METHODOLOGY

METHODOLOGY
	Chapter 1 INTRODUCTION

These guidelines have been produced by a consortium consisting mainly of: (1) clinical specialists with experience helping patients with DSD; (2) adults with DSD; and (3) family members (especially parents) of children with DSD. These guidelines are therefore unique in that they benefit from the experiences of the three groups (clinicians, patients, and parents) that comprise the DSD clinical triad. A number of the contributors have been in meaningful communication with dozens or even hundreds of individuals and families with personal experience of DSD. They drew on those relationships in this work.

While this document benefits from the large literature (medical, sociological, and autobiographical) available on DSD, consultation with these three groups has helped to address the substantial evidentiary gaps in the medical literature on DSD treatment (e.g., the lack of evidence regarding long-term outcomes of current medical and surgical options). It has also provided an important three-way consensus surrounding the patient-centered care philosophy at the core of these guidelines.

The authors seek continued dialogue with those with personal and clinical DSD experience in order to refine these recommendations. This handbook represents only the first of numerous anticipated editions. Feedback may be provided by using the “contact” link available at http://www.dsdguidelines.org.

Note: Readers of this clinical handbook are encouraged to utilize the companion “Handbook for Parents” available through http://www.dsdguidelines.org. A pair of handbooks is also planned for adults with DSD and for the clinicians who care for them.

	HOW DO DSD HAPPEN?
Sex development in the human is the result of a complex interaction of an individual’s genes and his or her environment. DSD by definition occur when an individual’s sex development takes a path different from that of the typical female or typical male.[Grumbach1998 Horowitz1992 New1992 Kupfer1992] Typical male development begins with a 46,XY chromosomal complement. By the 6^th week after conception, the embryo has developed two bipotential gonads. The SRY gene (located on the Y chromosome) causes production of the SRY transcription factor which, in conjunction with genes not located on the Y chromosome, induces the gonads to differentiate into testes. Although the embryo initially forms both the Wolffian (male) and Mullerian (female) ducts, the testes produce Mullerian-inhibiting substance (MIS), causing the Mullerian ducts to regress. By about the 12^th week, testosterone produced by the testes cause the Wolffian ducts to form the spermatic ducts. The external genitalia are sexually undifferentiated until the 7^th week. Androgens produced by the testes cause the external genitalia to develop into the typical male; the proto-phallus becomes a penis, the labioscrotal folds fuse in the midline to form the scrotum, and the urethra migrates distally to a male-typical position. At puberty, testicular production of testosterone contributes to further sex differentiation. Sex differentiation in the brain appears to be the result of hormonal differentiation and social factors. Typical female development begins with a 46,XX chromosomal complement. Unless the SRY and TDF genes are present, the bipotential gonads develop into ovaries, the Wolffian ducts atrophy, and the Mullerian ducts develop into the uterus, Fallopian tubes, cervix, and the upper portion of the vagina. Because ovaries do not produce androgens, the proto-phallus becomes a clitoris, the labioscrotal folds become the labia, and the urethra maintains a female-typical position. At puberty, the ovaries produce estrogen and so contribute to further sex differentiation. Sex differentiation in the brain appears to be the result of hormonal differentiation and social factors. Causes of DSD include chromosomal and genetic anomalies, in utero exposure to sex hormones ingested or produced by the mother, and random developmental variation. Because sex development involves many points of differentiation—only a few of which are mentioned above—the potential for DSD exists at many stages of human development. Ascertaining the etiology of a DSD helps prepare patients and parents for what is to come, aids in deciding gender assignment, highlights potential problems like adrenal crisis or gonadoblastomas, and may help determine likelihood of a subsequent child being affected. Also, some family support groups are open only to patients with particular diagnoses. Nevertheless, it is not always possible to pinpoint the exact cause of a given patient’s sexual variation. An excellent animation of sex development is available at www.aboutkidshealth.ca/En/HowTheBodyWorks/SexDevelopmentAnOverview/

HOW DO DSD HAPPEN?

