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Pediatric andrology and endocrinology
Sirakov M., Andonova S., Savov A.
Medical Center "Maichin Dom", Sofia, Bulgaria National Genetic Laboratory, Sofia, Bulgaria
Corresponding author
Sirakov Milko - Professor, National Genetic Laboratory, Medical Center "Maichin Dom"
Address: st. Zdrave 2, 1431 Center, Sofia, Bulgaria E-mail: msirak@abv.bg
5-a-reductase type 2 deficiency
Over the past few years, the possibility of diagnosis in violation of the formation of the floor has expanded significantly. The article describes the sex reversion in autosomal recessive 46,XY-violation of sexual development as a result of deficiency of 5-a-reductase type 2. The geographical distribution of the described 5-ARD cases is presented. Keywords: deficiency of 5-a-reductase type 2, violation of sex formation
Pediatric and Adolescent Reproductive Health. 2018; 14 (4): 72-8.
doi: 10.24411/1816-2134-2018-14008. Received: 03.09.2018. Accepted: 10.12.2018.
Disorders of sex development (DSDs), formerly termed „intersex conditions", are among the most fascinating conditions encountered by the clinicians.
The ability to diagnose these conditions advanced rapidly in recent years. In most cases today, clinicians can promptly make an accurate diagnosis and counsel parents on therapeutic options. However, the paradigm of early gender assignment has been challenged by the results of clinical and basic science research, which show that gender identity development likely begins in utero.
While the techniques of surgical genital reconstruction have been mastered, the understanding of the psychological and social
implications of gender assignment has shifted the paradigm away from early reconstruction in some cases.
The deficiency of 5-a-reductase type 2 (5-ARD) is an autosomal recessive disorder of the group of 46,XY disorders of sexual development (DSD) [1].
It is caused by reduced or absent function of the steroid 5-a-reductase type 2 enzyme (SRD5A2), which converts testosterone (T) into dihydrotestosterone (DHT) [2].
Because DHT is required for the normal masculinization of the external genitalia in utero, genetic males with 5-ARD usually are born with ambiguous or female-like external genitalia [3].
They can have: male gonads, including testicles and Wolffian structures, micropenis or macroclitoris, hypospadia, and a rudimentary prostate. They can have also an ambiguous or externally normal female genitalia, and usually tend towards a female appearance. Therefore, they are often raised as girls, but usually have a male gender identity [4, 5].
Although the external genitalia may be female, the vagina consists of only the lower two-thirds of a normal vagina, creating a blind-ending vaginal pouch. Due to the normal action of Mullerian inhibiting factor produced by the testicles in utero, individuals with 5-ARD lack an uterus and Fallopian tubes.
Testicules are intact and are usually located in the inguinal canal or scrotum; however, cryptorchidism is frequently described, with testicules occasionally located in the abdomen [6].
The striking feature in these patients is the extreme and quick virilisation at puberty, presumably due to the preserved 5-a-reductase type 1 enzyme activity or to the direct action of the increased testosterone levels on the phallus.
At puberty, this includes descending of the testicules, dramatic penile growth and the individual develops a masculine voice, body hair and muscle mass. The only characteristics not develop are those that depend on DHT (prostatic enlargement, facial hair, acne) [7-9].
If the condition has not already been diagnosed until the puberty, it usually becomes evident at around age of 12 with primary amenorrhoea and virilisation [10].
The disease has been described in >50 families in several parts of the world and is prevalent in the Dominican Republic, Southern Lebanon, in the Eastern Highlands Province of Papua New Guinea and in Turkey. The high frequency in these areas represents the effect of consanguinity in specific kindreds [11].
In general, disorders of sexual differentiation as a whole are uncommon, with an overall incidence of 1:5500 (Fig. 1) [12].
The number of different mutations described in the countries is indicated by digits. In 5-ARD patients with Chinese origin, about 24 different mutations were identified; patients from Mexico shared 17 different mutations, the same - among the Brazilian cases.
The cases of the condition reported in the Dominican Republic are of greatest interest due to its prevalence in a very small remote village of Las Salinas, where 12 out of 13 families had one or more male family members that carried the genetic mutation, though not all the carriers of the mutation were affected.
In the Dominican Republic, the Spanish term for a person with the condition is «gue-vedoce». This comes from the phrase "huevo/ guevo a los doce" with the slang meaning of "ball[s]/penis at twelve [years of age]" [16].
It has been reported that in the cases seen in the Dominican Republic, locals celebrate when a child they previously believed to be a "girl" naturally transform into his male body upon reaching puberty and socially assumes his male gender role (in most cases, the gender identity had always been male even when the child was still socially a female).
Clinical, 5-ARD is limited to genetic males. Although the enzyme deficiency can be documented in homozygous females, they are asymptomatic.
5-ARD is not a life threatening condition, however, there is an increased risk of go-nadoblastoma if intra-abdominal testes are retained, or of osteoporosis if adequate hormone replacement therapy is not initiated in patient with a gonadectomy. Psychological consequences with occasional asynchrony of assigned gender and sexual identity are also possible.
