Ambiguous Genitalia

Ambiguous genitalia is a condition in which the sex of the newborn cannot be determined based on the macroscopic appearance of genitalia. Congenital adrenal hyperplasia is the most common cause, whereas numerous genetic and embryonal defects that affect androgen synthesis can cause impaired genital development. The clinical presentation depends on the karyotype of the fetus and an extensive diagnostic workup is necessary. Gender rearing and appropriate surgical correction is usually performed.

The disease is related to the following processes:  congenital and has an incidence of about  0 / 100.000.


Ambiguous genitalia belongs to a group of disorders of sexual development (DSDs) and is characterized by the appearance of genitalia that renders the physician unable to determine the sex of the newborn with 100% certainty [1]. Numerous causes have been identified over the last few decades and a distinction between etiologies based on the karyotype of the neonate (whether it is 46,XY or 46,XX) has been made [2]. In neonates who are considered as males based on their karyotype, gonadal dysgenesis, deficiency of male sex hormones and enzymes that are responsible for their conversion to active substances (such as testosterone and 5α-reductase, respectively), as well as abnormal activity of androgen receptors are established as most frequent causes [2]. On the other hand, congenital adrenal hyperplasia (CAH), a group of genetic disorders distinguished by insufficient synthesis of cortisol and/or aldosterone, high levels of adrenocorticotropic hormone (ACTH) and virilization of external genitalia is by far the most common cause of ambiguous genitalia in females that have 46,XX karyotype [3] [4]. In virtually all cases, the pathogenesis starts during embryogenesis, when the differentiation of gonadal structures occur under the influence of anti-Müllerian hormone, testosterone and various other hormones [5]. Although ambiguous genitalia is considered to be a disorder that is rarely encountered in clinical practice, with studies indicating a birth prevalence rate of 5.8 per 100 000 live births [6], the diagnosis must be made as soon as possible, primarily because underlying disorders such as mineralocorticoid insufficiency seen in CAH that may be life-threatening [7]. Absence of any of the typical male (bilateral descended testicles and formation of scrotal folds) or female (separation of labial folds, separate urethral and vaginal openings, impalpable gonads) genital features should immediately rise high suspicion toward this diagnosis [5]. In that case, an extensive genetic, imaging and hormonal workup should be conducted in order to determine the underlying cause. Karyotyping, polymerase chain reaction (PCR) to determine the presence of Y chromosome, estimation of 17-OH progesterone and beta human chorionic gonadotropin (β-hCG) levels in serum, ultrasonography and genitography are recommended [8]. Surgery is advocated as soon as the diagnosis is made, but many controversies exist about the role of parents in choosing the gender of their child and not letting the choice to him/her when they reach appropriate age for such decisions [9].


Causes of ambiguous genitalia may be numerous and a broad classification has been made on the distinction of conditions that appear in 46,XY and 46,XX individuals, respectively. In karyotypic males, the causative disorders are [2] [5] [10]:

  • Partial gonadal dysgenesis (as a result of leydig cell hypoplasia or genetic abnormalities that impair normal gonadal differentiation, such as Smith Lemli Opitz syndrome or Denys Drash syndrome and Frasier syndrome).
  • Several enzyme deficiencies in the steroidogenesis pathway that lead to inability of testosterone synthesis, including 5α-reductase deficiency (occurring due to steroid 5α-reductase type 2 (SRD5A2) gene mutations).
  • Abnormal activity of androgen receptors, which is primarily the end-result of numerous genetic mutations.

In 46,XX born individuals, congenital androgen hyperplasia (CAH) is by far the most common cause of ambiguous genitalia, comprising more than 80% of cases according to certain reports [11]. CAH comprises a group of disorders in which autosomal recessive mutations lead to various enzymes deficiencies, including 21-hydroxylase, 11β-hydroxylase and 17α-hydroxylase/17,20-lyase, resulting in their inactivity or complete deficiency. The end-result is insufficient production of cortisol and aldosterone from cholesterol [2]. Placental aromatase deficiency and maternal excess of androgens, usually from ovarian tumors, are considered as other potential etiologies [5].


