Partial Androgen Insensitivity Research Articles

Gynecomastia and Its Management In Boys With Partial Androgen Insensitivity Syndrome.

Partial androgen insensitivity syndrome (PAIS) is a rare condition that is reported to be commonly associated with gynecomastia in males. To assess the management of gynecomastia in male PAIS. Retrospective review of males with PAIS over the age of 10 years in the I-DSD registry. Of the 205 eligible cases, information was available for 57 from 13 centers. An androgen receptor gene variant was confirmed in 45 (79%) with a median age at first presentation of 1.0 year (range 0.1, 26.0). Of the 45 genetically confirmed cases, gynecomastia was present in 41 (91%) with a median age at the time of gynecomastia development of 13.5 years (11.0, 29.0). In the other 4 (9%) with no gynecomastia, the median age at last assessment was 15.7 years (10.6, 17.0). In 30 cases with information available, micropenis was present at the time of gynecomastia development in 23 (77%). Of the 35 with information available, 2 (6%) exhibited spontaneous resolution between the ages of 15 and 21 years and 25 (71%) had breast surgery at a median age of 15.7 years (14.0, 23.0). Of these 25, 9 (26%) had previously received medical therapy. The median clinician score of effectiveness for medical therapy was 3 (1, 8) compared to 10 (3, 10) for surgery (P < .0001). In 31 with information available, 13 (42%) had received psychology support. Gynecomastia is common in PAIS but not universal. Surgical management may be more effective than medical therapy, but there is a need for further standardized and systematic studies.

Recommendations for 46,XY Disorders/Differences of Sex Development Across Two Decades: Insights from North American Pediatric Endocrinologists and Urologists

Clinical decision-making for individuals with 46,XY disorders/differences of sex development (DSD) remains unsettled and controversial. The North American DSD Clinician Survey examines the recommendations of a large group of clinical specialists over the last two decades. Active members of the (Lawson Wilkins) Pediatric Endocrine Society and the Societies for Pediatric Urology were invited to respond to a web-based survey at three different timepoints: 2003–2004 (T1), 2010–2011 (T2), and 2019–2020 (T3). Data from 429 participants in T1, 435 in T2, and 264 in T3 were included in this study. The participants were presented with three XY newborn clinical case scenarios—micropenis, partial androgen insensitivity syndrome, and iatrogenic penile ablation—and asked for clinical management recommendations. The main outcomes assessed included the recommended gender of rearing, surgical decision-maker (parent or patient), timing of genital surgery, and age at which to disclose medical details and surgical history to the patient. For all scenarios, the overwhelming majority recommended rearing as male, including a significant increase across timepoints in those recommending a male gender of rearing for the infant with penile ablation. The proportions recommending female gender of rearing declined significantly across timepoints. In general, most recommended parents (in consultation with the physician) serve as surgical decision-makers, but these proportions declined significantly across timepoints. Recommendations on the timing of surgery varied based on the patient’s gender and type of surgery. There has been a shift in recommendations away from the “optimal gender policy” regarding gender of rearing and surgical interventions for patients with XY DSD.

Clinical, Hormonal, and Genetic Spectrum of 46 XY Disorders of Sexual Development (DSD) Patients.

To evaluate the clinical,hormonaland genetic characteristics of 46XY disorders of sexual development (DSD) patients from South India. 46XY DSD patients with a provisional diagnosis of 17β-hydroxysteroid dehydrogenase 3 (17BHSD3) deficiency, 5 alpha-reductase type 2 deficiency (5ARD2) or partial androgen insensitivity syndrome (PAIS) based on clinical and hormonal analysis were included in this study. All the patients underwent detailed clinical and hormonal evaluations. Targeted next-generation sequencing for all three genes (AR, HSD17B3, and SRD5A2) in parallel was carried out for all the included patients and their parents. Based upon the clinical and hormonal analysis, among the 37 children with 46XY DSD in the present study, 21 children were diagnosed with 5ARD2, 10 with PAIS, and six with 17BHSD3 deficiency. However, genetic analysis revealed pathogenic mutations in nine patients - six in the AR gene, two in the SRD5A2 gene, and one in the HSD17B3 gene. The concordance rate between provisional hormonal and genetic diagnosis was only 22.2%. Two out of six subjects with AR gene variants were positive for somatic mosaicism. In the present study, a positive genetic diagnosis was detected in nine patients (24%), including five novel variants. In this study, mutations in the AR gene was the most reported. The authors did not find the testosterone: dihydrotestosterone (T: DHT) ratio to be an accurate hormonal diagnostic tool.