Sex development in the human is the result of a complex interaction of an individual’s genes and his or her environment. DSD by definition occur when an individual’s sex development takes a path different from that of the typical female or typical male.[Grumbach1998 Horowitz1992 New1992 Kupfer1992]

Typical male development begins with a 46,XY chromosomal complement. By the 6^th week after conception, the embryo has developed two bipotential gonads. The SRY gene (located on the Y chromosome) causes production of the SRY transcription factor which, in conjunction with genes not located on the Y chromosome, induces the gonads to differentiate into testes. Although the embryo initially forms both the Wolffian (male) and Mullerian (female) ducts, the testes produce Mullerian-inhibiting substance (MIS), causing the Mullerian ducts to regress. By about the 12^th week, testosterone produced by the testes cause the Wolffian ducts to form the spermatic ducts. The external genitalia are sexually undifferentiated until the 7^th week. Androgens produced by the testes cause the external genitalia to develop into the typical male; the proto-phallus becomes a penis, the labioscrotal folds fuse in the midline to form the scrotum, and the urethra migrates distally to a male-typical position. At puberty, testicular production of testosterone contributes to further sex differentiation. Sex differentiation in the brain appears to be the result of hormonal differentiation and social factors.

Typical female development begins with a 46,XX chromosomal complement. Unless the SRY and TDF genes are present, the bipotential gonads develop into ovaries, the Wolffian ducts atrophy, and the Mullerian ducts develop into the uterus, Fallopian tubes, cervix, and the upper portion of the vagina. Because ovaries do not produce androgens, the proto-phallus becomes a clitoris, the labioscrotal folds become the labia, and the urethra maintains a female-typical position. At puberty, the ovaries produce estrogen and so contribute to further sex differentiation. Sex differentiation in the brain appears to be the result of hormonal differentiation and social factors.

Causes of DSD include chromosomal and genetic anomalies, in utero exposure to sex hormones ingested or produced by the mother, and random developmental variation. Because sex development involves many points of differentiation—only a few of which are mentioned above—the potential for DSD exists at many stages of human development. Ascertaining the etiology of a DSD helps prepare patients and parents for what is to come, aids in deciding gender assignment, highlights potential problems like adrenal crisis or gonadoblastomas, and may help determine likelihood of a subsequent child being affected. Also, some family support groups are open only to patients with particular diagnoses. Nevertheless, it is not always possible to pinpoint the exact cause of a given patient’s sexual variation. An excellent animation of sex development is available at www.aboutkidshealth.ca/En/HowTheBodyWorks/SexDevelopmentAnOverview/

	NOTE:
The challenges of clinical diagnosis for some DSD along with the variability in the presentation of some DSD mean that clinically DSD are sometimes identified by etiology and sometimes by phenotype. As a consequence, some of the following categories may overlap; for example, a patient may have sex-chromosome mosaicism and ovotestes. This list is not meant to be exhaustive of all conditions that might be considered DSD, nor is it meant to be exhaustive of diagnosis-specific concerns. All DSD have the potential to cause psychosocial distress for patients and their families, particularly if genital anatomy is atypical. Regardless of etiology or phenotype, parents’ and patient’s psychosocial concerns should be promptly addressed by qualified mental health professionals.

NOTE:

The challenges of clinical diagnosis for some DSD along with the variability in the presentation of some DSD mean that clinically DSD are sometimes identified by etiology and sometimes by phenotype. As a consequence, some of the following categories may overlap; for example, a patient may have sex-chromosome mosaicism and ovotestes. This list is not meant to be exhaustive of all conditions that might be considered DSD, nor is it meant to be exhaustive of diagnosis-specific concerns.

All DSD have the potential to cause psychosocial distress for patients and their families, particularly if genital anatomy is atypical. Regardless of etiology or phenotype, parents’ and patient’s psychosocial concerns should be promptly addressed by qualified mental health professionals.

