Complete Androgen Insensitivity Research Articles

A CASE REPORT OF COMPLETE ANDROGEN INSENSITIVITY SYNDROME RISING A CONCERN ABOUT THE TIME OF SURGERY AND THE ROLE OF PARENTS' BEHAVIOR

Purpose: This case study refers to a case of complete androgen insensitivity syndrome, which presented with amenorrhea back in the past. Case: After conformation of the diagnosis, parents decided not to reveal the condition’s specifics to the patient. At the age of 34 years, she attended our hospital with abdominal swelling, and the following CT scan showed an abdominal mass arising from the ovary of 13 cm x 14 cm size. A laparotomy was done, and a mixture of solid and cystic mass of 20 cm in diameter was found and removed with the ovary. Histopathology of the tumor showed features of testicular seminoma. Conclusion: The aim of this case report is to outline the difficulties in choosing whether and when to do the gonadectomy and whether and how to explain the condition to the patient.

Magnetic resonance imaging features of complete androgen insensitivity syndrome in comparison to Mayer-Rokitansky-Küster-Hauser syndrome.

Complete androgen insensitivity syndrome (CAIS) and Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) share common clinical features such as female phenotype, vaginal hypoplasia, and primary amenorrhea. Magnetic resonance imaging (MRI) is performed to investigate the cause of primary amenorrhea. However, the MRI features are also similar in both disorders. They are ultimately diagnosed by chromosome testing, but there is a possibility of misdiagnosis if chromosome testing is not performed. This study aimed to identify MRI features that are useful for differentiating CAIS from MRKHS. This multicenter retrospective study included 12 patients with CAIS and 19 patients with MRKHS. Three radiologists blindly evaluated the following features: (1) detection of vagina, (2) detection of nodular and cystic structures in the lateral pelvis; undescended testicles and paratesticular cysts in CAIS and rudimentary uteri and ovaries in MRKHS, (3) their location, (4) number of cysts in the cystic structures, and (5) signal intensity on diffusion-weighted images (DWI) and apparent diffusion coefficient (ADC) values of the nodular structures. Statistical comparisons were performed using Mann-Whitney U and Fisher's exact tests. Compared with MRKHS, the CAIS group showed significantly detectable vagina, more ventrally located nodular and cystic structures, fewer cysts within the cystic structures, and nodular structures with higher signal intensity on DWI and lower ADC values. MRI features of detectable vagina, location of nodular and cystic structures, number of cysts within the cystic structures, signal intensity on DWI and ADC values of the nodular structures were useful in differentiating CAIS from MRKHS.

19. Case of complete androgen insensitivity syndrome with gonads containing rudimentary penile tissue and both Mullerian and Wolffian type structures

19. Case of complete androgen insensitivity syndrome with gonads containing rudimentary penile tissue and both Mullerian and Wolffian type structures

Androgen insensitivity syndrome: preventive gonadectomy, pros and cons

Androgen insensitivity syndrome is a genetic disorder characterized by complete or partial androgen insensitivity in individuals with a 46XY genotype. It is also the most common cause of disorders of sexual differentiation in patients with a 46XY karyotype. This condition is caused by a defect in the androgen receptor gene (AR), leading to abnormal development of male genitalia, impaired formation of male secondary sexual characteristics, and phenotypic features resembling the female sex.One of the important aspects related to the management of androgen insensitivity syndrome is the necessity of preventive gonadectomy. However, the rationale for prophylactic removal of gonads remains a subject of debate. This article presents a clinical case of a 37-year-old woman with complete androgen insensitivity syndrome who, despite recommendations for gonadectomy based on suspicious MRI characteristics of the gonads, made the decision to decline surgical intervention, justifying her choice by the positive impact of gonadal hormonal activity on her external appearance and physical characteristics. This clinical case highlights the complexity of decision-making in the management of androgen insensitivity syndrome, where patient preferences and needs may play a significant role, despite potential risks and concerns surrounding the preservation of gonads.

