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IntroductionParents 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.Methods34 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.ResultsDecisions 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.DiscussionParents 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.

IntroductionParents and guardians of infants and young children with differences of sex development (DSD) often face numerous health and social decisions about their child’s condition. While proxy health decisions can be stressful in any circumstance, they are further exacerbated in this clinical context by significant variations in clinical presentation, parental lack of knowledge about DSD, irreversibility of some options (e.g., gonadectomy), a paucity of research available about long-term outcomes, and anticipated decisional regret. This study aimed to engage clinicians, parents, and an adult living with DSD to collaboratively co-design a suite of patient decision aids (PDAs) to respond to the decisional needs of parents and guardians of infants and young children diagnosed with DSD.MethodsWe used a systematic co-design process guided by the Ottawa Decision Support Framework and the International Patient Decision Aids Standards (IPDAS). The five steps were: literature selection, establish the team, decisional needs assessment, create the PDAs, and alpha testing.ResultsOur team of health professionals, parents, adult living with DSD and PDA experts, co-designed four PDAs to support parents/guardians of infants or young children diagnosed with DSD. These PDAs addressed four priority decisions identified through our decisional needs assessment: genetic testing, gender of rearing, genital surgery and gonadal surgery. All four PDAs include information for parents about DSD, the options, reasons to choose or avoid each option, and opportunities for parents/guardians to rate the importance of features of each option to clarify their values for these features. Qualitative feedback was positive from our team and when alpha tested with an interprofessional DSD speciality team in a single center.ConclusionsThese PDAs are clinical tools designed to support parents/guardians to be involved in making informed DSD decisions; next steps are to determine parents’ decisional outcomes. While these tools are specific to DSD, the process through which they were co-designed is transferable to co-design of PDAs in other pediatric populations.

Contains fulltext : 244176.pdf (Publisher’s version ) (Closed access) Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21- hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000 there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in congenital adrenal hyperplasia with special attention to these new developments.

Parents of infants born with differences in sex development (DSD) face many difficult decisions. As part of a larger project designed to develop educational interventions to promote shared decision making, this study assessed healthcare professionals' (HCPs) perceptions of parental decision-making needs when an infant is born with a DSD.A cross-sectional web-based survey following the Ottawa Decision Support Framework was conducted in two waves, between October 2020 and June 2022. Survey domains included: common DSD decisions, indicators of parents' decisional needs, and resources and approaches to support parental decision making. Eligible participants were HCPs working within interprofessional pediatric DSD centers in the USA. Up to three reminders were sent. Descriptive analysis was conducted.71 HCPs participated; most (90%) reported parents experience signs of decisional conflict including feeling unsure, worrying about what could go wrong, and fear of choosing a "wrong," irreversible option. The majority (90%) reported parents experience strong emotions interfering with their receptivity to information or deliberation. The majority (70%) identified inadequate parental knowledge of the DSD as a barrier to decision making, coupled with information overload (90%). HCPs rated several factors as "very" important, including: parents having information on benefits, harms, and other features of options (93%), having information about all the available options (87%), and having access to providers to discuss the options (84%). Providers endorsed using a variety of approaches to support parents' decision making; however, access to decision aids was not universally rated as highly important (very, 44%; somewhat, 46%; a little, 10%).Overall, HCPs expressed favorable attitudes toward supporting active parental participation in medical decision making. Opportunities for enhanced support of shared decision making included: a) recognizing and addressing parental emotional distress and informational overload at a time when parents need to consider complex options for their infant or young child; and b) the need for HCPs to encourage values clarification in decision-making encounters with parents.

Objective To determine the efficacy of a 4-month school-based health, nutrition and exercise intervention on body fatness and examine possible effects of demographic and anthropometric covariates. Methods Height, weight, waist circumference and body composition were measured in a diverse population of 644 NYC middle school students (mean ± SD age 12.7 ± 0.9 years; 46% male; 38% Hispanic, 17% East Asian, 15% South Asian, 13.5% African American, 8.5% Caucasian, 8% other) during the fall and spring semesters. Year 1 participants (n = 322) were controls. Experimental participants (year 2, n = 469) received a 12-session classroom-based health and nutrition educational programme with an optional exercise intervention. Results Groups were demographically and anthropometrically similar. The intervention resulted in significant reductions in indices of adiposity (ΔBMI z-scores [-0.035 ± 0.014; p = 0.01], Δ% body fat [-0.5 ± 0.2; p

Background Females with congenital adrenal hyperplasia (CAH) and atypical genitalia often undergo complex surgeries; however, their outcomes remain largely uncertain. Methods We searched several databases through 8 March 2016 for studies evaluating genital reconstructive surgery in females with CAH. Reviewers working independently and in duplicate selected and appraised the studies. Results We included 29 observational studies (1178 patients, mean age at surgery, 2.7 ± 4.7 years; mostly classic CAH). After an average follow-up of 10.3 years, most patients who had undergone surgery had a female gender identity (88.7%) and were heterosexual (76.2%). Females who underwent surgery reported a sexual function score of 25.13 using the Female Sexual Function Index (maximum score, 36). Many patients continued to complain of substantial impairment of sensitivity in the clitoris, vaginal penetration difficulties, and low intercourse frequency. Most patients were sexually active, although only 48% reported comfortable intercourse. Most patients (79.4%) and treating health care professionals (71.8%) were satisfied with the surgical outcomes. Vaginal stenosis was common (27%), and other surgical complications, such as fistulas, urinary incontinence, and urinary tract infections, were less common. Data on quality of life were sparse and inconclusive. Conclusion The long-term follow-up of females with CAH who had undergone urogenital reconstructive surgery shows variable sexual function. Most patients were sexually active and satisfied with the surgical outcomes; however, some patients still complained of impairment in sexual experience and satisfaction. The certainty in the available evidence is very low.

