Luigi Avolio, MD
BASICS
DESCRIPTION
• Pseudohermaphroditism is an obsolete term that referred to pathologic conditions in which chromosomal sex is inconsistent with phenotypical sex
• Disorders of sexual development (DSDs) is the preferred term which indicates a congenital condition in which development of chromosomal, gonadal or anatomic sex is atypical (1)
• Female pseudohermaphroditism is now defined as XX DSD
– Karyotype 46XX
– Gonads: Normal ovaries
– External genitalia: Varying degree of virilization
• Male pseudohermaphroditism is now defined as XY DSD
– Karyotype 46XY
– Gonads: Normal testes
– External genitalia: Incomplete virilization
EPIDEMIOLOGY
Incidence
• 1 in 5,000 live births
– 21-hydroxylase deficiency is the most common cause of 46XX DSD; 90% of congenital adrenal hyperplasia (CAH); 1:15,000 live births
Prevalence
N/A
RISK FACTORS
• Family history
• In utero exposure to androgens
Genetics
See “Disorders of Sex Development” chapter
PATHOPHYSIOLOGY
• XX DSD (Female pseudohermaphroditism) Disorders of androgen excess
– 21-hydroxylase deficiency (21-OHD) is the most common cause for CAH, a family recessive disorders involving impaired synthesis of cortisol from cholesterol by the adrenal cortex
– 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
ALERT
Newborns with salt-wasting 21-OHD CAH are at risk for life-threatening salt-wasting crises.
• β-Hydroxysteroid dehydrogenase (HSD3B2) deficiency: Deficiency of this enzyme results in adrenal insufficiency due to lack of conversion of δ5 steroids to δ-4 and consequent accumulation of pregnenolone, dehydroepiandrosterone (DHEA) and androstenediol. Phenotypically girls with mild virilization
• 11b-Hydroxylase (CYP11B1) deficiency: Characterized by accumulation of 11-deoxycorticosterone. This is the 2nd most common causes of virilizing CAH (5% of all cases)
• P450 oxidoreductase (POR) deficiency: Combined deficiencies of 21α-hydroxylase, 17α-hydroxylase and aromatase enzymes.
– Familial glucocorticoid resistance: Rare condition with mutation in the glucocorticoid receptor determining high ACTH, cortisol, mineralocorticoids and androgens levels.
– Aromatase (CYP19) deficiency: High serum androgens and low estrogen concentrations with progressive virilization.
• Maternal androgen excess:
– Ovarian tumors (luteoma, arrhenoblastoma)
– Ingestion of androgens, progestogens
• XY DSD (male pseudohermaphroditism)
– Disorders of androgen synthesis
Cholesterol synthesis defects: Deficiency of 7-dehydrocholesterol reductase (DHCR7) results in a failure of cholesterol synthesis and elevated levels of its precursor 7-dehydrocholesterol. Causative factor of Smith–Lemli–Opitz syndrome (multiple congenital malformation and mental retardation syndrome)
Leydig cell hypoplasia: A defect of LH receptors leads to Leydig cells hypoplasia or agenesia. Genital anomalies range from hypospadias to completely normal female external genitalia
Lipoid CAH: Severe disorder of steroid hormone biosynthesis, caused by a defect in the conversion of cholesterol to pregnenolone, the 1st step in adrenal and gonadal steroidogenesis. All affected individuals are phenotypic females with a severe salt-losing syndrome, fatal if not promptly treated in early infancy
P450 side-chain cleavage deficiency: Rare disorder with ACTH and plasma renin activity grossly elevated and adrenal steroids inappropriately low or absent; patients have female external genitalia, sometimes with clitoromegaly
β-Hydroxysteroid dehydrogenase (HSD3B2) deficiency: (see XX DSD). 46 XY patients phenotype ranges from isolated hypospadias or micropenis to more severe undermasculinization
17α-Hydroxylase/17,20-lyase deficiency: Production of excessive corticosterone and deoxycorticosterone with hypertension and hypokalemic alkalosis; aldosterone synthesis almost totally absent. Variable degree of undermasculinization
P450 oxidoreductase (POR) deficiency: (see XX DSD). The genitalia in 46 XY patients range from isolated hypospadias or micropenis to more severe undermasculinization
