Handbook of Genetic Counseling/Androgen Insensitivity Syndrome

Androgen Insensitivity Syndrome Contracting Greet and welcome clients Acknowledge prior contact Thank them for taking time to do the phone intake Acknowledge their previously stated concerns I know you have a lot of questions and concerns and we are going to try and give you as much information as we have regarding this condition/diagnosis Overview of the agenda Since we already have a very detailed medical history, we will talk about family history a little bit Discuss AIS Symptoms Development Inheritance/Recurrence risk Answer any questions Review Intake Family History I know you main concern is AIS, but while we are taking the family history I am going to be asking a lot of questions about other conditions It is not b/c these things are associated with AIS, this is just to see if there is anything running in your family that we might be concerned about while you are here in genetics Any history of: AIS? Miscarriages, stillbirths, infant deaths? Chromosome abnormalities (like Down syndrome) MR, learning disabilities? Cancer? Heart problems? Hearing or vision problems? Birth defects (ex. CL/P, NTDs)? Metabolic disorders? Unusual facial features? Extra fingers or toes? Consanguinity? Ethnic backgrounds? Psychosocial Assessment What information have you found out regarding AIS? Where are your main sources of info? Internet, books, media How have you two been dealing with the diagnosis? Who have you been talking to about this besides doctors and other medical professionals? Family Friends Have these people been supportive? What are you planning to tell S about the diagnosis? When will you tell her? Have you sought support from other families with AIS? Are you interested in hearing about support group information? Are your doctors providing you with the information/care that you need? Do you have any concerns about finances? Being able to pay for hormone replacement/surgeries/medical care Genes & Chromosomes Basics of genes and chromosomes Cells à Chromosomes à Genes 23 pairs of chromosomes, one-copy Karyotype pictures Genetics of AIS "De novo" mutations X-linked Recessive Inheritenace Chromosomes show 46, XY Gene change is on the X chromosome 25% chance with each pregnancy 50% chance with boys Androgen Insensitivity Syndrome Mode of Inheritance: X-linked recessive Chromosome Location: Xq11-q12 Gene: AR gene Gene Product: Androgen receptor Molecular Genetics Sequence analysis available for all three subtypes of AIS >95% detection rate in patients with complete AIS There are normal allelic variants There are pathologic variants At least 150 point mutations in the AR gene cause AIS Majority are missense mutations Impair DNA or androgen binding that cause CAIS or PAIS Point mutations in exon one are relatively infrequent Also small deletions or insertions that cause frameshifts can cause CAIS Prevalence 2-5/100,000 for CAIS PAIS about as common as CAIS Clinical Features Subdivisions of 3 phenotypes Complete AIS (CAIS) Partial AIS (PAIS) Mild Androgen Insensitivity (MAIS) Diagnosis CAIS diagnosed clinically and with lab findings PAIS and MAIS may require a family history/X-linked inheritance General Clinical Features Absence of extragenital abnormalities Two nondysplastic testes Absent or rudimentary mǘllerian structures (i.e. no fallopian tubes, uterus, or cervix) and presence of a short vagina Undermasculinization of the external genitalia at birth Impaired spermatogenesis and/or somatic virilization at puberty CAIS Absent OR rudimentary wolfian duct derivatives Inguinal OR labial testes, short, blind-ending vagina Scant OR absent pubic AND/OR axillary hair PAIS (3 categories) Predominantly Female (incomplete AIS) Inguinal OR labial testes Clitomegaly and labial fusion Distinct urethral and vaginal openings OR a urogenital sinus Ambiguous Microphallus with clitoris-like underdeveloped glans; labia majora-like bifid scrotum Descended OR undescended testes Perineoscrotal hypospadias OR urogenital sinus Gynecomastia Predominantly male Simple (glandular or penile) OR severe isolated hypospadias with a normal-size penis and descended testes OR severe hypospadias with micropenis, bifid scrotum, and either descended OR undescended testes Gynecomastia in puberty MAIS Male (undervirilized male syndrome) Impaired spermatogenesis AND/OR impaired pubertal virilization Gynecomastia in puberty Testing Laboratory findings needed for diagnosis 46,XY karyotype Evidence of normal or increased synthesis of testosterone (T) by the testes Evidence of normal conversion of testosterone to dihydrotestosterone (DHT) Evidence of normal or increased luteinizing hormone (LH) production by the pituitary gland Evidence of deficient or defective androgen-binding activity of genital skin fibroblasts Family History Diagnosis of PAIS and MAIS may require a family history of the condition with X-linked recessive inheritance Carriers may have asymmetric distribution and sparse or delayed growth of pubic and/or axillary hair Carriers may also have a history of late (15 yrs) or delayed (16 yrs) menarche Molecular genetic testing Greater than 90% of patients with CAIS have an identifiable disease-causing mutations in the AR gene Fewer than 50% of patients with PAIS have identifiable disease-causing mutations in the AR gene Sequence analysis is currently available clinically in USA and Canada Sequencing if eight exons is performed >95% detection rate in patients with CAIS Linage analysis Not clinically available Testing Laboratories All Children's Hospital Molecular Genetics Laboratory St. Petersburg, FL email: muellert@allkids.org phone: (727) 892-8985 fax: (727) 892-8367 Test performed Diagnostic direct mutation analysis Sequence analysis is performed for the entire coding region of the androgen receptor (AR) gene associated with complete, partial and mild androgen insensitivity syndromes. Specimen requirements In most cases, a single tube of 4 cc whole blood collected in EDTA [lavender top] tubes is sufficient. Minimum specimen on infants is 0.5 cc EDTA whole blood. Turn around time Most testing is completed within a target turn-around time of 21 days following specimen receipt. Test results are phoned in or faxed, as requested, in addition to the written report GeneDx, Inc Gaithersburg, MD email: cheryl@genedx.com phone:(301) 519-2100 ext103 fax: (301) 519-2892 Test performed Direct mutation analysis Mutations in the X-linked AR gene are identified by complete sequence analysis of each of 8 AR exons and intron/exon boundaries. The analysis is done on genomic DNA obtained from buccal swabs. Prenatal diagnosis is available once the mutation in a family has been defined. Specimen requirements Prefer buccal swabs Turn around time ~6 weeks For prenatal diagnosis where mutation is known: ~2 weeks Costs Mutation detection requires an affected individual and costs $1500 DNA testing of relatives for a known mutation is $350 Prenatal diagnosis $700 plus any additional cost for ruling out maternal contamination of fetal sample Management Modalities Surgery Psychological Support Hormone replacement or supplementation CAIS Removal of testes Estrogen replacement therapy to initiate puberty, maintain feminization, and avoid osteoporosis PAIS and predominantly female genitalia Prepubertal gonadectomy Psychological support HRT PAIS and ambiguous genitalia Sex assignment in infancy Reconstructive surgeries After puberty, surgery to correct gynecomastia if necessary Androgen replacement therapy to maintain libido MAIS Reduction mammoplasty for gynecomastia Trial of androgen pharmacotherapy to improve virilization Differential Diagnosis Hypospadias not resulting from AR gene mutations MAIS sue to point mutations of the androgen receptor gene Undermasculinization of the external genitalia and pubertal undervirilization are components of many syndromes unrelated to AIS Prenatal Options Prenatal Diagnosis Can look for complete AIS with direct DNA squencing for mutations To prepare for birth of another baby with AIS or to consider termination Can be done with CVS or with Amniocentesis Preimplantation genetic diagnosis Analyzes eggs prior to implantation to find out sex Daughters are not affected with AIS Conclusions Review what was discussed in the session Answer any final questions Give resource information and phone number Notes The information in this outline was last updated in 2003.