Deborah P Merke

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Роквилл, Maryland, United States

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Publications (94)603.32 Total impact

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    ABSTRACT: Objective: This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency. Participants: The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recommendations and the quality of evidence. Consensus process: The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies identified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine Society's Clinical Guidelines Subcommittee and Clinical Affairs Core Committee, members responding to a web posting, and the Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. Conclusions: We recommend diagnostic tests for the exclusion of primary adrenal insufficiency in all patients with indicative clinical symptoms or signs. In particular, we suggest a low diagnostic (and therapeutic) threshold in acutely ill patients, as well as in patients with predisposing factors. This is also recommended for pregnant women with unexplained persistent nausea, fatigue, and hypotension. We recommend a short corticotropin test (250 μg) as the "gold standard" diagnostic tool to establish the diagnosis. If a short corticotropin test is not possible in the first instance, we recommend an initial screening procedure comprising the measurement of morning plasma ACTH and cortisol levels. Diagnosis of the underlying cause should include a validated assay of autoantibodies against 21-hydroxylase. In autoantibody-negative individuals, other causes should be sought. We recommend once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15-25 mg/d) or cortisone acetate replacement (20-35 mg/d) applied in two to three daily doses in adults. In children, hydrocortisone (∼8 mg/m(2)/d) is recommended. Patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticosteroids and associated autoimmune diseases, particularly autoimmune thyroid disease.
    No preview · Article · Jan 2016 · The Journal of Clinical Endocrinology and Metabolism
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    Full-text · Dataset · Jan 2016
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    Full-text · Dataset · Jan 2016
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    ABSTRACT: Our goals were to (1) develop an improved micro-method usable for neonates for steroid profile measurements and a method to measure androsterone, a key steroid in the recently described androgen backdoor pathway together, with dehydroepiandrosterone and (2) to assess if dehydroepiandrosterone diurnal concentration fluctuations exist potentially necessitating strict adherence to time of blood sample draw and requirement of separate time-dependent reference intervals. Liquid chromatography-tandem mass spectrometry was performed with an atmospheric pressure photoionization source [1]. For each sample 50μL (100μL for the backdoor pathway) of serum was deproteinized by adding 75μL (150μL for the backdoor pathway) of acetonitrile containing the internal standards. After centrifugation, 75μL (150μL for the backdoor pathway) of supernatant was diluted with 250μL of water and injected onto a Poroshell 120 EC-C8 column (SB-C8 column for the backdoor pathway). Within-run coefficients of variation ranged from 2.4-10.4% and between-day coefficients of variation from 2.9-11.2%. Comparison studies yielded correlation coefficient between 0.97 and 1.00 with recoveries of 90% or greater. Our methods analyze a 9 steroid profile and an additional 2 steroid profile (backdoor pathway) with minimal sample volume (usable in neonates optimizing early diagnosis of endocrinopathies and genetic diseases). Low limits of quantitation make these methods ideal for steroid measurement in women and prepubertal children. As diurnal variations of dehydroepiandrosterone and other steroids [2] concentrations are clinically significant we recommend that separate reference intervals be developed for 8 am, 8 pm, and midnight sample draws. The use of this approach in improving the diagnosis of patients with adrenal insufficiency and congenital adrenal hyperplasia is discussed.
    No preview · Article · Dec 2015 · The Journal of steroid biochemistry and molecular biology
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    Full-text · Article · Oct 2015