Cohen Children’s Medical Center of New York and Hofstra University School of Medicine (P.W.S.), New Hyde Park, New York 11040; Cedars-Sinai Medical Center (R.A.), Los Angeles, California 90048; University of California San Francisco (L.S.B., W.L.M.), San Francisco, California 94143; University of Turin (L.G.), 10129 Turin, Italy; Columbia University (T.W.H.), New York, New York 10032; National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.P.M.), Bethesda, Maryland 20892; New York State Psychiatric Institute/Columbia University (H.F.L.M.-B.) and Children’s Hospital of New York-Presbyterian and Columbia University College of Physicians & Surgeons (S.E.O.), New York, New York 10032; Mayo Clinic (V.M.M.), Rochester, Minnesota 55905; Karolinska Institute (M.R.), 17176 Stockholm, Sweden; and University of Texas Southwestern Medical Center (P.C.W.), Dallas, Texas 75390

Background: Thyroid hormone actions are mediated by nuclear receptors, thyroid receptor TRα and TRβ encoded by THRA and THRB. Resistance to thyroid hormone (RTH) is characterized by elevated thyroid hormone (TH) along with non-suppressed thyroid-stimulating hormone (TSH). Approximately 85 percent of cases are due to a defect in the THRβ gene (RTH-β). The clinical spectrum ranges from isolated biochemical abnormalities to hyperthyroidism or hypothyroidism. Case description: An adolescent female was initially evaluated by an outside endocrinologist at age 15 for hand tremors, tachycardia, and hypertension. She was diagnosed with hyperthyroidism and treated with methimazole in escalating doses without complete symptom remission. In reviewing her records, thyroid function tests had been abnormal since age 3.5 years with high total T4 (TT4) 20.3 ng/dl, high total T3 (TT3) 294 ng/dl, and normal TSH 3.6 µIU/mL. Iodine-123 uptake was 41% at 24 hours, slightly elevated. No treatment had been prescribed before age 15. Family history revealed that father & multiple paternal relatives had high levels of thyroid hormones but no apparent symptoms of hyperthyroidism. Mother, MGM and maternal aunt had hypothyroidism. The proband’s physical exam was notable for normal pulse and blood pressure and a prominent goiter. Thyroid function tests while taking up to 25 mg methimazole daily showed markedly elevated TT4 20.3 ng/dl, TT3 254 ng/dl, progressively rising TSH (3.6 up to 10 µIU/ml), normal TBG 22 µg/ml and negative titers to TSH receptors, TSI, and anti-thyroid peroxidase antibodies. Due to intermittent tachycardia to 200 bpm, atenolol was increased from 25 to 50 mg/day. Cardiac evaluation showed no intrinsic abnormalities. The gradual tapering of methimazole resulted in increasing TT4 and TT3 with normalization of TSH. Repeat I-123 uptake obtained 1 month after discontinuing methimazole was markedly elevated at 24h (75%). Estimated thyroid weight was 40 grams. Genotyping was heterozygous for the c.1313G>A (p.Arg438His), a known pathogenic variant in the THRβ gene. Conclusion: Resistance to thyroid hormone should be suspected in the setting of variable symptoms of hyperthyroidism, abnormally high serum levels of thyroid hormone with non-suppressed TSH, and negative Graves’ disease antibodies. Elevated I-123 uptake may be found in RTH, but also may have been caused by prior methimazole treatment. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

All 50 United States and the District of Columbia incorporate newborn screening for congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency. Filter paper blood specimens are typically collected in full-term infants on day two of life for 17-hydroxyprogesterone (17OHP) fluoroimmunoassay (DELFIA). Prematurity, low birth weight, or critical illness are known to cause falsely elevated results. Protocols differ for each state laboratory as to assay cut-points by birthweight or gestational age, which are key in determining the positive predictive value. As a preliminary step to quality improvement, we investigated the diversity of approaches to CAH screening nationally among the states representing members of the DSD-Translational Research Network. Ten data sets were returned from a survey circulated to state laboratory directors with qualitative and quantitative information about individual screening programs. Disease incidence generally correlated with published worldwide data, ranging from 1:10,000 to 1: 28,500 live births. Screening results are typically reported by direct phone call to the designated healthcare provider and/or coordinator at each referral center, followed by a faxed written report. Specialists are notified of unequivocally high 17OHP results; however, borderline results are not usually referred to a pediatric endocrinologist. Only one state laboratory required a mandatory second screen for healthy term infants regardless of initial screen result; most did for infants in intensive care units. Nine of 10 programs utilized birthweight cut-points, but cutoffs for normal results varied widely - from 17OHP values of 25 to 75 ng/mL for birthweights >2250-2500 grams. One program used gestational age cut-points. The positive predictive values for term or normal birthweight infants varied from 1.2 to 9.6%, implying differences in sensitivity and/or specificity of screening between states. There was no apparent correlation between the total number of infants each state screened annually, assay cut-point and positive predictive value. Data were unavailable for negative predictive values. Conclusion: There is a need for standardization of newborn screening protocols for CAH to improve the positive predictive value. Future efforts will be directed to expanding this survey and determining best practices. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Congenital adrenal hyperplasia is the name applied to a class of autosomal recessive disorders resulting from deficiency of one of five enzymes necessary for cortisol synthesis by the adrenal cortex. Congenital adrenal hyperplasia is most often attributable to steroid 21-hydroxylase deficiency, accounting for more than 90% of cases. This discussion will be limited to the most common form of the disease, highlighting methods of diagnostic screening and challenges in disease management.