Detection of Molecular Variations at Androgen Receptor Gene in 46,XY Differences in Sex Development Cases

Abstract Introduction: One of the common causes of 46,XY differences in sex development (DSD) cases is androgen insensitivity syndrome. This X-linked recessive inherited condition is associated with pathological variations of the AR gene, leading to defects in androgen action. Affected 46,XY infants or individuals experience variable degrees of undervirilization and those with severe form will have female-like external genitalia. Therefore, they were more likely assigned and reared as females. The confirmatory molecular test is often needed due to similar clinical manifestations with other conditions causing 46,XY DSD. Since in our country, the molecular test for the AR gene is lacking, the study is conducted as a preliminary study to elaborate on the possibility of developing a molecular test for the AR gene in 46,XY DSD cases. Methods: Archived DNAs of 13 46,XY DSD cases were analyzed using polymerase chain reaction and direct sequencing for molecular defects in the AR gene. Clinical and hormonal data were collected and analyzed. Results: The study successfully amplified and visualized the eight exons of the AR gene and revealed two subjects carrying AR gene variants at exon 7. In the first case, 1.2-year-old boy carried heterozygous p.Gln825Arg, which has never been reported elsewhere, and the second subject, a 2.1-year-old girl with heterozygous p.Arg841His. Both subjects presented with severe undervirilization of external genitalia with external genitalia masculinization scores (EMS) of 1.5 and 3. Conclusion: In this series, two of 13 46,XY DSD cases carried variants at the AR gene, resulting in complete androgen insensitivity syndrome.

Low androgen signaling rescues genome integrity with innate immune response by reducing fertility in humans

Development of the gonads under complex androgen regulation is critical for germ cells specification. In this work we addressed the relationship between androgens and genomic integrity determining human fertility. We used different study groups: individuals with Differences of Sex Development (DSD), including Complete Androgen Insensitivity Syndrome (CAIS) due to mutated androgen receptor (AR), and men with idiopathic nonobstructive azoospermia. Both showed genome integrity status influenced by androgen signaling via innate immune response activation in blood and gonads. Whole proteome analysis connected low AR to interleukin-specific gene expression, while compromised genome stability and tumorigenesis were also supported by interferons. AR expression was associated with predominant DNA damage phenotype, that eliminated AR-positive Sertoli cells as the degeneration of gonads increased. Low AR contributed to resistance from the inhibition of DNA repair in primary leukocytes. Downregulation of androgen promoted apoptosis and specific innate immune response with higher susceptibility in cells carrying genomic instability.

In Silico Analysis of Functional SNPs in Genes of Complete Androgen Insensitivity Syndrome (CAIS): A Retrospective, Case-Control Study.

Complete androgen insensitivity syndrome (CAIS) is one of the categories of androgen insensitivity syndrome (AIS) described as complete failure of the cell to react to androgens with external genitalia of a normal female. People with AIS condition are genetically male, with XY karyotype in each cell, but their bodies are unable to respond to male sex hormones (called androgens). It is associated with infertility as well as developing cancerous conditions. The genetic association of CAIS involves polymorphism of genes such as NR5A1, SOX9, SRD5A2, CBX2, GATA4, and SRY. Their mutation and participation in genetics of CAIS can be studied by Single Nucleotide polymorphism (SNP) analysis which is a way to detect genetic variations. SNP in coding region leads to synonymous and non-synonymous mutations. Hence, this study highlights analysis of SNPs associated with CAIS. Our aim is to study SNP analysis of NR5A1, SOX9, SRD5A2, CBX2, GATA4, SRY genes in Complete Androgen Insensitivity Syndrome. SIFT and Polyphen analysis was performed for all the genes and samples were subjected for PCR-SSCP technique. SNPs were analyzed for the genes associated with CAIS. Benign and damaging SNPs were identified. DNA Samples were amplified using PCR technique and they will be analyzed using Single-strand conformation polymorphism (SSCP). As SNPs have decreased stability, damaging and benign character, they can be used as candidate hallmarks in study of Complete Androgen Insensitivity Syndrome.