The role of pre- and postnatal investigations in suspected isolated hypospadias

IntroductionPrenatal investigations are usually performed to diagnose severe or associated forms of hypospadias. However, the value of this workup and the correlation with the postnatal diagnosis and follow-up have not been studied in the literature. The aims of the study were to describe postnatal outcomes. Material and methodsWe conducted a single-center retrospective study. We included fetuses with a prenatal suspicion of isolated hypospadias (no associated ultrasound abnormality). Postnatal findings were described including neonatal examination with confirmation of the diagnosis or not of hypospadias, the diagnosis of isolated or associated hypospadias, investigations and management. ResultsA total of 21 patients with a suspicion of isolated hypospadias on prenatal ultrasound and available postnatal follow-up were included. The diagnosis of hypospadias was confirmed at neonatal examination for 17/21 (81 %) children. All 17 confirmed cases underwent at least one urological surgical procedure. Postnatally, the diagnosis of hypospadias in 4/17(23.5 %) cases was found to be associated with the following diagnosis: Denys-Drash syndrome, deletion of chromosome9 and duplication of chromosome20 involved in genital development, significant duplication of the short arm of chromosome 16, mosaic karyotypic abnormality [45, X (64 %)/46, XY (36 %)]. The hormonal assessment revealed 3/17(17.6 %) abnormalities: one diagnosis of partial androgen insensitivity syndrome and two cases of gonadal dysgenesis with low AMH and inhibin B. ConclusionPrenatal diagnosis of isolated hypospadias may be associated with postnatal genetic abnormalities. In this context, a prenatal assessment by amniocentesis with chromosomal microarray analysis can be an option after discussion with the woman.

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.

Adult Outcome After Partial Androgen Insensitivity Syndrome: Diagnosed and Assigned Female in Infancy.

This patient, now in her 40s, was evaluated because of genital ambiguity and diagnosed with pAIS in infancy based upon elevated testosterone and gonadotropin levels and significantly reduced binding affinity of the androgen receptor. Such reduced binding is consistent with a structural abnormality of the receptor protein precluding expected activity of the androgen receptor. Based on this information and counseling, her parents chose a female sex assignment. She had clitoral recession and testes removal as an infant and neovaginal surgery using a distal ileum segment at age 11 years and was begun on estrogen therapy at age 12 years. She is being reported now to point out that the data known at her birth provided as specific information to guide sex assignment and genital surgery as is currently available. More importantly, long-term outcome data is very positive showing clear female gender identity, successful marriage of more than 20 years, excellent social relationships including family and friends, an active social life. Since this diagnosis is lifelong, it is inevitable that there will be reminders, hopefully rare, that may be traumatizing. Unfortunately, in this patient, such reminders have been related to access to health care.

Navigating the complexities of partial androgen insensitivity syndrome: A comprehensive case study

Partial Androgen Insensitivity Syndrome (PAIS) is a rare genetic disorder that poses unique challenges in clinical management. This case study delves into the clinical presentation, diagnostic journey, and management of a patient diagnosed with PAIS. The complexities of androgen receptor dysfunction and its impact on sexual development are explored, providing valuable insights for clinicians and researchers alike.

Urethral reconstruction using amniotic membrane allograft in hereditary androgen insensitivity syndrome: a case series

Abstract Partial androgen insensitivity syndrome is a rare X-linked disorder. While most cases are sporadic, familial cases are less frequent. The management of this syndrome follows a multidisciplinary approach involving hormone substitution, psychological counseling, and surgical procedures. We present a case series of three young siblings with familial partial androgen insensitivity syndrome who presented with a female phenotype. All of them were managed with hormonal treatment for 6 months followed by surgical reconstruction. The operative procedure involved phalloplasty and urethroplasty using amniotic membrane transplant, which is considered a novel technique in this group of patients. No intraoperative or postoperative complications were observed and good results were achieved within 2 years of follow-up.

