Background:

Androgen effects in humans are usually (but not always) mediated by the androgen receptor which is coded for by the androgen receptor gene (AR gene). Androgen Insensitivity Syndrome (AIS) is a rare condition in which the body cannot sense the male hormones in the blood or tissue. Both women and men can be affected by AIS. Researchers want to learn more about the health of people with AIS over time.

With a natural history study in individuals with AIS, data and tests may provide information regarding health risks (including the risks and benefits of gonadectomy and best ways to monitor for tumor) and optimal management of individuals with AIS as well as elucidate the role of the androgen receptor in human health. This study does not involve any interventions and we can provide clinical care while collecting data.

Objective:

The objective of this natural history study is to describe and define a comprehensive phenotype (characteristic) of patients with AIS based on confirmed androgen receptor (AR) gene difference. We will evaluate hormones, bone density and markers, cardiovascular and metabolic parameters, as well as quality of life and tumor formation risk and evaluation. The purpose is to obtain a better understanding of the overall health issues that people with AIS may have through the study procedures listed.

Eligibility:

People ages 8-99 with AIS and their adult relatives

Design:

Participants will go through a series of study procedures for data and specimen collection. This will be done to understand how AIS affects individuals since the androgen receptor is found in many tissues in the body including skin, bone, muscle, and the neurologic, immune and metabolic systems. All tests will be performed by skilled and trained study professionals.

Participants will be screened with:

Medical history

Physical exam

Medical record review

Lab tests.

Participants will have physical exams. Their body measurements will be taken. They will have blood and urine tests. They will have electrocardiograms to check heart health. They may complete questionnaires. They may have an Oral Glucose Tolerance Test.

Participants may have x-rays and HRpQCT scans taken of the hand, wrist, and other bones.

Participants will have body scans to measure bone thickness.

Participants will have magnetic resonance imaging (MRI) or sonogram of the pelvis. For MRI, they may get a contrast agent via intravenous (IV) catheter.

Adult participants may have the following:

MR elastography. It uses MRI and low-frequency vibrations to map stiffness of body tissues.

MR spectroscopy. It uses MRI to take pictures of chemicals in the liver and body fat.

Cardiac computed tomography scan. It uses x-rays to make pictures of the heart. Participants may get a contrast agent via IV.

Optional genital exam.

Optional one-time vaginal swab.

Participants will have visits every 1-2 years. Participation lasts indefinitely.

Adult relatives will also be invited to participate but will have only 1 visit. It will include some of the above tests.

Study Description: This is a natural history study of individuals with androgen receptor gene abnormalities.

Objectives:

Primary Objectives:

To define and describe a comprehensive phenotype of patients with androgen insensitivity (based on confirmed androgen receptor

(AR) gene difference), including hormonal, metabolic, immunologic, and cardiovascular aspects of AIS, as well as quality life and tumor formation risk and evaluation.

Secondary Objectives:

1. Bone Health:

   - Follow a large population of patients with androgen receptor abnormalities for:

   • Longitudinal assessment of bone mineral density (BMD) before and after gonadectomy

   • Development of normative values for dual-energy X-ray absorptiometry (DEXA) and high-resolution peripheral quantitative computed tomography (HRpQCT) scans in individual with complete androgen insensitivity syndrome (CAIS) and family members.

   • Studies to determine bone geometry, strength and shape,

     • Studies to determine muscle-skeletal unit inferences
     • Studies to evaluate skin tone

   • Evaluation of bone accrual from childhood to adolescence

2. Metabolic and Immune Abnormalities:

   - Follow a large population of patients with androgen receptor abnormalities for studies of metabolic abnormalities and auto-immune disease screening

   • Metabolic syndrome,

     • Insulin resistance
     • Cardiovascular markers
     • Endometabolic imaging

   • Autoimmune screening tests

3. Testicular Tumor Risk and Monitoring:

   - Follow a large population of patients with androgen receptor abnormalities in order to:

   -- Describe the typical and atypical appearance of testes on ultrasound and magnetic resonance imaging (MRI) in young individual with

   CAIS.

   • Evaluate gonadal tumor markers as a tool to assess for gonadal tumor.

     - When individuals with androgen receptor abnormalities decide to undergo gonadectomy, perform tissue evaluation in order to:

   • Investigate the pathophysiology of gonadal tumor formation

   • Assess fertility potential in testis of individual with androgen receptor abnormalities

4. Quality of Life:

   • Follow a large population of patients with androgen receptor abnormalities to characterize quality of life measures throughout the lifespan
   • Evaluate the effects of androgen receptor abnormalities on individual s sexual function. Compare sexual function in adult individuals with androgen receptor abnormalities to individual with classic congenital adrenal hyperplasia (CAH) and unaffected individual of

   similar ages.

5. Hormone Replacement:

   - Evaluate different types and delivery of hormone replacement therapy on quality of life, sexual function, bone health and metabolic parameters in individual who have undergone gonadectomy

6. Follow a sample population of relatives of individuals with androgen insensitivity syndrome (AIS) in order to assess the effects of AR gene difference carrier status phenotype including hormonal, metabolic, immunologic, quality of life, and tumor formation. Family members without AR gene abnormalities will serve as controls.

Follow a large population of patients with AIS for referral to future treatment studies.

Endpoints:

Primary Endpoint: Longitudinal evaluation of 500 individuals with AIS.

Secondary:

• DEXA and HRpQCT scans and bone metabolism markers will be evaluated longitudinally in all individuals with AIS. Additionally, these will be correlated with muscle grip and skin tone studies.
• Compare metabolic parameters in all individuals with AIS.
• Compare gonadal tissue with MRI or ultrasound in all individuals with AIS.
• Evaluate Quality of life with Quality of Life (QoL) questionnaire.

• INCLUSION CRITERIA:

Inclusion Criteria for AIS Subjects

In order to be eligible to participate in this study, an individual must meet all the following criteria:

1. Individuals ages 8-99 years old with known androgen insensitivity based on pathologic androgen receptor gene mutation or based on clinical diagnosis of complete androgen insensitivity (CAIS) based on 46 XY karyotype, presence of testis, absence of uterus, high testosterone without signs of virilization at birth or during puberty and/or multiple members in the family also presenting with clinical CAIS.
2. Identify as male or female
3. Patients with both complete, partial, and mild androgen insensitivity are eligible
4. Stated willingness to comply with all study procedures and availability for the duration of the study
5. Ability of subject or guardian to understand and the willingness to sign and date a written informed consent document.

Inclusion Criteria for Relative of AIS Subjects

1) Adult Relatives of patients with AIS

EXCLUSION CRITERIA:

Exclusion Criteria for AIS Subjects

1. An individual who meets any of the following criteria will be excluded from participation in this study: Patients with other diagnoses such as partial or complete gonadal dysgenesis, 5-alpha reductase deficiency, and 46 XY. If, following a diagnostic work-up, a patient is determined to have causes for 46 XY DSD other than androgen insensitivity; they will no longer be followed on this protocol. They will have the opportunity to continue care with the team under the Data Collection Protocol or may be referred to an expert or multidisciplinary DSD team in the community.
2. Patients with significant non-endocrine medical conditions.

Exclusion Criteria for Relative of AIS Subjects

1) Patients with significant non-endocrine medical conditions.

We will enroll and evaluate 500 patients with confirmed androgen receptor mutations. We will enroll 50 female relatives who are carriers of the AR gene difference and 50 female relatives who are not carriers of the AR gene and 50 healthy male relatives.