Deborah P Merke

National Institutes of Health, Maryland, United States

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Publications (81)541.61 Total impact

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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.
    Clinical Endocrinology 05/2014; · 3.40 Impact Factor
  • Medical Hypotheses 03/2014; · 1.18 Impact Factor
  • 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.
    The lancet. Diabetes & endocrinology. 12/2013; 1(4):341-352.
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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.
    The Journal of molecular diagnostics: JMD 09/2013; · 3.48 Impact Factor
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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.
    Clinical Endocrinology 08/2013; · 3.40 Impact Factor
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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.
    The Journal of Clinical Endocrinology and Metabolism 01/2013; · 6.31 Impact Factor
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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.
    European journal of medical genetics 01/2013; · 1.57 Impact Factor
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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.
    The Journal of Clinical Endocrinology and Metabolism 09/2012; · 6.31 Impact Factor
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    ABSTRACT: Little is known about how steroid hormones contribute to the beneficial effect of incentives on cognitive control during adolescent development. In this study, 27 adolescents with Congenital Adrenal Hyperplasia (CAH, mean age 15.6 years, 12 female), a disorder of cortisol deficiency and androgen excess, and 36 healthy participants (mean age 16.3 years, 18 female) completed a reward-based antisaccade task. In this mixed-saccade task, participants performed eye movements towards (prosaccades) or away (antisaccades) from a peripherally occuring stimulus. On incentive trials, monetary reward was provided for correct performance, while no such reward was provided on no-incentive trials. Consistent with the hypothesis, the results showed that healthy, but not CAH adolescents, significantly improved their inhibitory control (antisaccade accuracy) during incentive trials relative to no-incentive trials. These findings were not driven by severity of CAH (salt wasters vs. simple virilizers), individual hormone levels, sex, age-at-diagnosis, or medication type (dexamethasone vs. hydrocortisone). In addition, no significant differences between groups were found on orienting responses (prosaccades). Additional analyses revealed an impact of glucocorticoid (GC) dosage, such that higher GC dose predicted better antisaccade performance. However, this effect did not impact incentive processing. The data are discussed within the context of steroid hormone mediated effects on cognitive control and reward processing.
    Psychoneuroendocrinology 08/2012; · 5.59 Impact Factor
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    ABSTRACT: Context:Adrenalectomy is an experimental treatment option for select patients with congenital adrenal hyperplasia who have failed medical therapy. After adrenalectomy, adrenal rest tissue can remain in extraadrenal locations, cause recurrent hyperandrogenism, and be difficult to localize.Objective:The aim of the study was to investigate the usefulness of positron emission tomography/computerized tomography (PET/CT) in identifying adrenal rest tissue.Subject:A female with salt-wasting 21-hydroxylase deficiency who had bilateral adrenalectomy at age 17 yr presented with hyperandrogenism at age 32 yr. Pelvic magnetic resonance imaging and ultrasound imaging were nondiagnostic for the source of androgen production.Methods and Results:A baseline F-18 labeled fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT scan showed no active uptake; however, a second scan preceded by a 250-μg cosyntropin injection identified three areas of active uptake near both ovaries. Subsequent ovarian venous sampling showed elevations in 17-hydroxyprogesterone, androstenedione, and 21-deoxycortisol in both ovarian veins compared to a peripheral vein at baseline and more so after cosyntropin administration. At laparoscopy, three well-circumscribed nodules (2.4 × 0.9 × 1.3 cm, 1.2 × 1.5 × 1.5 cm, and 2 × 1.5 × 1 cm) lying lateral to the fallopian tubes adjacent to the broad ligaments were removed. The paraovarian nodules and previously removed adrenal glands had similar histology and immunohistochemistry. Postoperatively, androgen concentrations were undetectable, with no response to cosyntropin stimulation.Conclusions:