> <B>Female ("</B><B>testicular</B><B> </B><B>feminization</B><B>") </B></div> </tD> <tD VALIGN=CENTER><NOBR><div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Absent or rudimentary wolffian duct derivatives </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Inguinal or labial testes; short blind-ending vagina </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Scant or absent pubic and/or axillary hair </B></div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER ROWSPAN=3 HEIGHT= 77 ><NOBR><div> <B>PAIS </B></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="120"><div> <B>Predominantly female ("incomplete AIS") </B></div> </tD> <tD VALIGN=CENTER WIDTH="478"><div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Inguinal or labial testes </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Clitoromegaly and labial fusion </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Distinct urethral and vaginal openings </B><B>or</B><B> a urogenital sinus </B></div> </tD> </tR> <tR> <tD VALIGN=CENTER><NOBR><div> <B>Ambiguous </B></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="478"><div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Microphallus (<1 cm) with clitoris-like underdeveloped glans; labia majora-like bifid scrotum </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Descended or undescended testes </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Perineoscrotal hypospadias </B><B>or</B><B> urogenital sinus </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Gynecomastia in puberty </B></div> </tD> </tR> <tR> <tD VALIGN=CENTER WIDTH="120"><div> <B>Predominantly male </B></div> </tD> <tD VALIGN=CENTER WIDTH="478"><div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Simple (glandular or penile) or severe (perineal) "isolated" hypospadias with a normal-sized penis and descended testes or severe hypospadias with micropenis, bifid scrotum, and either descended or undescended testes </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Gynecomastia in puberty </B></div> </tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 77 ><NOBR><div> <B>MAIS </B></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="120"><div> <B>Male ("undervirilized male </B><B>syndrome</B><B>") </B></div> </tD> <tD VALIGN=CENTER WIDTH="478"><div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Impaired spermatogenesis and/or impaired pubertal virilization </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Gynecomastia in puberty </B></div> </tD> </tR> </TABLE></B></div> <bR> <div> <B> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="626" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 20 WIDTH="622"><div> <B>Adapted from </B><B>Sinnecker et al 1997</B><B> </B></div> </tD> </tR> </TABLE></B></div> <bR> <div> <B>The </B><B>laboratory findings</B><B> required for the diagnosis of AIS include the following:</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">46,XY karyotype </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Evidence of normal or increased synthesis of testosterone by the testes </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Evidence of normal conversion of testosterone to dihydrotestosterone </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Evidence of normal or increased luteinizing hormone production by the pituitary gland </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Evidence of deficient or defective androgen-binding activity of genital skin fibroblasts </B></div> <div> <B>The diagnosis of CAIS can be established by clinical and laboratory findings alone; however, the diagnosis of PAIS and MAIS may require a family history of other affected individuals related to each other in a pattern consistent with X-linked recessive inheritance. "Other affected family members" refers to both affected 46,XY individuals and manifesting female (46 XX) carriers. Within families, there is a strong tendency for CAIS or MAIS to run true. In contrast, in families with PAIS, phenotypic disparity may warrant opposite sexes-of-rearing [</B><B>Rodien et al 1996</B><B>, </B><B>Evans et al 1997</B><B>]. About 10% of carrier females are manifesting carriers with asymmetric distribution and sparse or delayed growth of pubic or axillary hair; they may also have a history of late (15 years) or delayed (16 years or older) menarche.