Key points

Introduction

A request to see a newborn with genital ambiguity is an uncommon experience in the career of most pediatricians. However, when including the full range of disorders of sex development (DSD), the prevalence is approximately 1 in 1500 births with significant genital ambiguity found in about 1 in 5000 births. The pediatrician is faced with the clinical concerns of acute threats to the infant’s clinical status, establishing a differential diagnosis, determining appropriate investigations and, importantly, providing explanation and support to the parents in an honest and sensitive way. This article reviews normal sexual differentiation, highlights key points in the medical history and physical examination noting normal findings, suggests a rational approach to investigation, and provides guidance on support for parents and families.

Sexual differentiation

The components of physical sexual differentiation include chromosomes, gonads, and internal and external genitalia. Other important concepts include gender identity, one’s internal sense of gender, and gender role, one’s gender-related behavior and interests in society. The recognition that all infants begin sexual differentiation with the same bipotential structures and that the expression of many genes, transcription factors, enzymes, and receptors leads to typical male and female development is critical ( Fig. 1 ). Explanation of these concepts to parents is helpful in describing how atypical sexual differentiation occurs.

Overview of the major events involved in sex determination and sex differentiation. Mutations or deletions in the genes shown in upper case letters have been reported or proposed as causes of disorders of sex development or gonadal failure in humans. The genes and factors shown in lower case letters have been proposed to play an important role in sex development, largely from studies of mice. DHT, dihydrotestosterone; hCG, human chorionic gonadotropin; LH, luteinizing hormone.

( From Kronenberg HM, Melmed S, Polonsky KS, et al. Textbook of Endocrinology, 12th edition. Philadelphia: Elsevier; 2011. p. 868–934; with permission.)

Development occurs in 2 phases, first “sex determination”, the development of the undifferentiated gonad into a testis or ovary and then, “sexual differentiation”, where phenotypic sex develops through the action of gonadal and other hormones. In typical male development, action of the SRY gene (which resides on the Y chromosome) and many other genes lead to the development of testes at around 6 weeks of gestation. Primordial germ cells then migrate to the gonad. In early pregnancy human chorionic gonadotropin (hCG) stimulates the Leydig cells of the testes to produce androgens. Luteinizing hormone (LH) from the pituitary gland takes over this function during the second and third trimesters. Signaling through the androgen receptor then leads to the development of the Wolffian ducts to form the internal genital structures of vas deferens, seminal vesicles, and epididymis during the first trimester. Anti-Müllerian hormone (AMH) production by the Sertoli cells of the testes leads to regression of the Müllerian ducts. Androgens and AMH act on the internal genitalia in a local fashion. Testosterone converted in the external genital structures to dihydrotestosterone (DHT) by the enzyme, 5α-reductase, leads to pigmentation, rugation, and fusion of the labioscrotal folds, growth of the phallic structure to form the penis, and migration of the urethra to the tip of the penis. The majority of these events occur in the first trimester with ongoing growth of the penis throughout gestation and descent of the testes in the last half of the third trimester.

In typical female development, actions of genes on the X chromosome and other autosomal genes such as WNT4, R-spondin 1, and FOXL2 lead to ovarian development. Estrogen secretion by the ovary is not required for female internal or external genital development. The WNT4 gene is also required for formation of the Müllerian structures of the uterus, fallopian tubes, and upper third of the vagina. Without testis, the lack of AMH allows the Müllerian structures to persist, whereas lack of androgen leads to regression of the Wolffian ducts and allows typical female external genitalia to develop.

Introduction

A request to see a newborn with genital ambiguity is an uncommon experience in the career of most pediatricians. However, when including the full range of disorders of sex development (DSD), the prevalence is approximately 1 in 1500 births with significant genital ambiguity found in about 1 in 5000 births. The pediatrician is faced with the clinical concerns of acute threats to the infant’s clinical status, establishing a differential diagnosis, determining appropriate investigations and, importantly, providing explanation and support to the parents in an honest and sensitive way. This article reviews normal sexual differentiation, highlights key points in the medical history and physical examination noting normal findings, suggests a rational approach to investigation, and provides guidance on support for parents and families.

Sexual differentiation

The components of physical sexual differentiation include chromosomes, gonads, and internal and external genitalia. Other important concepts include gender identity, one’s internal sense of gender, and gender role, one’s gender-related behavior and interests in society. The recognition that all infants begin sexual differentiation with the same bipotential structures and that the expression of many genes, transcription factors, enzymes, and receptors leads to typical male and female development is critical ( Fig. 1 ). Explanation of these concepts to parents is helpful in describing how atypical sexual differentiation occurs.

Overview of the major events involved in sex determination and sex differentiation. Mutations or deletions in the genes shown in upper case letters have been reported or proposed as causes of disorders of sex development or gonadal failure in humans. The genes and factors shown in lower case letters have been proposed to play an important role in sex development, largely from studies of mice. DHT, dihydrotestosterone; hCG, human chorionic gonadotropin; LH, luteinizing hormone.