Partial Androgen Insensitivity Syndrome: Incidentally Diagnosed in an Adolescent

Background: Androgen insensitivity syndrome is an X-linked genetic disease characterized by resistance to the actions of androgen in an individual with 46, XY karyotype. It is one of the most common causes of Disorders of sex development (DSD). Clinical Description: A 10-year-7-month-old child, reared as female, was incidentally detected with minor virilization of external genitalia. She had achieved thelarche and adrenarche with a Prader Stage 2. Management and Outcome: Routine investigations showed normal hemogram and kidney and liver functions, as also normal values of serum electrolytes. Ultrasonogram showed the absence of Mullerian structures and the presence of prostate- and testis-like structures. Karyotyping showed 46, XY. There were grossly elevated levels of testosterone and dihydrotestosterone, as well as raised follicle-stimulating hormone and luteinizing hormone levels. Diagnostic laparoscopy showed inguinal testis-like structures and biopsy from the same confirmed testicular tissue. Parents were counseled regarding the prognosis, need for gonadectomy, and hormone replacement. Conclusion: Our case creates awareness regarding the importance of early identification of minor virilizing features in a child, so as to avoid late revelation of an underlying DSD leading to undue anxiety and psychological trauma to parents and child.

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.

Serum steroid metabolite profiling by LC-MS/MS in two phenotypic male patients with HSD17B3 deficiency: Implications for hormonal diagnosis

Although 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency is diagnosed when a testosterone/androstenedione (T/A-dione) ratio after human chorionic gonadotropin (hCG) stimulation is below 0.8, this cut-off value is primarily based on hormonal data measured by conventional immunoassay (IA) in patients with feminized or ambiguous genitalia. We examined two 46,XY Japanese patients with undermasculinized genitalia including hypospadias (patient 1 and patient 2). Endocrine studies by IA showed well increased serum T value after hCG stimulation (2.91 ng/mL) and a high T/A-dione ratio (4.04) in patient 1 at 2 weeks of age and sufficiently elevated basal serum T value (2.60 ng/mL) in patient 2 at 1.5 months of age. Despite such partial androgen insensitivity syndrome-like findings, whole exome sequencing identified biallelic ″pathogenic″ or ″likely pathogenic″ variants in HSD17B3 (c .188 C>T:p.(Ala63Val) and c .194 C>T:p.(Ser65Leu) in patient 1, and c.139 A>G:p.(Met47Val) and c.672 + 1 G>A in patient 2) (NM_000197.2), and functional analysis revealed reduced HSD17B3 activities of the missense variants (∼ 43% for p.Met47Val, ∼ 14% for p.Ala63Val, and ∼ 0% for p.Ser65Leu). Thus, we investigated hCG-stimulated serum steroid metabolite profiles by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in patient 1 at 7 months of age and in patient 2 at 11 months of age as well as in five control males with idiopathic micropenis aged 1 – 8 years, and found markedly high T/A-dione ratios (12.3 in patient 1 and 5.4 in patient 2) which were, however, obviously lower than those in the control boys (25.3 – 56.1) and sufficiently increased T values comparable to those of control males. The elevated T/A-dione ratios are considered be due to the residual HSD17B3 function and the measurement by LC-MS/MS. Thus, it is recommended to establish the cut-off value for the T/A-dione ratio according to the phenotypic sex reflecting the residual function and the measurement method.

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 &amp;lt; 0,0001; DSD-GCT n = 46, p &amp;lt; 0,0001; CAIS n = 33, NS; TGCT n = 40, p &amp;lt; 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 &amp;lt; 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

PARTIAL ANDROGEN INSENSITIVITY SYNDROME- FEMINIZING GENITOPLASTY

We describe a case of 20 years old patient presented to us with ambiguous genitelia diagnosed as partial androgen insensitivity syndrome. Patient was raised as female and she intended to live as female. Key factor in deciding the Gender and management of such cases is briey described in this case.

