Overview
Definition:
Disorders of Sex Development (DSD) encompass a group of congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical
These conditions arise from variations in sex chromosomes, gonadal development, or sex hormone production/action, leading to discrepancies between external and internal genitalia, or between chromosomal sex and phenotypic sex.
Epidemiology:
The prevalence of DSD is estimated to be around 1 in 2000 births for all variations, with specific conditions having varying frequencies
For instance, classical congenital adrenal hyperplasia (CAH) has a prevalence of about 1 in 10,000 to 1 in 20,000 live births, while ovotesticular DSD (formerly true hermaphroditism) is estimated to occur in 1 in 30,000 to 1 in 100,000 births
The incidence varies widely based on the specific type of DSD.
Clinical Significance:
DSD presents significant challenges for affected individuals, families, and healthcare providers
Early and accurate diagnosis is crucial for appropriate medical and surgical management, psychological support, and long-term health outcomes
It requires a multidisciplinary approach involving pediatricians, endocrinologists, geneticists, urologists, surgeons, psychologists, and social workers to address the complex medical, ethical, and psychosocial aspects.
Clinical Presentation
Symptoms:
Presentation varies significantly with the underlying cause and degree of virilization or feminization
Common presentations include: Ambiguous genitalia at birth, including a phallus of variable size, hypospadias, bifid scrotum, or a urogenital sinus
Inability to pass meconium in the first 24-48 hours of life, suggesting intestinal obstruction due to CAH
Undescended testes or inguinal hernias containing gonads in individuals with a 46,XY karyotype
Primary amenorrhea and lack of secondary sexual development in individuals with a 46,XX karyotype
Recurrent urinary tract infections or suspected intersex condition in childhood.
Signs:
Physical examination findings are critical and should be meticulous: External genitalia: Assess for micropenis, clitoromegaly, hypospadias (penile, perineal, scrotal), bifid scrotum, labial fusion, or undescended testes
Gonads: Palpable gonads in the scrotum, labia, inguinal region, or abdomen
Urogenital sinus: Presence of a single opening for urethra and vagina
Karyotype: May be inferred from clinical presentation but requires genetic confirmation
Internal genitalia: Assessment may require imaging or surgical exploration.
Diagnostic Criteria:
There are no universal diagnostic criteria for all DSDs, but a systematic approach guided by clinical suspicion, karyotype, and hormonal profiling is essential
The consensus statement on DSD (2006) emphasizes a multidisciplinary team approach for diagnosis and management
Key elements include: Karyotype (e.g., 46,XX, 46,XY, mosaicism, or sex chromosome aneuploidies)
Gonadal histology
Hormonal assays (e.g., testosterone, 17-hydroxyprogesterone, androstenedione, AMH, FSH, LH)
Imaging studies (pelvic ultrasound, MRI)
Molecular genetic testing for specific genes.
Diagnostic Approach
History Taking:
Detailed family history is paramount: history of similar conditions, consanguinity, infertility, or unexplained deaths in the family
Maternal history: exposure to androgens or progestins during pregnancy, medical conditions like CAH or diabetes
Neonatal history: any concerns regarding genitalia, feeding difficulties, or vomiting
Red flags: ambiguous genitalia, non-palpable testes in a male infant, delayed puberty, or failure to menstruate by age 15.
Physical Examination:
A thorough and sensitive examination is crucial
This includes: General physical examination: assessment for dysmorphic features, growth parameters, and signs of endocrine dysfunction
Genital examination: precise description of external genitalia, noting the size of the phallus (length measured from pubic bone to tip), degree of hypospadias, and the presence and location of gonads
Pelvic examination (if appropriate and feasible): assess for vaginal opening and cervix
Assess for breast development and pubic hair (Tanner staging).
Investigations:
Initial investigations should be guided by the clinical presentation: Karyotyping: Blood sample to determine chromosomal sex (46,XX, 46,XY, or mosaic)
Hormone levels: Serum 17-hydroxyprogesterone (17-OHP) and androstenedione (for suspected CAH)
Testosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione (for virilized 46,XX females)
AMH, FSH, LH, testosterone (for suspected 46,XY individuals with disorders of testicular development)
Serum electrolytes (especially sodium and potassium in suspected CAH)
Imaging: Pelvic ultrasound to visualize gonads, uterus, and vagina
MRI may be used for better delineation
Gonadotropins (FSH, LH) to assess pituitary-gonadal axis
Consider human chorionic gonadotropin (hCG) stimulation test to assess gonadal steroidogenic capacity.
Differential Diagnosis:
The differential diagnosis for DSD is broad and depends on the karyotype and phenotype: 46,XX DSD: Congenital Adrenal Hyperplasia (21-hydroxylase deficiency is most common), Androgen Insensitivity Syndrome (partial), Ovotesticular DSD, Gonadal dysgenesis
46,XY DSD: Androgen Insensitivity Syndrome (complete or partial), 5-alpha-reductase deficiency, 17-beta-hydroxysteroid dehydrogenase deficiency, Leydig cell hypoplasia, Ovotesticular DSD, Klinefelter syndrome, Disorders of gonadal development
Sex Chromosome DSD: Turner syndrome (45,X), Klinefelter syndrome (47,XXY), mixed gonadal dysgenesis (e.g., 45,X/46,XY mosaicism).