Background/Aims: Utilization of a psychosocial screener to identify families affected by a disorder/difference of sex development (DSD) and at risk for adjustment challenges may facilitate efficient use of team resources to optimize care. The Psychosocial Assessment Tool (PAT) has been used in other pediatric conditions. The current study explored the reliability and validity of the PAT (modified for use within the DSD population; PAT-DSD). Methods: Participants were 197 families enrolled in the DSD-Translational Research Network (DSD-TRN) who completed a PAT-DSD during a DSD clinic visit. Psychosocial data were extracted from the DSD-TRN clinical registry. Internal reliability of the PAT-DSD was tested using the Kuder-Richardson-20 coefficient. Validity was examined by exploring the correlation of the PAT-DSD with other measures of caregiver distress and child emotional-behavioral functioning. Results: One-third of families demonstrated psychosocial risk (27.9% “Targeted” and 6.1% “Clinical” level of risk). Internal reliability of the PAT-DSD Total score was high (α = 0.86); 4 of 8 subscales met acceptable internal reliability. A priori predicted relationships between the PAT-DSD and other psychosocial measures were supported. The PAT-DSD Total score related to measures of caregiver distress (r = 0.40, p < 0.001) and to both caregiver-reported and patient self-reported behavioral problems (r = 0.61, p < 0.00; r = 0.37, p < 0.05). Conclusions: This study provides evidence for the reliability and validity of the PAT-DSD. Given variability in the internal reliability across subscales, this measure is best used to screen for overall family risk, rather than to assess specific psychosocial concerns.

Adrenarche is when a child's adrenal cortex starts to secrete adrenal androgen precursors. Dehydroepiandrosterone (DHEA) is the most abundant product of the adrenal cortex, and is a weak androgen agonist thought to be responsible for the clinical signs of pubarche by conversion to more potent androgens, testosterone, and dihydrotestosterone. DHEA's extra-adrenal sulfation product, dehydroepiandrosterone sulfate, is a stable marker for adrenal androgenic activity. Pubarche is the physical manifestation of androgenic hormone production, and includes the development of pubic and axillary hair, adult body odor, and acne. This stage is usually considered premature if it commences before age 8 years in girls or age 9 years in boys. Premature adrenarche is a diagnosis of exclusion, as true centrally mediated precocious puberty, congenital adrenal hyperplasia, exogenous androgen exposure, and androgen-secreting tumors must be ruled out. Premature adrenarche may be associated with a history of an infant who was small for gestational age at birth who then gained weight rapidly thereafter or became obese. In some instances, premature adrenarche may predict functional ovarian hyperandrogenism in adolescence. Management of premature adrenarche is largely aimed at observation, lifestyle adjustments for weight concerns, and monitoring for future possible persistent androgen excess and insulin resistance. [ Pediatr Ann. 2018;47(1):e7–e11.]

Objective Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome. The mainstays of treatment involve chronic red cell transfusions, long-term glucocorticoid therapy, and stem cell transplantation. Systematic data concerning endocrine function in DBA are limited. We studied patients in the DBA Registry (DBAR) of North America to assess the prevalence of various endocrinopathies.

