Disorders of Sexual Development

31.1Introduction

•The birth of a new baby is one of the most dramatic events in a family, and the first question is usually “is it a boy or a girl?”

•When a child is born with ambiguous external genitalia it often comes as a surprise for the parents and diagnostic dilemma for the treating physicians.

•It is also considered as an endocrine emergency situation presenting a problem of sex assignment.

•It is important for clinicians to promptly make an accurate diagnosis and counsel parents on therapeutic options.

•It is also important to understand the psychological and social implications of gender assignment in some of these patients.

•In the past several names such as intersex or ambiguous genitalia were used to describe disorders of sexual development but they were not accurately descriptive.

•Intersex (Figs. 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, and 31.7):

–Intersex literally means that the body is between the two sexes, male and female.

–This is a term that is no longer used; it has now been replaced by disorders of sexual development (DSD).

•In the past the term “hermaphrodite” was sometimes erroneously used to describe people with intersex/DSD conditions. The term hermaphroditism, was used after the Greek god of sexuality Hermes and the goddess of love and sexuality, Aphrodite. The correct technical definition of a hermaphrodite is a single organism that has complete sets of both male and female sexual organs. This term is also no longer used to describe humans.

•The nomenclatures such as ‘intersex’, ‘hermaphrodite’, and ‘pseudohermaphrodite’ are no longer used. They are confusing terms and

Fig. 31.3 A clinical photograph of a patient with DSD. It is difficult to decide whether this is a true male or not. This patient was investigated and found to have severe virilization secondary to congenital adrenal hyperplasia leading to enlargement of the clitoris resembling a male penis

Figs. 31.4 and

31.5 Clinical photographs of two new born with cloacal exstrophy. Note there are no clear external genitalia and these patients need further evaluation prior to sex assignment. The external genitalia in these patients are usually small and not well developed

could be perceived to be pejorative by some affected families.

•All these were replaced by the term Disorders of Sexual Development (DSD).

•This was coined by International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology in 2006.

•It replaces the earlier terms Intersex and ambiguous genitalia which were controversial and associated with a lot of social stigma and confusion.

•Disorders of sex development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical.

•The use of the term disorder of sex development (DSD) is controversial among many activists and community organizations.

•Although there are potential criticisms to the new nomenclature, the DSD terminology has been generally accepted and is now popularly used in the literature.

•The medical term disorders of sex development (DSDs) is used to describe individuals with an atypical composition of chromosomal, gonadal and phenotypic sex, which leads to differences in the development of the urogenital tract and reproductive system.

•The term DSD has a comprehensive definition including any problem noted at birth in which

Fig. 31.6 Clinical photograph of a newborn with imperforated hymen with hydrocolpos causing abnormalities of external genitalia

Fig. 31.7 A clinical photograph showing abnormal external genitalis. This female patient was found to have a dermoid cyst over the clitoris causing abnormaliities of the external genitalia

the genitalia are atypical in relation to the chromosomes or gonads. The karyotype is used as a prefix defining the classification of DSD.

•The newly proposed terminology and classifications have eliminated some confusion for both the patient and the family, as well as for health professionals.

•DSDs are rare and complex.

•It is estimated that the overall incidence of DSDs is 1 in 4,500–5,500 live births.

•Congenital adrenal hyperplasia (CAH) and mixed gonadal dysgenesis are the most common causes of ambiguous genitalia, constituting approximately over 50 % of all cases of genital ambiguity in the newborn period (Figs. 31.8 and 31.9).

•The incidence of CAH and mixed gonadal dysgenesis is 1:15,000 and 1:10,000, respectively.

•Currently, many countries screen newborns for CAH by use of filter-paper blood spot 17-hydroxyprogesterone measurements.

•Disorders of sexual development includes a variety of conditions in which the reproductive system or the external genitalia are not normal for a female or male.

•There are three general descriptive terms to describe the sex of a person:

–Genotypic sex (Chromosomal sex): This refers to the sex based on the number of sex chromosomes. This depends on the presence of 46,XX or 46,XY chormosomes.

–Anatomical sex (Gonadal sex): This refers to the sex according to the gonadal differentiation. This depends on the presence of a uterus, ovaries and tubes or testes, epididymis, seminal vesicles, ejaculatory ducts and prostate.

–Phenotypic sex: This refers to the sex based on the external anatomy of the genitalia. This results from the differentiation of the external genitalia under the influence of sex-determining genes and hormones.

•Abnormalities in any of these result in a range of conditions that lead to abnormal development of the sex organs and genitalia (Disorders of sex development).

•Children with DSD often have both male and female characteristics internally as well as externally.

•Gender identity:

–This refers to the individual’s perception about his/her own gender. In some individuals, gender identity is different from the phenotypic sex.

•When a child is born with DSD, the gender may not be obvious.

•The development of sex organs and external genitalia is a very complex process that starts at around 7–8 weeks of pregnancy in the developing fetus and is complete by 12 weeks.

•Great advances have been made over recent years in understanding the genetics and pathology of DSD.

•The Chicago Consensus new nomenclature is based on the primary genetic defect.

•It includes three broad categories: 1. Sex chromosome DSD

2. 46, XX DSD

3. 46, XY DSD

•The most common DSD is Congenital Adrenal Hyperplasia (CAH).

–This results in a female (XX chromosomes) having genitals that look somewhat masculine.

–In mild cases, CAH results in a slightly enlarged clitoris.

–In more severe cases it can be difficult to decide whether a baby is male or female.

–Most children with CAH think of themselves as girls.

–CAH when it occurs in males (XY chromosomes), the result is over-masculinization and premature puberty.

•Mixed gonadal dysgenesis (MGD) is the second most common cause of DSDs.

•Another common DSD is Androgen Insensitivity Syndrome (AIS).

–This occurs in males (XY chromosomes) who do not respond to testosterone normally.

–This results in a feminine appearance.

–There are two types, complete and partial.

–In Complete Androgen Insensitivity Syndrome (CAIS) the result is a totally feminine appearance, including typical female breast development.

–Diagnosis in 46,XY phenotypic females with complete androgen insensitivity usually occurs after puberty during an evaluation for primary amenorrhea.

–In the Partial Androgen Insensitivity Syndrome (PAIS), the genitals can vary from mostly female to almost completely male.

•One of the more unusual DSDs is 5-Alpha Reductase Deficiency (5ARD), popularly known as “Penis at 12.”

–It is caused by a deficiency of the enzyme 5-Alpha Reductase which converts testesterone to dihydrotestesterone in males (XY).

–Dihyrotestesterone is responsible for the development of the male external genitalia.

•The classic presentation of MIS (Mullerian inhibiting substance) deficiency is a boy with a hernia on one side and an impalpable contralateral gonad. At the time of surgery, a uterus and fallopian tubes are noted along with normal Wolffian structures.

•Clinicians should suspect the possibility of a DSD in patients with both hypospadias and cryptorchidism.

•Infants born with ambiguous genitalia represent a true medical and social emergency.