Current Advances in the Management of Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic condition caused by various enzyme deficiencies that result in disruptions of pathways of adrenal steroidogenesis. 21-hydroxylase deficiency is the most common form of CAH and has a variable phenotype which ranges a spectrum, from the most severe salt-wasting type to the simple-virilizing type and the least severe nonclassical form. Patients with CAH are at risk for various comorbidities due to the underlying adrenal hormone production imbalance as well as the treatment of the condition, which typically includes supraphysiologic glucocorticoid dosing. Children and adults require frequent monitoring and careful medication dosing adjustment. However, there are multiple novel therapies on the horizon that offer promise to patients with CAH in optimizing their treatment regimens and reducing the risk of comorbidities.

Diagnosis and management of non-CAH 46,XX disorders/differences in sex development.

Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11ß-hydroxylase, 3ß-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1, resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1. Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.

Prenatal diagnosis and in utero treatment of congenital adrenal hyperplasia: An up-to-date comprehensive review.

Congenital adrenal hyperplasia (CAH) is a term that encompasses a wide range of conditions that affect the adrenals. Diagnosis and treatment before birth are important as irreparable birth defects can be avoided, decreasing the need for surgical intervention later in life, especially regarding genitalia anomalies. Although early implementation of dexamethasone in the prenatal treatment of CAH has been controversial, there is recent evidence that this treatment can reduce long-term complications.

Congenital Adrenal Hyperplasia.

We describe congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, which is the most common primary adrenal insufficiency in children and adolescents. In this comprehensive review of CAH, we describe presentations at different life stages depending on disease severity. CAH is characterized by androgen excess secondary to impaired steroidogenesis in the adrenal glands. Diagnosis of CAH is most common during infancy with elevated 17-hydroxyprogesterone levels on the newborn screen in the United States. However, CAH can also present in childhood, with late-onset symptoms such as premature adrenarche, growth acceleration, hirsutism, and irregular menses. The growing child with CAH is treated with hydrocortisone for glucocorticoid replacement, along with increased stress doses for acute illness, trauma, and procedures. Mineralocorticoid and salt replacement may also be necessary. Although 21-hydroxylase deficiency is the most common type of CAH, there are other rare types, such as 11ß-hydroxylase and 3ß-hydroxysteroid dehydrogenase deficiency. In addition, classic CAH is associated with long-term comorbidities, including cardiometabolic risk factors, impaired cognitive function, adrenal rest tumors, and bone health effects. Overall, early identification and treatment of CAH is important for the pediatric patient.

Transition from Paediatric to Adult Care in CAH: 20 Years of Experience at a Tertiary Referral Center.

Transition medicine aims at the coordinated transfer of young patients with a chronic disease from paediatric to adult care. The present study reflects 20 years of experience in transitioning patients with congenital adrenal hyperplasia (CAH) in a single center setting. Our endocrine transition-clinic was established in 2002 and offers joint paediatric and adult consultations. Data were evaluated retrospectively from 2002 to 2005 and 2008 to present. Fifty-nine patients (29 males) were transferred. Median age was 18.4 years (17.6-23.6). Ninety percent of the patients presented with 21-hydroxlase-deficiency (21-OHD), 38 patients (23 m) with salt-wasting (sw), 7 (1 m) with simple-virilising (sv) and 8 (3 m) with the non-classic (nc) form. Rarer enzyme deficiencies were found in 6 cases: 17α-OHD (2 sisters), P450-oxidoreductase-deficiency (2 siblings), 3ß-hydroxysteroid-dehydrogenase-deficiency (1 m) and 11ß-OHD (1 female). Thirty-four patients (57.6%, 20 m) are presently still attending the adult clinic, 1 patient (1.7%, m) moved away and 24 (40.7%, 8 m) were lost to follow-up (13 sw-21-OHD, 6 sv-21-OHD, 5 nc-21-OHD). Thirty-seven patients (62.7%) attended the adult clinic for >2 years after transfer, 17 (28.8%) for >10 years. In the lost to follow-up group, median time of attendance was 16.3 months (0-195.2). Defining a successful transfer as two or more visits in the adult department after initial consultation in the transition clinic, transfer was efficient in 84.7% of the cases. A seamless transfer to adult care is essential for adolescents with CAH. It requires a continuous joint support during the transition period, remains challenging, and necessitates adequate funding.

