Mixed Gonadal Dysgenesis: A Narrative Literature Review and Clinical Primer for the Urologist.

PURPOSE: Mixed gonadal dysgenesis is a difference of sex development that is often confused with other conditions. Individuals have a 45,X/46,XY karyotype. Gonads are characterized by a streak gonad and a dysgenetic testis at varying levels of descent. Persistent Müllerian structures are typical (eg, hemi-uterus). There is significant phenotypic heterogeneity of the internal and external genitalia that, together with different interpretations of the definition, have contributed to a poor understanding of the condition among pediatric urologists. Mixed gonadal dysgenesis is one manifestation of the 45,X/46,XY karyotype. 45,X/46,XY mosaicism can also be associated with typical female or male external genitalia. This review aims to clarify the mixed gonadal dysgenesis definition and to provide urologists with diagnostic and management considerations for affected individuals. MATERIALS AND METHODS: We searched 3 medical databases for articles related to mixed gonadal dysgenesis. Two hundred eighty-seven full-text abstracts and manuscripts were reviewed for content pertinent to: (1) clarifying the definition of mixed gonadal dysgenesis, and (2) describing the following related to the care of affected individuals: prenatal and neonatal evaluation and management, genital surgery, gonadal malignancy risk and management, fertility, gender dysphoria/incongruence, puberty and long-term outcomes, systemic comorbidities, and transitional care. RESULTS: Fifty articles were included. Key points and implications for each of the above topics were summarized. CONCLUSIONS: Mixed gonadal dysgenesis exists on a wide phenotypic spectrum and management considerations reflect this heterogeneity. Care for individuals with mixed gonadal dysgenesis is complex, and decisions should be made in a multidisciplinary setting with psychological support.

46,ΧΥ DSD in an adolescent with a novel de novo variant of the NR5A1 gene - case report and literature review.

PURPOSE: In addition to chromosomal abnormalities, several genes have been implicated as causes of disorders of sex development (DSD). The NR5A1 gene expresses SF1, a transcription factor that plays a role in steroidogenesis by controlling multiple stages of adrenal and gonadal development, its mutations having been reported in cases of DSD. CASE PRESENTATION: A 15-year-old teenager was admitted to the Children's ICU of a tertiary center due to acute encephalitis. On physical examination, labia majora and minora, open vaginal opening, and a 4.8 cm phallus (stretched length) in the anatomical position of the clitoris were identified. The patient also presented with hirsutism, breast development was Tanner stage I, and pubic hair was Tanner V. Medical history revealed primary amenorrhea. Imaging studies revealed oval formations primarily compatible with testicular parenchyma in the anatomical location of the inguinal ducts. The karyotype identified a 46,XY individual, while whole exome sequencing (WES) revealed the presence of a heterozygous pathogenic splice site variant of the NR5A1 gene (NM_004959.5), c.990G > C, p.Glu330Asp, which, on further genetic testing of the parents, was proven to be de novo. According to psychiatric assessment, the patient self-identifies as a female. Laparoscopic exploration showed no residual Mullerian ducts or the presence of testicular tissue. A gonadectomy was performed and hormone replacement therapy with estrogens was initiated. CONCLUSION: We describe a rare case of 46,XY DSD in an phenotypically female adolescent carrying the novel de novo p.Glu330Asp variant of the NR5A1 gene. We also highlight the frequent delay in diagnosis of ambiguous external genitalia.

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.

Cytogenomic description of a Mexican cohort with differences in sex development.