An Atypical Case of Complete Androgen Insensitivity Syndrome Presenting in Adulthood

An Atypical Case of Complete Androgen Insensitivity Syndrome Presenting in Adulthood

Pre-germ cell neoplasia in-situ in a patient with complete androgen insensitivity syndrome

Abstract Introduction/Objective Complete androgen insensitivity syndrome is a disorder of sex development in 46, XY individuals with external female genitalia and undescended testes, often presenting with inguinal hernia in infancy and/or primary amenorrhea in adolescents. Given the increased risk for the development of germ cell neoplasms in the ectopic testis, early gonadectomy or orchidopexy may be indicated. Methods/Case Report We report a 21-year-old patient assigned female at birth (46, XY) with a history of bilateral inguinal hernia repairs (age 2) and later with lack of menarche (age 16). Additional work-up showed an elevated testosterone level (394 ng/mL) and normal luteinizing and follicle stimulating hormone values. On pelvic ultrasound, retained intraabdominal gonads were identified, but female sex organs were absent. During a gonadal relocation procedure, the gonads appeared irregular in shape with multiple cysts and small nodules, and bilateral gonadectomy was performed. Grossly, the gonads measured 4.9 and 4.3 cm with a smooth external surface and a lobulated cut surface with multiple cysts, up to 1.6 cm, containing clear, serous fluid. Histologic sections showed most seminiferous tubules were lined only by Sertoli cells with only occasional spermatogonia. Leydig cell hyperplasia and areas of ovarian-like stroma were seen. OCT4 immunostain highlighted the nuclei of individually disposed germ cells in the base of tubules (singly dispersed, non-linear pattern), raising concern for germ-cell neoplasia in-situ (GCNIS). However, the histology and staining pattern were better interpreted as diagnostic of germ cells with delayed maturation and pre-GCNIS. Additionally, OCT4 showed rare single cells within the stroma and considered to represent residual undifferentiated gonadal tissue. After gonadectomy, the patient was started on hormone replacement therapy. Results (if a Case Study enter NA) NA Conclusion This case highlights the potential pitfalls in the interpretation of OCT4 immunostain to avoid misdiagnosis of germ cell neoplasia.

Early diagnosis of androgen insensitivity syndrome with cell-free fetal DNA screening: A case report.

SynopsisNon‐invasive prenatal testing provides an early opportunity to identify patients with genotype–phenotype sex discordance and can be used to screen for complete androgen insensitivity syndrome.

Late presentation of complete androgen insensitivity syndrome: a case report

Late presentation of complete androgen insensitivity syndrome: a case report

Virilization at puberty in adolescent girls may reveal a 46,XY disorder of sexual development.

Although hyperandrogenism is a frequent cause of consultation in adolescent girls, more severe forms with virilization must lead to suspicion of an adrenal or ovarian tumor. However, they may also reveal a 46,XY disorder of sexual development (DSD). Here, we describe four adolescent girls referred for pubertal virilization and in whom we diagnosed a 46,XY DSD. We performed gene mutation screening by Sanger sequencing (all patients) and by next-generation sequencing (NGS) in patient #4. We identified new heterozygous NR5A1 gene variants in patients #1 and #2 and a homozygous SRD5A2 gene deletion in patient #3. Patient #4 received a diagnosis of complete androgen insensitivity in childhood; however, due the unusual pubertal virilization, we completed the gene analysis by NGS that revealed two heterozygous HSD17B3 variants. This work underlines the importance of considering the hypothesis of 46,XY DSD in adolescent girls with unexplained virilization at puberty.