Testicular adrenal rest tumors - Epidemiology, diagnosis and treatment.

INTRODUCTION: Testicular adrenal rest tumors (TART) are common in males suffering from congenital adrenal hyperplasia (CAH). Correct and timely diagnosis is important for differential diagnosis with malignant testis tumors, related infertility and as TART may worsen in time, especially in the absence of adequate and continuous hormonal control. The rarity of the disease, predominance of small cohorts and case reports and research heterogeneity (concerning type of CAH, patients' age and specific focus of the paper) complicate the understanding of this condition. OBJECTIVES: To review epidemiological and clinical aspects of TART, including treatment and prognosis. METHODS: Non-systematic review of CAH-related TART research. RESULTS: TART's prevalence grows progressively over time, predominating after puberty, affecting a mean of 20-40 % of CAH males. There is no proof of more frequent proportional affection of specific CAH phenotypes or types of enzyme deficiency, but cases of TART among non-classic CAH patients have been rarely reported. Chronic undertreated are more frequently affected and present larger tumors. Systematic ultrasound screening of CAH males is the state-of-the art for diagnosis, but TART are still often diagnosed in CAH adults seeking infertility treatment. TART are usually asymptomatic and present normal testicular volume. Biopsies are not recommended, except when the differential diagnosis between TART and testicular tumors cannot be guaranteed. Abnormal semen analysis is common. Leydig cell tumors are the main differential diagnosis, due to histological similarities to TART. Misdiagnosis may lead to unnecessary orchiectomies. Preservation of gonadal functions is inversely proportional to the total tumor volume. Tumors tend to regress under adequate adrenal suppression with steroids. Surgery in not indicated to treat TART. DISCUSSION: The reported prevalence of TART depends on age, usage of systematic follow-up ultrasound, and adequate CAH control. Timely detection of the disease is important to avoid irreversible gonadal dysfunction (not clinically apparent, due to high serum levels of androgen) and infertility. The relationship between TART and specific CAH phenotypes/genotypes has not been proved, and some cases do not present abnormal serum ACTH levels. Knowledge about TART should be disseminated among non-experts, to avoid unnecessary orchiectomies and false diagnosis of malignant testis tumors. Infertility is frequent, but has not been not satisfactorily addressed by physicians, even among experts. Sperm cryopreservation should be early offered to CAH adult males, but there are offer problems related to high cost.

Therapeutic management of congenital forms of endocrine hypertension.

Congenital forms of endocrine hypertension are rare and potentially life-threatening disorders, primarily caused by genetic defects affecting adrenal steroid synthesis and activation pathways. These conditions exhibit diverse clinical manifestations, which can be distinguished by their unique molecular mechanisms and steroid profiles. Timely diagnosis and customized management approach are crucial to mitigate unfavorable outcomes associated with uncontrolled hypertension and other related conditions. Treatment options for these disorders depend on the distinct underlying pathophysiology, which involves specific pharmacological therapies or surgical adrenalectomy in some instances. This review article summarizes the current state of knowledge on the therapeutic management of congenital forms of endocrine hypertension, focusing on familial hyperaldosteronism (FH), congenital adrenal hyperplasia, apparent mineralocorticoid excess, and Liddle syndrome. We provide an overview of the genetic and molecular pathogenesis underlying each disorder, describe the clinical features, and discuss the various therapeutic approaches available and their risk of adverse effects, aiming to improve outcomes in patients with these rare and complex conditions.

Diagnostic challenges and management advances in cytochrome P450 oxidoreductase deficiency, a rare form of congenital adrenal hyperplasia, with 46, XX karyotype.

Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and menstrual disorders caused by cytochrome P450 oxidoreductase (POR) mutations affecting electron transfer to all microsomal cytochrome P450 and some non-P450 enzymes involved in cholesterol, sterol, and drug metabolism. With the advancement of molecular biology and medical genetics, increasing numbers of PORD cases were reported, and the clinical spectrum of PORD was extended with studies on underlying mechanisms of phenotype-genotype correlations and optimum treatment. However, diagnostic challenges and management dilemma still exists because of unawareness of the condition, the overlapping manifestations with other disorders, and no clear guidelines for treatment. Delayed diagnosis and management may result in improper sex assignment, loss of reproductive capacity because of surgical removal of ruptured ovarian macro-cysts, and life-threatening conditions such as airway obstruction and adrenal crisis. The clinical outcomes and prognosis, which are influenced by specific POR mutations, the presence of additional genetic or environmental factors, and management, include early death due to developmental malformations or adrenal crisis, bilateral oophorectomies after spontaneous rupture of ovarian macro-cysts, genital ambiguity, abnormal pubertal development, and nearly normal phenotype with successful pregnancy outcomes by assisted reproduction. Thus, timely diagnosis including prenatal diagnosis with invasive and non-invasive techniques and appropriate management is essential to improve patients' outcomes. However, even in cases with conclusive diagnosis, comprehensive assessment is needed to avoid severe complications, such as chromosomal test to help sex assignment and evaluation of adrenal function to detect partial adrenal insufficiency. In recent years, it has been noted that proper hormone replacement therapy can lead to decrease or resolve of ovarian macro-cysts, and healthy babies can be delivered by in vitro fertilization and frozen embryo transfer following adequate control of multiple hormonal imbalances. Treatment may be complicated with adverse effects on drug metabolism caused by POR mutations. Unique challenges occur in female PORD patients such as ovarian macro-cysts prone to spontaneous rupture, masculinized genitalia without progression after birth, more frequently affected pubertal development, and impaired fertility. Thus, this review focuses only on 46, XX PORD patients to summarize the potential molecular pathogenesis, differential diagnosis of classic and non-classic PORD, and tailoring therapy to maintain health, avoid severe complications, and promote fertility.

Models of Congenital Adrenal Hyperplasia for Gene Therapies Testing.

The adrenal glands are important endocrine organs that play a major role in the stress response. Some adrenal glands abnormalities are treated with hormone replacement therapy, which does not address physiological requirements. Modern technologies make it possible to develop gene therapy drugs that can completely cure diseases caused by mutations in specific genes. Congenital adrenal hyperplasia (CAH) is an example of such a potentially treatable monogenic disease. CAH is an autosomal recessive inherited disease with an overall incidence of 1:9500-1:20,000 newborns. To date, there are several promising drugs for CAH gene therapy. At the same time, it remains unclear how new approaches can be tested, as there are no models for this disease. The present review focuses on modern models for inherited adrenal gland insufficiency and their detailed characterization. In addition, the advantages and disadvantages of various pathological models are discussed, and ways of further development are suggested.

Congenital adrenal hyperplasia: New biomarkers and adult treatments.

Congenital adrenal hyperplasia (CAH) is a genetic disease caused by an enzyme deficiency interrupting adrenal steroidogenesis. It most frequently involves 21-hydroxylase, which induces adrenal insufficiency with hyperandrogenism. Restoring hormonal balance is difficult with glucocorticoids, which are the gold-standard treatment. Strict normalization of conventional biomarkers (17-hydroxyprogesterone and delta-4 androstenedione) is often obtained at the cost of iatrogenic hypercortisolism. Optimizing the management of these patients first involves using more specific biomarkers of adrenal steroidogenesis in difficult situations, and secondly using therapeutics targeting the induced hypothalamic-pituitary-adrenal axis disorder. 11-oxygenated androgens are candidates for biochemical monitoring of Congenital adrenal hyperplasia (CAH), in particular 11-ketotestosterone. Numerous new therapeutic agents are currently being explored, the prime goal being to reduce glucocorticoid exposure, as no strategy can fully replace it at present. They can be divided into 3 categories. The first includes "more physiological" hydrocortisone administration (modified-release hydrocortisone and continuous subcutaneous infusion of hydrocortisone hemisuccinate); the second includes corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) receptor antagonists and anti-ACTH antibodies; and the third includes steroidogenesis inhibitors. Finally, experiments on gene and cell therapies suggest the possibility of lasting remission or even cure in the future.

