Introduction
Androgen insensitivity syndrome (AIS) is an X-linked genetic condition caused by pathogenic variants in the androgen receptor (AR) gene. AIS can present in a range of symptoms, from mild to complete androgen insensitivity. Individuals with complete AIS (CAIS) commonly present with normal external female genitalia, an XY karyotype, internal or descended testicles, and absent Müllerian ducts. Most cases of CAIS are diagnosed postnatally, and often not until puberty.

Case Presentation
A 27-year-old female, G1P0, presented to clinic for routine prenatal care, with no overall medical concerns. She elected to undergo routine prenatal testing, including cell-free DNA (cfDNA) screening. The cfDNA screening was consistent with an XY chromosomal complement, however the ultrasound showed normal fetal external female genitalia. In a follow up appointment to discuss the discordance of cfDNA screening and ultrasound results, this patient noted a family history of AIS. All four sisters have a diagnosis of AIS, normal female external genitalia, an XY karyotype, and had surgical removal of the testes. There was no suspicion or diagnosis of AIS in any other of the patient’s maternal family members. No family members have pursued genetic testing for pathogenic variants of AIS. The patient had no symptoms of AIS and has a 46,XX karyotype, indicating she does not have AIS but may be a carrier.

 

Diagnostic Workup
At 13 weeks gestational age, the patient underwent in-house cfDNA screening resulting in a fetal fraction of 10.5% with low risk for trisomies 21, 18, and 13 and a result consistent with a single X and Y chromosome. An initial ultrasound at 14 weeks gestational age noted a viable singleton pregnancy with no abnormal findings. At 21 weeks gestational age, ultrasound showed no abnormal findings and normal fetal external female genitalia. However, the presence of normal fetal external female genitalia contradicted the previous cfDNA screening results of an XY chromosomal complement. Along with the family history of AIS, this suggests that the fetus has AIS.

Treatment and Management
A genetic counselor reviewed prenatal testing options to confirm the fetal sex and molecular testing for pathogenic variants of AIS for her sisters with AIS, herself, and the fetus.

 

Outcome and Follow-Up
The patient declined any further follow up testing and discussed how she understood the medical issues involved with AIS due to growing up with sisters with AIS. There was no follow up with this patient after the healthy delivery of a neonate.

Discussion
This case demonstrates how ultrasound and cfDNA screening, together, can be used to prenatally identify a child who may have AIS. This supports a limited number of case studies that have shown discrepancies of individuals with XY cfDNA screening results and normal external female genitalia through ultrasound and/or immediately after birth. Some of these cases included confirmatory testing, with these patients having pathogenic variants of AIS. An increasing frequency of cfDNA screening in routine prenatal care, along with already routine ultrasounds, may result in increased identification of AIS cases, prenatally. Prenatal suspicion or diagnosis of AIS allows for parents of children with AIS to plan for future medical care and education. This provides a more supportive environment for the child, including less confusion when the child reaches puberty, in some cases.

Conclusion
Here, we show how the use of ultrasound and cfDNA screening assists in prenatal diagnosis of AIS. Despite the fact this patient declined further genetic testing, the strong family history of AIS indicates she is likely a carrier for AIS and the child has AIS. However, in patients without a family history of AIS, it would be beneficial to perform maternal carrier testing and genetic testing for AIS of the child to further confirm ultrasound and cfDNA screening results.