THU209 Small INDELs In The Androgen Receptor Gene: Phenotype Implications And Mechanisms Of Mutagenesis In Androgen Insensitivity Syndrome

Abstract Disclosure: R.L. Batista: None. R.M. Ramos: None. A.F. Afonso: None. R.J. Petroli: None. M.Y. Nishi: None. M.M. Ferrari: None. S. Domenice: None. B.B. Mendonca: None. Small indels are insertions or deletions of one or more nucleotides into the DNA sequence. Indels are highly abundant in human genomes and have contributed massively to genome evolution. However, the role of indels and their underlined mechanisms of mutagenesis in Mendelian disorders still needs to be appreciated. To explore the contribution of indels in a monogenic disorder, we analyzed all indels in the androgen receptor gene, including three novel indels, using Androgen Insensitivity Syndrome (AIS) as a model. The goal was to profile indels in AIS. To build this profile, we analyzed the indel distribution through the AR coding region, compared with genomic and exonic populational data, and analyzed their impact on the AIS phenotype and their likely mechanism of mutagenesis. We present 82 different indels in the AR gene reported in individuals with AIS. In most cases (n=78; 95.1%), the phenotype is complete AIS (CAIS). There are four AR indels reported in mild AIS. Most short indels in the AR gene among AIS are frameshift indels (n=64; 79%). Indels are distributed along the entire AR gene, with NTD domain predominance (n=45; 54.9%), followed by LTD domain (n=28; 34.1%). Most are small deletions (n=49; 59.7%), followed by small insertions (n=29; 35.3%) and complex frameshift indels (n=4; 4.8%). Most indels are short (<10 bp; n=81 = 98.8%), with an average of 2.4 nucleotides by indel. Most indels are at non-repetitive sequences with no changes in copy counting (n = 68; 82.9%). Thirteen indels were identified within tandem repeats (15.8%), whereas seven indels were at homopolymers run (8.5%). Trinucleotide regions (Poly-Q, Poly-G) are prone to indels, but indels also happen in other trinucleotide stretches (Poli-L, Poly-P). Regarding the change in copy counting, thirty-nine (47.5%) indels are CCC indels. Indel reported in MAIS is all located at tandem repeats, while all at non-repetitive sequences caused CAIS. 3.65% of AR indels are at a 6bp consensus sequence (TG A/G A/G G/T A/C). In summary, indels represent a significant portion of the variants identified in the AR gene in patients with AIS. Unlike the non-synonymous variants related to this gene, there is a genotype-phenotype correlation (indel - CAIS congruency). However, small NFS indels at small triplet runs can slightly compromise AR function leading to the mild phenotype. Homopolymer runs, and trinucleotide repeats are exonic regions at risk for indels. Slippage explains half of the cases of AR indels. These results increase the molecular understanding of the androgen receptor disruption and the underlined mechanisms of indel mutagenesis in exonic regions and their implication on phenotype. Presentation: Thursday, June 15, 2023

FRI445 A Late Diagnosis Of Complete Androgen Insensitivity Syndrome

Abstract Disclosure: J. Muuse: None. R.J. Shah: None. P.A. Belany: None. Introduction: Complete Androgen Insensitivity Syndrome (CAIS) is a rare disorder of hormone resistance characterized by a female phenotype in an individual with an XY karyotype. Individuals with CAIS are born unambiguously female without any apparent abnormalities. They develop a short blind ending vaginal canal, with absence of Wolffian duct derived structures (vas deferens, seminal vesicles). Breast development advances regularly at puberty, while there is absent pubic and axillary hair, both due to peripheral conversion of testosterone to estrogen. Testes remain undescended in the abdominal cavity. Case: A 28 year old female with a past medical history of bipolar disorder presented to her primary care physician’s office with a chief complaint of fatigue. Blood work revealed an elevated testosterone level of 686, at which time she was referred to endocrinology for further work up. On further history gathering, she endorsed a life long history of amenorrhea. She saw an OB-GYN at 19 years old and was told she had a short vaginal canal. A pelvic ultrasound revealed no uterus and one left ovary. She was not given a diagnosis other than congenital absence of a uterus. She was lost to follow up until 28 years of age when she sought medical help for her fatigue. Physical exam was pertinent for a tall female with no signs of hirsuitism. Additional blood work revealed normal LH, FSH, and DHEA-S. A chromosomal analysis revealed XY. She was referred to gynecology for further management and assessment for orchiectomy. Discussion: This was an unusual case of CAIS, as this was diagnosed far past menarche. Most cases are diagnosed during puberty- which aids in an early approach towards the psychological and social well being of the individual as well as close follow up for evaluation of orchiectomy. Orchiectomy is recommended due to the increased risk of gonadal malignancy following puberty. The risk of developing malignancy increases with age, and has been reported to be between 15-22%. Thus it is important to identify this syndrome early in life to ensure this is addressed. It is followed by long term hormonal therapy with estrogen to maintain normal breast and bone development. This case highlights the importance of maintaining a high clinical suspicion of CAIS in females presenting with short vaginal canal and absence of a uterus in order to prevent malignancy and provide optimal psychological support to the individual. Presentation: Friday, June 16, 2023

