Luigi Avolio, MD
BASICS
DESCRIPTION
• Congenital condition in which development of chromosomal, gonadal, or anatomic sex is atypical (1)
• Chromosomal sex is inconsistent with phenotypical sex
• DSD is the result of a discordance among the 3 sex determination processes (chromosomal, gonadic, and phenotypic)
• Ambiguous genitalia and intersex disorders are no longer considered correct terms
– Classification
Sex chromosome DSD
XX DSD
XY DSD
EPIDEMIOLOGY
Incidence
• 1 in 5,000 live births
– Congenital adrenal hyperplasia (CAH) represents 60–70% of neonatal DSD (1 case per 15,000 live births)
Prevalence
N/A
RISK FACTORS
• Family history of DSD
• In utero exposure to androgens
– Ovarian tumors
– Maternal ingestion
Genetics
• XX DSD
– 21α-hydroxylase deficiency (21OHD), Mendelian Inheritance in Man, MIM #201910 (online reference http://www.ncbi.nlm.nih.gov/omim/)
– CYP21 gene-chr.6p21.33. Autosomal recessive
– 3β-hydroxysteroid dehydrogenase deficiency, MIM #201810, HSD3B2 gene-chr.1p12. Autosomal recessive
– P450 oxidoreductase deficiency, MIM#613571, POR gene-chr.7q11.23. Autosomal recessive
– 11β-hydroxylase deficiency, MIM#103900, CYP11B1 gene-chr.8q24.3. Autosomal dominant
– Aromatase deficiency, MIM#613546, CYP19 gene-chr.15q21.2. Autosomal recessive
– Familial glucocorticoid resistance, MIM+138040, NR3C1 gene-chr.5q31.3
• XY DSD
– Deficiency of 7-dehydrocholesterol reductase, MIM#270400, DHCR7 gene-chr.11q13.4. Autosomal recessive
– Leydig cell hypoplasia, MIM#238320, LHCGR gene-chr.2p16.3. Autosomal recessive
– Steroid 5α-reductase Type 2 deficiency, MIM#264600, SRD5A2 gene-chr.2p23.1. Autosomal recessive
– Steroidogenic acute regulatory protein, MIM#201710, StAR gene-chr.8p11.23. Autosomal recessive
– P450 side-chain cleavage deficiency, MIM#613743, CYP11A1 gene-chr.15q24.1. Autosomal recessive
– 3β-hydroxysteroid dehydrogenase deficiency, MIM #201810, HSD3B2 gene-chr.1p12. Autosomal recessive
– P450 oxidoreductase deficiency, MIM#613571, POR gene-chr.7q11.23. Autosomal recessive
– 17α-hydroxylase/17,20-lyase deficiency, MIM#202110, CYP17A1 gene-chr.10q24.32. Autosomal recessive
– 17β-hydroxysteroid dehydrogenase Type 3 deficiency, MIM#264300, HSD17B3 gene-chr.9q22.32. Autosomal recessive
– Disorder of the Androgen Receptor (AR), MIM#300068, AR gene-chr.Xq12. X-linked recessive
– Anti-müllerian hormone (AMH) gene or its receptor, MIM#300068, AMH gene-chr.19p13.3 (type I), AMHR2 gene-chr.12q13.13 (type II). Autosomal recessive (2).
ALERT
The possible risk of an immediate life-threatening adrenal crisis must be considered in case of neonatal salt-wasting CAH and the general status of the child, including hydration, blood pressure, and jaundice, should be documented.
PATHOPHYSIOLOGY
• XX DSD
– Disorders of ovarian development
(ovotesticular DSD): Ovary may contain some testicular tissue (unilateral 50%—ovotestis on one side and normal gonad in the other side; lateral 20%—a testis on one side and an ovary on the other; bilateral ovotestis 30%) that secretes adequate amounts of testosterone and AMH
– Disorders of androgen excess
21-hydroxylase deficiency is the most common cause of 46XX DSD. Impaired cortisol biosynthesis relieves feedback inhibition and thus increases ACTH secretion, which leads to hyperplasia of the adrenals and to disordered steroidogenesis: As a consequence cortisol precursors are shunted to androgen synthesis.