A study for early results and complications of feminizing genitoplasy in children welfare teaching hospital ,medical city

Background Differences of sexual development (DSD), is a congenital conditions in which the development of the chromosomal, gonadal,and anatomic sex are atypical. Aim of the study To evaluate early results and complications of feminizing genitoplastyPatients and methods It’s a prospective descriptive study conducted in children welfare teaching hospital, Baghdad medical city from Feb.2019 to Oct.2021 for patients with feminizing genitoplasty.Results A total of 24 patients were enrolled in this study with age from1-13 years. The gender assigned at birth was female in(62.5%) and male in(37.5%) of patients.CAH was the diagnosis in (95.83%) while Partial androgen insensitivity syndrome was (4.16%).The chromosomal study was XX in(95.83%) and XY in(4.16%) . Prader3 and Prader 4 represented( 74.07%)of cases .The length of the urogenital sinus was 3 cm in (16.66%) of patients.type of surgery was partial urogenital mobilization with clitoroplasty, monsplasty, labioplasty and Fortunoff flap was done in(70.83%) , and cutback vaginoplasty in (16.66%), and staged repair with clitoroplasy monsplasty and labioplasty without vaginal replacement (12.5%) of the patients. early post operative complications (8.33%) minor bleeding, (4.14%) seroma, (16.66%) wound infection, (4.16%) minor wound dehiscence of labia majora, and none of the cases had clitoral loss.no urinary incontinence were found in the patients who were previously continent. 87.5% of patientd and family reported good results, and 12.5% reported satisfactory results. Conclusion feminizing genitoplasty is a safe surgery with relatively low complication rates and good cosmetic outcome when performed by surgeons with experience in this field.

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

Introduction: 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. Methods: 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. Results: 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. 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 tumor.

Categorization of differences of sex development among Egyptian children and the role of antimullerian hormone and inhibin B.

Differences of sex development (DSD) are congenital conditions linked to atypical development of chromosomal, gonadal, or anatomical sex. The aim of this study was to demonstrate our experiences at the Diabetes Endocrine and Metabolism Pediatric Unit (DEMPU), Faculty of Medicine, Cairo University in the field of DSD by focusing on the clinical presentation, laboratory profile, classification, and etiological diagnosis of these conditions. In addition, the present study intended to delineate the importance of serum anti-Müllerian hormone (AMH) and inhibin B in detecting the presence of functioning testicular tissue. This cohort study included 451 infants and children with various clinical presentations of DSD. The study performed a retrospective analysis on medical records of established DSD cases to evaluate the clinical importance of AMH and inhibin B. In addition, newly diagnosed patients were prospectively analyzed. Three hundred thirty-six (74.5%) patients were 46,XY DSD, 98 (21.7%) were 46,XX DSD, 14 patients had other karyotypes and 3 had missing karyotypes. Among the 46XY DSD patients, the most common cause was partial androgen insensitivity. In contrast, congenital adrenal hyperplasia constituted the most common diagnosis in 46,XX DSD cases. The cut off value of serum AMH was 14.5 ng/ml with 100% sensitivity and 55.1% specificity. Partial androgen insensitivity was the most important cause of 46,XY DSD in Egyptian children, and congenital adrenal hyperplasia was the most common cause of 46,XX DSD. AMH was valuable in detecting functioning testicular tissue.

ODP381 Changes in Perceptions of Pediatric Endocrinologists (PE) and Urologists (PU) to Infants and Children regarding care of individuals with 46,XY DSD

