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Ambiguous Genitalia in Newborns

, MD, , , MD, and , MD.

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Last Update: April 12, 2015.

Clinical Recognition

The phenotypic sex of a newborn is the result of external genital development that is under the influence of sex-determining genes as well as both endogenous and exogenous hormone exposures. Approximately 1-2% of live births are affected with ambiguous genitalia. [1] In 2006, new nomenclature for intersex conditions was proposed in a consensus statement from the Lawson Wilkins Pediatric Endocrine Society and European Society of Paediatric Endocrinology in response to advanced identification of molecular genetic causes of abnormal sex. [2] Disorders of sexual development (DSD) are classified as 46XX DSD, 46XY DSD, Ovotesticular DSD, 46XX testicular DSD, and 46XY complete gonadal dysgenesis.

Patients with 46XX DSD are genotypic females with virilized characteristics. In 46XX DSD, the degree of genital virilization can be classified into five Prader stages. Stage 1, with the mildest degree of virilization, is characterized by clitoromegaly without labial fusion. Stage 5, with the highest degree of virilization, is characterized by clitoromegaly with the urethral meatus at the tip, labial fusion, and scrotal-like appearance of the labia. [3]

Patients with 46XY DSD are genotypic males with undervirilization. In 46XY DSD, micropenis is defined as a penile length less than 2.5 standard deviations below the mean (penile length <2.5 cm in a fullterm newborn). The severity of hypospadias is based on the distance of the urethral opening from its normal position at the tip of the phallus. Lack of testicular palpation in the scrotum may signify cryptorchidism, vanishing testes, or gonadal dysgenesis.

Ovotesticular DSD, one of the rarest forms of DSD, describes patients that were previously categorized as true hermaphrodites. The gonads of patients with ovotesticular DSD contain both ovarian and testicular tissue. Thus, the presentation of genital ambiguity can be variable. [2]

46XX testicular DSD describes patients that were previously referred to as XX male or XX sex reversal and 46XY complete gonadal dysgenesis describes XY female or XY sex reversal. [2]

Pathophysiology

Genetic sex is determined by the paternally inherited sex chromosome. Once sexual determination is established, the commitment of the primordial gonads to become testes or ovaries occurs. Testicular differentiation is controlled by a number of time and dosage-sensitive genes including the SRY gene on the Y chromosome. Gonadal differentiation is followed by differentiation of the ductal structures and external genitalia. Fetal productions of testicular androgens and Mullerian inhibiting hormones (MIH) are required to support the development of Wolffian ducts in males. In females, mullerian ductal structures develop in the absence of MIH. External genitalia differentiation begins around the 9th week of gestation and is under the influence of androgens, mainly dihydrotestosterone. [4] A defect anywhere in this process can cause disorders of sexual differentiation.

Diagnosis and Differential

46XY DSD can be caused by atypical testicular formation, low testosterone or dihydrotesterone production, or defects in the androgen receptor. [5] Partial androgen insensitivity syndrome has a variable presentation and can mimic other enzyme defects. [6] Endocrine disruptors with anti-androgenic effects such as diethylstilbestrol or phthalates can also lead to ambiguous genitalia in males. (Table)

46XX DSD can result from exogenous androgen exposure, endogenous adrenal androgen production or placental aromatase deficiency. (Table) Congenital adrenal hyperplasia (CAH) leading to excess fetal adrenal androgen production is the most common cause of 46XX DSD. [3]

In ovotesticular DSD in which the gonads contain both ovarian and testicular tissue, the majority have an XX chromosomal constitution. Complex mosaicism (XX/XY) are seen in approximately 10% of cases.

The majority of 46XX testicular DSD cases are caused by translocation between the X and Y chromosome, involving the SRY gene. Mutations in genes responsible for sex determination such as SRY, SOX9, and SF1 lead to 46XY complete gonadal dysgenesis. [4]

Given the potential association with glucocorticoid and mineralocorticoid deficiencies in CAH, the birth of a child with ambiguous genitalia constitutes a medical emergency requiring immediate evaluation. Further, the parents’ reaction to the birth of a child with ambiguous genitalia is one of shock and concern about which gender to assign, whether or not to decide for early genital surgery, and what to expect regarding the long-term outcome in terms of gender, sexual function, and general quality of life. In order to provide appropriate counseling to the family, there is an urgency to determine the etiology.

