OVERVIEW: What every practitioner needs to know

Ambiguous genitalia is considered an emergency from a medical as well as a psychological standpoint. Medically, the rationale for this is that congenital adrenal hyperplasia (CAH) is one of the most common causes of ambiguous genitalia and, if present, would put an infant at risk for an adrenal salt-wasting crisis. Psychologically, the inability to tell the parents of a newborn what their baby’s gender is can be emotionally devastating. Therefore, utmost care must be taken to ensure that the evaluation is expedited and that the communication with the family be undertaken with appropriate sensitivity. The extensive differential diagnosis and unavoidable waiting time for test results only adds to the challenge. While a pediatric endocrinologist should take the lead, the availability of a multidisciplinary team is believed to be essential in optimizing outcomes for infants and parents dealing with a diagnosis of ambiguous genitalia.

Are you sure your patient has ambiguous genitalia? What are the typical findings for this disease?

Ambiguous genitalia refers to a situation in which the gender of an individual (in this case, an infant) is not readily apparent from the appearance of the external genitalia. Thus, there is rarely any debate about whether this designation is an appropriate one. The one exception would be instances in which there is failure to appreciate normal variations of genital anatomy.

What other disease/condition shares some of these symptoms?

By definition, infants with ambiguous genitalia have a disorder of sex development (DSD). DSDs refer to congenital conditions in which development of chromosomal, gonadal or anatomic sex is atypical. Therefore, while all infants with ambiguous genitalia have a DSD, not all patients with DSDs have ambiguous genitalia.

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What caused this disease to develop at this time?

The process of sexual differentiation takes place very early in embryogenesis. It begins with establishment of the genetic sex at the moment of conception, and includes gonadal development, differentiation of the internal reproductive structures, and differentiation of the external genitalia. The entire process is complete by the end of the first trimester of pregnancy. Therefore, any factor that causes sex development to occur in an atypical fashion can result in an infant being born with ambiguous genitalia.

The diagnostic process begins with a comprehensive history, including family and pregnancy history. The physical examination includes a search for dysmorphic features and a careful description of the genitalia using gender-neutral terminology. This includes documentation (and measurement) of phallic tissue, labioscrotal folds, presence and location of palpable gonads, number and location of perineal openings, degree of skin pigmentation and rugation, and any other relevant findings. Palpable gonads imply that a Y-chromosome containing cell line is present.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The DSD classification scheme is based on karyotype. Therefore, this is the most important test in terms of the ultimate diagnosis. However, a rapid karyotype takes approximately 3 days. Additional studies done in the interim, depending on the specific situation, often include electrolytes,
17OHP, androgens, gonadotropins and Müllerian-inhibiting substance (MIS). It is important to be aware that sex steroids may change rapidly in the first days and weeks of life. For example, a 17OHP should not be drawn for at least 24 hours after birth, as it will be elevated from the stress of delivery. In contrast, testosterone should be obtained as soon as possible, as it falls quickly during the first week of life in normal boys. However, all tests should be ordered only after consultation with a pediatric endocrinologist.

Would imaging studies be helpful? If so, which ones?

A pelvic ultrasound gives the quickest immediate information since a uterus, if present in a newborn, will be readily apparent. The one caveat here is that the study should be performed by a pediatric ultrasonographer, preferably at a children’s hospital, as imaging studies done in less experienced venues are notoriously inaccurate. A genitogram can also be very helpful in delineating the internal reproductive structures and any connection between the GU systems.

Confirming the diagnosis

The first step is to determine which of the 3 general categories of DSD the patient belongs in. As mentioned above, this is based on the karyotype. Within each category, there is a differential diagnosis. In some disorders, there is an obvious diagnostic study. However, in others, a descriptive label may have to suffice when the exact underlying cause is unknown.

While some diagnoses may be made on the basis of first-line testing, other diagnoses may require additional studies. Examples of second- and third-line testing would include things like a human chorionic gonadotropin (HCG) stimulation test, adrenocorticotropic hormone (ACTH) stimulation test, molecular genetic analysis, and gonadal biopsy.

The differential diagnosis of each of the 3 classifications of DSDs utilizing current nomenclatureis delineated below. As mentioned above, the diagnosis and treatment of an infant with ambiguous genitalia should be undertaken by a pediatric endocrinologist.