	DSD AND RELATED CONCERNS
17-beta reductase deficiency (XX or XY)—Appearance female but can’t make estrogen or testosterone; consequently no pubertal changes. Monitor undescended testes for malignancies. Risk of adrenal insufficiency. 46,XY 3-beta-hydroxysteroid dehydrogenase (HSD) deficiency—Usually lethal; risk of severe adrenal deficiency. Endocrine management necessary for maintenance of health and fertility. 5-alpha reductase (5-AR) deficiency—Evidence suggests substantial variation in gender identity outcomes.[Cohen-Kettenis2005] If patient raised as girl, decisions need to be made before puberty about management of masculinizing puberty (e.g., patient may elect orchidectomy). Complete Androgen Insensitivity Syndrome (CAIS)—Raise as girls. Infertile with current technologies. Undescended testicular tissue presents increased risk of malignancy after puberty; counsel patient to consider orchidectomy following puberty. (Delay until puberty allows patient to experience a natural feminizing puberty and to choose orchidectomy.) Vagina may be shorter than average; if patient wishes to lengthen her vagina, she may elect pressure dilation or secondarily surgical intervention. Partial Androgen Insensitivity Syndrome (PAIS)—Initial gender assignment should take into account that higher degrees of prenatal androgen exposure may direct the brain to develop in a more classically-masculine fashion. (It is probable that the more virilized the genitalia, the more likely the brain has been masculinized.) Testosterone injections can be used to test responsiveness. Note that, if the patient is being raised as a girl, the testes will cause some pubertal virilization; leuprolide (marketed as Lupron) may be used to delay puberty so that patient’s decision-making about orchidectomy is not rushed. If patient wishes to lengthen her vagina, she may elect pressure dilation or secondarily surgical intervention. If the patient is being raised as a boy, offer the patient hormone therapy at puberty. aphallia—If normal testes, assume the brain has been masculinized. Evidence exists that, if assigned as girls, a notable percentage of these children transition later to become boys. May be fertile; preserve fertility. Any urethro-rectal communication must be repaired to avoid infection and kidney damage. clitoromegaly—Test for CAH, PAIS, etc. Test mother for virilizing condition. 46,XY cloacal exstrophy—Complex disorder with variable presentation; long-term survival approximately 70%. In the past many of these children were raised as girls; a notable number of these children have transitioned to boys. Removal of healthy testes should not be performed without patient’s consent as it eliminates fertility. 46,XX congenital adrenal hyperplasia (CAH)—CAH is potentially life-threatening. Until it has been ruled out, prompt diagnosis and treatment should be considered in all children with genital ambiguity. In cases of CAH, endocrine management is necessary for maintenance of health and fertility and to prevent premature puberty. Menses require drainage opening (separate from urinary system) to avoid pain and infection. Internalized vagina may be a source of urine pooling and infection if left uncorrected. gonadal dysgenesis (partial and complete)—Dysgenetic gonads present substantially elevated risk for malignancies. Infertile. Karyotype varies. hypospadias—Test for CAH, PAIS, etc. If associated with chordee, there may be significant pain with erection. Increased risk of urinary tract infections. Location of meatus may interfere with sperm delivery (fertility); patient may decide to address this with artificial insemination or surgery. Patient may also spray urine or need to urinate in a seated position; see general note above on psychosocial concerns. Hypospadias in conjunction with cryptorchidism increases likelihood of underlying DSD. Kallman Syndrome—Raise in concordance with chromosomal sex. Males potentially fertile. Anosmia (absence of sense of smell). 47,XXY (Klinefelter Syndrome)—Genitalia typically unambiguously male, although testes may be small. Gynecomastia common at puberty. Likelihood of azoospermia; reproductive technologies may be used to enhance fertility. Some learning disabilities are associated with 47,XXY; address with help from learning disability specialists. Mayer, Rokitansky, Kuster, Hauser Syndrome (also known as MRKH, Mullerian agenesis, vaginal agenesis)—Ovaries present with uterus absent, misshapen, or small; associated with kidney and spine anomalies in a minority of patients. Patient may elect pressure dilation or secondarily surgical augmentation if she seeks increased vaginal length. 46,XY micropenis—In the past many experts counseled raising these children as girls. Evidence suggests these children can do well as boys and that, if assigned as girls, they may transition later to become boys. Causes variable; one cause of 46,XY micropenis is congenital pan-hypopituitarism, which in males is commonly associated with potentially lethal hypoglycemia, the result of growth hormone and ACTH deficiencies. Unless the pan-hypopituitarism is corrected, this hypoglycemia is typically unresponsive to most standard interventions. ovary and testis, and/or ovotestes (historically called true hermaphroditism)—Testicular tissue presents an increased risk for malignancies. (Note: Use of the term “true hermaphroditism” unnecessarily frightens parents and patients; explain that this is the official term in the medical literature, but that it is a misnomer.) Persistent Mullerian Duct Syndrome—Risk of cryptorchidism and associated complications. Increased risk of infertility. progestin-induced virilization—History of virilizing hormone exposure is limited to prenatal life, so virilization will not progress. sex-chromosome mosaicism (e.g., 45,X/46,XY)—Genotypes and phenotypes vary; may appear ambiguous or may appear unambiguously male or female. Monitor for gonadal malignancies. Swyer Syndrome (another name for 46,XY gonadal dysgenesis)—See gonadal dysgenesis, above. 45,X (Turner Syndrome)—High phenotypic variability. Genitalia typically unambiguously female. Usually infertile except through egg donation and in vitro fertilization. Short stature. Association with cardiac and renal anomalies. Heightened risk of non-verbal learning disabilities; address with help from learning disability specialists.

