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 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) . 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 , in which case an immediate diagnostic workup and appropriate treatment is necessary.
Entire Body System
- Surgical Procedure
In every case, there was no need for a second surgical procedure. CONCLUSION: The total mobilization of the urogenital sinus is a feasible and safe technique. The technique permits good cosmetic results, and urinary incontinence is absent. [ncbi.nlm.nih.gov]
The team consistently performs some of the most cutting-edge surgical procedures available, including newborn surgery, minimally invasive surgery, and robotic surgery, when appropriate. [childrensmn.org]
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), are surgical procedures conducted in infants in whom male gender [symptoma.com]
The occasional patient with a urogenital sinus complicated by urinary stasis and/or infection may require an early surgical procedure. [adc.bmj.com]
The surgical procedure of clitororeduction relies anatomically on the precise incision of the corpora cavernosa and preservation of innervation of the glans clitoris. [tandfonline.com]
The genital swellings form the labial folds; the branches of the genital tubercle (corpora cavernosa) surround the urogenital groove and located deep inside in the genital swellings. [tandfonline.com]
The genital tubercle becomes the clitoris, the unfused urethral folds become the labium minus, and the unfused labioscrotal swellings become the labium majus. [pedclerk.bsd.uchicago.edu]
The swelling in the external genital region looking like vulva along with elongated clitoris mimicking a penile part of male external-genitalia attracted the attention of parents to seek medical advice. Initially, the child was reared as a girl. [ijpmonline.org]
Labioscrotal swellings fuse and enlarge to become scrotum. In the female, genital tubercle becomes the clitoris, labioscrotal swellings the labia majora and urethral folds the labia minora. [patient.info]
Percentage (%) Age group 0-3 Years 27 54.0 4-7 Years 09 18.0 8-11 Years 02 04.0 12-15 Year 02 04.0 =16 10 20.0 Dwelling Rural 35 70.0 Urban 15 30.0 Consanguinity Yes 10 20.0 No 40 80.0 Clinical condition Hypospadias 08 16.0 AIS 04 08.0 CAH 07 14.0 Inguinal swelling [omicsonline.org]
- Short Stature
Girls with Turner syndrome (45,XO) may be detected earlier by noting the characteristic associated anomalies of short stature, webbing of the neck, and wide-spaced nipples. [emedicine.medscape.com]
Inadequate steroid replacement will lead to inadequate metabolic control of androgen production, resulting in excessive virilization and precocious puberty, as well as rapid bone age advancement and eventual short stature. [tp.amegroups.com]
List of conditions' is provided below, at the end of 'Medical classifications'): Intersex Condition Sex Specificity Approximate Prevalence Late onset congenital adrenal hyperplasia/nonclassic congenital adrenal hyperplasia female, males are generally asymptomatic [en.wikipedia.org]
- Failure to Thrive
- Loss of Appetite
In most cases, symptoms include fever, chills, loss of appetite, nausea, muscle pains particularly in the back, and headaches. Symptoms typically improve within five days. [play.google.com]
In most cases, symptoms include fever, chills, loss of appetite, nausea, muscle pains particularly in the back, and headaches. Symptoms typically improve within five days. [play.google.com]
Urgent medical assessment is needed; for example, 75% of infants with CAH have associated salt-wasting nephropathy which can cause hypotension, collapse and death. [patient.info]
The high androgen levels virilize the infant, and the block in cortisol synthesis leads to adrenal insufficiency which risks electrolyte imbalance, hyponatremia, hyperkalemia, hypotension, vomiting, and if untreated, cardiovascular collapse, shock and [tp.amegroups.com]
Because of clitoromegaly and scrotal-like hypertrophy of the labia majora, she had an endocrine evaluation the results of which were normal. The findings are thought to represent local genital hypertrophy. [ncbi.nlm.nih.gov]
Ultrasound diagnosis: Female fetus: clitoromegaly with normal labia. Male fetus: micropenis, hypospadias, undescended testes, bifid scrotum. [fetalmedicine.org]
On examination, the child had fully developed vagina and clitoromegaly [Figure 1]a]. However no skin pigmentation, labioscrotal fusion, palpable gonads were noted. The general health of the child was normal. [ijpmonline.org]
Newborn examination by a pediatrician revealed a phallus 2 cm in length with urethral opening at its base (apparent clitoromegaly) and separate labial-scrotal folds with palpable masses (apparent testes). [nature.com]
All the reported patients with lissencephaly are males who presented with a posterior-to-anterior gradient, moderately increased thickness of the brain cortex, agenesis of corpus callosum, micropenis, and cryptorchidism. [ncbi.nlm.nih.gov]
Am J Epidemiol 2008;167:251-256 Moreno-Garcia M, Miranda EB: Chromosomal anomalies in cryptorchidism and hypospadias. [karger.com]
Small penis and the male sexual role. would suggest that the penis of boys with a microphallus who are given testosterone in infancy will be adequate after puberty. [goldjournal.net]
In this present study, we report a normal male karyotype manifesting microphallus, bifid scrotum/labia majora with bilateral palpable gonads, and a blind-ended pseudovagina. [ncbi.nlm.nih.gov]
Apparent male genitalia with bilateral undescended testes, a microphallus, proximal hypospadias or distal or mid-shaft hypospadias with undescended testis. [pedclerk.bsd.uchicago.edu]
Genitalia can be ambiguous and are frequently assigned to the female gender because of microphallus, fused scrotum, absent testes, and absence of the uterus. Many such infants are found to have XY karyotypes. [disorders.eyes.arizona.edu]
Three patients had microphallus. Two had only one palpable gonad and one patient looked apparently female (patient 12). [mmj.eg.net]
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 . Palpating the gonads in the genital folds or in the inguinum may provide enough clues to establish a valid initial diagnosis . Together with patient history of the mother that may reveal endocrine abnormalities, unexplained miscarriages or presence of genital anomalies in first-degree relatives , 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 . Additional laboratory test include serum levels of ACTH, 17-hydroxyprogesterone and β-hCG , while imaging studies such as ultrasonography and genitography are recommended for visualization of the genitalia .