I. 46, XX DSDs

– congenital adrenal hyperplasia (CAH) due to:

  • 21-hydroxylase deficiency, 11-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase deficiency, P450 oxidoreductase deficiency

  • maternal/fetal tumor

  • placental aromatase deficiency

  • exogenous androgens or teratogens

  • defect in ovarian development

  • congenital anomalies/syndromes

II. 46, XY DSDs

– defect in testosterone or dihydrotestosterone (DHT) biosynthesis due to:

  • 3-beta-hydroxysteroid dehydrogenase deficiency, 5 alpha reductase deficiency, 17 ketosteroid reductase deficiency (also known as 17-beta hydroxysteroid dehydrogenase 3 deficiency), 17, 22 lyase deficiency

  • receptor abnormality (androgen or luteinizing hormone (LH) receptor)

  • first trimester testicular failure

  • defect in testicular development

  • other (includes syndromic / cloacal exstrophy / congenital aphallia / teratogen / mechanical / idiopathic)

III. Sex Chromosome DSD

  • 45X/46XY mixed gonadal dysgenesis

  • 45, X (Turner syndrome)

  • 47, XXY (Klinefelter syndrome)

  • 46XX/46XY chimeric

If you are able to confirm that the patient has ambiguous genitalia, what treatment should be initiated?

1. Psychological treatment:

The birth of an infant with ambiguous genitalia is typically extremely distressful for parents. Adding to this is the fact that the diagnostic work-up takes several days to weeks in some cases. During this time, the parents must endure the uncertainty of “not knowing” what their baby’s gender and ultimate diagnosis is. Thus, it is imperative that psychological support and counseling be provided. Many practitioners are advocates of a multidisciplinary team approach to the birth of an infant with ambiguous genitalia. However, other than anecdotally, exactly how such a team should be structured and how it should function have not been rigorously studied. As long as the necessary expertise is available, the rapport established between the parents and any one provider may be the most important factor in the child’s well-being.

2. Medical treatment:

The only DSDs typically requiring immediate medical treatment are forms of CAH. This involves glucocorticoid and mineralocorticoid therapy as well as salt supplementation. Infants with CAH are at risk for an adrenal crisis. Therefore, careful monitoring of electrolytes is important in any infant in whom CAH is part of the differential diagnosis. A course of depot testosterone is sometimes undertaken in infants with 46XY DSDs with the goal of increasing the size of the penis. However, this should only be done after careful consideration of the possible outcomes, and after an initial decision has been made to proceed with a male sex assignment.

3. Sex assignment:

Decisions regarding sex assignment should be made by the parents in consultation with different members of the DSD team. Factors that impact this decision include the diagnosis, potential for fertility and sexual function, cultural beliefs, need for genital surgery and long-term outcomes. Sex assignment is straightforward in some conditions and much less so in others.

4. Surgical treatment:

Genital surgery is typically cosmetic in nature and is elective. Decisions to proceed with genital surgery need to be made after careful consideration of the pros and cons, potential outcomes, and impact on factors such as fertility and sexual function.

Patients with CAH require lifelong ongoing clinical follow-up and treatment. Other forms of DSDs may require sex steroid replacement at the time of puberty.

What are the adverse effects associated with each treatment option?

The treatment of CAH is inherently challenging, as one must “walk a fine line” between under-treating and over-treating with glucocorticoid therapy.

There is a small risk of gender dysphoria in all patients with DSDs. However, this is not felt to be a consequence of treatment.

What are the possible outcomes of ambiguous genitalia?

Information about prognosis varies widely depending on the etiology of the DSD. For example, much is known about CAH, while very little is known about rarer conditions such as congenital aphallia. In addition, some conditions are heritable, and families need genetic counseling regarding risks to future children.

Full disclosure regarding the risks and potential benefits of genital surgery need to be provided.

What causes this disease and how frequent is it?

  • There are many potential etiologies of ambiguous genitalia. These range from genetic mutations to exposures to mechanical to syndromic to sex chromosome aneuploidy to idiopathic.

  • What is known about the frequency of specific disorders varies widely. Classic CAH, for example, occurs in 1 in 10,000-15,000 individuals.