DSD AND RELATED CONCERNS

17-beta reductase deficiency (XX or XY)—Appearance female but can’t make estrogen or testosterone; consequently no pubertal changes. Monitor undescended testes for malignancies. Risk of adrenal insufficiency.

46,XY 3-beta-hydroxysteroid dehydrogenase (HSD) deficiency—Usually lethal; risk of severe adrenal deficiency. Endocrine management necessary for maintenance of health and fertility.

5-alpha reductase (5-AR) deficiency—Evidence suggests substantial variation in gender identity outcomes.[Cohen-Kettenis2005] If patient raised as girl, decisions need to be made before puberty about management of masculinizing puberty (e.g., patient may elect orchidectomy).

Complete Androgen Insensitivity Syndrome (CAIS)—Raise as girls. Infertile with current technologies. Undescended testicular tissue presents increased risk of malignancy after puberty; counsel patient to consider orchidectomy following puberty. (Delay until puberty allows patient to experience a natural feminizing puberty and to choose orchidectomy.) Vagina may be shorter than average; if patient wishes to lengthen her vagina, she may elect pressure dilation or secondarily surgical intervention.

Partial Androgen Insensitivity Syndrome (PAIS)—Initial gender assignment should take into account that higher degrees of prenatal androgen exposure may direct the brain to develop in a more classically-masculine fashion. (It is probable that the more virilized the genitalia, the more likely the brain has been masculinized.) Testosterone injections can be used to test responsiveness. Note that, if the patient is being raised as a girl, the testes will cause some pubertal virilization; leuprolide (marketed as Lupron) may be used to delay puberty so that patient’s decision-making about orchidectomy is not rushed. If patient wishes to lengthen her vagina, she may elect pressure dilation or secondarily surgical intervention. If the patient is being raised as a boy, offer the patient hormone therapy at puberty.

aphallia—If normal testes, assume the brain has been masculinized. Evidence exists that, if assigned as girls, a notable percentage of these children transition later to become boys. May be fertile; preserve fertility. Any urethro-rectal communication must be repaired to avoid infection and kidney damage.

clitoromegaly—Test for CAH, PAIS, etc. Test mother for virilizing condition.