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    ABSTRACT: The treatment goal in congenital adrenal hyperplasia (CAH) is to replace glucocorticoids while avoiding androgen excess and iatrogenic Cushing's syndrome. However, there is no consensus on how to monitor disease control. Our main objectives were to evaluate hormonal circadian rhythms and use these profiles to identify optimal monitoring times and novel disease biomarkers in CAH adults on intermediate- and long-acting glucocorticoids. This was an observational, cross-sectional study at the National Institutes of Health Clinical Center in 16 patients with classic CAH. Twenty-four hour serum sampling for corticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione (A4), androsterone, dehydroepiandrosterone (DHEA), testosterone, progesterone and 24-hour urinary pdiol and 5β-pdiol was carried out. Bayesian spectral analysis and cosinor analysis were performed to detect circadian rhythmicity. The number of hours to minimal (TminAC) and maximal (TmaxAC) adrenocortical hormone levels after dose administration were calculated. A significant rhythm was confirmed for ACTH (r2 0.95;P<0.001), 17OHP (r2 0.70; P=0.003), androstenedione (r2 0.47;P=0.043), androsterone (r2 0.80;P<0.001), testosterone (r2 0.47;P=0.042) and progesterone (r2 0.64;P=0.006). The mean (SD) TminAC and TmaxAC for 17OHP and A4 were: morning prednisone [4.3(2.3) and 9.7(3.5) hours], evening prednisone [4.5(2.0) and 10.3(2.4) hours], and daily dexamethasone [9.2(3.5) and 16.4(7.2) hours]. AUC0-24hr progesterone, androsterone and 24-hour urine pdiol were significantly related to 17OHP. In CAH patients adrenal androgens exhibit circadian rhythms influenced by glucocorticoid replacement. Measurement of adrenocortical hormones and interpretation of results should take into account the type of glucocorticoid and time of dose administration. Progesterone and backdoor metabolites may provide alternative disease biomarkers.
    Full-text · Article · Sep 2015 · European Journal of Endocrinology
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    ABSTRACT: The contiguous gene deletion syndrome, CAH-X, was described in a subset (7%) of congenital adrenal hyperplasia (CAH) patients with a TNXA/TNXB chimera resulting in deletions of CYP21A2, encoding 21-hydroxylase necessary for cortisol biosynthesis, and TNXB, encoding the extracellular matrix glycoprotein tenascin-X (TNX). This TNXA/TNXB chimera is characterized by a 120 bp deletion in exon 35 and results in TNXB haploinsufficiency, disrupted transforming growth factor-β (TGF-β) signaling, and an Ehlers Danlos syndrome (EDS) phenotype. To determine the genetic status of TNXB and resulting protein defects in CAH patients with a CAH-X phenotype but not the previously described TNXA/TNXB chimera. Design, Settings, Participants, Intervention: A total of 246 unrelated CAH patients were screened for TNXB defects. Genetic defects were investigated by Southern blotting, multiplex ligationdependent probe amplification, Sanger, and next-generation sequencing. Dermal fibroblasts and tissue were used for immunoblotting, immunohistochemical, and co-immunoprecipitation experiments. The genetic and protein status of tenascin-X in phenotypic CAH-X patients. Seven families harbor a novel TNXB missense variant c.12174C>G(p.C4058W) and a clinical phenotype consistent with hypermobility-type EDS. Fourteen CAH probands carry previously described TNXA/TNXB chimeras and 7 unrelated patients carry the novel TNXB variant resulting in a CAH-X prevalence of 8.5%. This highly conserved pseudogene-derived variant in the TNX fibrinogen- like domain is predicted to be deleterious and disulfide bonded, results in reduced dermal elastin and fibrillin-1 staining and altered TGF-α binding, and represents a novel TNXA/TNXB chimera. Tenascin-X protein expression was normal in dermal fibroblasts, suggesting a dominant negative effect. CAH-X syndromeiscommonlyfoundinCAHdueto 21-hydroxylase deficiencyandmay result from various etiological mechanisms.
    Full-text · Article · Jun 2015 · The Journal of Clinical Endocrinology and Metabolism
  • M DiSandro · D P Merke · R C Rink
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    ABSTRACT: Although pediatric urologists can successfully reconstruct even the most severe forms of atypical external male genitalia, and the cosmetic and functional results can be quite good, many of these patients will require multiple operations [25] and a significant percentage [30] will develop complications secondary to the operation(s). Although upon first glance, creating more typical male genitalia in boys who were born with atypical genitalia seems like a noble idea, studies are lacking regarding longterm outcome and quality of life. Long-term studies are needed to better assess surgical outcome, as well as the long-term results of nonoperative intervention - data of which are clearly lacking in the study of DSD patients, especially those reared male with ambiguous external genitalia. The best approach going forward would be further research utilizing networks of DSD teams where all stakeholders, including advocacy groups, are included in the research process.
    No preview · Article · May 2015 · Hormone and Metabolic Research