</B></div> <bR> <div> <B>Additional findings in sporadic cases </B><B>that substantiate the apparent diagnosis of PAIS in an individual with the "predominantly male" phenotype (</B><B>Table 1</B><B>) are: 1) impaired development of the prostate and of the Wolffian duct derivatives demonstrated by ultrasonography or genitourography; 2) less than normal decline of sex hormone-binding globulin (SHBG) in response to a standard dose of the anabolic androgen, Stanozolol [</B><B>Sinnecker et al 1997</B><B>]; and/or 3) higher than normal levels of anti-müllerian hormone during the first year of life or after puberty has begun [</B><B>Rey et al 1994</B><B>].</B></div> <bR> <div> <B>Molecular Genetic Testing </B></div> <div> <B>More than 90% of patients with CAIS and fewer than 50% of patients with PAIS have identifiable disease-causing mutations in the </B><B>AR</B><B> gene detected by direct sequencing of the gene. The proportion of patients with MAIS who have mutations in the </B><B>AR</B><B> gene is unknown.</B></div> <bR> <div> <B>Mutation analysis. </B><B>Mutation analysis for all three subtypes of AIS is available on a research basis only.</B></div> <bR> <div> <B>Linkage analysis. </B><B>Although linkage analysis (on a blood sample) using variable polyglutamine and/or polyglycine tract size as a marker for the mutant allele is theoretically possible, it is not clinically available.</B></div> <bR> <div> <B>Table 2: Testing Used in the Molecular Diagnosis of AIS </B></div> <div> <B> <TABLE BORDER="2" CELLPADDING="1" CELLSPACING="1" WIDTH="641" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 20 WIDTH="244"><div> <B>% of Patients </B></div> </tD> <tD VALIGN=CENTER><NOBR><div> <B>Genetic Mechanism </B></div> </NOBR></tD> <tD VALIGN=CENTER><NOBR><div> <B>Test Type </B></div> </NOBR></tD> <tD VALIGN=CENTER><NOBR><div> <B>Availability </B></div> </NOBR></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 20 ><NOBR><div> <B>>90% of patients with CAIS </B></div> </NOBR></tD> <tD VALIGN=CENTER ROWSPAN=2><NOBR><div> <B>AR</B><B> gene mutation </B></div> </NOBR></tD> <tD VALIGN=CENTER ROWSPAN=2 WIDTH="91"><div> <B>DNA </B></div> </tD> <tD VALIGN=CENTER ROWSPAN=2 WIDTH="118"><div> <B>Research </B></div> </tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 20 ><NOBR><div> <B><50% of patients with PAIS </B></div> </NOBR></tD> </tR> </TABLE></B></div> <bR> <div> <B>Undoubtedly, some of the negative mutation searches in patients with decreased or defective androgen-binding activity [</B><B>Allera et al 1995</B><B>, and references therein] reflect covert mutations in regulatory or deep intronic portions of the </B><B>AR</B><B> gene. However, the great majority of them very probably reflect a "timing" problem; in other words, the acquisition of normal testosterone synthetic capacity or normal androgen responsiveness is delayed beyond the critical periods for normal external and/or internal male genital differentiation. Mutation in genes whose products collaborate with the AR, or that are subject to androgenic control, could also explain a fraction of these cases.</B></div> <bR> <div> <B>In the presence of deficient or defective androgen-binding activity in genital skin fibroblasts, the likelihood of finding a mutation in the androgen-binding domain of the </B><B>AR</B><B> gene approaches 40% [</B><B>Batch et al 1992</B><B>, </B><B>Weidemann et al 1996</B><B>]. In the presence of normal androgen binding in genital skin fibroblasts, the likelihood of finding a disease-causing mutation in the </B><B>AR</B><B> gene is 10% or less, even when exon 1 is screened and/or sequenced in its entirety.</B></div> <bR> <div> <B> <A NAME="clinicaldescription"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B></div> <div> <B>Clinical Description </B></div> <div> <B>Complete AIS (CAIS; </B><B>testicular</B><B> </B><B>feminization</B><B>; Tfm). </B><B>These individuals have normal female external genitalia. They typically present either before puberty with inguinal masses that are subsequently identified as testes or at puberty with primary amenorrhea and sparse to absent pubic or axillary hair. Breasts and female adiposity develop normally. Sexual identity and orientation are unaffected. CAIS almost always runs true in families; that is, affected XY relatives usually have normal female external genitalia and seldom have any sign of external genital masculinization, such as clitoromegaly or posterior labial fusion.