The management of congenital adrenal hyperplasia during preconception, pregnancy, and postpartum.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of steroidogenesis of the adrenal cortex, most commonly due to 21-hydroxylase deficiency caused by mutations in the CYP21A2 gene. Although women with CAH have decreased fecundity, they are able to conceive; thus, if pregnancy is not desired, contraception options should be offered. If fertility is desired, women with classic CAH should first optimize glucocorticoid treatment, followed by ovulation induction medications and gonadotropins if needed. Due to the possible pregnancy complications and implications on the offspring, preconception genetic testing and counseling with a high-risk obstetrics specialist is recommended. For couples trying to avoid having a child with CAH, care with a reproductive endocrinology and infertility specialist to utilize in vitro fertilization can be offered, with or without preimplantation genetic testing for monogenic disorders. Prenatal screening and diagnosis options during pregnancy include maternal serum cell free-DNA for sex of the baby, and chorionic villus sampling and amniocentesis for diagnosis of CAH. Pregnant women with classic CAH need glucocorticoids to be adjusted during the pregnancy, at the time of delivery, and postpartum, and should be monitored for adrenal crisis. Maternal and fetal risks may include chorioamnionitis, maternal hypertension, gestational diabetes, cesarean section, and small for gestational age infants. This review on CAH due to 21-hydroxylase deficiency highlights reproductive health including genetic transmission, contraception options, glucocorticoid management, fertility treatments, as well as testing, antenatal monitoring, and management during pregnancy, delivery, and postpartum.

Getting pregnant with congenital adrenal hyperplasia: Assisted reproduction and pregnancy complications. A systematic review and meta-analysis.

Many patients with congenital adrenal hyperplasia (CAH) refrain from seeking pregnancy, suffer from infertility or worry about pregnancy complications, mainly due to genitalia abnormalities, anovulation, unreceptive endometrium and metabolic disturbances. Despite those challenges, many live births have been reported. In this systematic review, we focused on the key to successful assisted reproduction strategies and the potential pregnancy complications. We did a systematic literature search of Pubmed, Medline and Scopus for articles reporting successful pregnancies in CAH other than 21-hydroxylase deficiency, and found 25 studies reporting 39 pregnancies covering deficiency in steroidogenic acute regulatory protein, 17α-hydroxylase/17,20-lyase, 11ß-hydroxylase, P450 oxidoreductase, cytochrome b5 and 3ß-hydroxysteroid dehydrogenase. We summarized various clinical manifestations and tailored reproduction strategy for each subtype. Furthermore, a meta-analysis was performed to evaluate the pregnancy complications of CAH patients. A total of 19 cross-sectional or cohort studies involving 1311 pregnancies of classic and non-classic CAH patients were included. Surprisingly, as high as 5.5% (95% CI 2.3%-9.7%) of pregnancies were electively aborted, and the risk was significantly higher in those studies with a larger proportion of classic CAH than those with only non-classical patients (8.43% (4.1%-13.81%) VS 3.75%(1.2%-7.49%)), which called for better family planning. Pooled incidence of miscarriage was 18.2% (13.4%-23.4%) with a relative risk (RR) of 1.86 (1.27-2.72) compared to control. Glucocorticoid treatment in non-classical CAH patients significantly lowered the miscarriage rate when compared to the untreated group (RR 0.25 (0.13-0.47)). CAH patients were also more susceptible to gestational diabetes mellitus, with a prevalence of 7.3% (2.4%-14.1%) and a RR 2.57 (1.29-5.12). However, risks of preeclampsia, preterm birth and small for gestational age were not significantly different. 67.8% (50.8%-86.9%) CAH patients underwent Cesarean delivery, 3.86 (1.66-8.97) times the risk of the control group. These results showed that fertility is possible for CAH patients but special care was necessary when planning, seeking and during pregnancy. Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=342642, CRD42022342642.

Cohort profile: pathways to care among people with disorders of sex development (DSD).

