Purpose: 46,XX disorders of sex development (DSD) involve atypical genitalia accompanied by a normal female karyotype. This study was performed to investigate the clinical characteristics and long-term outcomes of patients with 46,XX DSD. Methods: The study included 34 patients with 46,XX DSD who presented with ambiguous genitalia or delayed puberty. Patients with congenital adrenal hyperplasia were excluded. Clinical phenotypes and overall outcomes were analyzed retrospectively. Results: Age at presentation ranged from birth to 40 years (median, 0.6 years), and the follow-up period ranged from 0.3 to 29.7 years (median, 8.8 years). Twenty patients were assigned female (58.8%). Etiologies included disorders of gonadal development (n=22), exogenous androgen exposure during pregnancy (n=5), association with syndromic disorders or genital anomalies (n=2), and unclassified causes (n=5). Ovotestis was the most frequent gonadal pathology (41.7%). Müllerian duct remnants were usually underdeveloped (52.9%) or absent (23.5%). Spontaneous puberty occurred in 17 of the 21 patients of pubertal age, while 9 patients required sex hormone replacement therapy. Gonadal complications were observed in 4 patients (gonadal tumors [n=3], and spontaneous gonadal rupture [n=1]), and gender dysphoria occurred in 1 patient who was assigned male. Conclusion This study described the wide phenotypic spectrum and pubertal outcome of patients with 46,XX DSD. Long-term multidisciplinary monitoring for pubertal development, fertility, gender identity, and gonadal complications is recommended.

Purpose: 46,XX disorders of sex development (DSD) involve atypical genitalia accompanied by a normal female karyotype. This study was performed to investigate the clinical characteristics and long-term outcomes of patients with 46,XX DSD. Methods: The study included 34 patients with 46,XX DSD who presented with ambiguous genitalia or delayed puberty. Patients with congenital adrenal hyperplasia were excluded. Clinical phenotypes and overall outcomes were analyzed retrospectively. Results: Age at presentation ranged from birth to 40 years (median, 0.6 years), and the follow-up period ranged from 0.3 to 29.7 years (median, 8.8 years). Twenty patients were assigned female (58.8%). Etiologies included disorders of gonadal development (n=22), exogenous androgen exposure during pregnancy (n=5), association with syndromic disorders or genital anomalies (n=2), and unclassified causes (n=5). Ovotestis was the most frequent gonadal pathology (41.7%). Müllerian duct remnants were usually underdeveloped (52.9%) or absent (23.5%). Spontaneous puberty occurred in 17 of the 21 patients of pubertal age, while 9 patients required sex hormone replacement therapy. Gonadal complications were observed in 4 patients (gonadal tumors [n=3], and spontaneous gonadal rupture [n=1]), and gender dysphoria occurred in 1 patient who was assigned male. Conclusion This study described the wide phenotypic spectrum and pubertal outcome of patients with 46,XX DSD. Long-term multidisciplinary monitoring for pubertal development, fertility, gender identity, and gonadal complications is recommended.

Purpose: 46,XX disorders of sex development (DSD) involve atypical genitalia accompanied by a normal female karyotype. This study was performed to investigate the clinical characteristics and long-term outcomes of patients with 46,XX DSD. Methods: The study included 34 patients with 46,XX DSD who presented with ambiguous genitalia or delayed puberty. Patients with congenital adrenal hyperplasia were excluded. Clinical phenotypes and overall outcomes were analyzed retrospectively. Results: Age at presentation ranged from birth to 40 years (median, 0.6 years), and the follow-up period ranged from 0.3 to 29.7 years (median, 8.8 years). Twenty patients were assigned female (58.8%). Etiologies included disorders of gonadal development (n=22), exogenous androgen exposure during pregnancy (n=5), association with syndromic disorders or genital anomalies (n=2), and unclassified causes (n=5). Ovotestis was the most frequent gonadal pathology (41.7%). Müllerian duct remnants were usually underdeveloped (52.9%) or absent (23.5%). Spontaneous puberty occurred in 17 of the 21 patients of pubertal age, while 9 patients required sex hormone replacement therapy. Gonadal complications were observed in 4 patients (gonadal tumors [n=3], and spontaneous gonadal rupture [n=1]), and gender dysphoria occurred in 1 patient who was assigned male. Conclusion This study described the wide phenotypic spectrum and pubertal outcome of patients with 46,XX DSD. Long-term multidisciplinary monitoring for pubertal development, fertility, gender identity, and gonadal complications is recommended.

