Ambiguous genitalia is a very rare problem encountered in newborns, with the prevalence of 1 in 4500 live births. Even with the recent advances in the technology like genetic workup, assay of hormones, karyotyping, only 20 to 40% of the time can the diagnosis be made in these children. 5 alpha-reductase type 2 (5alpha-RD2) deficiency is one of the important causes of ambiguous genitalia in children. The phenotype of children with 5α-RD2 deficiency can vary from under-developed male genitalia to a complete female phenotype.
Although testosterone is considered a predominant male sex hormone, not all tissues are responsive to testosterone. The 5alpha-RD2 enzyme converts testosterone into a more potent form of the male sex hormone called dihydrotestosterone (DHT). During male fetal development, testosterone and DHT have a specific predetermined role in sexual development. Testosterone is the driver for the development of male internal genitalia including the Wolffian duct, whereas DHT has a role in the genesis of male external genitalia. At puberty, testosterone is responsible for aggressive psychosexual behavior, deepening of the voice, increased muscle mass and initiating spermatogenesis. On the contrary, DHT has a role in the development of prostate and male pattern of hair growth at the time of puberty. 5alpha-RD2 deficiency is a very rare disorder seen most commonly due to a mutation in the gene SRD5A2 located on the short arm of chromosome 2. Children with deficiency of 5 alpha-reductase will have decreased production of DHT during fetal development, and this leads to defective external genital development and ambiguous genitalia.
The disease is very rare among Caucasians. Due to a large number of consanguineous marriages, there is a high prevalence of 5alpha-RD2 deficiency in the population of the Dominican Republic; the first reported case of 5alpha-RD2 deficiency was also from the same island. Apart from the Caribbean, this disease is also present in southern Lebanon and Papua New Guinea.
The human embryo possesses the capability to develop and differentiate into both male and female reproductive systems. By the timeline of the 6th week of gestation, the fetus would have developed the primordial structures that could either form a male or female reproductive system. In the absence of testosterone, the fetus would develop the female reproductive system. Differentiation of the primordial undifferentiated gonadal ridge into the male reproductive system initiates during the embryonic life by SRY gene located on the short arm of the Y chromosome. Testosterone produced by the testes leads to differentiation of Wolffian duct in males to form the male internal genitalia including seminal vesicles, epididymis and vas deferens. The overlying skin on the external genitalia has the activity of 5alpha-RD2 activity which helps in conversion of testosterone to di-hydro testosterone. DHT will then start forming the external genitalia. By 12 weeks of gestation, the male external genitalia differentiates. After 12 weeks the penis starts to grow in size and testes begins its descent into the scrotum.
5alpha-RD2 deficiency is an inherited autosomal recessive disease. The deficiency is due to mutations in the gene which encodes for the enzyme 5α-RD2 on the short arm of chromosome 2. Up to 40 different types of mutations have been reported leading to this disease. The levels of DHT will be low in these children, which will affect the sexual differentiation of male external genitalia. Although the genotype of these children is 46 XY, the phenotype varies from case to case.
The presentation of patients with deficiency of 5α-RD2 can be varying. This condition is an autosomal recessive disorder of sex development associated with the mutation in the SRD5A2 gene. There has been no direct association seen between the phenotype and the genotype in this disorder. Two individuals with the same gene defects in SRD5A2 can present with completely different phenotype, which clearly shows that there are other additional genes which probably controls the phenotype along with the gene under discussion.
The newborns might have genitalia resembling labia majora which in reality would be an unfused labioscrotal folds. The phallus in these children may more look like a clitoris than a penis. At the same time, the internal genitalia in these children will include seminal vesicles, epididymis, vas deferens, and ejaculatory duct and one may not see any Mullerian structures. The testes in these children might be present in the inguinal sac, and very rarely they can also be found within the abdomen. These children tend to be raised as females till puberty, by which time they start exhibiting virilization. At puberty the phallus may grossly enlarge to form a penis, the testes may descend into the unfused labioscrotal folds, the voice deepens, and the beard starts growing. Development of all these secondary sexual characteristics during puberty does not need the presence of DHT, but only the presence of testosterone.
GENDER IDENTITY PROBLEMS IN CHILDREN WITH 5alpha-RD2 DEFICIENCY: Although some children with this enzyme deficiency are raised as girls, many would change their gender to males at puberty after virilization. There are multiple factors like the culture and environmental pressures which can influence the gender changes in these children, but the most significant factor responsible for the gender change is the exposure of the child's brain to androgen, including testosterone and not to the female sex hormone. A brain exposed to androgens will develop more masculine behavior and influences the child to identify itself as a male child rather than a female.