PURPOSE: The 'DSD Pathways' study was initiated to assess health status and patterns of care among people enrolled in large integrated healthcare systems and diagnosed with conditions comprising the broad category of disorders (differences) of sex development (DSD). The objectives of this communication are to describe methods of cohort ascertainment for two specific DSD conditions-classic congenital adrenal hyperplasia with 46,XX karyotype (46,XX CAH) and complete androgen insensitivity syndrome (CAIS). PARTICIPANTS: Using electronic health records we developed an algorithm that combined diagnostic codes, clinical notes, laboratory data and pharmacy records to assign each cohort candidate a 'strength-of-evidence' score supporting the diagnosis of interest. A sample of cohort candidates underwent a review of the full medical record to determine the score cutoffs for final cohort validation. FINDINGS TO DATE: Among 5404 classic 46,XX CAH cohort candidates the strength-of-evidence scores ranged between 0 and 10. Based on sample validation, the eligibility cut-off for full review was set at the strength-of-evidence score of ≥7 among children under the age of 8 years and ≥8 among older cohort candidates. The final validation of all cohort candidates who met the cut-off criteria identified 115 persons with classic 46,XX CAH. The strength-of-evidence scores among 648 CAIS cohort candidates ranged from 2 to 10. There were no confirmed CAIS cases among cohort candidates with scores <6. The in-depth medical record review for candidates with scores ≥6 identified 61 confirmed cases of CAIS. FUTURE PLANS: As the first cohort of this type, the DSD Pathways study is well-positioned to fill existing knowledge gaps related to management and outcomes in this heterogeneous population. Analyses will examine diagnostic and referral patterns, adherence to care recommendations and physical and mental health morbidities examined through comparisons of DSD and reference populations and analyses of health status across DSD categories.

Integration of child life services in the delivery of multi-disciplinary differences in Sexual Development (DSD) and Congenital Adrenal Hyperplasia (CAH) care.

INTRODUCTION: Multiple studies have demonstrated the benefit of incorporating certified child life specialist (CCLS) services in various aspects of pediatric care. Although the significance of psychosocial support of patients with Disorders of Sexual Development (DSD) and Congenital Adrenal Hyperplasia (CAH) is increasingly recognized, the involvement of CCLS services into the DSD and CAH multidisciplinary care model has yet to be described. OBJECTIVE: To evaluate the feasibility, acceptability, and patient and family experience of routinely incorporating CCLS services into the multidisciplinary DSD and CAH care model. STUDY DESIGN: As part of a quality improvement initiative, CCLS services were routinely incorporated in the multidisciplinary DSD and CAH clinics at our institution. Encounters for patients seen in clinic between July 2018 through October 2019 were reviewed for demographic information, DSD diagnosis classification, CCLS documentation, and whether an exam under anesthesia (EUA) was required due to an incomplete clinical exam. CCLS documentation was reviewed for assessments, interventions, whether patients tolerated their physical exams, time of CCLS services, and additional CCLS support beyond the physical exam. All patients were limited to one physical exam per clinic visit. RESULTS: Out of the 45 encounters with CCLS involvement, 42 (93.3%) exams were well-tolerated. CCLS assessments considered patient development, communication considerations, temperament, medical stressors, coping preferences, and patient preferences for activities and distractions. Interventions included preparing patients for their physical exams, encouragement before and during exams, addressing patient stressors, distractions and coping mechanisms, and advocating for the patient. No patients required an EUA. DISCUSSION: The CCLS aimed to provide families with a sense of control during clinic visits and teach them to advocate for themselves. The CCLS helped prepare and distract patients for their clinic visit and addressed the sensitive nature of the physical exam by focusing on the emotional and development needs of patients. CCLS contributions to a positive patient experience are consistent with multiple studies demonstrating the benefit of CCLS services for pediatric care. This quality improvement initiative ultimately helped to create a positive experience for patients and families. CONCLUSION: This study demonstrates the feasibility, acceptability, and positive impact of CCLS services in the delivery of patient and family-centered care for patients with DSD and CAH as part of the multidisciplinary team model.