46,XY cloacal exstrophy—Complex disorder with variable presentation; long-term survival approximately 70%. In the past many of these children were raised as girls; a notable number of these children have transitioned to boys. Removal of healthy testes should not be performed without patient’s consent as it eliminates fertility.

46,XX congenital adrenal hyperplasia (CAH)—CAH is potentially life-threatening. Until it has been ruled out, prompt diagnosis and treatment should be considered in all children with genital ambiguity. In cases of CAH, endocrine management is necessary for maintenance of health and fertility and to prevent premature puberty. Menses require drainage opening (separate from urinary system) to avoid pain and infection. Internalized vagina may be a source of urine pooling and infection if left uncorrected.

gonadal dysgenesis (partial and complete)—Dysgenetic gonads present substantially elevated risk for malignancies. Infertile. Karyotype varies.

hypospadias—Test for CAH, PAIS, etc. If associated with chordee, there may be significant pain with erection. Increased risk of urinary tract infections. Location of meatus may interfere with sperm delivery (fertility); patient may decide to address this with artificial insemination or surgery. Patient may also spray urine or need to urinate in a seated position; see general note above on psychosocial concerns. Hypospadias in conjunction with cryptorchidism increases likelihood of underlying DSD.

Kallman Syndrome—Raise in concordance with chromosomal sex. Males potentially fertile. Anosmia (absence of sense of smell).

47,XXY (Klinefelter Syndrome)—Genitalia typically unambiguously male, although testes may be small. Gynecomastia common at puberty. Likelihood of azoospermia; reproductive technologies may be used to enhance fertility. Some learning disabilities are associated with 47,XXY; address with help from learning disability specialists.

Mayer, Rokitansky, Kuster, Hauser Syndrome (also known as MRKH, Mullerian agenesis, vaginal agenesis)—Ovaries present with uterus absent, misshapen, or small; associated with kidney and spine anomalies in a minority of patients. Patient may elect pressure dilation or secondarily surgical augmentation if she seeks increased vaginal length.

46,XY micropenis—In the past many experts counseled raising these children as girls. Evidence suggests these children can do well as boys and that, if assigned as girls, they may transition later to become boys. Causes variable; one cause of 46,XY micropenis is congenital pan-hypopituitarism, which in males is commonly associated with potentially lethal hypoglycemia, the result of growth hormone and ACTH deficiencies. Unless the pan-hypopituitarism is corrected, this hypoglycemia is typically unresponsive to most standard interventions.

ovary and testis, and/or ovotestes (historically called true hermaphroditism)—Testicular tissue presents an increased risk for malignancies. (Note: Use of the term “true hermaphroditism” unnecessarily frightens parents and patients; explain that this is the official term in the medical literature, but that it is a misnomer.)

Persistent Mullerian Duct Syndrome—Risk of cryptorchidism and associated complications. Increased risk of infertility.

progestin-induced virilization—History of virilizing hormone exposure is limited to prenatal life, so virilization will not progress.

sex-chromosome mosaicism (e.g., 45,X/46,XY)—Genotypes and phenotypes vary; may appear ambiguous or may appear unambiguously male or female. Monitor for gonadal malignancies.

Swyer Syndrome (another name for 46,XY gonadal dysgenesis)—See gonadal dysgenesis, above.

45,X (Turner Syndrome)—High phenotypic variability. Genitalia typically unambiguously female. Usually infertile except through egg donation and in vitro fertilization. Short stature. Association with cardiac and renal anomalies. Heightened risk of non-verbal learning disabilities; address with help from learning disability specialists.


DEFINITION OF PATIENT-CENTERED CARE FOR DSD		Chapter 2 TREATMENT GUIDELINES