Ambiguous genitalia is rarely encountered in medical practice, as large-scale reports suggest a prevalence rate of 5.8 per 100,000 live births [6]. In Germany, however, studies show that the condition is much more commonly observed, estimating a prevalence rate of 2 per 10,000 live births every year [12]. Based on the findings that corrective genital surgery is performed in 1-2 individuals per 1,000 live births, the overall prevalence rate may be as high as 2% [13]. Apart from use of synthetic progestins during pregnancy (which is now avoided) [2], and a positive family history (necessitated by the fact that many underlying diseases have an autosomal recessive pattern of inheritance), risk factors for this condition are currently not established.

Sex distribution
Age distribution


During normal embryogenesis, sexual differentiation occurs under the influence of anti-Müllerian hormone (which suppresses the proliferation of the Müllerian duct from which the fallopian tubes, the uterus and the upper parts of the vagina) and testosterone (which stimulates growth of Wolffian duct from which vas deferens, seminal vesicles and the epididymis arise) [5]. If the SRY gene of the short arm of the Y chromosome becomes activated, production of testosterone and subsequent conversion to dihydrotestosterone (DHT) leads to masculinization of the external genitalia by the end of 12th week of embryogenesis. In the absence of SRY gene activity, a female genital tract is formed [5].During this process, numerous defects at various levels may render normal genital maturation, both male and female. In the setting of 5α-reductase deficiency, testosterone is not able to convert to DHT, leading to incomplete fusion of the genital folds that form the penis and incomplete growth of the genital tubercle, thus affecting proper masculinization [14]. In leydig cell hypoplasia, insufficient production of testosterone is the underlying pathophysiological mechanism [3], whereas genetic mutations in androgen receptor sensitivity reduces the capacity for the utilization of androgenic effects [2]. On the other hand, the excess androgenic effects in CAH stimulate prenatal virilization (masculinization) of genitalia among 46,XX females [4], as a result of several types of enzyme deficiencies that disrupt the pituitary-adrenal axis [15].


Patients with ambiguous genitalia require prompt and detailed evaluation, as life-threatening complications, such as salt-losing crisis seen in CAH, may be observed [7]. Gender assignment is equally important in early stages, so that future social, medical, but also psychological complications may be minimized or even avoided [7], which is why an early diagnosis carries a much better prognosis. But in more than 50% of all infants, unfortunately, the diagnosis is not made in the first 6 months of their life [12], indicating that stronger efforts are needed during neonatal assessment.


The clinical presentation of neonates is starts as early as birth, with typical absence of some of the basic male or female genital features. Bilateral nonpalpable testes and hypospadia (opening of the urethra on the inferior side of the penis) that is associated with scrotal sac separation are main clinical findings encountered in apparently male neonates (46,XY), whereas hyperthrophy of the clitoris, inguinal hernia that contains a gonad and a single opening in the vulva are hallmarks of ambiguous genitalia in apparent females (46,XX) [5]. Newborns who are suffering from CAH may suffer from severe dehydration as a result of excessive vomiting and diarrhea due to insufficient production of aldosterone [3], in which case an immediate diagnostic workup and appropriate treatment is necessary.


Having in mind the fact that many children are not diagnosed at birth or during neonatal period, it is necessary to emphasize the importance of a detailed physical examination soon after birth. Inspection and palpation of the genitalia is vital in establishing a clinical suspicion toward ambiguous genitalia. Signs such as dark skin pigmentation is indicative of high ACTH levels, which may be suggestive of CAH, whereas scrotal asymmetry points to imbalanced secretion of testosterone [5]. Palpating the gonads in the genital folds or in the inguinum may provide enough clues to establish a valid initial diagnosis [8]. Together with patient history of the mother that may reveal endocrine abnormalities, unexplained miscarriages or presence of genital anomalies in first-degree relatives [5], biochemical, molecular and imaging evaluation should be performed. Karyotyping is usually the first test that should be ordered, but PCR for the presence of Y chromosome that yields results within 24 hours is an efficient method in assessing the gender of the neonate [8]. Additional laboratory test include serum levels of ACTH, 17-hydroxyprogesterone and β-hCG [5], while imaging studies such as ultrasonography and genitography are recommended for visualization of the genitalia [8].