Abstract Introduction Over recent decades, controversy regarding standards of care has contributed to questioning past management recommendations for infants and children with a 46,XY DSD. Surveys conducted in 3 waves (2003, 2010, 2020) provide evidence of changes in recommendations for care have changed over this period. Methods Online surveys of the members of the Pediatric Endocrine Society (PE) and Societies for Pediatric Urology (PU) included case vignettes representing partial androgen insensitivity syndrome (PAIS), micropenis resulting from primary testicular failure, and penile ablation (non-DSD). Survey items included questions regarding recommended gender of rearing (GoR), genital surgery (and timing), and disclosure of diagnostic details to patient. Results The newborn PAIS vignette included elevated LH and FSH and a 1.2 cm. phallus that increased to 1.7 after exogenous testosterone. Male GoR was chosen by 47, 55 &amp; 55% PE and 81, 83 &amp; 69% of PU in waves 1 to 3, respectively; 27 PE and 28% PU chose an added "non-binary" option in 2020. The recommendation that parents, rather than patients, should decide about perineal hypospadias repair was chosen by 70, 60 &amp; 50% of PE and 93, 90 &amp; 79% of PU. Recommending against surgery were 25, 22 &amp; 10% PE and 23, 13 &amp; 8% PU. Recommending surgery be completed at &amp;lt;1 year of age: 56, 59, 66% PE and 69, 78, 84% PU. Recommendation against disclosure of the underlying condition to the patient 12, 17 &amp; 28% PE and 17, 19 &amp; 22% PU, while 35, 28 to 32% PE and 34, 43 &amp; 30% PU recommended that disclosure occur by 11 years of age. For the penile ablation vignette, 78, 92 &amp; 92% PE and 98, 95 &amp; 97% PU recommended male GoR. The 2020 non-binary option was chosen by 4 and 2% PE and PU. The majority of both groups recommended male GoR for the micropenis vignette with testicular failure; 94, 94 &amp; 89% PE and 96, 97 &amp; 88% PU. The decline in 2020 resulted from the recommendation of the non-binary option by 9% PE and 8% PU. Conclusions It seems clear that a female GoR recommendation is currently rare across 46,XY vignettes with evidence of testicular function during at least some of fetal life. It is also apparent that the current emphasis/controversy regarding GoR has resulted in confusion as to how to apply this poorly understood concept. The resulting shift of delaying decisions regarding surgery until the patient can decide is inconsistent with the recommendation that hypospadias repair occur before age 1 year. Finally, lack of or delayed disclosure is inconsistent with patient centered care recommendations. Presentation: No date and time listed

OR18-3 Case Series of 16 Patients With 17β-Hydroxysteroid Dehydrogenase Type 3 Deficiency at Five Children's Hospitals in the United States

Abstract Objectives The 17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) enzyme, expressed in the testes, converts androstenedione to testosterone. Deficiency of 17βHSD3 causes a 46,XY difference of sex development (DSD). Until recently, just 12 cases of 17βHSD3 deficiency had been reported in the literature in the United States. We report a series of 16 patients diagnosed at five children's hospitals in the United States. Methods We performed a multi-center chart review of patients with 17βHSD3 deficiency diagnosed based on hormone values and/or sequencing and deletion/duplication analysis of the HSD17B3 gene. Results Sixteen patients were identified, ranging in age at diagnosis from birth to 22.3 years (average age 9.5 years). One patient, assigned female at birth, was diagnosed due to a positive family history of the condition. Three patients underwent testing due to discordance between the sex predicted by prenatal cell-free DNA testing and the external genital appearance on prenatal ultrasound or at birth (two were assigned female, one was assigned male). An additional four patients had non-binary (atypical) appearing external genitalia at birth (two assigned female, two assigned male). Two children assigned female at birth were diagnosed after undescended testes were identified during hernia repair in early childhood. Six patients who were assigned female at birth came to medical attention peri-pubertally due to signs of excess/undesired androgen effects and/or primary amenorrhea. Data on gender identity is limited by the current age of many of the patients, but as of most recent follow-up, one patient assigned male and one assigned female are reported to be exploring their gender identities. Four patients had a prior diagnosis of complete or partial androgen insensitivity syndrome and 8 had a prior diagnosis of 46,XY DSD of unknown etiology. Eleven patients had genetic testing confirming pathogenic or likely pathogenic variants in the HSD17B3 gene (two identified on whole exome, one on a DSD-specific multi-gene panel, and the remaining 8 on single gene testing). Of the patients without genetically confirmed 17βHSD3 deficiency, one had a clinical diagnosis due to a genetically-confirmed diagnosis in a sibling. The remaining four declined or have not completed genetic testing, but had hormonal testing consistent with the diagnosis. Conclusions 17βHSD3 deficiency is likely much more common in the US than previously appreciated, and can present at any age with a range of physical findings. Accurate diagnosis is important, as the broad category of 46,XY DSD encompasses a wide spectrum of gonadal malignancy risk, potential for pubertal hormone function and fertility, and gender identity outcomes. We suggest evaluating for this potential diagnosis with genetic and/or hormonal testing in cases of 46,XY DSD with absent uterus. Presentation: Monday, June 13, 2022 11:30 a.m. - 11:45 a.m.