In general, individuals with 5-ARD are capable of producing viable sperm. In individuals with feminized or ambiguous genitalia, the phallus may be capable of erections as well as ejaculations, but may be insufficient for intercourses. Fertility is sometimes compromised by the underdevelopment of seminal vesicles and prostate or due to azoospermia or oligo-spermia associated with undescended testes.
Fig. 1. You can see here the geographic distribution of reported cases of 5-ARD. Countries where cases with mutations in SRD5A2 have been reported are put in gray; white are non-reported yet countries.
The diagnosis of 5-ARD in young infants and especially in newborns and pre-puber-tal individuals with 46,XY DSD is difficult because of the great variety of phenotypical outcomes [15].
Some conditions such as Partial Androgen Insensitivity Syndrome or 17p-hydroxysteroid dehydrogenase type 3 enzyme deficiency may lead to similar clinical characteristics and could be clinically indistinguishable [16, 17].
The clinical spectrum is heterogeneous, ranging from a female with a blind vaginal pouch to a fully male phenotype with hypospadias and micropenis, clitoris-like phallus, bifid scrotum, cryptorchid (with normal or reduced spermatogenesis), and rudimentary prostate.
Actually, 2/3 of the patients are initially assigned female gender.
The testes are usually in the inguinal canals bilaterally; however, in some individuals they can be found in the labioscrotal folds or retained in the abdomen. The uterus and cervix are absent. Diagnosis is confirmed by genetic screening.
The most individuals with 5-ARD are identified in the neonatal period with ambiguous genitalia [18].
However, in some children with this phenotype, diagnosis is often delayed until the time
of puberty [19, 20].
The anomalies and syndromes that we have
to consider are shown on the next table.
• 17ß-Hydroxysteroid Dehydrogenase Deficiency.
• 17-Hydroxylase Deficiency Syndrome.
• 3ß-Hydroxysteroid Dehydrogenase Deficiency.
• Adrenal Hypoplasia.
• Androgen Insensitivity Syndrome.
• Partial Androgen Insensitivity Syndrome.
• Congenital Adrenal Hyperplasia.
• Denys-Drash Syndrome.
• Disorders of Sex Development.
• Gonadal Dysgenesis.
• Hypopituitarism (Panhypopituitarism).
• Kallmann Syndrome and Idiopathic Hypo-gonadotropic.
• Hypogonadism.
• LH Receptor Defect.
• Microphallus.
• Ovotesticular Disorder of Sexual Development.
• P450 Oxidoreductase Deficiency.
• Smith-Lemli-Opitz Syndrome.
• STAR Deficiency.
• Leydig cell hypoplasia.
Differential diagnosis
Elevated serum Testosterone-to-DiHidroT-testosterone ratio (due to dihydrotestosterone deficiency) is a hallmark of 5-ARD.
Normal patients respond with ratios from 8-16, while in patients with 5-ARD it is about 35-84.
Testosterone and anti-Mullerian hormone concentrations are normalMutation analysis of the 5-ARD gene (SRD5A2) is now commercially available. It allows for confirmation of clinical diagnosis and the differentiation of 5-ARD from other causes of 46,XY DSD, the prenatal diagnosis for known familial mutations and carrier testing for at-risk relatives.
At least 96 mutations in SRD5A2 have been reported in 5-ARD patients.
You can see on this table the main mutations [23] reported in 5-ARD patients and their geographic distribution.
As we have already mentioned at the beginning, one of the main dilemma in DSD cases refers to what approach we have to take - to wait - how long... (?) or to act - when, and how to intervene. Anyway, although the 5-ARD is a rare condition, we have to think about it and be careful not to undertake any rash, especially surgical intervention, because it could cause irreparable harm.
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Fig. 2. You can see here a 14 y.o. boy from Dominican Republic with 5-ARD before (photo) and after puberty
One of the basic problems connecting with the treatment actually refers to the gender assignment. There are different opinions in the literature.
Some authors claimed that all patients should be raised as males [24].
Mutation Country Reference
Asia
p.Q6X China, Thailand, Mongolia, Japan, Korea Zhu et al., 2014, Maimoun et al., 2010, Sasaki et al., 2003, Sahakitrungruang et al, 2008, Nie et al., 2011, Sinnecker et al., 1996, Fern6ndez-Cancio M et al., 2011, Marzuku et al., 2010
p.L20P China, Thailand
p.Q71X China, Thailand
p.R227Q China, Mongolia, Vietnam, Laos, Japan, Indonesia
Middle East
p.L55Q Turkey, Jordania, Iraq, Palestina Maimoun et al., 2010, Thigpen et al., 1992, Di Marco et al., 2013, Akcay et al., 2014
p.Q56R Turkey, Jordania, Tunisia; France
p.Y91H Turkey, Iraq, Palestina
Mediterranean
p.R171S Spain, Italy, Malta, Turkey, Cyprus, and occasionally - Mexico* Akcay et al., 2014, Vilchis et al., 2010, Fern6ndez-Cancio M et al., 2011, Skordis et al.,2010,Thigpen et al., 1992, Bertelloni et al., 2016
Other had opposite opinion that only the most extremely virilized infants should receive a male assignment.