BACKGROUND: Differences in Sex Development (DSD) is a heterogeneous group of congenital alterations that affect inner and/or outer primary sex characters. Although these conditions do not represent a mortality risk, they can have a severe psycho-emotional impact if not appropriately managed. The genetic changes that can give rise to DSD are diverse, from chromosomal alterations to single base variants involved in the sexual development network. Epidemiological studies about DSD indicate a global frequency of 1:4500-5500, which can increase to 1:200-300, including isolated anatomical defects. To our knowledge, this study is the first to describe epidemiological and genetic features of DSD in a cohort of Mexican patients of a third-level care hospital. METHODS: Descriptive and retrospective cross-sectional study that analyzed DSD patients from 2015 to 2021 attended a Paediatric Hospital from Mexico City. RESULTS: One hundred one patients diagnosed with DSD were registered and grouped into different entities according to the Chicago consensus statement and the diagnosis defined by the multidisciplinary group. Of the total, 54% of them belong to the chromosomal DSD classification, 16% belongs to 46, XX and 30% of them belongs to the 46, XY classification. CONCLUSION: The frequency for chromosomal DSDs was consistent with the literature; however, we found that DSD 46, XY is more frequent in our cohort, which may be due to the age of the patients captured, the characteristics of our study population, or other causes that depend on the sample size.

Clinical spectrum of human STAR variants and their genotype-phenotype correlation.

Biallelic variants of steroidogenic acute regulatory protein (STAR/STARD1) may cause primary adrenal insufficiency and 46,XY disorder of sex development. STAR plays a pivotal role in transporting cholesterol into mitochondria where cholesterol serves as an essential substrate for initiating steroid biosynthesis by its conversion to pregnenolone. Generally, loss-of-function mutations of STAR cause the classic form of lipoid congenital adrenal hyperplasia (LCAH) where steroidogenesis of the adrenal cortex and the gonads is severely affected. By contrast, partial activity of STAR causes a less severe phenotype, the non-classic LCAH, which is characterized by later onset and initial manifestation with isolated adrenal insufficiency only. Disease-causing STAR variants are very rare. Numerous variants of all types have been described worldwide. Prevailing variants have been reported from Japan and Korea and in some population clusters where STAR is more common. Genotype-phenotype correlation is pretty good for STAR variants. While the exact mechanisms of cholesterol transport into mitochondria for steroidogenesis are still under investigation, the important role of STAR in this process is evident by inactivating STAR variants causing LCAH. The mechanism of disease with STAR deficiency is best described by a two-hit model: the first hit relates to impaired cholesterol import into mitochondria and thus lack of substrate for all steroid hormone biosynthesis; the second hit then relates to massive cytoplasmic lipid overload (evidenced by typically enlarged and fatty adrenal glands) leading to cell death and organ destruction. This review summarizes phenotype and genotype characteristics of human STAR variants found through the ClinVar database.

Long-term outcomes in non-CAH 46,XX DSD.

Differences/disorders of sex development (DSD) comprise a large group of rare congenital conditions. 46,XX DSD, excluding congenital adrenal hyperplasia (CAH), represent only a small number of these diseases. Due to the rarity of non-CAH 46,XX DSD, data on this sex chromosomal aberration were confined to case reports or case series with small numbers of patients. As the literature is still relatively sparse, medical data on the long-term effects of these pathologies remain scarce. In this review, we aim to provide an overview of current data on the long-term follow-up of patients with non-CAH 46,XX DSD, by covering the following topics: quality of life, gender identity, fertility and sexuality, global health, bone and cardiometabolic effects, cancer risk, and mortality. As non-CAH 46,XX DSD is a very rare condition, we have no accurate data on adult QoL assessment for these patients. Various factors may contribute to a legitimate questioning about their gender identity, which may differ from their sex assigned at birth. A significant proportion of gender dysphoria has been reported in various series of 46,XX DSD patients. However, it is difficult to give an accurate prevalence of gender dysphoria and gender reassignment in non-CAH 46,XX DSD because of the rarity of the data. Whatever the aetiology of non-CAH 46,XX DSD, fertility seems to be impaired. On the other hand, sexuality appears preserved in 46,XX men, whereas it is impaired in women with MRKH syndrome before treatment. Although there is still a paucity of data on general health, bone and cardiometabolic effects, and mortality, it would appear that the 46,XX DSD condition is less severely affected than other DSD conditions. Further structured and continued multi-center follow-up is needed to provide more information on the long-term outcome of this very rare non-CAH 46,XX DSD condition.

Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development.

BACKGROUND: 46,XY sex reversal 11 (SRXY11) [OMIM#273250] is characterized by genital ambiguity that may range from mild male genital defects to gonadal sex reversal in severe cases. DHX37 is an RNA helicase that has recently been reported as a cause of SRXY11. So far, a total of 21 variants in DHX37 have been reported in 58 cases with 46,XY disorders of sex development (DSD). METHODS: Whole exome sequencing (WES) was conducted to screen for variations in patients with 46,XY DSD. The subcellular localization of mutant DHX37 proteins was detected by immunofluorescence. And the levels of mutant DHX37 proteins were detected via Western blotting. RESULTS: A novel pathogenic variant of DHX37 was identified in a patient with 46,XY DSD c.2012G > C (p.Arg671Thr). Bioinformatics analysis showed that the protein function of the variant was impaired. Compared with the structure of the wild-type DHX37 protein, the number of hydrogen bonds and interacting amino acids of the variant protein were changed to varying degrees. In vitro assays revealed that the variant had no significant effect on the intracellular localization of the protein but significantly reduced the expression level of the protein. CONCLUSIONS: Our finding further expands the spectrum of the DHX37 variant and could assist in the molecular diagnosis of 46,XY DSD patients.

Prenatal DEHP exposure induces lifelong testicular toxicity by continuously interfering with steroidogenic gene expression.

Background: Epidemiologic studies suggested the association between prenatal di-(2-ethylhexyl) phthalate (DEHP) exposure and disorders of sex development (DSD), adult male disorders, and reproductive aging. Inhibiting testosterone synthesis by interfering with steroidogenic gene expression induces testicular toxicity, however, whether prenatal DEHP exposure induces testicular toxicity through this mechanism remains uncertain. Methods: C57BL/6JGpt male mice underwent different doses (0, 100, 500, 1,000 mg/kg) of prenatal DEHP exposure during gestational day 10 to delivery day, the testicular toxicity (genital development, testosterone, semen quality, and morphology of testis tissue) in the neonatal, post-puberal and middle-aged stages was observed, and the steroidogenic gene (Lhcgr, Star, Cyp11a1, Cyp17a1, Hsd17b3, and Hsd3b2) expression was analyzed by quantitative polymerase chain reaction (qPCR) and Western blot (WB). The interference of steroidogenic gene expression in TM3 cells after mono-(2-ethylhexyl) phthalate (MEHP) exposure was also explored for verification. Results: Prenatal DEHP exposure induced immediate testicular injury in the neonatal stage [reduced anogenital distance (AGD) and intratesticular testosterone], DSD in the post-puberal stage (poor genital development), and reproductive aging in the middle-aged stage (obesity, reduced testosterone and semen quality, and atrophic seminiferous tubules), especially in the high dose. Prenatal DEHP exposure continuously interfered with steroidogenic gene expression (Hsd3b2, Hsd17b3) in RNA and protein levels. MEHP inhibited testosterone synthesis of TM3 cells by interfering with steroidogenic gene expression (Hsd3b2, Hsd17b3) in RNA and protein levels. Conclusions: Prenatal DEHP exposure induces lifelong testicular toxicity by continuously interfering with steroidogenic gene expression, thus indicating the association between prenatal exposure and DSD, adult male disorders, and reproductive aging.

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

INTRODUCTION: Prenatal 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 METHODS: We 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. RESULTS: A 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. CONCLUSION: Prenatal 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.

Current Diagnostic Approaches in the Genetic Diagnosis of Disorders of Sex Development.

