Management of Gonads in Adults with Androgen Insensitivity: An International Survey.

Complete and partial androgen insensitivity syndrome (CAIS, PAIS) are associated with an increased risk of gonadal germ cell cancer (GGCC). Recent guidelines recommend gonadectomy in women with CAIS in late adolescence. Nevertheless, many adult women prefer to retain their gonads. This study aims to explore attitudes towards gonadectomy in AIS in centres around the world, estimate the proportion of adults with retained gonads and/or who developed GGCC, and explore reasons for declining gonadectomy. A survey was performed among health care professionals who use the International DSD Registry (I-DSD). Data were provided from 22 centres in 16 countries on 166 women (CAIS) and 26 men (PAIS). In CAIS, gonadectomy was recommended in early adulthood in 67% of centres; 19/166 (11.4%) women refused gonadectomy. Among 142 women who had gonadectomy, evidence of germ cell neoplasm in situ (GCNIS), the precursor of GGCC, was reported in 2 (1.4%) out of 8 from whom pathology results were formally provided. Nine out of 26 men with PAIS (34.6%) had retained gonads; 11% of centres recommended routine gonadectomy in PAIS. Although development of GGCC seems rare, gonadectomy after puberty is broadly recommended in CAIS; in PAIS this is more variable. Overall, our data reflect the need for evidence-based guidelines regarding prophylactic gonadectomy in AIS.

Tack LJW ，Maris E ，Looijenga LHJ ，Hannema SE ，Audi L ，Köhler B ，Holterhus PM ，Riedl S ，Wisniewski A ，Flück CE ，Davies JH ，T'Sjoen G ，Lucas-Herald AK ，Evliyaoglu O ，Krone N ，Iotova V ，Marginean O ，Balsamo A ，Verkauskas G ，Weintrob N ，Ellaithi M ，Nordenström A ，Verrijn Stuart A ，Kluivers KB ，Wolffenbuttel KP ，Ahmed SF ，Cools M ... -  《-》

Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis.

Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive disorder of sex development (DSD) where affected individuals are phenotypically female, but have an XY karyotype and testes. The risk of gonadal tumour development in CAIS may increase with age; incidence rates have been reported to be 0.8-22% in patients who have retained their gonads into adulthood. Consequently, gonadectomy has been recommended either during childhood or after puberty is complete, although there is no consensus on the optimal timing for this procedure. To establish the frequency of histological abnormalities in CAIS in relation to the age at gonadectomy. Data were collected from the Cambridge DSD database on patients with CAIS (n = 225; age range 3-88 years) who had undergone gonadectomy, and their age of gonadectomy, gonadal histology and immunohistochemistry. Evaluable data were obtained from 133 patients. Median age at gonadectomy was 14.0 years (range: 18 days-68 years). Pubertal status was: prepuberty, n = 62; postpuberty, n = 68. Thirteen cases were aged >20 years at gonadectomy. The pattern of histology is summarised in the Summary table. In this large case series of CAIS patients who had undergone gonadectomy, while the combined malignant and premalignant gonadal histology prevalence was 6.0%, the findings confirm the low occurrence of gonadal malignancy in CAIS, with a frequency of 1.5%. The two cases of malignancy were postpubertal. Germ cell neoplasia in situ (GCNIS) was observed in six cases, of which one occurred prepuberty and five postpuberty. The study highlighted difficulties in diagnosis of GCNIS and the need for histological analysis in expert centres. The results support the current recommendation that gonads in CAIS can be retained until early adulthood. The small number of individuals with gonadectomy after age 20 years do not allow firm conclusion regarding later adulthood. Therefore, it is recommended that the option of gonadectomy be discussed in adulthood. Some form of regular surveillance of the gonads is then recommended, although none of the available options are ideal.

Chaudhry S ，Tadokoro-Cuccaro R ，Hannema SE ，Acerini CL ，Hughes IA ... -  《-》

Malignant testicular germ cell tumors in postpubertal individuals with androgen insensitivity: prevalence, pathology and relevance of single nucleotide polymorphism-based susceptibility profiling.