Background Elevated levels of alanine aminotransferase (ALT) are associated with obesity and are often a consequence of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to assess the relationship between ALT and risk factors for adiposity-related co-morbidities in a diverse population of middle school children. Methods We measured height, weight, body fatness (bioelectrical impedance), waist circumference, insulin sensitivity, phase 1 insulin release (acute insulin response following intravenous glucose), beta-cell function (acute insulin response corrected for insulin sensitivity), ALT, lipid profiles, and circulating concentrations of interleukin-6 (IL-6), C-reactive protein, adiponectin, and tumor necrosis factor-α (TNF-α) in a multi-ethnic/racial population of 106 middle school students (aged 11–14 years, 45 female) of varying body mass indexes (BMI). Results Alanine aminotransferase was significantly correlated with BMI, % body fat, fat mass, waist circumference, fasting insulin, insulin resistance, triglycerides, and was inversely correlated with high-density lipoprotein cholesterol in children, even though all values of ALT were “normal” (range of 4.0–33.0 U/L). ALT was significantly higher in males than females even when corrected for body fatness. Significant correlations with lipids and insulin resistance persisted even when adjusted for age, gender, and body fatness. Conclusion Even within the normative range, ALT levels were significantly correlated with anthropomorphic and biochemical risk factors for adiposity-related co-morbidities in youth. Therefore, because ALT is correlated with dyslipidemia, insulin resistance, and central fat distribution, it might also serve as a marker of risk for adiposity-related co-morbidities beyond NAFLD. 摘要 背景： 丙氨酸氨基转移酶（alanine aminotransferase，ALT）水平升高与肥胖相关，这通常是非酒精性脂肪性肝病（non-alcoholic fatty liver disease，NAFLD）的结果。这项研究的目的是在不同的中学儿童人群中评估ALT与肥胖相关合并症危险因素之间的关系。 方法： 我们在106名体重指数（BMI）不同的多种族/人种中学生人群（年龄为11–14岁，有45名女性）中测量了身高、体重、体脂（生物电阻抗）、腰围、胰岛素敏感性、1相胰岛素释放（静脉注射葡萄糖后的急性胰岛素反应）、β-细胞功能（校正胰岛素敏感性后的急性胰岛素反应）、ALT、血脂谱、循环中的白细胞介素-6（IL-6）、C-反应蛋白、脂联素以及肿瘤坏死因子-α（TNF-α）浓度。 结果： 在儿童中，ALT与BMI、体脂百分比、脂肪含量、腰围、空腹胰岛素、胰岛素抵抗、甘油三酯显著相关，并且与高密度脂蛋白胆固醇负相关，即使所有的ALT值都是“正常的”（范围为4.0–33.0 U/L）。即便校正体脂后，男性ALT仍显著高于女性。血脂与胰岛素抵抗之间存在显著的相关性，即便在校正年龄、性别与体脂之后。 结论： 在年轻人中，即使ALT水平处在标准范围，它仍然与肥胖相关合并症的人体测量学以及生化危险因素显著相关。因此，由于ALT与血脂异常、胰岛素抵抗以及中心性脂肪分布相关，所以除了NAFLD之外它还可以作为一个肥胖相关合并症风险的标志物。

Context Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) require lifelong treatment with glucocorticoids. In growing children, the drug of choice is hydrocortisone. Commercially available hydrocortisone tablets do not conform to very low doses prescribed to infants and toddlers, and compounded hydrocortisone is often dispensed to meet therapeutic needs. However, safety, efficacy, and uniformity of compounded products are not tested. We report a case of Cushing syndrome in a child with CAH who was inadvertently receiving excessive hydrocortisone in compounded form. Design A 20-month-old girl with CAH developed growth deceleration, excessive weight for length, irritability, increased facial fat, plethora, and excess body hair while receiving hydrocortisone from a local compounding pharmacy. The signs and symptoms persisted despite decreasing hydrocortisone dose. Iatrogenic Cushing syndrome was suspected. The prescribed hydrocortisone capsules were sent for analysis to the Sports Medicine Research & Testing Laboratory, where testing revealed that each 1-mg hydrocortisone capsule contained five to 10 times the dose prescribed and listed on the label. Conclusion Physicians must be aware that errors in compounded medications may lead to unanticipated adverse effects. Iatrogenic Cushing syndrome should be suspected in any child receiving compounded glucocorticoid treatment who develops growth arrest and excess weight gain.

Premature ovarian failure (POF) associated with amenorrhea and elevated gonadotropins before the age of 40 years may prevent or interrupt normal pubertal progression. Early ovarian dysfunction or failure before or during puberty is a heterogeneous disorder with both genetic and acquired causes. Diagnosis of POF is contingent on a detailed history and physical examination in order to determine the underlying etiology. While most cases are idiopathic, specific isolated gene defects related to the X-chromosome may present with associated dysmorphic features or ambiguous genitalia. Alternatively, inflammatory, infiltrative, or autoimmune oophoritis may be less apparent. Laboratory investigation including sex steroids, gonadotropins, inflammatory markers, antibodies, and genetic tests should be performed to reach an accurate diagnosis. Treatment of POF will require hormone replacement therapy designed to induce and maintain secondary sexual characteristics and bone mineral density. Maximization of growth potential should be considered prior to initiating treatment. Anticipatory counseling, screening for and management of comorbidities, including infertility, will likely improve overall quality of life for patients with POF.

Symptoms related to androgen excess in girls and women are a frequent cause for referrals to the endocrinologist or gynecologist. History and physical examination provide important data regarding the chronicity, severity, and exact nature of the complaints. Laboratory determinations contribute to understanding the source of androgen production, and aid in the decision of how to best treat the patient. Imaging studies may be used judiciously to augment these findings. At the other end of the spectrum and less frequently seen are conditions in which there is inadequate sex hormone production. The latter cases may be difficult to distinguish from idiopathic or functional causes of pubertal disruption, and often require dynamic tests of the pituitary–adrenal or ovarian axes, along with a more in-depth search for genetic causes. This chapter will provide a case-based approach to solving typical cases encountered in adolescence.