  • No preview · Article · May 2015
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    Full-text · Article · Dec 2014 · Clinical Chemistry
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    ABSTRACT: Context: Treatment of congenital adrenal hyperplasia (CAH) is suboptimal. Inadequate suppression of androgens and glucocorticoid excess are common and current glucocorticoid formulations cannot replace the cortisol circadian rhythm. Objectives: The primary objective was to characterize the pharmacokinetic profile of Chronocort®, a modified-release hydrocortisone formulation, in adults with CAH. Secondary objectives included examining disease control following 6 months of Chronocort® with dose titration. Design, Setting and Patients: Sixteen adults (8 females) with classic CAH participated in an open label, non-randomized, Phase 2 study at the National Institutes of Health Clinical Center. 24-hour blood sampling was performed on conventional glucocorticoids and following 6 months of Chronocort®. Chronocort® was initiated at 10mg (0700h) and 20mg (2300h). Dose titration was performed based on androstenedione and 17-hydroxyprogresterone (17-OHP) levels and clinical symptomatology. Main Outcome Measures: Cortisol pharmacokinetics of Chronocort® and biomarkers of CAH control (androstenedione and 17-OHP). Results: In CAH patients, Chronocort® cortisol profiles were similar to physiologic cortisol secretion. Compared to conventional therapy, 6 months of Chronocort® resulted in a decrease in hydrocortisone dose equivalent (28 ± 11.8 vs. 25.9 ± 7.1mg/day), with lower 24-hour (P = 0.004), morning (0700h - 1500h; P = 0.002), and afternoon (1500h - 2300h; P = 0.011) androstenedione area under the curve (AUC) and lower 24-hour (P = 0.023) and morning (0700h - 1500h; P = 0.02) 17-OHP AUC. Conclusions: Twice daily Chronocort® approximates physiologic cortisol secretion, and was well tolerated and effective in controlling androgen excess in adults with CAH. This novel hydrocortisone formulation represents a new treatment approach for patients with CAH.
    No preview · Article · Dec 2014 · Journal of Clinical Endocrinology & Metabolism
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    ABSTRACT: Background Prior studies reveal that bone mineral density (BMD) in congenital adrenal hyperplasia (CAH) is mostly in the osteopenic range and is associated with lifetime glucocorticoid dose. The forearm, a measure of cortical bone density, has not been evaluated.Objective We aimed to evaluate BMD at various sites, including the forearm, and the factors associated with low BMD in CAH patients.Methods Eighty CAH adults (47 classic, 33 nonclassic) underwent dual-energy-x-ray absorptiometry and laboratory and clinical evaluation. BMD Z-scores at the AP spine, total hip, femoral neck, forearm, and whole body were examined in relation to phenotype, body mass index, current glucocorticoid dose, average 5-year glucocorticoid dose, vitamin D, 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate (DHEAS).ResultsReduced BMD (T-score < -1 at hip, spine, or forearm) was present in 52% and was more common in classic than nonclassic patients (P = .005), with the greatest difference observed at the forearm (P = .01). Patients with classic compared to nonclassic CAH, had higher 17-hydroxyprogesterone (P = .005), lower DHEAS (P = .0002), and higher non-traumatic fracture rate (P = .0005). In a multivariate analysis after adjusting for age, sex, height standard deviation, phenotype, and cumulative glucocorticoid exposure, higher DHEAS was independently associated with higher BMD at the spine, radius, and whole body.Conclusion Classic CAH patients have lower BMD than nonclassic patients, with the most affected area being the forearm. This first study of forearm BMD in CAH patients suggests that low DHEAS may be associated with weak cortical bone independent of glucocorticoid exposure.This article is protected by copyright. All rights reserved.
    No preview · Article · May 2014 · Clinical Endocrinology
  • Rachel Morissette · Nazli B McDonnell · Deborah P Merke