Induction of lactation in a patient with complete androgen insensitivity syndrome.

With rising rates of adoption and surrogacy, induced lactation is likely to become increasingly relevant, allowing women who did not undergo pregnancy to breastfeed. We describe the case of a woman with complete androgen insensitivity syndrome (CAIS) on conventional oestrogen therapy who was expecting a child via surrogacy and who wished to breastfeed. The woman was commenced on supplementary oestrogen therapy, domperidone and breast stimulation by mechanical breast pump 8 weeks prior to the delivery of her child. Following delivery, the patient produced a small, unquantified amount of milk, allowing her to suckle the infant for a short period of time. Induced lactation is possible in chromosomally XY individuals. It has been most successful in cis-women and transwomen, both of whom have had progesterone/progestogen exposure to the breast. We suggest that the addition of a progestogen to our patient's treatment regimen, either as part of her original hormone therapy or part of the lactation induction program, would have improved her changes of establishing successful lactation. Induced lactation is possible in chromosomally XY individuals with the use of pharmacological and non-pharmacological therapies. There are no standardised guidelines regarding the optimal regimen for induced lactation. Progesterone exposure to the breast is essential for ductal branching and alveolar maturation. In the published literature, induced lactation is more successful in transwomen and other XY individuals who have had prior progesterone exposure. The addition of progestogen to our patient's treatment regimen would have improved her chances of establishing successful lactation.

Clinical outcomes and genotype-phenotype correlations in patients with complete and partial androgen insensitivity syndromes.

Androgen insensitivity syndrome (AIS) is a rare X-linked recessive disorder caused by unresponsiveness to androgens because of mutations in the AR gene. Here, we investigated the clinical outcomes and molecular spectrum of AR variants in patients with AIS attending a single academic center. This study included 19 patients with AIS who were confirmed by molecular analysis of AR. Clinical features and endocrinological findings were retrospectively collected, including presenting features, external genitalia, sex of rearing, timing of gonadectomy, pubertal outcomes, and sex hormone levels. Molecular analysis of AR was performed using Sanger, targeted gene panel, or whole-exome sequencing. Among all 19 patients, 14 (74%) were classified as having complete AIS (CAIS), whereas 5 (26%) had partial AIS (PAIS). All patients with CAIS, and 3 patients with PAIS were reared as female. One patient with CAIS manifested a mixed germ cell tumor at the age of 30 years. Molecular analysis of AR identified 19 sequence variants; 12 (63%) were previously reported, and the remaining 7 (37%) were novel. Missense mutations were the most common type (12 of 19, 63%), followed by small deletions, nonsense mutations, an insertion, and a splice site mutation. Here, we describe the clinical outcomes and molecular characteristics of 19 Korean patients with AIS. Patients with PAIS manifested various degrees of masculinization of the external genitalia. Nonsense and frameshift mutations were frequent in patients with CAIS, whereas patients with PAIS harbored exclusively missense mutations.