Congenital adrenal hyperplasia (CAH) in children, the majority of which is due to 21-hydroxylase deficiency, represents a group of disorders in which there is impaired cortisol synthesis and abnormalities in adrenal hormonal profiles. There continues to be debate regarding the optimal management of and treatment for these children. This review will highlight the most recent advances in neonatal screening for CAH, as well as the timeliest recommendations for the treatment and management of 21-hydroxylase deficiency, both the classic and nonclassic forms of the disorder.Substantive advancements have been made with regard to neonatal screening for CAH, allowing for earlier diagnosis, while minimizing the morbidity and mortality associated with delayed detection. Although the achievement of normal growth and development remains the ultimate goal of treatment, recent studies have provided further insight into the management and refinement of therapy in these children.The optimal management and treatment for children with CAH is still unclear. Although there have been recent advances in the diagnosis and treatment of this group of disorders, there is still much to learn in order to optimize therapy for these individuals.

Combined 17alpha-hydroxylase/17,20-lyase deficiency is a rare autosomal recessive form of congenital adrenal hyperplasia presenting with hypertension and sexual infantilism. This disorder is caused by defects in P450c17, encoded by the CYP17A1 gene.We describe a 14-yr-old female with clinical and hormonal features of 17alpha-hydroxylase/17,20-lyase deficiency and identify and characterize the activities of her CYP17A1 mutations.The coding regions of the CYP17A1 gene were amplified by PCR and sequenced. Mutations were recreated in P450c17 cDNA expression vectors; activities in transfected COS-1 cells were assayed by conversion of radiolabeled precursor steroids. One mutant was also expressed in Escherichia coli, and the reduced adsorption spectrum was measured.The patient carried the previously described mutation R96W and the novel missense mutation H373D. Neither mutant had detectable activity when expressed in COS-1 cells. Membrane preparations from E. coli expressing the H373D mutant vector produced an absorption peak at 420 nm, whereas the wild-type produced a peak at 450 nm, suggesting that the H373D mutation interferes with protein folding.The novel P450c17 mutation H373D abolished enzyme activity because of protein misfolding. These data indicate an important role for this residue in P450c17 activity.

OBJECTIVE—The purpose of this study was to screen adolescents with type 1 diabetes using ambulatory blood pressure monitoring (ABPM) to 1) test the hypothesis that using a preset sleep time results in an overdiagnosis of abnormal nocturnal dipping in systolic blood pressure and 2) assess the reproducibility of an abnormal nocturnal systolic blood pressure dip. RESEARCH DESIGN AND METHODS—For aim 1, ABPM from 53 adolescent patients with type 1 diabetes was reviewed. Nocturnal dips in systolic blood pressure calculated by actual sleep time were compared with those from a preset sleep time. For aim 2, blood pressure monitoring from 98 patients using actual reported sleep time was reviewed. Reproducibility of the nocturnal dip in systolic blood pressure was assessed in a subset of “nondippers.” RESULTS—For aim 1, the actual mean ± SE decline in nocturnal systolic blood pressure was 11.6 ± 4.7%, whereas the mean decline in nocturnal systolic blood pressure calculated using the preset sleep time was 8.8 ± 4.9% (P < 0.0001). For aim 2, 64% of patients had a normal nocturnal decline in systolic blood pressure (14.9 ± 3.1% mmHg), whereas 36% had an abnormal dip (5.7 ± 2.8% mmHg). Repeat ABPM performed in 22 of the 35 nondippers revealed that only 36% had abnormal systolic dipping confirmed on the repeat ABPM. CONCLUSIONS—The use of actual reported sleep time is required to accurately determine the nocturnal dip in systolic blood pressure. Repeating ABPM in nondippers is essential to confirm this abnormality.

Mice deficient in prokineticin 2(PROK2) and prokineticin receptor2 (PROKR2) exhibit variable olfactory bulb dysgenesis and GnRH neuronal migration defects reminiscent of human GnRH deficiency.We aimed to screen a large cohort of patients with Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (IHH) for mutations in PROK2/PROKR2, evaluate their prevalence, define the genotype/phenotype relationship, and assess the functionality of these mutant alleles in vitro.Sequencing of the PROK2 and PROKR2 genes was performed in 170 KS patients and 154 nIHH. Mutations were examined using early growth response 1-luciferase assays in HEK 293 cells and aequorin assays in Chinese hamster ovary cells.Four heterozygous and one homozygous PROK2 mutation (p.A24P, p.C34Y, p.I50M, p.R73C, and p.I55fsX1) were identified in five probands. Four probands had KS and one nIHH, and all had absent puberty. Each mutant peptide impaired receptor signaling in vitro except the I50M. There were 11 patients who carried a heterozygous PROKR2 mutation (p.R85C, p.Y113H, p.V115M, p.R164Q, p.L173R, p.W178S, p.S188L, p.R248Q, p.V331M, and p.R357W). Among them, six had KS, four nIHH, and one KS proband carried both a PROKR2 (p.V115M) and PROK2 (p.A24P) mutation. Reproductive phenotypes ranged from absent to partial puberty to complete reversal of GnRH deficiency after discontinuation of therapy. All mutant alleles appear to decrease intracellular calcium mobilization; seven exhibited decreased MAPK signaling, and six displayed decreased receptor expression. Nonreproductive phenotypes included fibrous dysplasia, sleep disorder, synkinesia, and epilepsy. Finally, considerable variability was evident in family members with the same mutation, including asymptomatic carriers.Loss-of-function mutations in PROK2 and PROKR2 underlie both KS and nIHH.