Determination of genetic sex by karyotype and pelvic ultrasound to evaluate for the presence of a uterus should be done immediately. Currently, the only newborn screening test for steroid disorders is the measurement of 17-hydroxyprogesterone for 21-hydroxylase deficiency. Further laboratory evaluation to accurately diagnose the specific underlying defect should be directed by a pediatric endocrinologist. If CAH is suspected, measurement of adrenal hormones, ACTH stimulation testing, and molecular genetic testing can elucidate the form of CAH. [3] Each form of CAH has its own unique hormonal profile, consisting of elevated levels of precursors and elevated or diminished levels of adrenal steroid products. HCG stimulation testing to assess testosterone and dihydrotestosterone response may be particularly helpful in 46XY DSD.

Table 1Laboratory values to differentiate between etiologies of ambiguous genitalia in newborns with a 46,XY chromosomal complement.

DiagnosisTDHTMIS
Androgen Insensitivity
Syndrome (AIS)
Normal/upNormal/upNormal
5α-Reductase DeficiencyNormal/upLowNormal
Testosterone Biosynthetic Defect orLeydig Cell HypoplasiaLowLowNormal
Gonadal DysgenesisLowLowLow
T=testosterone, DHT=dihydrotestosterone and MIS=müllerian inhibiting substance.

Treatment

When considering the gender of rearing, the prognosis for masculinization of brain and behavior, the anatomic and physiologic character of the reproductive tract with its potential for development and function in regard to both sexuality and fertility, and the social environment of the infant should be taken into account along with the genetic sex. In 46XY DSD, both male and female gender assignment should be thoroughly considered.

Sex hormone replacement is needed to induce pubertal development. Testosterone is used in the treatment of patients with testosterone deficiency (46XY DSD). Different forms of testosterone (topical and intramuscular) are available and treatment will vary depending on what is best for the patient. A short course of testosterone can be given during infancy to induce penile growth prior to surgical correction. For 46XY DSD patients with functioning Sertoli cells, HCG can be used to stimulate testicular production. Estrogen is used in the treatment of those reared female. Estrogen is available as an oral tablet or transdermal patch. Estrogen doses should be initiated at the lowest dose possible and slowly increased to a maximum of 0.625 mg/day of conjugated estrogen to allow for gradual breast development.

Glucocorticoids are needed to treat congenital adrenal hyperplasia. They suppress the pituitary gland’s oversecretion of adrenocorticotropic hormone and thus decrease the production of precursor hormones. This also leads to a decrease in adrenal androgen production in forms of CAH associated with 46XX DSD. [3]

The aim of surgical repair in newborns with ambiguous genitalia reared in the female gender is generally to remove the redundant erectile tissue, preserve the sexually sensitive glans clitoris, and provide a normal vaginal orifice. [2] A medical indication for early surgery other than for sex assignment is recurrent urinary tract infections as a result of pooling of urine in the vagina or urogenital sinus. In the past, it was routine to recommend early corrective surgery for neonates born with ambiguous genitalia. However, in recent years, the implementation of early corrective surgery has become increasingly controversial due to lack of data on long-term functional outcome. [3]

The process of assigning and accepting a gender of rearing for a child with ambiguous genitalia and of deciding the necessity of genital surgery is challenging. A team approach that combines the insights of the DSD-experienced pediatrician, endocrinologist, psychologist/psychiatrist, surgeon, and the child’s parents or guardian is essential. [2] Although there is no consensus as to the appropriate age to disclose a condition, it is recommended to proceed gradually in line with the child’s cognitive and psychological development.

References

Blackless M, Charuvastra A, Derryck A, Fausto-Sterling A, Lauzanne K, Lee E. How Sexually Dimorphic Are We? Review and Synthesis. Am J Hum Biol. 2000; 12(2): 151-166.

Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus statement on management of intersex disorders. Pediatrics. 2006; 118 (2): 488-500.

Yau M, Pina C, Khattab A, Yuen T, Lekarev O, Lin-Su K, Parsa A, New MI. Congenital Adrenal Hyperplasia. In Pediatric Endocrinology:www.endotext.org

Krishnan S, Wisniewski A. “Ambiguous genitalia in newborns.” In: Genetic Steroid Disorders. Ed. New MI. San Diego: Elsevier. 2014

Mendonca BB, Arnhold I, Domenice S, Costa E. 46,XY Disorders of Sexual Development. In Pediatric Endocrinology:www.endotext.org

Sultan C, Philibert P, Gaspari L, Audran F, Maimoun L, Kalfa N, Paris F. “Androgen Insensitivity Syndrome.” In: Genetic Steroid Disorders. Ed. New MI. San Diego: Elsevier. 2014

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