    No preview · Article · Mar 2014 · Medical Hypotheses
  • Dr Deborah P Merke · Dix P Poppas
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    ABSTRACT: The management of congenital adrenal hyperplasia involves suppression of adrenal androgen production, in addition to treatment of adrenal insufficiency. Management of adolescents with congenital adrenal hyperplasia is especially challenging because changes in the hormonal milieu during puberty can lead to inadequate suppression of adrenal androgens, psychosocial issues often affect adherence to medical therapy, and sexual function plays a major part in adolescence and young adulthood. For these reasons, treatment regimen reassessment is indicated during adolescence. Patients with non-classic congenital adrenal hyperplasia require reassessment regarding the need for glucocorticoid drug treatment. No clinical trials have compared various regimens for classic congenital adrenal hyperplasia in adults, thus therapy is individualised and based on the prevention of adverse outcomes. Extensive patient education is key during transition from paediatric care to adult care and should include education of females with classic congenital adrenal hyperplasia regarding their genital anatomy and surgical history. Common issues for these patients include urinary incontinence, vaginal stenosis, clitoral pain, and cosmetic concerns; for males with classic congenital adrenal hyperplasia, common issues include testicular adrenal rest tumours. Transition from paediatric to adult care is most successful when phased over many years. Education of health-care providers on how to successfully transition patients is greatly needed.
    No preview · Article · Dec 2013
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    Zhi Xu · Wuyan Chen · Deborah P Merke · Nazli B McDonnell
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    ABSTRACT: Congenital adrenal hyperplasia, due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of adrenal steroidogenesis caused by mutations in the CYP21A2 gene. Direct comparison of established and novel methodologies of CYP21A2 genetic analysis in a large cohort representing a wide range of genotypes has not been previously reported. We genotyped a cohort of 129 unrelated patients with 21-OHD, along with 145 available parents, using Southern blot analysis (SBA), multiplex ligation-dependent probe amplification (MLPA), PCR-based restriction fragment length polymorphism (RFLP) analysis, multiplex minisequencing and conversion-specific PCR, duplication-specific amplification, and DNA sequencing. CYP21A2 genotyping identified four duplicated CYP21A2 genes (1.53%) and 79 chimeric CYP21A1P/CYP21A2 genes (30.15%). Parental SBA data were essential for determining the CYP21 haplotype in three cases, whereas PCR-RFLP was necessary for MLPA results to be accurately interpreted in the majority of cases. The comparison of different methods in detecting deletion and duplication showed that MLPA+PCR-RFLP was comparable with SBA, with parental data of 100% sensitivity and specificity. DNA sequencing was required for the identification of 16 (6.1%) rare point mutations and determination of clinically significant chimera junction sites. MLPA+PCR-RFLP is an excellent substitute for SBA in detecting CYP21A2 deletion and duplication and a combination of MLPA, PCR-RFLP, duplication-specific amplification, and DNA sequencing is a convenient and comprehensive strategy for mutation analysis of the CYP21A2 gene in patients with 21-OHD.
    Full-text · Article · Sep 2013 · The Journal of molecular diagnostics: JMD
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    ABSTRACT: It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multi-particulate technology. Screening by in-vitro dissolution profiles, pharmacokinetic testing in dexamethasone suppressed dogs and humans, and comparison to a reference population. Field laboratories and clinical research facility. Formulations were generated using an enteric (delayed-release) design configuration with an extended (sustained-release) dissolution profile. In-vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained release functionality. Pharmacokinetic characterisation of DIURF-006 showed that, despite absence of a sustained release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n=16) receiving a twice daily 'toothbrush' regimen (20mg at 23:00h and 10mg at 07:00h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 hr*nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8.5h vs clock time 08:12 hours for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89% and cortisol levels increased linearly with doses between 5 and 30mg. A multi-particulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a 'toothbrush' regimen provides physiological cortisol exposure. This article is protected by copyright. All rights reserved.
    Full-text · Article · Aug 2013 · Clinical Endocrinology