Nonclassic adrenal hyperplasia is most commonly attributable to mutations in CYP21A2 (also termed CYP21) encoding steroid 21-hydroxylase. Partial deficiency of this enzyme causes an imbalance in cortisol synthesis with consequent adrenal androgen excess. Unlike more severe forms of congenital adrenal hyperplasia, this condition is rarely recognized in infants, but rather is a potential cause of premature adrenarche and pubarche in children, virilization in young women, and variable symptoms in young men. This article will review relevant clinical, hormonal and genetic aspects of nonclassic adrenal hyperplasia.

Objective: Our objective was to formulate practice guidelines for the treatment and prevention of pediatric obesity.Conclusions: We recommend defining overweight as body mass index (BMI) in at least the 85th percentile but < the 95th percentile and obesity as BMI in at least the 95th percentile against routine endocrine studies unless the height velocity is attenuated or inappropriate for the family background or stage of puberty; referring patients to a geneticist if there is evidence of a genetic syndrome; evaluating for obesity-associated comorbidities in children with BMI in at least the 85th percentile; and prescribing and supporting intensive lifestyle (dietary, physical activity, and behavioral) modification as the prerequisite for any treatment. We suggest that pharmacotherapy (in combination with lifestyle modification) be considered in: 1) obese children only after failure of a formal program of intensive lifestyle modification; and 2) overweight children only if severe comorbidities persist despite intensive lifestyle modification, particularly in children with a strong family history of type 2 diabetes or premature cardiovascular disease. Pharmacotherapy should be provided only by clinicians who are experienced in the use of antiobesity agents and aware of the potential for adverse reactions. We suggest bariatric surgery for adolescents with BMI above 50 kg/m2, or BMI above 40 kg/m2 with severe comorbidities in whom lifestyle modifications and/or pharmacotherapy have failed. Candidates for surgery and their families must be psychologically stable and capable of adhering to lifestyle modifications. Access to experienced surgeons and sophisticated multidisciplinary teams who assess the benefits and risks of surgery is obligatory. We emphasize the prevention of obesity by recommending breast-feeding of infants for at least 6 months and advocating that schools provide for 60 min of moderate to vigorous daily exercise in all grades. We suggest that clinicians educate children and parents through anticipatory guidance about healthy dietary and activity habits, and we advocate for restricting the availability of unhealthy food choices in schools, policies to ban advertising unhealthy food choices to children, and community redesign to maximize opportunities for safe walking and bike riding to school, athletic activities, and neighborhood shopping.

Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome. The mainstays of treatment involve chronic red cell transfusions, long-term glucocorticoid therapy, and stem cell transplantation. Systematic data concerning endocrine function in DBA are limited. We studied patients in the DBA Registry (DBAR) of North America to assess the prevalence of various endocrinopathies.In a pilot study, retrospective data were collected for 12 patients with DBA. Subsequently, patients with DBA aged 1-39 years were recruited prospectively. Combined, 57 patients were studied; 38 chronically transfused, 12 glucocorticoid-dependent, and seven in remission. Data were collected on anthropometric measurements, systematic screening of pituitary, thyroid, parathyroid, adrenal, pancreatic, and gonadal function, and ferritin levels. Descriptive statistics were tabulated and group differences were assessed.Fifty-three percent of patients had ≥ 1 endocrine disorder, including adrenal insufficiency (32%), hypogonadism (29%), hypothyroidism (14%), growth hormone dysfunction (7%), diabetes mellitus (2%), and/or diabetes insipidus (2%). Ten of the 33 patients with available heights had height standard deviation less than -2. Low 25-hydroxy vitamin D (25(OH)D) levels were present in 50%. A small proportion also had osteopenia, osteoporosis, or hypercalciuria. Most with adrenal insufficiency were glucocorticoid dependent; other endocrinopathies were more common in chronically transfused patients.Endocrine dysfunction is common in DBA, as early as the teenage years. Although prevalence is highest in transfused patients, patients taking glucocorticoids or in remission also have endocrine dysfunction. Longitudinal studies are needed to better understand the etiology and true prevalence of these disorders.