</B></div> <bR> <div> <B>Partial AIS (PAIS) and predominantly female external genitalia </B><B>(</B><B>Table 1</B><B>) will present in a manner similar to those with CAIS; however, they have signs of external genital masculinization including clitoromegaly or posterior labial fusion.</B></div> <bR> <div> <B>Partial AIS with ambiguous genitalia or predominantly male genitalia (PAIS; Reifenstein </B><B>syndrome</B><B>). </B><B>Determining the sex of rearing may be an issue for children with frank genital ambiguity. Individuals with PAIS and predominantly male genitalia are raised as males. Gynecomastia at puberty and impaired spermatogenesis occur in all individuals with PAIS. Pubic hair is usually moderate; facial, body, and axillary hair are often reduced.</B></div> <bR> <div> <B>Mild AIS (MAIS; undervirilized male </B><B>syndrome</B><B>). </B><B>The external genitalia of these individuals are unambiguously male. They usually present with gynecomastia at puberty. They may have undermasculinization that includes sparse facial and body hair and small penis. Impotence may be a complaint. Spermatogenesis may or may not be impaired [</B><B>Tsukada et al 1994</B><B>, </B><B>Pinsky et al 1989</B><B>, </B><B>Grino et al 1988</B><B>, </B><B>Larrea et al 1978</B><B>].</B></div> <bR> <div> <B>Genotype-Phenotype Correlations </B></div> <div> <B>A statistically useful correlation exists among certain missense </B><B>AR</B><B> mutations, their functional consequences, and external genital development. This information is available through the </B><B>Androgen Receptor Gene Mutations Database</B><B>.</B></div> <bR> <div> <B>Recently, it has been appreciated that variable expressivity of a particular point mutation may be attributed to somatic mosaicism for the mutation, rather than the modifying influence of "background" genetic factors [</B><B>Holterhus et al 1997</B><B>, </B><B>Boehmer et al 1997</B><B>].</B></div> <bR> <div> <B>It remains to be determined whether specific missense mutations can be correlated with normal or impaired spermatogenesis and with absence or presence of localized expressions of undervirilization such as gynecomastia, high-pitched voice, and impotence.</B></div> <bR> <div> <B>Prevalence </B></div> <div> <B>Standard references quote rates of 2-5/100,000 for complete AIS (CAIS) and are based on estimates derived from otherwise healthy phenotypic females found to have histologically normal inguinal or abdominal testes.</B></div> <bR> <div> <B>Partial AIS (PAIS) is at least as common as complete AIS.</B></div> <bR> <div> <B>The frequency of mild AIS (MAIS) has not been determined.</B></div> <bR> <div> <B> <A NAME="differentialdiagnosis"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B></div> <div> <B>Differential Diagnosis </B></div> <div> <B>Hypospadias that results from an </B><B>AR</B><B> gene mutation (and thus is part of the spectrum of PAIS) cannot be distinguished from hypospadias resulting from other (largely undefined causes) by the examination of the genitalia alone. Several investigators have determined how often hypospadias of varying severity can be attributed to </B><B>AR</B><B> gene mutations. </B><B>Sutherland et al</B><B> (</B><B>1996</B><B>), using SSCP followed by sequencing, found one </B><B>AR</B><B> gene mutation among 40 subjects with penile hypospadias. </B><B>Hiort et al</B><B> (</B><B>1994</B><B>), using SSCP and sequencing, did not find any </B><B>AR</B><B> mutations in 12 patients with coronal (glandular) or penile hypospadias, but did find one patient with an </B><B>AR</B><B> mutation among nine patients with severe (penoscrotal, perineal) hypospadias. </B><B>Batch et al</B><B> (</B><B>1992</B><B>, </B><B>1993</B><B>) found an </B><B>AR</B><B> mutation in two brothers with isolated severe (perineal) hypospadias. </B><B>Allera et al</B><B> (</B><B>1995</B><B>) sequenced the </B><B>AR</B><B> gene in 9 patients with isolated severe hypospadias and found an </B><B>AR</B><B> mutation in one. </B><B>McPhaul et al</B><B> (</B><B>1997</B><B>) found that two of the remaining eight patients originally studied by </B><B>Allera et al</B><B> (</B><B>1995</B><B>) had androgen receptors that were transactivation-deficient when their genital skin fibroblasts were infected with a recombinant adenovirus carrying an androgen-responsive reporter gene.