  • No preview · Article · Mar 2013
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    ABSTRACT: Context:The gene for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, CYP21A2, is flanked by the gene encoding tenascin-X (TNXB), a connective tissue extracellular matrix protein that has been linked to both autosomal dominant and autosomal recessive Ehlers-Danlos syndrome (EDS). A contiguous deletion of CYP21A2 and TNXB has been described.Objective:The objective of the study was to determine the frequency and clinical significance of TNXB haploinsufficiency in CAH patients.Design, Setting, and Participants:A total of 192 consecutive unrelated CAH patients being seen as part of an observational study at the National Institutes of Health Clinical Center (Bethesda, MD) were prospectively studied during 2006-2010. Patients were evaluated for clinical evidence of EDS, including cardiac evaluation. DNA was analyzed by PCR, multiplex ligation-dependent probe amplification, Southern blot, and TNXB sequencing. Tenascin-X expression was evaluated by Western blot analysis of fibroblasts and immunostaining of the skin. CAH patients with TNXB haploinsufficiency were compared with age-matched CAH patients with normal TNXB (controls). Phenotyping of 7 parents with TNXB haploinsufficiency was performed.Main Outcome Measures:The frequency of TNXB haploinsufficiency among CAH patients and the frequency of EDS symptomatology among CAH patients with TNXB haploinsufficiency and controls.Results:TNXB haploinsufficiency, here termed CAH-X syndrome, was present in 7% of CAH patients. Twelve of 91 patients carrying a CYP21A2 deletion (13%) carried a contiguous deletion that extended into TNXB. One patient carried a TNXB premature stop codon. Twelve of 13 patients with CAH-X had EDS clinical features. Patients with CAH-X were more likely than age-matched controls to have joint hypermobility (P < .001), chronic joint pain (P = .003), multiple joint dislocations (P = .004), a structural cardiac valve abnormality by echocardiography (P = .02), and reduced tenascin-X expression by Western blot and immunostaining. A subset of parents had clinical findings.Conclusions:Clinical evaluation for connective tissue dysplasia should be routinely performed in CAH patients, especially those harboring a CYP21A2 deletion.
    Full-text · Article · Jan 2013 · The Journal of Clinical Endocrinology and Metabolism
  • Rachel Morissette · Deborah P. Merke · Nazli B. McDonnell
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    ABSTRACT: Patients with congenital adrenal hyperplasia (CAH) with tenascin-X deficiency (CAH-X syndrome) have both endocrine imbalances and characteristic Ehlers Danlos syndrome phenotypes. Unlike other subtypes, tenascin-X-related Ehlers Danlos syndrome is caused by an extracellular matrix protein deficiency rather than a defect in fibrillar collagen or a collagen-modifying enzyme, and the understanding of the disease mechanisms is limited. We hypothesized that transforming growth factor-β pathway dysregulation may, in part, be responsible for connective tissue phenotypes observed in CAH-X, due to this pathway’s known role in connective tissue disorders. Fibroblasts and direct tissue from human skin biopsies from CAH-X probands and age- and sex-matched controls were screened for transforming growth factor-β biomarkers known to be dysregulated in other hereditary disorders of connective tissue. In CAH-X fibroblast lines and dermal tissue, pSmad1/5/8 was significantly upregulated compared to controls, suggesting involvement of the bone morphogenetic protein pathway. Additionally, CAH-X samples compared to controls exhibited significant increases in fibroblast-secreted TGF-β3, a cytokine important in secondary palatal development, and in plasma TGF-β2, a cytokine involved in cardiac function and development, as well as palatogenesis. Finally, MMP-13, a matrix metalloproteinase important in secondary palate formation and tissue remodeling, had significantly increased mRNA and protein expression in CAH-X fibroblasts and direct tissue. Collectively, these results demonstrate that patients with CAH-X syndrome exhibit increased expression of several transforming growth factor-β biomarkers and provide a novel link between this signaling pathway and the connective tissue dysplasia phenotypes associated with tenascin-X deficiency.
    No preview · Article · Jan 2013 · European journal of medical genetics
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    ABSTRACT: Context:Patients with congenital adrenal hyperplasia (CAH) often suffer from long-term complications secondary to chronic glucocorticoid therapy and suboptimal treatment regimens.Objective:The aim of the study was to describe clinical characteristics of a large cohort of pediatric and adult CAH patients.Design and Setting:We conducted a cross-sectional study of 244 CAH patients [183 classic, 61 nonclassic (NC)] included in a Natural History Study at the National Institutes of Health.Main Outcome Measure(s):Outcome variables of interest were height sd score, obesity, hypertensive blood pressure (BP), insulin resistance, metabolic syndrome, bone mineral density, hirsutism (females), and testicular adrenal rest (TART).Results:The majority had elevated or suppressed androgens, with varied treatment regimens. Mean adult height sd score was -1.0 ± 1.1 for classic vs. -0.4 ± 0.9 for NC patients (P = 0.015). Obesity was present in approximately one third of patients, across phenotypes. Elevated BP was more common in classic than NC patients (P ≤ 0.01); pediatric hypertensive BP was associated with suppressed plasma renin activity (P = 0.001). Insulin resistance was common in classic children (27%) and adults (38% classic, 20% NC); 18% of adults had metabolic syndrome. The majority (61%) had low vitamin D; 37% of adults had low bone mineral density. Hirsutism was common (32% classic; 59% NC women). TART was found in classic males (33% boys; 44% men).Conclusions:Poor hormonal control and adverse outcomes are common in CAH, necessitating new treatments. Routine monitoring of classic children should include measuring BP and plasma renin activity. Osteoporosis prophylaxis and TART screening should begin during childhood. A longitudinal study is under way.
    Full-text · Article · Sep 2012 · The Journal of Clinical Endocrinology and Metabolism

Publication Stats

3k Citations
603.32 Total Impact Points

Institutions

  • 1999-2015
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      • Program in Developmental Endocrinology and Genetics (PDEGEN)
      Роквилл, Maryland, United States
  • 1999-2014
    • National Institutes of Health
      • Center for Clinical Research
      Maryland, United States
  • 2008
    • Northern Inyo Hospital
      BIH, California, United States
  • 2004-2008
    • National Institute of Mental Health (NIMH)
      • Child Psychiatry Branch
      베서스다, Maryland, United States
  • 2001-2008
    • National Institute of Child Health and Human Development
      Maryland, United States
  • 2007
    • Walter Reed National Military Medical Center
      Washington, Washington, D.C., United States
  • 2002
    • New York Presbyterian Hospital
      • Department of Pediatrics
      New York City, New York, United States
    • Cornell University
      • Department of Pediatrics
      Итак, New York, United States
  • 2000
    • University of North Carolina at Chapel Hill
      • Department of Pediatrics
      North Carolina, United States