most common example of this phenomenon is Cushing syndrome due to high endogenous or exogenous cortisol exposure. Iatrogenic Cushing syndrome, characterized by inhibition of statural growth in children, excess weight gain, metabolic syndrome, and hypertension, may be ob-served in CAH patients receiving excessive glucocorti-coid treatment [6] . This is why it is important to balance the need for suppression of adrenal androgen precursors with the opposing practical dictum of minimizing gluco-corticoid exposure, particularly in growing children.One way to achieve the desired balance is to treat clas- sic CAH patients from infancy with a combination of moderate doses of both glucocorticoid and mineralocor-ticoid supplements. A systematic review and meta-analy-sis of treatment outcomes in CAH patients revealed that those children who received long-term treatment with mineralocorticoids achieved significantly better adult heights compared with those who were prescribed gluco-corticoids alone [7] . On the other hand, investigators have observed elevated 24-hour ambulatory blood pres-sure in children [8] and adults [9] with CAH. However, it has not been demonstrated that young adults with CAH suffer clinically significant cardiac morbidities or mortal-ity [10] . Taken together, the implication of the available data is that clinicians should prudently prescribe miner- The study by Mooij et al. [1] in this issue underscores the interrelatedness of adrenal cortical steroids in achiev-ing balance in the treatment of patients with congenital adrenal hyperplasia (CAH). In this set of in vitro experi-ments, the investigators delineate the nature of 17-hy-droxyprogesterone and progesterone interference with the ability of aldosterone to transactivate the mineralo-corticoid receptor (MR). This occurs at the level of recep-tor transactivation, rather than nuclear translocation. It is reasonable to infer from these data that a similar in vivo phenomenon occurs at the high 17-hydroxyprogesterone levels and low physiologic aldosterone levels measured in inadequately controlled classic CAH patients. It has long been recognized that elevated plasma renin levels reflect-ing low aldosterone production and/or activity are found among CAH patients with elevated steroid 21-hydroxy-lase precursors [2, 3] . Previous in vitro studies have con-firmed the hypothesis that progesterone and its analogs are the culprits inhibiting MR [4] . An obvious corollary of these findings is exacerbation of sodium wasting in CAH patients, potentially impeding normal growth and even triggering adrenal crisis. In contrast to the ability of progesterones to interfere with aldosterone-induced MR activity, cortisol may bind to and activate the MR causing hypertension [5] . The

In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community.

Congenital adrenal hyperplasia (CAH) is among the group of inherited disorders now included in newborn screening programs throughout the USA and in many other developed countries. As patients are diagnosed earlier and survive longer into adult life, current therapeutic dilemmas concern individual quality of life, adherence to ethical principles of medical practice, and cost–benefit analysis. This paper will discuss current thinking on selected controversies in the medical and surgical management of CAH. This discussion is based mainly on expert opinion and consensus of the endocrine community, as reflected in The Endocrine Society’s 2010 Clinical Practice Guidelines for the treatment of CAH (J Clin Endocrinol Metab 95: 4133–60).

Congenital adrenal hyperplasia (CAH) is a group of disorders caused by inborn errors of steroid metabolism. The most common form owing to 21-hydroxylase deficiency (CAH-21OHD) is present in about 1:10,000- 1:15,000 live births worldwide. In its classic salt-wasting form (-66-75% of cases) patients may suffer potentially lethal adrenal insufficiency. Non-salt-wasting forms of CAH-21 OHD are recognized by genital ambiguity in affected females, and by signs of androgen excess in later childhood in males. Non-classic CAH-21 OHD may be detected in up to 1-3% of certain populations, and is often mistaken for idiopathic precocious pubarche in children or polycystic ovary syndrome in young women. This chapter will address issues relating to transition of CAH care from the pediatric to the adult endocrinologist.

Background: Obesity, increasingly prevalent among children, causes major morbidities, among which is earlier onset of type 2 diabetes mellitus (DM). Methods: We reviewed charts of children aged 3 to 18 years (n=106). The population was divided into four age groups. Anthropomorphic measurements, family history, diet and exercise patterns, and selected endocrine/metabolic measurements were recorded, and descriptive statistics were calculated. Results: Obesity in one or both parents correlated with a higher percent of ideal body weight (IBW) (p=0.01). Fifty-eight percent of the children had first- or second-degree relatives with a history of type 2 DM; 9% had relatives with type 1 DM. Fifty-four percent had dieted and exercised regularly. Mean onset of obesity was at 4.2 ± 0.9 years. Mean cholesterol was elevated at 176 mg/dl. Average BMI was 26.6 in the youngest children (Group 1; normal mean for this age ~15.5), and increased to 37.8 in adolescents (Group 4; normal mean ~21). Elevated TSH was present in 1:4) increased with age. Conclusions: Childhood obesity in children is correlated with family histories of obesity and DM. Thyroid dysfunction is seldom found, although mild hypercholesterolemia and insulin insensitivity are prevalent, especially among adolescents.

Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is the most common cause of genital ambiguity in the newborn and is present in about 1 in 15,000 live births worldwide. The disease is further characterized in its classic salt-wasting form (-75% of cases) by potentially lethal adrenal insufficiency. A non-salt-wasting form of classic CAH with 21-hydroxylase deficiency is also recognized by genital ambiguity in affected females and by signs of androgen excess in later childhood in males. Nonclassic CAH with 21-hydroxylase deficiency may be detected in 1% to 3% of populations and is often mistaken for idiopathic precocious pubarche in children or polycystic ovary syndrome in young women. This article presents an overview of clinical and genetic aspects of the various forms of CAH with 21hydroxylase deficiency. Other articles in this issue provide a detailed discussion of special topics, including prenatal diagnosis and treatment, neonatal screening, growth, and cognitive, psychosexual, reproductive, and novel treatment aspects of this disease. Table 1 (see Appendix) summarizes the genetic, hormonal, and clinical features of the steroidogenic defects discussed in this issue.