</B></div> <bR> <div> <B>MAIS due to point mutations of the androgen receptor (</B><B>AR</B><B>) gene [</B><B>Tsukada et al 1994</B><B>, </B><B>Wang et al 1998</B><B>] may be clinically indistinguishable from MAIS due to the decreased androgenicity associated with polymorphic expansion of the polyglutamine tract in the AR protein [</B><B>Tut et al 1997</B><B>]. Pathological expansion of this tract is the cause of </B><B>spinobulbar muscular atrophy</B><B> (SBMA), also known as Kennedy disease [</B><B>La Spada et al 1991</B><B>]. Detection of a CAG trinucleotide repeat expansion in the </B><B>AR</B><B> gene will identify those individuals with MAIS associated with SBMA. Such testing is available clinically.</B></div> <bR> <div> <B>Undermasculinization of the external genitalia and pubertal undervirilization are components of many different </B><B>syndrome</B><B>s that have no etiologic relation to the androgen receptor (</B><B>AR</B><B>) gene. They may, or may not, have a pathogenic relation to the AR protein. The one exception is a contiguous gene deletion </B><B>syndrome</B><B> that includes the </B><B>AR</B><B> gene locus and results in mental retardation and genital abnormalities [</B><B>Davies et al 1997</B><B>].</B></div> <bR> <div> <B>Findings that suggest the presence of other identifiable disorders in 46,XY individuals with predominantly female, ambiguous, or predominantly male genitalia include the following:</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Elevated levels of testosterone precursors due to a partial testosterone biosynthetic defect in which compensatory supranormal LH levels stimulate a normal plasma testosterone level</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The presence of müllerian duct derivatives due to a </B><B>testicular</B><B> organogenesis defect with impaired Sertoli cell production of anti-müllerian hormone</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The presence of wolffian duct-derived internal male reproductive structures that differentiate in response to testosterone, which suggests 5a-reductase deficiency; however, these structures are also found in patients with a partial testosterone biosynthetic defect or PAIS. </B></div> <div> <B>Issues to consider in patients with some, but not all, of the clinical features of AIS:</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Normal levels of T, DHT and LH levels after birth do not prove that the level was normal during the critical period of fetal genital masculinization.</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Normal responsiveness to androgen after birth does not prove that it was normal before birth. In other words, early developmental delay in the acquisition of normal androgen biosynthesis or normal androgen sensitivity may simulate androgen insensitivity after birth.</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Subnormal sensitivity to androgen after birth may involve components of the overall androgen-response system (AR-interacting proteins) beyond the androgen receptor itself. </B></div> <bR> <div> <B> <A NAME="management"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B></div> <div> <B>Management </B></div> <div> <B>The modalities of management - surgery, psychologic support, and hormone replacement or supplementation - depend on the AIS phenotype.</B></div> <bR> <div> <B>CAIS. </B><B>A common practice is to remove the testes after puberty when </B><B>feminization</B><B> of the affected individual is complete. </B><B>Feminization</B><B> occurs partly by </B><B>testicular</B><B> estrogen, and partly by peripheral conversion of androgen to estrogen. The rationale for postpubertal gonadectomy is that </B><B>testicular</B><B> malignancy, which develops at the usual rate for cryptorchid testes, seldom occurs before puberty. Prepubertal gonadectomy is indicated if inguinal testes are physically or esthetically uncomfortable, and if inguinal herniorrhaphy is necessary. In this event, estrogen replacement therapy is necessary to initiate puberty, maintain </B><B>feminization</B><B>, and avoid osteoporosis. Vaginal length may be sufficiently short to require dilatation in an effort to avoid dyspareunia. The questions of how much to tell patients with CAIS, and when to tell them, have not been resolved uniformly. It has become obvious, however, that systematic disclosure in an empathic setting is much more preferable than systematic concealment or self-discovery of the diagnosis in an environment devoid of support from family, professionals, and other affected individuals.