How do these pathogens/genes/exposures cause the disease?

A few examples would be:

  • Mutations in genes involved in testicular or ovarian developmentinterfere with normal gonadal development.

  • Mutations in genes encoding for enzymes needed for cortisol biosynthesis result in adrenal androgen excess

  • Abnormalities in gonadal development interfere with normal sex steroid biosynthesis

  • Mutations in genes encoding for receptors affect end organ responsiveness to gonadal hormones

  • Non-dysjunction events result in sex chromosome aneuploidy

  • Exogenous exposures/teratogens have direct effects on developing tissues

Other clinical manifestations that might help with diagnosis and management


What complications might you expect from the disease or treatment of the disease?

Children with CAH are at increased risk of obesity. Girls with CAH are at increased risk for polycystic ovary syndrome (PCOS). Children on glucocorticoid therapy are at risk for adrenal crisis if stress coverage is not given appropriately. Therefore, all such patients should wear a medic-alert.

Are additional laboratory studies available; even some that are not widely available?

There are a number of research labs around the world that offer testing for rare or previously unidentified genetic mutations in children with DSDs.

How can the occurrence of ambiguous genitalia be prevented?

Although prenatal dexamethasone therapy to prevent virilization of an affected female fetus with CAH has been shown to be moderately effective, the potential risks are felt to outweigh the benefits. This treatment is only recommended in the context of an IRB-approved clinical trial.

What is the evidence?

Baetens, D, Mladenov, W, Chiaie, B. “Extensive clinical, hormonal and genetic screening in a large consecutive series of 46,XY neonates and infants with atypical sexual development”. Orph J Rare Dis. vol. 9. 2014. pp. 209(Describes the likelihood of identifying a genetic diagnosis in 46,XY DSD using state of the art techniques including microarray, competitive genomic hybridization and whole exome sequencing.)

Mendonca, BB, Domenice, S, Arnhold, IJ, Costa, EM. “46,XY disorders of sex development (DSD)”. Clin Endocrinol (Oxf) . vol. 70. 2009. pp. 173-87. (Comprehensive review of etiologies of XY DSDs.)

Hughes, IA, Houk, C, Ahmed, SF, Lee, PA. “(Erica Eugster, Consensus Group member). LWPES/ESPE Consensus statement on management of intersex disorders”. Arch Dis Child . vol. 91. 2006. pp. 554-63. (Proceedings of intersex consensus conference.)

Speiser, PW, Azziz, R, Baskin, LS. ” Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline”. J Clin Endocrinol Metab. vol. 95. 2010. pp. 4133-60. (Clinical guidelines regarding the care of patients with CAH.)

Migeon, CJ, Wisniewski, AB, Gerhardt, JP. “Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome”. Pediatrics . vol. 110. 2002. pp. e31(Examines long-term outcome in 46XY DSDs including those sex-assigned, both male and female.)

Amaral, RC, Inacio, M, Brito, VN. “Quality of life of patients with 46,XX and 46,XY disorders of sex development”. Clin Endocrinol. vol. 82. 2015. pp. 159-64. (Evaluation of QOL in a cohort of patients with DSDs followed at a single center until adulthood.)

Parisi, MA, Ramsdell, LA, Burns, MW. ” A Gender Assessment Team: experience with 250 patients over a period of 25 years”. Genet Med . vol. 9. 2007. pp. 348-57. (One example of a multidisciplinary team approach.)

Rey, RA, Belville, C, Nihoul-Fékété, C. “Evaluation of gonadal function in 107 intersex patients by means of serum antimüllerian hormone measurement”. J Clin Endocrinol Metab . vol. 84. 1999. pp. 627-31. (Describes the use of MIS in the evaluation of DSDs.)

Bertelloni, S, Dati, E, Baroncelli, GI. “Disorders of sex development: hormonal management in adolescence”. Gynecol Endocrinol . vol. 24. 2008. pp. 339-46. (Discussion of sex steroid replacement in hypogonadal adolescents with DSDs.)

Anderson, S. “Disorders of sexual differentiation: ethical considerations surrounding early cosmetic genital surgery”. Pediatr Nur . vol. 41. 2015. pp. 176-86. (Review of ethical considerations regarding genital surgery in children with DSDs.)