What is the prevalence of malignant testicular germ cell tumors (TGCT) and its precursors, (pre-) germ cell neoplasia in situ (GCNIS), in late teenagers and adults who have androgen insensitivity syndrome (AIS) and the impact of an individual's genetic susceptibility to development of TGCT? No GCNIS or TGCT was diagnosed, but pre-GCNIS was identified in 14 and 10% of complete and partial AIS patients, respectively, and was associated with a higher genetic susceptibility score (GSS), with special attention for KITLG (rs995030) and ATFZIP (rs2900333). Many adult women with AIS decline prophylactic gonadectomy, while data regarding the incidence, pathophysiology and outcomes of TGCT in postpubertal individuals with AIS are lacking. The relevance of genetic factors, such as single nucleotide polymorphisms (SNPs), in predisposing AIS individuals to TGCT is unknown. This multicenter collaborative study on prophylactically removed gonadal tissue was conducted in a pathology lab specialized in germ cell tumor biology. Material from 52 postpubertal individuals with molecularly confirmed AIS (97 gonadal samples) was included; the median age at surgery was 17.5 (14-54) years. Immunohistochemical studies and high-throughput profiling of 14 TGCT-associated SNPs were performed. The main outcome measures were the prevalence of pre-GCNIS, GCNIS and TGCT, and its correlation with a GSS, developed based on the results of recent genome-wide association studies. The earliest recognizable change preceding GCNIS, referred to as pre-GCNIS, was present in 14% of individuals with complete and 10% of those with partial AIS at a median age of 16 years. No GCNIS or invasive TGCT were found. The median GSS was significantly greater for those with, compared to those without, pre-GCNIS (P = 0.01), with an overlap between groups. Our data suggest important roles for risk alleles G at KITLG (rs995030) and C at ATFZIP (rs2900333), among the 14 studied TGCT-associated SNPs. N/A. A limited number of cases were included. Our data suggest that the prevalence of pre-GCNIS in individuals with AIS beyond puberty is around 15%. Genetic susceptibility likely contributes to pre-GCNIS development in AIS but factors related to malignant progression remain unclear. Although data in older patients remain scarce, malignant progression appears to be a rare event, although the natural history of the premalignant lesion remains unknown. Therefore, the practice of routine prophylactic gonadectomy in adults with AIS appears questionable and the patient's preference, after having been fully informed, should be decisive in this matter. This study was supported by research grants from the Research Foundation Flanders (FWO) (to M.C.), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq G0D6713N) (to B.B.M. and M.C.) and the European Society for Pediatric Endocrinology (ESPE), granted by Novo Nordisk AB (to J.K.). There are no competing interests.

Cools M ，Wolffenbuttel KP ，Hersmus R ，Mendonca BB ，Kaprová J ，Drop SLS ，Stoop H ，Gillis AJM ，Oosterhuis JW ，Costa EMF ，Domenice S ，Nishi MY ，Wunsch L ，Quigley CA ，T'Sjoen G ，Looijenga LHJ ... -  《-》

Abdominal Mass in a Phenotypic Female with 46,XY Differences in Sex Development.

We present a case of a large intra-abdominal mass found to be localized pure seminoma within a retained gonad of a 53-year-old phenotypic female with 46,XY differences in sex development (DSD) and androgen insensitivity syndrome (AIS). Our management included extirpation of the mass with contralateral gonadectomy. Historically, patients with AIS would undergo gonadectomy to mitigate the lifetime risk of testicular germ cell tumor development; however, growing evidence suggests safety in retention and surveillance of these gonads into adulthood. This case highlights the importance of lifetime surveillance of patients with 46,XY DSD who elect to retain their gonads.

Alam R ，Gabrielson AT ，Rabinowitz MJ ，Kates M ，Di Carlo HN ... -  《-》

Pubertal and Gonadal Outcomes in 46,XY Individuals with Partial Androgen Insensitivity Syndrome Raised as Girls.

Although it was common in the 1970s-1990s to assign female gender of rearing to 46,XY infants with limited virilization 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. The current study interrogated the International Disorders of Sex Development Registry for available data on management and pubertal outcomes in individuals with genetically confirmed PAIS who were raised as girls. Among the 11 individuals who fulfilled the key criteria for inclusion, the external masculinization score (EMS) at presentation 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 the last assessment. 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 tumor.

Guaragna-Filho G ，Guerra-Junior G ，Tadokoro-Cuccaro R ，Hughes IA ，Barros BA ，Hiort O ，Balsamo A ，Guran T ，Holterhus PM ，Hannema S ，Poyrazoglu S ，Darendeliler F ，Bryce J ，Ahmed SF ，Quigley CA ... -  《-》