</B></div> <bR> <div> <B>PAIS and predominantly female genitalia (incomplete AIS). </B><B>The issues are similar to those discussed under CAIS, except prepubertal gonadectomy will avoid the emotional discomfort of increasing clitoromegaly at the time of puberty.</B></div> <bR> <div> <B>PAIS and ambiguous genitalia or predominantly male genitalia. </B><B>The issue of sex assignment in infancy when the child is being evaluated for ambiguous genitalia is paramount. It requires delicate decision-making by parents and healthcare personnel, and should be resolved as early as feasible. Aside from purely anatomical and surgical considerations, the choice of a male sex-of-rearing demands a therapeutic trial with pharmacologic doses of androgen in an effort to predict potential androgen responsiveness at puberty. Furthermore, appreciable phallic growth in response to administered androgen will facilitate reconstructive surgery. Based on a small number of cases, the role of long-term androgen pharmacotherapy in individuals with PAIS who are raised as males remains unclear [</B><B>Jukier et al 1984</B><B>, </B><B>Price et al 1984</B><B>, </B><B>McPhaul et al 1991</B><B>, </B><B>Hiort et al 1993</B><B>]. There is reason to believe that response to androgen treatment may be substantial in patients with certain missense mutations in the DNA-binding domain of the androgen receptor [</B><B>Weidemann et al 1998</B><B>]. Gynecomastia which develops in puberty eventually requires reduction mammoplasty.</B></div> <bR> <div> <B>Those individuals with PAIS who are raised as females and who have gonadectomy after puberty may need combined estrogen and androgen replacement therapy, the latter to maintain libido.</B></div> <bR> <div> <B>MAIS. </B><B>Men with MAIS often require reduction mammoplasty for treatment of gynecomastia. A trial of androgen pharmacotherapy is recommended to attempt to improve virilization.</B></div> <bR> <div> <B> <A NAME="geneticcounseling"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B></div> <div> <B>Genetic Counseling </B></div> <div> <B>Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal or cultural issues that individuals may face or to substitute for a consultation with a genetics professional.To find a genetics or prenatal diagnosis clinic, see</B><B> . —ED. </B></div> <div> <B>Mode of Inheritance </B></div> <div> <B>AIS is inherited in an X-linked recessive manner. </B></div> <div> <B>Risk to Family Members </B></div> <div> <B>Parents of a proband. </B><B>Individuals who are 46,XY and have any of the subtypes of AIS (i.e., CAIS, PAIS, MAIS) are infertile. Women who have an affected child and one other affected relative are obligate heterozygotes. However, if pedigree analysis reveals that the proband is the only affected family member, the question that must be resolved is whether the mother and other 46,XX females in her family are carriers of an </B><B>AR</B><B> gene mutation. Five possible genetic explanations exist for the occurrence of a single affected 46,XY individual in a family:</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The affected individual has a new </B><B>AR</B><B> gene mutation. There are two mechanisms by which a new </B><B>AR</B><B> gene mutation could occur:</B></div> <bR> <div> <B>The mutation was present in the egg at the time of that person's conception and therefore is present in every cell of the affected individual's body. In this instance, the patient's mother does not have an </B><B>AR</B><B> gene mutation and no other family member is at risk.</B></div> <bR> <div> <B>The mutation occurred after conception and therefore is present in some, but not all, cells of the affected individual's body (termed "somatic mosaicism") [</B><B>Holterhus et al 1997</B><B>]. In this instance the likelihood that the mother is a heterozygote is low but not zero. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The affected individual's mother has a new </B><B>AR</B><B> gene mutation. There are two mechanisms by which a new </B><B>AR</B><B> gene mutation occurred in the mother:</B></div> <bR> <div> <B>The mutation was present in the egg or sperm at the time of her conception, is present in every cell of her body, and is detectable in a blood sample.</B></div> <bR> <div> <B>The mutation is present only in her ovaries (termed "germline mosaicism") [</B><B>Boehmer et al 1997</B><B>] and is not detectable in a blood sample.</B></div> <bR> <div> <B>In both instances (3 and 4), each of her offspring has a risk to inherit the </B><B>AR</B><B> mutation; none of her sisters, however, is at risk to inherit the </B><B>AR</B><B> mutation. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The affected individual's maternal grandmother has a new gene mutation.</B></div> <bR> <div> <B>In this instance, all of the maternal grandmother's daughters are at risk to be </B><B>AR</B><B> mutation carriers. </B></div> <div> <B>In 22 of 30 single-case families with CAIS or PAIS, the mother was proven to be an </B><B>AR</B><B> heterozygote. Of the eight patients with new mutations, three appeared to be somatic mosaics [</B><B>Hiort et al 1998</B><B>].</B></div> <bR> <div> <B>Offspring of carrier women. </B><B>The risks to the offspring of females who are known </B><B>AR</B><B> mutation carriers (heterozygotes) are: 25% that a child is 46,XY and is affected; 25% that a child is 46,XY and is unaffected; 25% that a child is 46,XX and is a carrier; and 25% that a child is 46,XX and is not a carrier. The phenotype of 46,XY offspring with CAIS or MAIS is predictable. Although the genital phenotype of PAIS tends to vary less within a family, the wide range of phenotypes observed for the same mutation in different families makes genetic counseling more difficult.</B></div> <bR> <div> <B>Related Genetic Counseling Issues </B></div> <div> <B>Carrier (heterozygote) detection. </B><B>Female carriers may be identified through a combination of family history, clinical findings, linkage analysis, or androgen-binding studies on genital skin fibroblasts.</B></div> <bR> <div> <B>Family history. </B><B>In families with two or more affected individuals, certain women can be identified as obligate heterozygotes by pedigree analysis. For example, a woman who has an affected sib and an affected offspring is an obligate carrier.</B></div> <bR> <div> <B>Clinical findings. </B><B>10% of carriers are manifesting carriers with asymmetric distribution and sparse or delayed growth of pubic or axillary hair. This finding results from random X chromosome inactivation. The presence of normal pubic and axillary hair does not rule out the 46,XX carrier state.</B></div> <bR> <div> <B>Androgen binding studies. </B><B>If a linkage study cannot be performed or is uninformative, and if an affected 46,XY family member is known to have deficient or defective androgen-binding activity in a genital skin fibroblast cell line, heterozygotes may be identified by the assay for deficient or defective androgen-building activity of single-cell clones from a genital skin fibroblast line.</B></div> <bR> <div> <B>Prenatal Testing </B></div> <div> <B>Prenatal testing by mutation analysis or linkage analysis is not available clinically.</B><B> <A NAME="moleculargenetics"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B></div> <bR> <div> <B> <A NAME="moleculargenetics_1"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B></div> <div> <B>Molecular Genetics </B></div> <div> <B>Table 3. Molecular Genetics of Androgen Insensitivity </B><B>Syndrome</B><B> </B></div> <div> <B> <TABLE BORDER="2" CELLPADDING="1" CELLSPACING="1" WIDTH="454" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 39 WIDTH="88"><div> <B>Gene Symbol </B></div> </tD> <tD VALIGN=CENTER><NOBR><div> <B>Locus </B></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="145"><div> <B>Normal Gene Product </B></div> </tD> <tD VALIGN=CENTER WIDTH="130"><div> <B>Genomic Databases </B></div> </tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 39 WIDTH="88"><div> <B>AR</B><B> </B></div> </tD> <tD VALIGN=CENTER WIDTH="66"><div> <B>Xq11-q12 </B></div> </tD> <tD VALIGN=CENTER><NOBR><div> <B>Androgen receptor </B></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="130"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="130" HSPACE="0" VSPACE="0"></tD> </tR> </TABLE></B></div> <div> <B>Androgen Insensitivity </B><B>Syndrome</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Gene: </B><B>AR</B><B> </B><B>(androgen receptor) </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Pathologic allelic variants: </B><B>At least 150 different point mutations in the </B><B>AR</B><B> have been found to cause AIS [</B><B>Gottlieb et al 1998</B><B>]. The great majority are missense mutations that impair DNA or androgen binding and that cause CAIS or PAIS; a small number have been proven to cause MAIS. Point mutations in exon 1 are relatively infrequent. The great majority of them are nonsense, and small deletions or insertions that frameshift to nonsense; hence, they almost always cause CAIS. Thus, PAIS is seldom due to exon 1 mutation [</B><B>Choong, Quigley et al 1996</B><B>]. A small number of major </B><B>AR</B><B> deletions and intronic alterations have been described.