46 XY, kobieta. Zespół całkowitej niewrażliwości na androgeny

Zespół niewrażliwości na androgeny (AIS) to wrodzone zaburzenie rozwoju płciowego spowodowane mutacjami w genie kodującym receptor wiążący androgeny. U pacjentki w 17 rż., podczas diagnostyki pierwotnego braku miesiączki, rozpoznano zespół całkowitej niewrażliwości na androgeny. Badania cytogenetyczne wykazały kariotyp 46 XY. W badaniu ginekologicznym narządu rodnego wykazano ślepo zakończoną pochwę, nie stwierdzono obecności macicy. W badaniu przedmiotowym stwierdzono prawidłowo rozwinięte gruczoły piersiowe oraz skąpe owłosienie pachowe i łonowe. W 18 rż. chora przeszła obustronną gonadektomię metodą laparoskopową. Przed operacją poziom testosteronu wynosił 5,6 ng/ml, a po 0,6 ng/ml. Badanie histopatologiczne wykazało obecność tkanki jąder w usuniętych gonadach, a w jednej z nich wykryto gruczolaka cewkowego. Po zabiegu pacjentka pozostawała pod kontrolą lekarską i przyjmowała 1 mg estradiolu dziennie, doustnie. W 24 rż. zdiagnozowano osteoporozę, T-SCORE wyniósł -2,6 SD, natomiast 3 lata później -2,76 SD. Pacjentka przyjmowała alendronian sodu oraz kwas ibandronowy. W 34 rż. rozpoznano u chorej cukrzycę typu 2, włączono leczenie metforminą i zalecono opiekę diabetologiczną. Stopień 6. i 7. w skali Quigleya odpowiada całkowitej niewrażliwości na androgeny. Narządy płciowe są całkowicie sfeminizowane, a noworodkom nadaje się płeć żeńską. Rozpoznanie zazwyczaj ustala się w trakcie diagnostyki pierwotnego braku miesiączki. CAIS wiąże się z koniecznością usunięcia nieprawidłowych gonad z powodu podwyższonego ryzyka wystąpienia zmian nowotworowych. Po gonadektomi niezbędne jest stosowanie substytucji estrogenowej m.in. w celu utrzymania drugorzędowych cech płciowych. Wysokie ryzyko rozwinięcia osteoporozy wymaga suplementacji wapnia i witaminy D oraz kontroli gęstości kości. Rokowanie jest dobre, a gonadektomia i estrogenowa terapia hormonalna dają zadowalające wyniki długoterminowe.

Complete androgen insensitivity syndrome: A tale of two sisters with primary amenorrhea

Complete androgen insensitivity syndrome (CAIS) is a rare disorder that is often diagnosed in the pubertal period during the evaluation of primary amenorrhea. Diagnosis is important not only in the context of early removal of undescended testis but also in terms of the grave psychological outcome of the diagnosis on the adolescent and family members. Here, we present case reports of two sisters who presented with primary amenorrhea. It is imperative to keep CAIS as a differential during the evaluation of primary amenorrhea. CAIS may also present as a case of a childhood inguinal hernia.

Incidental Inguinal Tubercular Lymphadenitis in a female of Androgen Insensivity Syndrome- A rarest of rare presentation

Androgen insensitivity syndrome (AIS) is a rare X-linked recessive disorder occurring in phenotypic women with male genotype (46, XY) resulting due to mutation in the X chromosome. On the other hand, tuberculosis (TB) is a chronic granulomatous infection caused by Mycobacterium tuberculosis, an acid-fast bacillus. We report a case of a 22-year-old unmarried female presenting with bilateral inguinal pain and primary amenorrhea, which, on comprehensive evaluation, revealed complete female external genitalia and intra-abdominal testes. The karyotype was 46 XY, hence a diagnosis of complete AIS was made. One of the ‘probable testes’ removed surgically was an inguinal lymph node with tuberculous lymphadenitis. Isolated inguinal tuberculous lymphadenopathy, by itself, is rare. Co-occurrence of Complete AIS and inguinal tuberculous lymphadenopathy is a highly unusual and rare association that has not been documented in the literature reviewed.