Much debate exists regarding the timing of surgery when it comes to ambiguous genitalia. Some authors believe that parents should, with the aid of a multidisciplinary team of physicians, make a decision about their child's gender early on, whereas other claim that the decision rests on the choice of the child once it reaches the age at which they are able to make such choices [4] [9]. Nevertheless, correctional surgery is the mainstay of therapy and various approaches exist. In the setting of preserving the female genitalia, procedures such as clitoral reduction, separation of the urogenital sinus and vaginoplasty are most commonly performed [4] [16], but several risks such as vaginal stenosis and impaired sexual function have been reported [17] [18]. On the other hand, repairs of hypospadia, prosthetic management of gonads, reconstruction of the prepenile scrotum and removal of Müllerian structures (in order to preserve the vas deferens) [15], are surgical procedures conducted in infants in whom male gender is chosen, most commonly between 6 and 18 months of age [5]. Hormonal replacement therapy with mineralocorticoids, glucoocorticoids and androgens are often necessary to facilitate proper maturation [15]. As this condition may present as a significant psychological burden for the patient later on, adequate long-term support may be of significant benefit [15].


Despite the fact that the cause of ambiguous genitalia is known in virtually all cases, prevention of these genetic and endocrine alterations that occur during embryogenesis are currently not possible. The only possible way of prevention may include prenatal DNA testing for couples with a positive family history for endocrine or genital anomalies [7]. For this reason, strategies to reduce the anatomical, social and functional challenges these patients may face are the main focus in life-long management [9].

Patient Information

Ambiguous genitalia is a term that describes the inability of the physician to determine the gender of the newborn due to indistinct features of the genitalia at birth. The causes may be numerous and are broadly categorized into conditions that impair development of genitalia in apparent males (individuals whose chromosomes indicate a male gender - the presence of one X and one Y chromosome) and females (newborns who have two X chromosomes). Underdevelopment of male genitalia is seen in conditions that interfere with the activity of testosterone and its conversion from cholesterol to other active metabolites, such as gonadal dysgenesis, various deficiencies of enzymes that regulate testosterone activity and functional changes in activities of androgen (sex hormone) receptors. On the other hand, congenital adrenal hyperplasia (CAH), maternal excess of sex hormones and deficiency of aromatase (enzyme responsible for conversion of estrogen into its active form) are main causes of female gonadal deficits. Virtually all diseases that trigger this condition occur as a result of genetic mutations occurring during the maturation of the fetus and its reproductive organs. It is estimated that ambiguous genitalia are seen in 5-6 individuals per 100,000 live births. Other reports show that 2 out of 10,000 individuals are born with ambiguous genitalia every year, suggesting that it may not be as uncommon as initially thought. To make an initial diagnosis, a properly conducted physical examination will reveal incomplete development of either male or female genitalia. To support these findings, a karyotype (the number and type of chromosomes) is necessary in order to assess the gender of the newborn. Imaging studies such as ultrasonography and genitography, evaluation of the most common deficient enzymes, as well as identification of testosterone and other sex hormone levels are necessary in establishing the underlying cause. Prior to initiating treatment (which is corrective surgery in all cases), parents should decide which sex should their child be. This decision is often difficult to make, which is why a team of several physicians that will carefully evaluate the pros and cons, as well as the risks that may be encountered during surgery with the parents. Some authors, on the other hand, have suggested that the infant should be involved in this decision as well and that the gender should be chosen once the child reaches an age when it is mature enough to decide for him/herself. Regardless, the outcomes are very good with appropriate surgical treatment, but the condition may present as a significant burden in terms of medical, social and psychological development of the affected child, which is why adequate long-term support may be necessary.

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  • Ambiguous genitalia with perineoscrotal hypospadias in 46, XY individuals: long-term medical, surgical, and psychosexual outcome - CJ Migeon, AB Wisniewski, JP Gearhart - Pediatrics, 2002 - Am Acad Pediatrics

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