17β-Hydroxysteroid dehydrogenase (17βHSD) type 3 deficiency: The HSD17B3 isozyme catalyzes the conversion of androstenedione to testosterone in the testis. Deleterious mutations in the HSD17B3 gene cause undermasculinization in genetic males attributable to impaired testosterone biosynthesis
Steroid 5α-reductase type 2 deficiency: Reduced activity of 5α-RD type 2 with defective conversion of testosterone to DHT. Patients show ambiguous genitalia at birth, including perineal hypospadias
– Disorders of the androgen receptor (AR): Patients with partial or complete androgen insensitivity syndrome (PAIS/CAIS) have normal testosterone level and DHT response to hCG stimulation; usually normal anti-müllerian hormone (AMH) level
PAIS: Phenotype ranges from normal male with infertility (mild form) or isolated hypospadias to ambiguous genitalia with blind vaginal pouch
CAIS: Patients have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes
• Persistent müllerian duct syndrome (PMDS): Phenotype produced by a mutation in the gene encoding AMH or by a mutation in the AMH receptor; it results from failure of müllerian duct regression in otherwise normal males. Patients usually present bilateral cryptorchidism and inguinal hernias: A uterus and fallopian tubes are found in the inguinal canal; gonads are testes (2)
ASSOCIATED CONDITIONS
• Hypospadias
• Cryptorchidism
• Inguinal hernia
GENERAL PREVENTION
See “Disorders of Sex Development” chapter
DIAGNOSIS
HISTORY
• Family history:
– Genital abnormalities
– Amenorrhea
– Sterility
– Hirsutism
– Early infant deaths (possible unrecognized CAH with salt-wasting crisis)
• Maternal exposure to androgens
• History of maternal virilization (androgen-producing tumor)
PHYSICAL EXAM
• External genitalia
– Phallic structure (length, breadth, and amount of erectile tissue)
– Position of urethral meatus
– Number of orifices in the perineum and their characteristics
– Labioscrotal folds (separated or fused)
• 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
See “Disorders of Sex Development” chapter
DIFFERENTIAL DIAGNOSIS
• Cryptorchidism
• Inguinal hernia, hydrocele
• Hypospadias
• Microphallus
• Gonadoblastoma
• Menstruation disorders
TREATMENT
GENERAL MEASURES
• Multidisciplinary team for evaluation of the patient
• Gender assignment early
MEDICATION
First Line
• 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) (See “Disorders of Sex Development” chapter)
• Feminizing genitoplasty (during the 1st 6 mo of life) (3)[A] (See “Disorders of Sex Development” chapter)
• Müllerian remnants (See “Disorders of Sex Development” chapter)
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
N/A
Complementary & Alternative Therapies
Actually some patient groups strongly advocate to delay any surgical procedures until patients are competent to provide informed consent
ONGOING CARE
PROGNOSIS
• Generally good with appropriate care
• Many patients have a good quality of life
• Many patients remain fertile
COMPLICATIONS
See “Disorders of Sex Development” chapter
FOLLOW-UP
Patient Monitoring
• Lifelong psychosocial support mandatory
• Monitoring for increased risk for developing malignancies
• Evaluation of sexual function
Patient Resources
• http://www.congenitaladrenalhyperplasia.org
• http://www.livingwithcah.com
• http://rch.org.au/cah_book/index.cfm?doc_id=1375
• http://www.ahn.org.uk
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 masculinized 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)
• Congenital Adrenal Hyperplasia
• Disorders of Sexual Development (DSD)
• Hypospadias
• Micropenis (Microphallus)
• Müllerian Duct Remnants and Persistent Müllerian Duct Syndrome (PMDS)
CODES
ICD9
752.7 Indeterminate sex and pseudohermaphroditism
ICD10
• Q56.1 Male pseudohermaphroditism, not elsewhere classified
• Q56.2 Female pseudohermaphroditism, not elsewhere classified
• Q56.3 Pseudohermaphroditism, unspecified
CLINICAL/SURGICAL PEARLS
• Infants with a DSD presenting with truly ambiguous genitalia are a rare occurrence.
• DSD should be regarded as a heterogeneous group of conditions with substantially different prognoses and treatment prospects.
• DSDs represent a broad complex field that requires the interaction of multiple disciplines with a diverse knowledge base.