Congenital adrenal hyperplasia (CAH) is an inherited disorder of steroid biosynthesis most often attributable to mutations in CYP21 (also termed CYP21A2) encoding the active steroid 21-hydroxylase enzyme. This review focuses on clinical and genetic aspects of CAH, and updates the reader on current methodology and applications for molecular genetic diagnosis. Genotyping patients with CAH has revealed50 mutations within CYP21, yet only 10 mutations account for approximately 95% of affected alleles. Many CYP21 mutations are gene conversions arising via transfer of gene sequences between the non-functional CYP21 pseudogene and CYP21. Phenotype is generally well-correlated with genotype. Historically, CAH has been divided into 3 types of disease: classic salt-wasting, classic simple virilizing (non-salt-wasting), and nonclassic. Recent findings support the notion that rather than discrete phenotypic categories, CAH is better represented as a continuum of phenotypes, from severe to mild. Molecular genetic diagnosis is most effectively employed now in prenatal diagnosis of classic CAH. As newborn screening for CAH becomes more widespread, genotyping may be implemented to resolve diagnostic difficulties encountered with hormonal testing. As automated methods of DNA diagnosis such as microarrays or gene chips are refined, it is likely that genetic screening will become less expensive and more readily available. The clinician should be aware of the potential for both false negatives and false positives with PCR-based gene screening. In short, whereas molecular genetic diagnosis is a valuable tool, it cannot replace clinical acumen and hormonal assays.

Characteristic presentation of nonclassical adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency was compared between women carrying a severe and a mild CYP21 mutation (Group 1, N = 26) versus homozygotes for mild mutations (Group 2, N = 8). The diagnosis was based on elevated ACTH-stimulated 17OH-progesterone (17OHP). Genotyping for 10 mutations was performed by PCR-based techniques. Jewish patients predominated among Group 2 (25% vs 11.5% in Group 1); however, 85% of all patients were non-Jewish Caucasians. Average age of presentation was 23-25 years, and did not differ between groups. Hirsutism, and to a lesser extent oligomenorrhea and acne, were more prevalent among Group 1 women. There was a trend to higher basal 17OHP among Group 1 patients (mean +/- SEM; 1354+/-323 vs 714+/-129 ng/dl, P< or =0.25). The lack of significant difference was perhaps due to the relatively few homozygotes for 2 mild mutations (24%). V281L was carried on approximately 48% of all alleles, and about 16% carried either P30L or P453S. Approximately 38% of alleles and 77% of patients carried a classic mutation. These data have important implications for genetic counseling. In summary, we describe differences in clinical, hormonal, and genetic characteristics among a multiethnic group of females with NCAH.

More than 90% of cases of congenital adrenal hyperplasia (CAH, the inherited inability to synthesize cortisol) are caused by 21-hydroxylase deficiency. Females with severe, classic 21-hydroxylase deficiency are exposed to excess androgens prenatally and are born with virilized external genitalia. Most patients cannot synthesize sufficient aldosterone to maintain sodium balance and may develop potentially fatal “salt wasting” crises if not treated. The disease is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombinations between CYP21 and the closely linked CYP21P pseudogene. Approximately 20% are gene deletions due to unequal crossing over during meiosis, whereas the remainder are gene conversions—transfers to CYP21 of deleterious mutations normally present in CYP21P. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disease in patients carrying it. Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females to minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before salt wasting crises develop, reducing mortality from this condition. Glucocorticoid and mineralocorticoid replacement are the mainstays of treatment, but more rational dosing and additional therapies are being developed.

We investigated the feasibility and diagnostic utility of genotyping 9 CYP21 mutations, linked chromosome 6p markers, and a dimorphic X-Y marker from neonatal screening samples. Blood-impregnated filter papers (Guthrie cards) from 603 randomly chosen New Zealand neonates were genotyped blind to 17-hydroxyprogesterone (17-OHP) levels. Another 50 samples from Swiss and North American infants with correlative hormonal data were also genotyped. DNA was extracted, and gene-specific PCR was performed. CYP21 PCR products were subjected to ligase detection reaction, simultaneously analyzing 9 CYP21 mutations; PCR products of other genes were subjected to direct gel analysis. CYP21 genotyping indicated a heterozygote rate of 2.8% for classic mutations (excluding CYP21 deletions), and 2.0% for nonclassic mutations in New Zealanders. Ten full-term affected neonates showed a wide range of 17-OHP levels (15–1400 nmol/L). Sick or preterm infants or infants screened on the first day of life with high 17-OHP proved genet...

Background: Clinical management of patients with congenital adrenal hyperplasia (CAH) involves treating hormonal deficiencies, addressing issues related to genital ambiguity, avoiding morbidities and communicating with the family about risk of CAH in other members. This article briefly reviews the prenatal and neonatal diagnosis of CAH caused by steroid 21-hydroxylase deficiency, as well as treatment options and neonatal screening approaches. Conclusions: Screening for CAH can reduce adrenal crises, avoid incorrect sex assignments, lower mortality (especially in males) and avoid inappropriate somatic growth and precocious puberty.