Surgical results of a masculinizing operation in a mildly virilized infant usually are poor, and the burden of growing up with inadequate genitalia hardly seems justified. And some authors prefer to recommend gonadectomy and feminizing genitoplasty [25].
In conclusion, most authors recommend -in cases when we have genetically or biochemically documented 5-ARD, it would be advisable to wait for the full development of puberty, to assess the degree and the kind of sexual development and then to act, according to the findings, strictly taking into account the spontaneous evolved sexual identity.
The clinical heterogeneity places an ethical and potentially legal, burden on the treatment team. The team is responsible for ensuring education of the parents, and, when appropriate - the patient, regarding the diagnosis and obtaining informed consent prior to medical or surgical intervention. This is especially important in the setting of gonadectomy and/or genitoplasty, which are irreversible procedures that could result in loss of fertility and have lifelong impact on gender satisfaction.
On the other hand, although delaying these procedures, provides a greater opportunity for the patient's involvement in the decision process, this alternative approach is not without risk. Some data suggest negative consequences of delayed repair of ambiguity on the development of self-esteem and gender satisfaction within cultures with low incidence of disease [26-28].
Multiple factors must be considered in recommending gender assignment for children born with ambiguous genitalia.
The ultimate goal of medical treatment is to restore external genitalia as close to a nonam-biguous appearance as possible while retaining full sensation and ability for sexual satisfaction (to include penetrative intercourse), and ideally, fertility.
Apart of the Dominican Republic and Papua New-Guinea, where gender role change is part
of their culture, in most other cultures, the third gender is normally not accepted, suggesting that a decision for gender assignment should be considered before the patient is able to make an individual choice.
Proponents of early surgery for female gender assignment suggest that early gonadec-tomy increases the likelihood of gender satisfaction and stability and that surgical outcome is improved due to increased tissue plasticity.
Opponents stress on the increased likelihood of repeat surgical interventions, the irreversible nature of the procedure, made at a time when patient consent is not attainable, and on the high incidence of gender dysphoria and sexual dissatisfaction.
The medical treatment depends on the gender assignment and the undertaken surgical intervention.
In patients with 5-ARD who are raised as male, testosterone or dihydrotestoster-one (DHT) therapy may increase penile shaft length and circumference, increase erectile potency and ejaculatory volume, increase facial hair and muscularity, and improve a sense of well-being.
In most cases, surgical repair of hypo-spadias (chordee correction, orchidopexia, etc.) is required and should be performed at 6-18 months of age.
Patients who have not undergone feminizing procedures may be fertile, although most of them would require in vitro fertilization or other assisted-fertilization techniques. Sperm counts are typically very low, with abnormal spermatogenesis and thick ejaculate.
In patients with 5-ARD who are raised female, management includes surgical correction of the external genitalia (vaginal opening, with early separation of the vagina and urethra), early removal of testicules to prevent masculinisation before puberty, clitoral reduction and hormonal therapy at puberty for development of secondary sexual characteristics. Sometimes is needed to perform postsurgical dilatation of the vagina.
Estrogen replacement therapy should be initiated at a bone age of 12 years or, once an
increase in gonadotropins is registered. The dose is tailored to reach adult replacement levels over a 3-4 year range.
Progesterone or cycling of estrogen therapy is not required due to the absence of a uterus*.
A pediatric psychiatrist or psychologist should be involved from the onset of the diagnosis. These might help the family members to overcome the psychological issues (eg. any feelings of guilt or blame) that accompany the birth of a child with 5-ARD and could facilitate any further communications between the family and the medical consultants. Any emotional support provided could help the family formulate questions regarding gender identity, gender role, gender satisfaction and potential change in gender role [29].
A detailed report on our experience with three proven 5-ARD cases is published in a journal "Sexual development": Andonova S., R. Robeva, R. Vazharova, S. Ledig, L. Grozdanova, E. Ste-fanova, I. Bradinova, T. Todorov, G. Hadzhidekov, M. Sirakov, P. Wiacker, P. Kumanov, A. Savov. New territory for an old disease: 5-a-reductase type 2 deficiency in Bulgaria. Sex Dev 2017; 11: 21-8 [30]. These were the first three proven cases ever identified in Bulgaria.
The specificity of the medical and psychological problems the 5-ARD brings us to solve, and the fact that we meet, and perhaps we will meet it more often than we expect, should cause us to sharpen our attention in this way.
Conflict of interest. The authors disclose no conflicts.
Information about authors
Sirakov Milko - MD, PhD, Professor, National Genetic Laboratory, Medical Center «Maichin Dom», Sofia, Bulgaria E-mail: msirak@abv.bg
Andonova Silvia - MSc, National Genetic Laboratory, Medical Center «Maichin Dom», Sofia, Bulgaria
Alexey Savov - PhD, Professor, National Genetic Laboratory, Medical Center «Maichin Dom», Sofia, Bulgaria
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