Disorders of sex development (DSD) are a clinically and genetically highly heterogeneous group of congenital disorders. The most accurate and rapid diagnosis may be possible with a complementary multidisciplinary diagnostic approach, including comprehensive clinical, hormonal, and genetic investigations. Rapid and accurate diagnosis of DSD requires urgency in terms of gender selection and management of the case. Despite the genetic tests performed in current daily practice, the genetic cause is still not elucidated in a significant proportion of cases. Karyotype analysis can be used as a standard for sex chromosome identification. In addition, quantitative fluorescent polymerase chain reaction (QF-PCR) or fluorescence in situ hybridization (FISH) analysis can be used for faster and more cost-effective detection of the sex chromosome and SRY gene. Multiplex ligation-dependent probe amplification (MLPA), single-gene sequence analysis, next-generation sequence analysis (NGSA), targeted NGSA, whole-exome sequencing (WES), and whole-genome sequencing (WGS) analyses can be performed according to preliminary diagnoses. Microarray analysis (array comparative genomic hybridization (aCGH) and single nucleotide polymorphism array (SNPa)) should be performed in cases with syndromic findings and if no pathology is detected with other tests. In DSD cases, the use of optical genome mapping and techniques, which will probably be in daily practice in near future, may be considered. In conclusion, the clinical and genetic diagnosis of DSD is difficult, and molecular genetic diagnosis is often not available. This has psychosocial and health implications for patients and their families. New genetic techniques, especially those targeting the whole genome, may provide a better understanding of DSD through the identification of little-known genetic causes. This review focuses on conventional genetic and next-generation genetic techniques used in the genetic diagnosis of DSD, as well as possible genetic diagnostic techniques and approaches that may be used in routine practice in near future.

Recommendations for 46,XX Congenital Adrenal Hyperplasia Across Two Decades: Insights from the North American Differences of Sex Development Clinician Survey.

Several aspects of clinical management of 46,XX congenital adrenal hyperplasia (CAH) remain unsettled and controversial. The North American Disorders/Differences of Sex Development (DSD) Clinician Survey investigated changes, over the last two decades, in clinical recommendations by specialists involved in the management of newborns with DSD. Members of the (Lawson Wilkins) Pediatric Endocrine Society and the Societies for Pediatric Urology participated in a web-based survey at three timepoints: 2003-2004 (T1, n = 432), 2010-2011 (T2, n = 441), and 2020 (T3, n = 272). Participants were presented with two clinical case scenarios-newborns with 46,XX CAH and either mild-to-moderate or severe genital masculinization-and asked for clinical recommendations. Across timepoints, most participants recommended rearing the newborn as a girl, that parents (in consultation with physicians) should make surgical decisions, performing early genitoplasty, and disclosing surgical history at younger ages. Several trends were identified: a small, but significant shift toward recommending a gender other than girl; recommending that adolescent patients serve as the genital surgery decision maker; performing genital surgery at later ages; and disclosing surgical details at younger ages. This is the first study assessing physician recommendations across two decades. Despite variability in the recommendations, most experts followed CAH clinical practice guidelines. The observation that some of the emerging trends do not align with expert opinion or empirical evidence should serve as both a cautionary note and a call for prospective studies examining patient outcomes associated with these changes.

Decoding the epigenetic mechanism of mammalian sex determination.

Sex determination embodies a dynamic and intricate developmental process wielding significant influence over the destiny of bipotential gonads, steering them towards male or female gonads. Gonadal differentiation and the postnatal manifestation of the gonadal phenotype involve a sophisticated interplay of transcription factors such as SOX9 and FOXL2. Central to this interplay are chromatin modifiers regulating the mutual antagonism during this interplay. In this review, the key findings and knowledge gaps in DNA methylation, histone modification, and non-coding RNA-mediated control throughout mammalian gonadal development are covered. Furthermore, it explores the role of the developing brain in playing a pivotal role in the initiation of gonadogenesis and the subsequent involvement of gonadal hormone/hormone receptor in fine-tuning sexual differentiation. Based on promising facts, the role of the developing brain through the hypothalamic pituitary gonadal axis is explained and suggested as a novel hypothesis. The article also discusses the potential impact of ecological factors on the human epigenome in relation to sex determination and trans-generational epigenetics in uncovering novel genes and mechanisms involved in sex determination and gonadal differentiation. We have subtly emphasized the disruptions in epigenetic regulations contributing to sexual disorders, which further allows us to raise certain questions, decipher approaches for handling these questions and setting up the direction of future research.