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  . 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  , but several risks such as vaginal stenosis and impaired sexual function have been reported  . 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) , are surgical procedures conducted in infants in whom male gender is chosen, most commonly between 6 and 18 months of age . Hormonal replacement therapy with mineralocorticoids, glucoocorticoids and androgens are often necessary to facilitate proper maturation . As this condition may present as a significant psychological burden for the patient later on, adequate long-term support may be of significant benefit .
Patients with ambiguous genitalia require prompt and detailed evaluation, as life-threatening complications, such as salt-losing crisis seen in CAH, may be observed . Gender assignment is equally important in early stages, so that future social, medical, but also psychological complications may be minimized or even avoided , 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 , indicating that stronger efforts are needed during neonatal assessment.
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   :
- 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 . 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 . Placental aromatase deficiency and maternal excess of androgens, usually from ovarian tumors, are considered as other potential etiologies .
Ambiguous genitalia is rarely encountered in medical practice, as large-scale reports suggest a prevalence rate of 5.8 per 100,000 live births . 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 . 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% . Apart from use of synthetic progestins during pregnancy (which is now avoided) , 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.
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) . 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 .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 . In leydig cell hypoplasia, insufficient production of testosterone is the underlying pathophysiological mechanism , whereas genetic mutations in androgen receptor sensitivity reduces the capacity for the utilization of androgenic effects . On the other hand, the excess androgenic effects in CAH stimulate prenatal virilization (masculinization) of genitalia among 46,XX females , as a result of several types of enzyme deficiencies that disrupt the pituitary-adrenal axis .
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 . For this reason, strategies to reduce the anatomical, social and functional challenges these patients may face are the main focus in life-long management .
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 . 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 . 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 . 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  . 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 . 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 , 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 . 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 . 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 . 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 .
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.
- Murphy C, Allen L, Jamieson MA. Ambiguous genitalia in the newborn: an overview and teaching tool. J Pediatr Adolesc Gynecol. 2011;24(5):236-50. Blackless M, Charuvastra A, Derryck A, et al. How sexually dimorphic are we? Am J Hum Biol 2000;12:151–166.
- Krishnan S, Wisniewski AB. Ambiguous Genitalia in the Newborn. [Updated 2015 Apr 29]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.
- Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.
- Eckoldt-Wolke F. Timing of surgery for feminizing genitoplasty in patients suffering from congenital adrenal hyperplasia. Endocr Dev. 2014;27:203-209.
- Kaye C, et al. Evaluation of Newborn with Developmental Anomalies of the External Genitalia. Pediatrics 2000;106 (1):138-142.
- Lloyd JC1, Wiener JS, Gargollo PC, Inman BA, Ross SS, Routh JC. Contemporary epidemiological trends in complex congenital genitourinary anomalies. J Urol. 2013;190(4):1590-1595.
- Al-Mutair A, Iqbal MA, Sakati N, Ashwal A. Cytogenetics and etiology of ambiguous genitalia in 120 pediatric patients. Ann Saudi Med. 2004;24(5):368-372.
- Sultan C, Paris F, Jeandel C, Lumbroso S, Galifer RB. Ambiguous genitalia in the newborn. Semin Reprod Med. 2002;20(3):181-188.
- Wolffenbuttel KP, Crouch NS. Timing of feminising surgery in disorders of sex development. Endocr Dev. 2014;27:210-221.
- Vidal I, Gorduza DB, Haraux E, Gay CL, Chatelain P, Nicolino M, et al. Surgical options in disorders of sex development (dsd) with ambiguous genitalia. Best Pract Res Clin Endocrinol Metab. 2010;24(2):311-324.
- Frimberger D, Gearhart JP. Ambiguous genitalia and intersex. Urol Int. 2005;75(4):291-297.
- Thyen U, Lanz K, Holterhus PM, Hiort O. Epidemiology and initial management of ambiguous genitalia at birth in Germany. Horm Res. 2006;66(4):195-203.
- Blackless M, Charuvastra A, Derryck A, et al. How sexually dimorphic are we? Am J Hum Biol 2000;12:151–166.
- Al-Jurayyan NAM. Ambiguous genitalia: two decades of experience. Ann Saudi Med. 2011;31(3):284-288.
- Federman DD, Donahoe PK. Ambiguous genitalia--etiology, diagnosis, and therapy. Adv Endocrinol Metab. 1995;6:91-116.
- Creighton S, Minto C. Managing intersex. BMJ 2001;323:1264–1265.
- Minto CL, Liao LM, Woodhouse CRJ, et al. The effect of clitoral surgery on sexual outcomes in individuals who have intersex conditions with ambiguous genitalia: a cross sectional study. Lancet. 2003;361:1252–1257.
- Göllü G, Yildiz RV, Bingol-Kologlu M, Yagmurlu A, Senyücel MF, Aktug T, et al. Ambiguous genitalia: an overview of 17 years' experience. J Pediatr Surg. 2007;42(5):840-844.