</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Expansion of the polyglutamine tract to >40 CAG repeats causes Kennedy disease (spinobulbar muscular atrophy with MAIS) [</B><B>La Spada et al 1991</B><B>]. All the foregoing information on disease-causing variants is stored in the </B><B>AR</B><B> Gene Mutations Database (see </B><B>Resources</B><B>). </B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Abnormal product: </B><B>1) Nearly all point mutations in the androgen-binding domain impair androgen binding and, therefore, transactivation by the AR. Some decrease only the apparent equilibrium affinity constant; some increase only the non equilibrium dissociation rate; others do both, either with all androgens, or selectively with certain androgens. Still others are thermolabile or degrade excessively in the presence of androgen. Point mutations in the zinc fingers or a-helical portions of the DNA-binding domain impair binding to a sequence of regulatory nucleotides known as an androgen response element. Such binding is essential for the AR to exert transcriptional regulatory control over most of its target genes. 2) The polyglutamine-expanded AR causes the spinobulbar muscular atrophy component of Kennedy </B><B>syndrome</B><B> by a gain-of-function that is selectively motor neuronotoxic. The precise mechanism of its neuronotoxicity has not been determined [</B><B>Abdullah et al 1998</B><B>]. The MAIS component of Kennedy </B><B>syndrome</B><B> is due to decreased transcriptional regulatory activity of the polyglutamine-expanded AR [</B><B>Kazemi-Esfarjani et al 1995</B><B>] or to its decreased synthesis [</B><B>Choong, Kemppainen et al 1996</B><B>]. </B></div> <div> <B>Gene Involved: </B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > <A NAME="ar"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></FONT><B>AR</B><B> </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Locus: </B><B>Xq11-q12 </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Normal allelic variants: </B><B>A polymorphic polyglutamine (CAG)</B><FONT SIZE="1" COLOR="#FFFFFF" FACE="Arial" ><B>n</B></FONT><B> CAA tract with n=10-33 starts at nt 172. A polymorphic polyglycine (GGT)</B><FONT SIZE="1" COLOR="#FFFFFF" FACE="Arial" ><B>3</B></FONT><B> GGG(GGT)</B><FONT SIZE="1" COLOR="#FFFFFF" FACE="Arial" ><B>2-4</B></FONT><B> GGC</B><FONT SIZE="1" COLOR="#FFFFFF" FACE="Arial" ><B>(n)</B></FONT><B> tract with n=4-25 starts at ~nt 1350 [</B><B>Lumbroso et al 1997</B><B>]. There is a silent G ® A transition at the third position of codon 211 in exon 1 (according to the numerology of Lubahn et al 1988, 1989; the same codon is numbered 207 in </B><B>Chang et al 1988</B><B>; its nt number is 709 in </B><B>Hiort et al 1994</B><B>; 995 in </B><B>Batch et al 1992</B><B>; and 1152 in </B><B>Chang et al 1988</B><B>). A </B><B>Hin</B><B>dIII RFLP is detectable by a 0.7 kb fragment of the AR cDNA that extends from near the 5' border of exon 2 to about the middle of exon 7. There are two polyA-addition signals about 220 nt apart. Coincidentally, there are two major species of AR mRNA (10-11 kb; ~7 kb) that result from alternative splicing of a very long 3'-UTR. Finally, there are two forms of the AR protein (A,B). Their size difference suggests that the short form (B) represents translation initiation at the internal Met-188 residue [</B><B>Wilson and McPhaul 1994</B><B>].</B></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f0ffffff00.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Normal product:</B><B> Androgen receptor. The entire N-terminal portion of the androgen receptor (~537 aa) is encoded by exon 1, the DNA-binding domain (aa 557-616) by exons 2 and 3, the bipartite nuclear localization signal (aa 617-636) by exons 3 and 4, and the androgen-binding domain (aa 645-919) by exons 4-8. The androgen receptor is a well defined transcriptional regulatory factor. Once activated by binding to androgen, it collaborates with other coregulatory proteins (some also DNA-binding, others not) to achieve vectorial control over the rate of transcription of an androgen target gene that is under the influence of a nearby promoter. </B></div> <bR> </tD> </tR> </TABLE></B></div> <bR> </td> </tr></table></body>