Background: Poor outcomes after acute ischemic stroke (AIS) revascularization are anticipated in patients with dementia due to advanced age, comorbidities, and reduced disease awareness. This study investigated clinical characteristics and short-term outcomes of AIS revascularization in patients undergoing dementia treatment. Methods: We retrospectively reviewed patients who underwent AIS revascularization therapy at eight centers of the Catholic University of Korea. Patients receiving anti-dementia medication for cognitive impairment before stroke onset were analyzed. Clinical characteristics and outcomes, including the modified Rankin Scale (mRS) score, hemorrhagic transformation, and mortality, were collected. Results: Among 1,379 patients who received AIS revascularization over 5 years, 13 (0.94%; mean age 83 years; 8 females) had a preexisting diagnosis of dementia (Alzheimer’s disease in 11, mild cognitive impairment in 2) and were on anti-dementia medication. Two patients underwent intravenous thrombolysis combined with endovascular therapy, whereas 11 underwent endovascular therapy alone. Most patients (11/13, 84.6%) presented with an unclear onset time. Stroke lesions were located in the right middle cerebral artery (MCA) in seven cases, left MCA in three, bilateral MCAs in one, and posterior circulation in two. Hemorrhagic transformation occurred in six patients (46%), of whom three (23%) were symptomatic. The mRS scores at discharge were 6 in two patients, 5 in one patient, 4 in nine patients, and 3 in one patient. Four patients died within 3 months of stroke onset. Conclusion The proportion of patients with cognitive impairment receiving anti-dementia medication among those undergoing stroke revascularization therapy was very small. The rates of hemorrhagic transformation and mortality were high. None of the patients achieved favorable outcomes at discharge.

Purpose: We aimed to identify the genetic causes of hypospadias in children using targeted gene panel sequencing for disorders of sex development (DSD). Materials and Methods: This study included 18 twin boys with hypospadias: seven and two pairs were monozygotic and dizygotic twins, respectively, and six were discordant and three were concordant twins. Targeted gene panel sequencing for 67 known DSD genes was performed. Sequence variants were classified into five different categories, pathogenic, likely pathogenic, variants of uncertain significance, likely benign, and benign, following the American College of Medical Genetics and Genomics Standards and Guidelines. Results: The mean gestational age and birth weight were 35.3±2.0 weeks and 1.96±0.61 kg, respectively, with seven patients being small for gestational age. Hypospadias was present in 12 patients, with posterior type in 33.3% and anterior type in 66.7%.In three families with twins, both siblings had hypospadias. In addition, cryptorchidism was observed in one subject. Surgical correction of hypospadias was performed at a mean age of 22.1 months. Molecular analysis identified 12 different genetic variants, including two pathogenic mutations in the AMH (p.E389*) and SRD5A2 (p.R246Q) genes, found in subjects with hypospadias, respectively. However, only heterozygous mutations were detected. Conclusions This study did not identify a definitive genetic component contributing to the development of hypospadias; however, the findings suggest that intrauterine growth retardation may play a significant role.

Purpose: As the survival rate from pediatric cancers has increased significantly with advances in treatment modalities, long-term endocrine complications have also risen. This study investigated the frequencies and risks of endocrine sequelae in childhood cancer survivors who received hematopoietic stem cell transplantation (HSCT). Methods: This study included 200 pediatric patients who underwent HSCT. Clinical and endocrinological findings were collected retrospectively. The median follow-up duration after HSCT was 14 years. Results: Endocrine complications occurred in 135 patients (67.5%). Children who underwent HSCT at pubertal age (n=100) were at higher risk of endocrine complications than those who received it at prepubertal age (79% vs. 56%, P=0.001). The most common complication was hypogonadism (40%), followed by dyslipidemia (22%). Short stature and diabetes mellitus were more prevalent in the prepubertal group, whereas hypogonadism and osteoporosis were more common in the pubertal group. Being female, pubertal age at HSCT, and glucocorticoid use were predictors of an increased risk for any complication. Radiation exposure increased the risk of short stature and hypothyroidism. Hypogonadism was significantly associated with being female, pubertal age at HSCT, and high-dose radiation. Pubertal age at HSCT also increased the risks of osteoporosis and dyslipidemia. Conclusion This study demonstrates that long-term endocrine complications are common after HSCT in children and adolescents. Age at HSCT is a critical factor for endocrine complications after HSCT. These findings suggest that surveillance strategies for endocrine complications in childhood cancer survivors should be specified according to age at HSCT.