The evaluation of 5alpha-RD2 deficiency includes biochemical assays and gene analysis.
Biochemical Assay: Traditionally the biochemical test of choice for the diagnosis of 5alpha-RD2 enzyme deficiency has been the estimation of the ratio between testosterone to DHT, after stimulation with human chorionic gonadotropin (hCG). With this disorder, the children will show an increase in the ratio of testosterone to DHT after hCG administration. It merits recall that this disorder cannot be ruled out entirely if the testosterone to DHT ratio does not rise with hCG stimulation, making it more difficult to diagnose this condition. Furthermore, this test is not very much reliable as the ratio of testosterone to DHT may vary based on various factors like severity of enzyme deficiency and age of the children. This biochemical test is also not useful in case of partial enzyme deficiencies.
Gene analysis: Human gene SRD5A2 gene encodes for a protein which makes up enzyme 5alpha-RD2 containing 254 amino acids. This variant has more affinity to testosterone than 5alpha-RD1. At least 54 different types of mutations have been seen involving this gene, among which the primary type is missense mutations. The severity of the disease depends on the degree of loss of enzymatic activity due to a gene mutation. About half of these missense mutations result in an enzyme with no functional biological activity and rest half of the times; the gene may produce an enzyme with a very little measurable biological activity.
The treatment of a child with 5alpha-RD2 deficiency depends on many factors, the most important being the phenotypic findings and gender of the child at the time the physician diagnoses the problem. If there is a critical defect in the formation of external male genitalia, then it will be better if the child is raised as a female. Further, if the child wants to be raised as a female, then the testes have to be removed, and the corrective surgery will be necessary. The removal of testes has to occur before the child attains puberty and virilization of the child. The surgical correction if the child opts to be a female would be external genitalia reconstruction, creating a vaginal opening in perineum with a clear separation of urethra and vagina. When the child becomes a teenager, then vaginoplasty would be a potential treatment option.
If the child is raised as a male, then corrective surgery should be done depending on the phenotype of the child. The developmental size of the penis at the time of diagnosis and its ability to develop into a functional penis is the main criteria of consideration before raising the child as a male. The corrective procedures in males include hypospadias correction, correction of chordee and reconstruction of the urethra. These surgeries are normally performed during the first or second year of life.
The parents of the child with ambiguous genitalia have legal rights to seek assistance, support and any information on the child's problem. They can take adequate time on deciding the treating options and deciding the gender of the child.
The differential diagnosis in ambiguous genitalia should be considered after a precise anatomical examination and hormonal assay. The significant differentials which can present similarly to 5alpha-RD2 deficiency include androgen insensitivity syndrome (AIS) and insufficiency of 17 beta-hydroxysteroid dehydrogenase type 3. The diagnosis of 5alpha-RD2 deficiency and AIS is critical because individuals with 5alpha-RD2 deficiency are usually raised as males and AIS as females. Sometimes the phenotype of 5alpha-RD2 deficiency can be similar to Leydig cell hypoplasia associated with a mutation on LH receptor on the Leydig cells.
The prognosis in individuals with 5alpha-RD2 deficiency is relatively good. There have been no reports on prostate malignancy and benign prostatic enlargement in these patients. There is reduced facial and body hair in these individuals, but with normal sebum production. Most males with a deficiency of 5alpha-RD2 are infertile. The reason for infertility could be undescended testes, decreased sperm count, urethral strictures and urethroscrotal fistulas. The good news is some of the individuals with 5alpha-RD2 deficiency can produce children, thanks to procedures including intrauterine insemination and in vitro fertilization.
The most significant complication associated with the deficiency of 5alpha-RD2 enzyme is the altered phenotype of the genital organs. The incidence of tumors of testes in these individuals remains unreported. There are some studies which have looked at the bone growth and development in these group of patients, but the bone mineral density was normal in all these patients. Females with genotype 46 XX having a homozygous mutation of the SRD5A2 gene can have a delay in their menarche, but their reproductive functions are normal.
5alpha-reductase deficiency usually produces severe male genital ambiguity with bifid scrotum, urogenital sinus, and a clitoris like a phallus. Inadequate endocrine evaluation in newborns may fail to make a correct diagnosis and determine a gender assignment opposed to genetic and gonadal sex with possible deterioration in long-term outcomes. It is vital that a multidisciplinary team that includes a geneticist, pediatrician, endocrinologist, pediatric surgeon, urologist, obstetrician, and a gynecologist help determine the appropriate course for the infant. At the same time, as the child gets older, a mental health nurse should provide counseling because some of these children do have ambivalent feelings about their gender assignment. [Level V]
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