Pubertal And Gonadal Outcomes In 46,XY Individuals With Partial Androgen Insensitivity Syndrome Raised As Girls

Purpose: Although it was common in the 1970s-1990s to assign female gender of rearing to 46,XY infants with limited virilisation of varying etiologies, including those with partial androgen insensitivity syndrome (PAIS), long-term data on outcomes for these individuals are sparse. Therefore, our goal was to use the power of an international registry to evaluate clinical features, surgical management and pubertal data in patients with a molecularly confirmed diagnosis of PAIS who were born before 2008 and were raised as girls. Methods: The current study interrogated the I-DSD Registry for available data on management and pubertal outcomes in individuals with genetically confirmed PAIS who were raised as girls. Results: Among the 11 individuals who fulfilled the key criteria for inclusion the external masculinization score at presentation (EMS) ranged from 2 to 6 (median 5); 7 girls underwent gonadectomy before the age of 9 years, whereas 4 underwent gonadectomy in the teenage years (≥ age 13). Clitoral enlargement at puberty was reported for 3 girls (27%) who presented initially at the time of puberty with intact gonads. In the 9 individuals (82%) for whom gonadal pathology data were provided, there was no evidence of germ cell tumor at median age of 8.1 years. All girls received estrogen replacement and 8/11 had attained Tanner stage 4-5 breast development at last assessment. Conclusion: In general, although it appears that female assignment in PAIS is becoming uncommon, our data provide no evidence to support the practice of prophylactic prepubertal gonadectomy with respect to the risk of a germ cell tumour.

The FKBP4 Gene, Encoding a Regulator of the Androgen Receptor Signaling Pathway, Is a Novel Candidate Gene for Androgen Insensitivity Syndrome

Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations.

SUN-038 Social and Psychological Aspects of Partial Androgen Insensitivity Syndrome, Therapeutic Challenges

Background: Partial Androgen Insensitivity Syndrome (PAIS) is a rare congenital condition with incongruence of chromosomal, gonadal and phenotypic sex and classified as differences of sex development. Distinct from complete Androgen Insensitivity by the presence of ambiguous genitals in a 46, XY individual with normal testis development and partial responsiveness to androgens. Clinical Case: 18 years phenotypic female presented with primary amenorrhea and ambiguous genitalia with poor secondary sexual characteristics after puberty. Born out of a consanguineous marriage, normal vaginal delivery conducted by midwife at home in a small village, who informed a female with ambiguous genital though. Since childhood she uses to dress up in female attire. She has 5 siblings, two brothers and three sisters, one year back she got engaged to her distant cousin and was about to get married when one of her younger sister now 8 years having similar problem alarmed family to report before the wedlock.Vitals:Weight 55kg,Height 167cm,Physical, biochemical, chromosomal testing and imaging revealed:micropenis 3cm(N=8cm) with hypospadias, a small blind vaginal orifice, hormones within normal male ranges, Karyotype: XY, MRI revealed no female internal organs or prostate gland, left testis seen in partly formed scrotal sac (4.6x2.5cm) right in superficial inguinal region (2.7x1.9cm),normal testes size(4x3cm), bilateral cavernous tissue,respectively. Findings suggested phenotypic female with PAIS. Further investigations could not be carried out due to poor affordability and non-availability of Genetic testing facility. Management: Male gender was preferred (after discussion with urologist and consent of the patient and the family) Assigning the gender, health-related quality of life (QoL), social and psychological well-being, and affective disorders, like fertility and sexual functions in PAIS were discussed. Psychometric data was obtained through psychological questionnaires: Beck Depression Inventory & Hospital Anxiety and Depression Scale revealed moderate depression. An important pre-decision analysis regarding the potential impact of clinical decisions such as the type and timing of genital surgeries on patient’s life is missing due to absence of a multidisciplinary team for counseling and decision making. Conclusion: After spending 18.yrs as a phenotypic female the patient and her family experienced considerable emotional distress. In our culture and society these types of cases are seldom reported. We as medical professionals need to be sensitive to the social and psychological wellbeing of patients so that they can be settled and acceptable in their part of the world.