Arguments for a ban on pediatric intersex surgery: A dis/analogy with Jehovah witness blood transfusion.

This article argues for a ban on the performance of medically unnecessary genital normalizing surgeries as part of assigning a binary sex/gender to infants with intersex conditions on the basis of autonomy, regardless of etiology. It does this via a dis/analogy with the classic case in bioethics of Jehovah Witness (JW) parents' inability to refuse life-saving blood transfusions for their minor children. Both cases address ethical medical practice in situations where parents are making irreversible medical decisions on the basis of values strongly held, identity, and relationship-shaping values-such as religious beliefs or beliefs regarding the inherent value of binary sex/gender-amidst ethical pluralism. Furthermore, it takes seriously-as we must in the intersex case-that the restriction of parents' right to choose will likely result in serious harms to potentially large percentage of patients, their families, and their larger communities. I address the objection that parents' capacity to choose is restricted in the JW case on the basis of the harm principle or a duty to nonmaleficence, given that the result of parent choice would be death. I provide evidence that this is mistaken from how we treat epistemic uncertainty in the JW case and from cases in which clinicians are ethically obligated to restrict the autonomy of nonminor patients. I conclude that we restrict the parents' right to choose in the JW case-and should in the case of pediatric intersex surgery-to secure patient's future autonomy.

Adult outcomes of urinary, sexual functions and fertility after pediatric management of differences in sex development: Who should be followed and how?

The management of Differences of Sex Development (DSD) has evolved considerably in recent years. The questioning of systematic early childhood treatment of DSD requires a better understanding of the outcomes of such treatments and long-term studies are therefore essential to better evaluate the prognosis of DSD. Unfortunately, limitations are numerous including the limited size of the series, the absence of standardized methodology, the evaluation of managements that no longer take place today and the absence of prospective and comparative studies. Despite these difficulties, the purpose of this paper is to present the current data on the long-term follow-up of patients with DSD from the urological, sexual and fertility points of view. Even if it remains difficult at present to establish precise recommendations, we recapitulate the most important points that should drive follow-up of these patients especially the constitution of a multidisciplinary team with a holistic approach, the organization of the transition between adolescence and adulthood, a particular attention to psychological care, a careful communication with the patients and his/her family and the use of standardized data collection systems.

Genotype-Phenotype Correlation Analysis of WT1 Gene Variants in Denys-Drash Syndrome and Frasier Syndrome / 罕见病研究

ObjectiveThis study aims to explore the association between different genotypes of WT1 gene variations and the phenotypes of Denys-Drash syndrome (DDS) and Frasier syndrome (FS).MethodsThrough searching and summarizing the case information of WT1 gene variations recorded in NCBI PubMed and CNKI databases from January 1, 1991 to October 31, 2023, we analyzed the association between variation types, occurrence locations, and phenotypes such as progressive renal function impairment, genitourinary developmental abnormalities, nephroblastoma, and gonadal tumors between DDS and FS.ResultsA total of 128 articles, including 304 subjects, were included in this study, and 86 pathogenic variations of the WT1 gene were detected.The distribution characteristics of these variations were as follows: the most common occurrence was in exon 9(24/86, 27.9%) and exon 8 (23/86, 26.7%); the most common variation type was missense mutation(51/86, 59.3%), followed by splice site mutation (13/86, 15.1%).The disease types caused by WT1 gene variations were as follows: DDS had the highest number of cases (174/304, 57.2%), followed by FS (83/304, 27.3%); DDS was mainly caused by missense mutations on exon 9 and exon 8 (143/174, 82.2%), while FS was mainly caused by splice site mutations on intron 9 (76/83, 91.6%).ConclusionsThe missense variants in exon 9 and exon 8 on the WT1 gene mainly resulted in DDS, while the splice variants in intron 9 mainly resulted in FS. Infants and children with progressive renal injury should undergo a comprehensive evaluation of the genitourinary system, and early genetic diagnosis should be established to improve prognosis.