P-704 Genomic DNA damage in individuals with sex determination defects and germ cell cancer

Abstract Study question Does genomic instability contribute to common mechanisms underlying variable defects of gonadal differentiation and susceptibility to germ cells cancer? Summary answer Genomic DNA damage and associated phenotypes in leukocytes and gonadal tissue indicate systemic dependence on DNA repair mechanisms, connected to germ cell tumorigenesis when defective. What is known already Variabilities related to dysfunctional sex chromosomes are associated to Differences of Sex Development (DSD), characterized by dysgenic gonads, deregulated gender specification and failed germ cell maturation. This causes infertility and elevated risk of germ cell tumors (GCT). DSD was described in individuals with Swyer syndrome (46,XY, females), complete or partial androgen insensitivity syndrome (CAIS, PAIS, 46,XY, females), Turner (45,X0, females) and Klinefelter (47,XXY, males) syndromes, characterized by malignant tumor development. Unbalanced karyotype is associated with genome-wide changes, including proliferation delay, defects in proteostasis, DNA damage and activation of innate immune response, that contribute to genome instability phenotypes. Study design, size, duration Individuals with DSD were enrolled into study during routine examination in our clinic. Samples from men with testicular germ cell tumors (TGCT) were used as positive controls for malignancy. The samples were collected with written patients’ informed consent. For this study we analyzed 40 individuals with DSD and 19 samples with GCT. Control group contained samples from fertile men and women of appropriate age interval. Participants/materials, setting, methods Study groups included individuals with Swyer (n = 7), Turner (n = 11), Klinefelter (n = 6), CAIS (n = 9) syndromes and men with TGCT (n = 14). Blood was collected in EDTA and DNA, RNA and protein were isolated from leukocytes. Individuals with Swyer and CAIS, that underwent gonadectomy, formed additional group with histologically proven GCT (DSD-GCT, n = 6). Samples were analyzed with quantitative real-time PCR (qRT-PCR), immunoblotting, mass spectrometry, immunofluorescence. Main results and the role of chance We described an increase of DNA damage compared to unaffected controls via γH2AX, labeling double strand brakes in DNA, in leukocytes (immunoblotting: Swyer p = 0,0438; DSD-GCT p = 0,0185; CAIS NS; Turner p = 0,0117; Klinefelter p = 0,0068; TGCT p = 0,0207) and gonads (immunofluorescence, γH2AX+ puncta per cell: Swyer n = 75, p < 0,0001; DSD-GCT n = 46, p < 0,0001; CAIS n = 33, NS; TGCT n = 40, p < 0,0001, n-number of cells analyzed). We associated malignancy in our study groups with DNA damage associated phenotypes by evaluating innate immune response activation via IFNβ and ISG15 RNA levels (DSD-GCT p = 0,0350 and p = 0,0411; TGCT p = 0,0007 and p = 0,0437) and inhibition of autophagy via decrease of LC3 and accumulation of P62 proteins (DSD-GCT p < 0,0001 and p = 0,0453; TGCT p = 0,036 and p = 0,0219). This was supported by whole proteome analysis. Compromised genomic DNA integrity suggested an involvement of DNA repair pathways, illustrated by upregulation of deltaTP53 (Swyer p = 0,0104; DSD-GCT p = 0,0478; CAIS p = 0,0046; Klinefelter p = 0,0426; TGCT p = 0,006). TP53 exhibited significant increase in missense mutations in sequences, encoding transactivation domains, which compromised protein stability, particularly, in samples with GCT. We also illustrated that leukocytes of individuals with DSD-GCT restore DNA damage upon direct DNA repair mechanisms activation by Enoxacin (p = 0,0056) or autophagy inhibition by Bafilomycin A1 (p = 0,0034). T test was used for statistical analysis. Limitations, reasons for caution This study is based on a limited number of samples available from the individuals with the rare genetic syndromes, for some observed only in 1 out of 10,000 clinical cases. Therefore, development of in vitro study models will promote the research in this area. Wider implications of the findings This study elucidated possibilities for prophylactic treatments of DSD-individuals as well as new diagnostic approaches of GCT. It additionally emphasized the importance to address genome integrity in infertility research. Trial registration number NA