Purpose: Deficiency of 21-hydroxylase (21-OHD) is an autosomal recessively inherited disorder that is characterized by adrenal insufficiency and androgen excess. This study was performed to investigate the clinical utility of prenatal diagnosis of 21-OHD using molecular genetic testing in families at risk. Methods: This study included 27 pregnant women who had previously borne a child with 21-OHD. Fetal tissues were obtained using chorionic villus sampling (CVS) or amniocentesis. After the genomic DNA was isolated, Sanger sequencing of CYP21A2 and multiplex ligation-dependent probe amplification were performed. The clinical and endocrinological findings were reviewed retrospectively. Results: A total of 39 prenatal genetic tests was performed on 27 pregnant women and their fetal tissues. The mean gestational age at the time of testing was 11.7 weeks for CVS and 17.5 weeks for amniocentesis. Eleven fetuses (28.2%) were diagnosed with 21-OHD. Among them, 10 fetuses (90.9%) harbored the same mutation as siblings who were previously diagnosed with 21-OHD. Among these, 4 fetuses (3 males and 1 female) identified as affected were born alive. All 4 patients have been treated with hydrocortisone, 9α-fludrocortisone, and sodium chloride since a mean of 3.7 days of life. The male patients did not show hyponatremia and dehydration, although they harbored pathogenic variants associated with the salt-wasting type of 21-OHD. Conclusion This study demonstrated the diagnostic efficacy and clinical consequences of diagnosis by prenatal genetic testing in families at risk for 21-OHD. All patients identified as affected were treated with hydrocortisone and 9α-fludrocortisone early after birth, which can prevent a life-threatening adrenal crisis.

Congenital adrenal hyperplasia (CAH) is a group of autosomally recessive disorders that result from impaired synthesis of glucocorticoid and mineralocorticoid. Most cases (~95%) are caused by mutations in the CYP21A2 gene, which encodes steroid 21-hydroxylase. CAH patients manifest a wide phenotypic spectrum according to their degree of residual enzyme activity. CYP21A2 and its pseudogene (CYP21A1P) are located 30 kb apart in the 6q21.3 region and share approximately 98% of their sequences in the coding region. Both genes are aligned in tandem with the C4, SKT19, and TNX genes, forming 2 segments of the RCCX modules that are arranged as STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB. The high sequence homology between the active gene and pseudogene leads to frequent microconversions and large rearrangements through intergenic recombination. The TNXB gene encodes an extracellular matrix glycoprotein, tenascin-X (TNX), and defects in TNXB cause Ehlers-Danlos syndrome. Deletions affecting both CYP21A2 and TNXB result in a contiguous gene deletion syndrome known as CAH-X syndrome. Because of the high homology between CYP21A2 and CYP21A1P, genetic testing for CAH should include an evaluation of copy number variations, as well as Sanger sequencing. Although it poses challenges for genetic testing, a large number of mutations and their associated phenotypes have been identified, which has helped to establish genotype-phenotype correlations. The genotype is helpful for guiding early treatment, predicting the clinical phenotype and prognosis, and providing genetic counseling. In particular, it can help ensure proper management of the potential complications of CAH-X syndrome, such as musculoskeletal and cardiac defects. This review focuses on the molecular pathophysiology and genetic diagnosis of 21-hydroxylase deficiency and highlights genetic testing strategies for CAH-X syndrome.

Purpose: 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. Methods: 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. Results: 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. Conclusion 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.

Purpose: Although previous research showed the importance of safety culture on health care workers' speaking up behaviors, it is not clear how particular safety culture domains are associated with the speaking up behaviors of hospital staff. Also, researchers have suggested that health care workers’ speaking up behaviors vary by profession, but there has been limited research into such differences. Thus, this study examined differences in perceptions of patient safety culture and the promotive and prohibitive speaking up behaviors of health care workers by profession and investigated the relationships between patient safety culture and the two types of speaking up behaviors. Methods: A descriptive correlational study was conducted using secondary data collected through an online survey of health care workers at a private, nonprofit, tertiary-level teaching hospital in South Korea. The sample (N = 831) consisted of nurses (54.0%), physicians (13.0%), and other licensed and unlicensed hospital personnel (33.0%). Analyses of variance were conducted to examine differences in study variables by profession. Hierarchical regression analyses were conducted to evaluate the effects of the seven patient safety culture factors on promotive and prohibitive voice after controlling for tenure and profession. Results: Perceptions of safety culture and promotive voice behaviors were higher for physicians compared with nurses. Communication openness, reporting patient adverse events, and unit supervisors' and hospital managements’ support for patient safety were significant predictors of both types of voice behaviors. Conclusion Hospital administrators and unit managers should create a supportive environment where staff feel free to voice their concerns and suggestions. They should also pay attention to the varying perspectives held by different groups of hospital workers and their different voice behaviors. Knowing which dimensions of patient safety culture are most strongly related to health care workers’ voice behaviors can guide patient safety improvement activities in health care organizations.