( From Kronenberg HM, Melmed S, Polonsky KS, et al. Textbook of Endocrinology, 12th edition. Philadelphia: Elsevier; 2011. p. 868–934; with permission.)

Development occurs in 2 phases, first “sex determination”, the development of the undifferentiated gonad into a testis or ovary and then, “sexual differentiation”, where phenotypic sex develops through the action of gonadal and other hormones. In typical male development, action of the SRY gene (which resides on the Y chromosome) and many other genes lead to the development of testes at around 6 weeks of gestation. Primordial germ cells then migrate to the gonad. In early pregnancy human chorionic gonadotropin (hCG) stimulates the Leydig cells of the testes to produce androgens. Luteinizing hormone (LH) from the pituitary gland takes over this function during the second and third trimesters. Signaling through the androgen receptor then leads to the development of the Wolffian ducts to form the internal genital structures of vas deferens, seminal vesicles, and epididymis during the first trimester. Anti-Müllerian hormone (AMH) production by the Sertoli cells of the testes leads to regression of the Müllerian ducts. Androgens and AMH act on the internal genitalia in a local fashion. Testosterone converted in the external genital structures to dihydrotestosterone (DHT) by the enzyme, 5α-reductase, leads to pigmentation, rugation, and fusion of the labioscrotal folds, growth of the phallic structure to form the penis, and migration of the urethra to the tip of the penis. The majority of these events occur in the first trimester with ongoing growth of the penis throughout gestation and descent of the testes in the last half of the third trimester.

In typical female development, actions of genes on the X chromosome and other autosomal genes such as WNT4, R-spondin 1, and FOXL2 lead to ovarian development. Estrogen secretion by the ovary is not required for female internal or external genital development. The WNT4 gene is also required for formation of the Müllerian structures of the uterus, fallopian tubes, and upper third of the vagina. Without testis, the lack of AMH allows the Müllerian structures to persist, whereas lack of androgen leads to regression of the Wolffian ducts and allows typical female external genitalia to develop.

Nomenclature

Terms used in this area such as “hermaphrodite,” “pseudohermaphrodite,” and “sex reversal” have been confusing to many and have been experienced as stigmatizing by patients. A consensus conference was held in 2005 that led to the development of new terminology that has been widely adopted. This terminology is based on the sex chromosomal constitution and uses the term “disorders of sex development” (DSD) to describe the wide range of conditions involved. Some criticism of this nomenclature has been presented, but overall it has been helpful. See Table 1 for details.

Care of the infant

Infants with genital ambiguity benefit from assessment and care by a specialized team with expertise in DSD. Subspecialty telephone consultation with the local team can help to determine the immediate plan of action, particularly when the distance to an experienced team is great or travel is difficult. Those babies with severe genital ambiguity need a rapid assessment by an expert team to facilitate efficient access to the appropriate consultations and investigations while providing support to the family. This goal can be accomplished by transferring the infant to the team’s site or by a timely outpatient multidisciplinary assessment.

The majority of infants with genital ambiguity are otherwise healthy. Concern about the possibility of an adrenal crisis in healthy full-term infants often leads to admission to a neonatal intensive care unit. Because clinically significant salt wasting is extremely uncommon until the second week of life, full-term infants without other health issues can stay in their mother’s room at the birthing hospital or, if transferred to a tertiary care hospital, be admitted to a ward competent in newborn care with the parents staying with the infant. This approach supports bonding with the infant and may reduce the trauma that some parents experience. It is also important that the baby undergo a careful physical examination by those involved in the infant’s care, but not be subjected to multiple examinations by junior learners, because parents may experience that the infant is “on display.” Care should be taken to use gender neutral terms such as “your baby,” avoiding the use of he or she and definitely not “it.” The role of the nursing staff caring for the infant is integral in ensuring sensitive care for the family. Establishing a single common person to communicate with the family can help to avoid confusion before being seen by the specialized team.

History

A thorough history can provide important clinical clues. Maternal virilization during pregnancy can point to an androgen-secreting tumor or placental aromatase deficiency. Maternal progestin use can lead to undervirilization of a genetically male infant. Other health issues in the infant can point to syndromes such as Smith–Lemli–Optiz or Denys–Drash syndromes. Consanguinity is important to ascertain, because many defects in androgen and/or adrenal hormone production are autosomal recessive. A family history of unexplained early infant death suggests congenital adrenal hyperplasia (CAH), and a history of hypospadias, primary amenorrhea, or infertility in the mother’s family raises the possibility of an androgen receptor mutation, because this is an X-linked condition. A family history of infants with genital ambiguity is frequently not known to the extended family, but infertility, hypospadias, and amenorrhea are known more commonly to family members. It is also important to ask parents what investigations were done during the pregnancy, whether the infant’s karyotype is known from prenatal testing, and what prenatal ultrasounds have shown. Finally, it is very helpful to understand what parents have been told by other health professionals.