Adeno-Associated Virus-Mediated Gene Therapy for Patients' Fibroblasts, Induced Pluripotent Stem Cells, and a Mouse Model of Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by steroidogenic enzymes containing monogenetic defects. Most steroidogenic enzymes are cytochrome P450 groups that can be categorized as microsomal P450s, including 21-hydroxylase and 17α-hydroxylase/17,20 lyase, and mitochondrial P450s, including 11ß-hydroxylase. It has been shown that ectopic administration of Cyp21a1 ameliorates steroid metabolism in 21-hydroxylase-deficient mice. However, the effectiveness of this approach for mitochondrial P450 has not yet been evaluated. In this study, primary fibroblasts from patients with 21-hydroxylase deficiency (CYP21A2D) (n = 4), 17α-hydroxylase/17,20 lyase deficiency (CYP17A1D) (n = 1), and 11ß-hydroxylase deficiency (CYP11B1D) (n = 1) were infected with adeno-associated virus type 2 (AAV2) vectors. Steroidogenic enzymatic activity was not detected in the AAV2-infected CYP11B1D fibroblasts. Induced pluripotent stem cells (iPSCs) of CYP11B1D were established and differentiated into adrenocortical cells by induction of the NR5A1 gene. Adrenocortical cells established from iPSCs of CYP11B1D (CYP11B1D-iPSCs) were infected with an AAV type 9 (AAV9) vector containing CYP11B1 and exhibited 11ß-hydroxylase activity. For an in vivo evaluation, we knocked out Cyp11b1 in mice by using the CRISPR/Cas9 method. Direct injection of Cyp11b1-containing AAV9 vectors into the adrenal gland of Cyp11b1-deficient mice significantly reduced serum 11-deoxycorticosterone/corticosterone ratios at 4 weeks after injection and the effect was prolonged for up to 12 months. This study indicated that CYP11B1D could be ameliorated by gene induction in the adrenal glands, which suggests that a defective-enzyme-dependent therapeutic strategy for CAH would be required. Defects in microsomal P450, including CYP21A2D and CYP17A1D, can be treated with extra-adrenal gene induction. However, defects in mitochondrial P450, as represented by CYP11B1D, may require adrenal gene induction.

Parents of Children With Newly Diagnosed Disorders of Sex Development Identify Major Concerns: A Qualitative Study.

OBJECTIVES: To develop a conceptual framework to understand and define the impact of DSD diagnosis and management from the perspective of parents of recently diagnosed children. METHODS: Semi-structured interviews were conducted with parents of children diagnosed with 46 XX, 46 XY, or chromosomal DSD including complete or partial androgen insensitivity, congenital adrenal hyperplasia, or 5-alpha reductase deficiency. Analysis was completed using content analysis with an inductive approach by three coders. RESULTS: Parents of 6 patients agreed to be interviewed, consistent with saturation points for prior similar studies; a total of 16 recurring themes were identified which were further grouped by similarity and categorized into 1 of 3 meta-themes: a) personal impact (effect of diagnosis on parents psyche, happiness, gender/sexual identity, anatomic function, mental health), b) family impact (relationships with parents/siblings, parental guilt); and c) societal impact (bullying, need for secrecy, future desirability, societal openness to DSD individuals). CONCLUSIONS: Personal, family, and societal concerns amongst parents following a DSD diagnosis have significant potential psychosocial impacts for both parents as well children. The nexus between these categories provides a framework for approaching diagnosis and management of DSD and has implications for patients, families, and clinicians. Improved resource allocation, education, and clinical tools conceived through this framework may considerably alleviate potent psychosocial stressors for parents of children born with DSD.

Current status of transition medicine for 21-hydroxylase deficiency in Japan: from the perspective of pediatric endocrinologists.

To manage of 21-hydroxylase deficiency (21-OHD), transition medicine from pediatric to adult health care is an important process and requires individually optimized approaches. We sent cross-sectional questionnaire surveys on the current status of transition from pediatric to adult health care in 21-OHD patients to all councillors of the Japanese Society for Pediatric Endocrinology. Many pediatric departments (42.2%) experienced adult 21-OHD patients, and 115 patients (53 males, mean age of 26) in 46 institutions were identified. Whereas almost two-thirds of pediatric endocrinologists regarded the problems of counterparts and cooperation as hindrance of transition medicine, the major reason for continuing to be treated in pediatrics was the patient's own request. The prevalence of long-term complications including obesity, osteoporosis, infertility, menstrual disorder, gender dysphoria, and testicular adrenal rest tumor were 27.5%, 8.8%, 11.1%, 26.3%, 7.1%, 12.5%, respectively, which is comparable to those of other cohorts previously reported. However, several items, especially infertility and osteoporosis were not checked well enough in adult 21-OHD patients treated in pediatrics. Though 44 of 62 female patients had genital reconstructive surgery, more than half of them were not followed up by gynecologists or pediatric urologists. Quite a few adult 21-OHD patients had been followed up in pediatrics even after coming of age; however, surveillance by pediatric endocrinologists of gynecological, reproductive, and mental problems may be insufficient. Therefore, multidisciplinary approaches should be required in transition medicine for 21-OHD and prerequisite for graduation of pediatrics. Pediatric endocrinologists will need to play a leading role in the development of transition systems.