OR07-6 Disrupting DNA-binding Domain Dimerization In The Androgen Receptor In Mice Results In a Partial Androgen Insensitivity Model

Abstract The androgen receptor (AR) plays a crucial role in the development and maintenance of the male phenotype, as shown in patients with androgen insensitivity syndrome (AIS). The AR is a nuclear receptor that needs to homodimerize to execute its role as transcription factor. Dimerization can occur through three different modes: via the DNA-binding domain (DBD), via the ligand-binding domain and via an interaction between the LBD and the aminoterminal domain. Dimerization via the DBD is very well known and occurs through the D-box located in the second zinc finger. DBD dimerization is generally accepted for all steroid receptors, but some of them show that D-box mutations do not inactivate them completely. However, for the AR, no monomeric transactivation capacity was described yet. To study the role of D-box independent activity of the AR, we introduced a double point mutation in the D-box that is predicted to disrupt DBD dimerization (ARDmon). These two point mutations were found in separate patients suffering from partial AIS. In vitro studies with this mutant suggest that the remaining activity depends on the androgen response element under investigation. We show that ligand binding was not affected by the D-box mutation. Furthermore, BioID assays indicated no changes in coregulatory interactions. When introducing the corresponding mutation in mice, this led to a phenotype that is intermediate between global ARKO and wild type (WT) males. Based on their anogenital distance (AGD) and the absence of nipples at early age, the ARDmon/Y mice were identified as males. Follow-up of their AGD and body weight, however, revealed clear differences with both WT males and females. Furthermore, hypospadias was observed in the ARDmon/Y mice. Testes were smaller in size compared to the WT males and first analysis showed almost no expression of well-known AR regulated genes. Reminiscent structures of the epididymis were found. In summary, the ARDmon mouse model shows an intermediate AIS phenotype. Via orchidectomy in combination with androgen replacement therapy, we will now investigate remaining androgen responses in the ARDmon/Y mice and elucidate response elements on which the AR can act in a D-box independent way. Additionally, we generated the first rodent PAIS model with a genetic cause of hypospadias. Presentation: Saturday, June 11, 2022 12:45 p.m. - 1:00 p.m.

Sex dimorphism of weight and length at birth: evidence based on disorders of sex development

Background Males have higher weight and length at birth than females. Aim To verify the influence of the Y chromosome and the action of intrauterine androgens on weight and length at birth of children with Disorders of Sex Development (DSD). Subjects and methods A cross-sectional and retrospective study. Patients with Turner syndrome (TS), complete (XX and XY), mixed (45,X/46,XY) and partial (XY) gonadal dysgenesis (GD), complete (CAIS) and partial (PAIS) androgen insensitivity syndromes and XX and XY congenital adrenal hyperplasia (CAH) were included. Weight and length at birth were evaluated. Results Weight and length at birth were lower in TS and mixed GD when compared to XY and XX DSD cases. In turn, patients with increased androgen action (117 cases) had higher weight and length at birth when compared to those with absent (108 cases) and decreased (68 cases) production/action. In birthweight, there was a negative influence of the 45,X/46,XY karyotype and a positive influence of increased androgen and gestational age. In birth length, there was a negative influence of the 45,X and 45,X/46,XY karyotypes and also a positive influence of increased androgen and gestational age. Conclusions The sex dimorphism of weight and length at birth could possibly be influenced by intrauterine androgenic action.