Disorders of sex development
Disorders of sex development, also known as differences in sex development, variations in sex characteristics, sexual anomalies, or sexual abnormalities, are congenital conditions affecting the reproductive system, in which development of chromosomal, gonadal, or anatomical sex is atypical.
DSDs are subdivided into groups in which the labels generally emphasize the karyotype's role in diagnosis: 46,XX; 46,XY; sex chromosome; XX, sex reversal; ovotesticular disorder; and XY, sex reversal.
In the cases when a baby is born with an atypical anatomical sex, families often experience confusion and distress. Sexual and psychological developpement are influenced by numerous factors that include, but are not limited to, gender differences in brain structure, genes associated with sexual development, prenatal androgen exposure, interactions with family, and cultural and societal factors. Because of the complex and multifaceted factors involved, communication and psychosexual support are all important.
A team of experts, or patient support groups, are usually recommended for cases related to sexual anomalies. This team of experts are usually derived from a variety of disciplines including pediatricians, neonatologists, pediatric urologists, pediatric general surgeons, endocrinologists, geneticists, radiologists, psychologists and social workers. These professionals are capable of providing first line and second line diagnostic tests to examine and diagnose sexual anomalies.
Overview
DSDs are defined as "any problem noted at birth where the genitalia are atypical in relation to the chromosomes or gonads". There are several types of DSDs, and their effect on the external and internal reproductive organs varies greatly.A frequently used, casual social adjective for people with DSDs is "intersex". Urologists were concerned that terms like intersex, hermaphrodite, and pseudohermaphrodite were confusing and pejorative with respect to humans. This led to the Chicago Consensus, recommending a new terminology based on the umbrella term disorders of sex development. However, intersex people have continued to prefer the term "intersex" over "DSD" by large margins. Other than disorders of sex development, another term is congenital conditions of sex development. Since 2006, people who were previously incorrectly categorized as hermaphrodites are now labelled as having ovotesticular syndrome.
DSDs are divided into the following categories, emphasizing the karyotype's role in diagnosis:
- 46,XX DSD: Genetic Female Sex Chromosomes. Mainly virilized females as a result of congenital adrenal hyperplasia and girls with aberrant ovarian development.
- 46,XY DSD: Genetic Male Sex Chromosomes. Individuals with abnormal testicular differentiation, defects in testosterone biosynthesis, and impaired testosterone action.
- Sex chromosome DSD: patients with sex chromosome aneuploidy or mosaic sex karyotypes. This includes patients with Turner Syndrome and Klinefelter Syndrome even though they do not generally present with atypical genitals.
- XX, Sex reversal: consist of two groups of patients with male phenotypes, the first with translocated Sex-determining region Y protein and the second with no SRY gene.
- Ovotesticular disorder: patients having both ovarian and testicular tissue. In some cases the ovarian tissue is functional.
- XY, Sex reversal: patients with female phenotypes where duplication in the Xp21.2 region of the X chromosome that contains the NR0B1 gene is associated with XY sex reversal.
Genital anatomy
Management of DSDs
Due to the significant and life-long impacts that DSDs can have on patients and their families, it is widely accepted that children with DSDs should be managed by an experienced multidisciplinary team. Health care providers generally agree that children with DSDs should be notified early.Appropriate and conservative medical intervention and age-appropriate child involvement in the treatment plan contribute greatly to successful outcomes for the entire range of DSDs.
Key hormones
In the normal prenatal stages of fetal development, the fetus is exposed to testosterone - albeit more in male fetuses than female ones. Upon the presence of the 5α-reductase enzyme, testosterone is converted to dihydrotestosterone. If DHT is present, the male external genitalia will develop.Development of male external genitalia:
- Genital tubercle forms the penis
- Urethral folds form the penile raphe
- Genital swellings form the scrotum
Development of female external genitalia :
- Genital tubercle forms the clitoris
- Urethral folds form the labia minora
- Genital swellings form the labia majora
In XX chromosome fetuses, excess androgens result in ambiguous genitalia. This makes identification of external genitalia as male or female difficult. Additionally, the individual may have clitoromegaly, a shallow vagina, early and rapid growth of pubic hair in childhood, delayed puberty, hirsutism, virilisation, irregular menstrual cycle in adolescence and infertility due to anovulation.
In XY chromosome fetuses, excess androgens result in a functional and average-sized penis with extreme virilisation, but the inability for sperm production. Additionally, the individual will also experience early and rapid growth of pubic hair during childhood and precocious puberty stages.
Causes
Sexual anomalies often generate from genetic abnormalities caused by many factors, leading to different sexual development. These genetic abnormalities occur during the prenatal stage of an individual's fetal development. During this stage, genetic mutations can result from endocrine disrupters in the mother's diet or environmental factors. The general causes of sexual anomalies can not be outlined due to the high variability of each individual's situations. Thus, the cause of each specific anomaly has to be studied independently.Sexual differentiation occurs through various processes during the prenatal development period of the fetus. These processes are initiated and regulated by biological metabolites such as DNA, hormones and proteins. The initial steps of sexual differentiation begin with the development of the gonads and genitals. This process is consistent with both genders spanning over the course of the first 6 weeks following conception, during which the embryo remains pluripotent. Differentiation of the gonads begins after the 6th week, which is determined by the sex-determining region Y gene in the Y chromosome.
The SRY gene plays an important role in developing the testes of a male individual. Following the development of the testes, hormones synthesized within the testes regulate the differentiation of both internal and external parts of the genitals. The absence of the testicles or the hormones synthesized may lead to irregular differentiation of the genitals. Genetic abnormalities or environmental factors that influence these procedures may lead to the incomplete development of the gonads and the genitals. These malformations can occur any time during the development or the birth of the embryo, manifesting as ambiguous genitals or dissonance within the genotypic and phenotypic sex of the individual, leading to a late onset of puberty, amenorrhea, a lack of or excess virilization, or later in life, infertility or early occurrence of menopause.
Chromosomal variation
DSDs caused by chromosomal variation generally do not present with genital ambiguity. This includes sex chromosome DSDs such as Klinefelter syndrome, Turner syndrome and 45,X or 46,XY gonadal dysgenesis.Males with Klinefelter syndrome usually have a karyotype of 47,XXY as a result of having two or more X chromosomes. Affected patients generally have normal genital development, yet are infertile and have small, poor functioning testes, breast growth and delayed puberty. The incidence for 47,XXY is 1 in 500 males, but severe and rare cases of Klinefelter syndrome presents as three or more X chromosomes.
Turner syndrome is classified as aneuploidy or structural rearrangement of the X chromosome. Signs and symptoms of affected females vary among them, such as low birth weight, low-set ears, short stature, short neck and delayed puberty. The incidence is 1 in 2,500 live-born females, while most patients do not survive for more than one year after birth.