Management
Initial Management:
Immediate management focuses on stabilizing the neonate and establishing a diagnosis
For neonates with ambiguous genitalia, particularly those at risk of adrenal crisis (e.g., suspected CAH), prompt hormonal assessment and supportive care are essential
If adrenal insufficiency is suspected, hydrocortisone therapy should be initiated immediately
Genetic counseling for the parents is a critical component from the outset.
Medical Management:
Medical management is directed at the specific underlying cause
For 21-hydroxylase deficiency CAH: Glucocorticoid replacement (e.g., hydrocortisone 10-15 mg/kg/day divided in 3 doses) to suppress ACTH and androgen production, and mineralocorticoid replacement (e.g., fludrocortisone 0.05-0.1 mg/day) to manage salt wasting
For other DSDs, management may involve hormonal replacement therapy to induce puberty or manage endocrine deficiencies
Surgical interventions are often part of the overall management plan.
Surgical Management:
Surgical management is controversial and should be carefully considered, ideally by a multidisciplinary team and in consultation with parents
It may involve: Feminizing genitoplasty for virilized 46,XX individuals to reduce clitoral size and reposition the urethra
Masculinizing genitoplasty for 46,XY individuals with hypospadias and undescended testes
Gonadectomy may be considered in individuals with ovotesticular DSD or those at high risk of gonadal malignancy (e.g., dysgenetic testes).
Supportive Care:
Psychosocial support is paramount for affected individuals and their families
This includes: Genetic counseling to explain the diagnosis, implications, and inheritance patterns
Psychological support to address anxiety, distress, and identity issues
Education for parents on the long-term management, potential for fertility, and sexual health
Ongoing support throughout childhood, adolescence, and adulthood.
Complications
Early Complications:
Adrenal crisis in neonates with CAH, characterized by vomiting, dehydration, hypoglycemia, and shock
Sepsis from urinary tract infections
Psychological distress in parents due to the uncertainty and complexity of the diagnosis.
Late Complications:
Infertility, psychological and social adjustment difficulties, gender dysphoria, sexual dysfunction, increased risk of gonadal tumors (especially in ovotesticular DSD and some forms of 46,XY DSD with dysgenetic testes), and complications from previous surgeries
Poorly managed CAH can lead to precocious puberty, virilization, and impaired growth.
Prevention Strategies:
Early diagnosis and appropriate management of underlying endocrine disorders like CAH can prevent adrenal crisis
Careful surgical planning and execution can minimize functional and cosmetic complications
Comprehensive psychosocial support helps in better long-term adjustment
Regular screening for gonadal tumors in individuals at risk is essential.
Prognosis
Factors Affecting Prognosis:
The prognosis for DSD depends on the specific diagnosis, the extent of associated anomalies, the timing and quality of diagnosis and management, and the availability of comprehensive multidisciplinary support
Early and accurate diagnosis, appropriate hormonal management, and timely surgical intervention (when indicated) improve outcomes.
Outcomes:
With optimal care, many individuals with DSD can lead healthy lives
Fertility outcomes vary widely depending on the specific DSD
Psychological and social well-being are significantly influenced by the level of support and individual adjustment
Long-term follow-up is crucial for managing endocrine issues, monitoring gonadal health, and addressing psychosocial needs.
Follow Up:
Lifelong multidisciplinary follow-up is typically required
This includes regular endocrinological assessment for hormonal status and growth, genetic follow-up, psychosocial counseling, and urological/surgical evaluation as needed
Individuals with a history of gonadal dysgenesis or ovotesticular DSD require ongoing monitoring for potential malignant transformation.
Key Points
Exam Focus:
Disorders of Sex Development (DSD) are a spectrum of conditions affecting sex differentiation
Initial evaluation hinges on karyotype, hormone levels (especially 17-OHP for CAH), and physical examination of genitalia
Congenital Adrenal Hyperplasia (CAH) is a common cause of virilization in 46,XX individuals and carries a risk of adrenal crisis
Management is multidisciplinary, involving medical, surgical, and psychosocial support.
Clinical Pearls:
Always consider DSD in neonates with ambiguous genitalia
A systematic approach with a multidisciplinary team is essential
Detailed family history is crucial
Promptly treat suspected adrenal crisis with hydrocortisone
Genetic counseling is as important as medical management
Avoid unnecessary or premature surgical interventions without thorough consideration and parental consent.
Common Mistakes:
Rushing to assign a sex or perform surgery without a complete workup
Inadequate hormonal assessment, particularly missing adrenal crisis in CAH
Lack of a multidisciplinary team approach
Insufficient psychosocial support for the patient and family
Over-reliance on surgical correction without addressing underlying endocrine or genetic issues.