Surgical Decision-Making for Individuals with Differences of Sex Development: Stakeholders' views.

Introduction: Advocacy and human rights organizations have called for a moratorium on elective surgical procedures until the patient is able to fully participate in the decision-making process. Due to the controversial nature surrounding surgery in differences of sex development (DSD) care, we aimed to assess the factors that teens and adults with DSD, parents, healthcare providers and other allied professionals consider pertinent to complex surgical decisions in DSD. Methods: Stakeholders (n=110) in DSD care participated in semi-structured interviews exploring features and potential determinants of successful healthcare outcomes. Audio-recordings were transcribed, coded, and analyzed using qualitative data software. Codes for "Process of Decision-Making" and "Successful Outcome-Surgery/Appearance/Function" were further searched using keywords "surgery," "procedure," and "timing." Results: Several themes were identified: 1) The nature or type of the decision being made; 2) Who should be involved in the decision-making process; 3) Timing of conversations about surgery; 4) Barriers to decision-making surrounding surgery; 5) The elements of surgical decision-making; and 6) The optimal approach to surgical decision-making. Many stakeholders believed children and adolescents with DSD should be involved in the process as developmentally appropriate. Conclusion: DSD include a wide range of diagnoses, some of which may require urogenital reconstruction to relieve obstruction, achieve continence, and/or address other anatomical differences whether cosmetic or functional. Adolescents and adults with DSD desired autonomy and to be part of the decision-making process. Parents were divided in their opinion of who should be involved in making elective surgical decisions: the child or parents as proxy medical decision-makers. Providers and other professionals stressed the importance of process and education around surgical decisions. Ongoing research examines how decision-makers evaluate tradeoffs associated with decision options.

Decisional Support Needed when Facing Tough Decisions: Survey of Parents with Children having Differences of Sex Development.

Introduction: Parents of infants and young children newly diagnosed with differences of sex development (DSD) commonly face medical and psychosocial management decisions at a time when they are first learning about the condition and cannot consult their child for input. The aim of this study was to identify areas of greatest need for parental decisional support. Methods: 34 parents of children receiving care for DSD at one of three US children's hospitals participated in a survey to learn what clinical and psychosocial decisions needed to be made on behalf of their child. Parents were then asked to identify and focus on a "tough" decision and respond to questions assessing factors affecting decision-making, decision-making preferences, decisional conflict, and decision regret. Descriptive analyses were conducted. Results: Decisions about surgery and aspects of sharing information about their child's condition with others were the two most frequently reported decisions overall, experienced by 97% and 88% of parents, as well as most frequently nominated as tough decisions. Many parents reported mild to moderate levels of decisional conflict (59%) and decision regret (74%). Almost all parents (94%) reported experiencing at least one factor as interfering with decision-making (e.g., "worried too much about choosing the 'wrong' option"). Parents universally reported a desire to be involved in decision-making - preferably making the final decision primarily on their own (79%), or together with their child's healthcare providers (21%). The majority of parents judged healthcare providers (82%) and patient/family organizations (58%) as trustworthy sources of information. Discussion: Parents of children with DSD encounter medical, surgical, and psychosocial management decisions. Despite difficulties including emotional distress and informational concerns (including gaps and overload), parents express strong desires to play key roles in decision-making on behalf of their children. Healthcare providers can help identify family-specific needs through observation and inquiry in the clinical context. Together with families, providers should focus on specific clinical management decisions and support parental involvement in making decisions on behalf of young children with DSD.