Basically, a complete virilization of a 46,XY fetus depends on either androgens or a functioning androgen receptor (AR). Through AR, androgens will drive the bipotential gonads to a male differentiation and further fetus virilization [Citation1]. Several defects on androgens synthesis, metabolism, or action result in undervirilization of a 46,XY fetus. Collectively, these conditions are named 46,XY differences of sexual development (DSD).
Androgen insensitivity syndrome (AIS) is the most common cause of DSD in individuals with 46,XY karyotype [Citation2]. At molecular level, it is caused by allelic variants in the AR gene, which is located at X chromosome, conferring a X-linked pattern of inheritance.
Since the AR sequencing in late 80s, many allelic variants in the AR gene have been reported either in AIS or in prostate cancer [Citation3]. Currently, uncommon mechanisms and rare genomic alterations have been contributed to expand the knowledge about AR and AR-related diseases making AIS a well-characterized molecular disease [Citation4–6].
In AIS, the severity of AR mutation give rise in a variable phenotypic expression of this disorder, and therefore it is classified into complete (CAIS) and partial androgen insensitivity syndrome (PAIS). Mutations in the AR gene are found in > 90% of individuals with CAIS while this holds true for only 40% of PAIS [Citation7]. This low frequency of AR variants in PAIS indicates that there are other factors beyond AR leading to AIS. However, the high frequency of AR variants found in CAIS increases the probability of molecular AIS diagnosis only by AR sequencing.
Regarding phenotype, individuals with CAIS have female external genitalia while those with PAIS have atypical external genitalia. As consequence, the diagnosis of CAIS individuals is usually later. Despite of the classical association with primary amenorrhea, CAIS is also related with inguinal hernias in girls and this association has been known for over 60 years [Citation8]. Hence, except in cases of affected family members, the diagnosis of CAIS should be suspicious either in front of a girl with primary amenorrhea or in cases of girls with inguinal hernia.
In several cases, the diagnosis of 46,XY DSD is a challenge. It is usually necessary karyotype analysis, image studies, and a combination of hormonal dosages either at basal or after gonadal stimulation. After that, molecular diagnosis is recommended through several strategies: parallel sequencing, next generation sequencing, or candidate gene sequencing. Despite this, the molecular etiology of most 46,XY DSD will remain unknown, which made the genetic diagnosis of 46,XY difficult and expansive. CAIS is an important exception. As mentioned above, allelic variants in the AR gene are found in an expressive percentage of CAIS patients. It made AR sequencing enough for CAIS diagnosis. For CAIS, a Sanger sequencing of the AR gene is more helpful than karyotype analysis. While the karyotype analysis is able to show the presence of Y chromosome, Sanger sequencing of the AR gene is able either to show the AR allelic variant and to suggest a XY karyotype (due to hemozigosity).
There are several reasons why a precocious diagnosis takes advantages in patients with CAIS. It allows adequate psychological support for the patient and their relatives, which is clear benefit for both. It also allows discussion about fertility, a recurrent issue among patients with 46,XY DSD [Citation9]. For a family with a patient with CAIS, earlier diagnosis is also helpful for genetic couseling, especially after mother’s and eventual sister’s AR screening.
Pediatric surgeons have potential to perform CAIS diagnosis earlier. For that it is necessary to consider CAIS as a possibility in girls with inguinal hernias. Unfortunately it is uncommon, may be because they are not familiar with that condition or because most of them consider CAIS so rare to find one sporadic case. In fact, CAIS is a rare condition with a prevalence of 1:20,000 to 1:60,000 in the general population. However, CAIS prevalence among girls with inguinal hernia has a huge difference: in this scenario, the prevalence ranges from 1 to 2.4%, which is not low enough to be ignored.
To improve the awareness about CAIS among girls with inguinal hernia, Listyasari et al. reported at Journal of Investigative Surgery, a surgical series with five CAIS patients in which that condition was diagnosed due to the presence of inguinal hernias [Citation10]. More than just put attention on this topic, the authors deeply discussed about clinical, molecular, and laboratorial data. That article is able to both: highlight CAIS possibility in girls with inguinal hernia and show other relevant aspects for CAIS diagnosis, as the genetic studies for molecular CAIS diagnosis.
According to serendipity concept, it is easier to find something when we are looking for. Considering CAIS as a possibility in girls with inguinal hernias, pediatric surgeons have an opportunity to put on practice this helpful concept.
Declaration of interest
The author reports no conflict of interest.
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