• XY DSD
– Disorders of testis development
– Disorders of androgen synthesis
Deficiency of 7-dehydrocholesterol reductase (DHCR7) results in a failure of cholesterol synthesis
– Disorders of androgen action
– Persistent müllerian duct syndrome (PMDS)
ASSOCIATED CONDITIONS
• Turner syndrome, Klinefelter syndrome, Reifenstein syndrome
• Inguinal hernia
• Amenorrhea
• Infertility
GENERAL PREVENTION
• Prenatal treatment of fetuses at risk for CAH with dexamethasone
• Chorionic villus sample
• Amniocentesis
DIAGNOSIS
HISTORY
• Family anamnesis
– DSDs, genital abnormalities, amenorrhea, sterility, hirsutism
– Early infant deaths (missed adrenogenital syndrome)
• Maternal exposure to androgens
• History of maternal virilization (androgen-producing tumor)
PHYSICAL EXAM
• External genitalia
– Phallic structure (length, breadth, and amount of erectile tissue)
Normal penile length is ≥2.5 cm, and normal penile diameter is ≥0.9 cm
Normal clitoral width is from 2 to 6 mm; length >9 mm unusual
– Position of urethral meatus
– Number of orifices in the perineum and their characteristics
– Labioscrotal folds (separated or fused)
– Asymmetry (ovotesticular DSD can produce virilization on only one side)
• Gonads
– Palpable gonads (testis, very rarely ovotestis)
• Abdomen
– Mass referable to enlarged uterus
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Karyotype
• Serum levels of sodium, potassium, and 17-hydroxyprogesterone
• Androgens (testosterone, dihydrotesterone, androstenedione)
• Cortisol, gonadotrophins, and AMH levels
• Stimulation test with human chorionic gonadotropin (suspected defect of androgen production)
Imaging
• Abdominal/Pelvic ultrasound (utero presence)
• Cystogram/genitogram (visualization of vagina, sinus)
• MRI
Diagnostic Procedures/Surgery
• Laparoscopy to define internal anatomy
• Cysto/vaginoscopy to confirm anatomy and level of confluence of urogenital sinus
• Gonadal biopsy to analyze presence of ovarian and/or testicular tissue
• Skin biopsy to obtain cellular lines
Pathologic Findings
Identification of ovarian tissue, testicular tissue, ovotestes, or streak gonads according to related specific disorders
DIFFERENTIAL DIAGNOSIS
• Hypopituitarism
• Hypospadias
• Hydrocele and hernia
• Menstruation disorders
• Microphallus
• Gonadoblastoma
TREATMENT
GENERAL MEASURES
• Gender assignment avoiding hasty decision
• Expert evaluation by an experienced multidisciplinary team
MEDICATION
First Line
• Newborn with salt-wasting CAH
– Fluid and electrolytes replacement
– Glucocorticoid and mineralocorticoid replacement
Hydrocortisone 10 mg/m2/d
Fludrocortisone 0.1–0.2 mg/d
Oral sodium chloride, 1–2 g/d added to formula or breast milk
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Masculinizing genitoplasty (between the ages of 6 and 18 mo)
– Hormonal treatment with testosterone preparation to stimulate phallus
– Surgical excision of müllerian structures
– Phalloplasty (hypospadias repair, chordee correction, scrotal transposition)
– Orchidopexy
• Feminizing genitoplasty (during the 1st 6 mo of life) (3)
– Clitoroplasty preserving innervation to reduce the size of the gland and shaft
– Vaginoplasty and labioplasty to separate vagina and urethra from the common urogenital sinus
• Gonads
– 46XX DSD: Normal ovaries, no treatment necessary
– 46XY DSD:
Female gender assigned: Orchiectomy (timing is subject of debate)
Male gender assigned: Orchidopexy
– Ovotesticular DSD:
Gonadal biopsy
Excision of dysgenetic gonads (streak)
• Müllerian remnants
– Small asymptomatics are managed conservatively
– Symptomatic remnants are treated surgically (endoscopic incision or unroofing, laparoscopic/robotic excision)
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
N/A
Complementary & Alternative Therapies
Some patient groups strongly advocate to delay any surgical procedures until patients are competent to provide informed consensus
ONGOING CARE
PROGNOSIS
Many patients can remain fertile (CAH, some ovotesticular DSD, XY DSD 5α-RD)
COMPLICATIONS
• Acute adrenal insufficiency in CAH not adequately treated
• Damages to clitoral innervation (clitoroplasty)
• Stenosis of the vaginal introitus (vaginoplasty)
• Meatal stenosis, fistula (hypospadias repair)
• Rectal injury (urogenital sinus mobilization)
FOLLOW-UP
Patient Monitoring
• Sexual function (adequate vaginal introitus, adequate penis reconstruction)
• Risk of gonadoblastoma in gonadal dysgenesis is 12% (occurrence of neoplasia is primarily associated with the Y chromosome containing karyotypes)
• Lifelong psychosocial support mandatory for all patients with DSD
Patient Resources
• http://www.hopkinschildrens.org (all DSDs)
• http://www.accordalliance.org (all DSDs)
• http://www.isna.org (all DSDs)
• http://www.caresfoundation.org (CAH)
• http://www.ahn.org.uk (CAH)
• http://heainfo.org (hypospadias and epispadias)
• http://www.aisdsd.org (androgen insensitivity DSD)
REFERENCES
1. Hughes IA, Houk C, Ahmed SF, et al. Consensus statement on management of intersex disorders. Arch Dis Child. 2006;91:554–563.
2. Ahmed SF, Rodie M. Investigation and initial management of ambiguous genitalia. Best Pract Res Clin Endocrinol Metab. 2010;24:197–218.
3. Romao RL, Salle JL, Wherrett DK. Update on the management of disorders of sex development. Pediatr Clin North Am. 2012;59:853–869.
ADDITIONAL READING
• Auchus RJ, Chang AY. 46,XX DSD: the masculinised female. Best Pract Res Clin Endocrinol Metab. 2010;24:219–242.
• Barbaro M, Wedell A, Nordenström A. Disorders of sex development. Semin Fet al Neonatal Med. 2011;16:119–127.
• Barthold JS. Disorders of sex differentiation: a pediatric urologist’s perspective of new terminology and recommendations. J Urol. 2011;185:393–400.
• http://www.ncbi.nlm.nih.gov/omim/ (Online Mendelian Inheritance in Man®)
See Also (Topic, Algorithm, Media)
• Androgen Insensitivity Syndrome (AIS; OR Androgen Resistance Syndrome), Complete (CAIS) and Partial (PAIS)
• Congenital Adrenal Hyperplasia
• Disorders of Sexual Development (DSD) Image 
• Disorders of Sexual Development (DSD) Algorithm 
• Müllerian Duct Remnants and Persistent Müllerian Duct Syndrome (PMDS)
• Pseudohermaphroditism, Male and Female
CODES
ICD9
• 255.2 Adrenogenital disorders
• 259.50 Androgen insensitivity, unspecified
• 752.7 Indeterminate sex and pseudohermaphroditism
ICD10
• E25.0 Congenital adrenogenital disorders assoc w enzyme deficiency
• E34.50 Androgen insensitivity syndrome, unspecified
• Q56.4 Indeterminate sex, unspecified
CLINICAL/SURGICAL PEARLS
• DSD should be managed by a specialized multidisciplinary team.
• Gender assignment should be made after thorough investigation by the team.
• DSD is a heterogeneous group of conditions with different underlying molecular causes. Many disease genes remain to be identified.
• Infants with a DSD and who present with truly ambiguous genitalia are a rare occurrence.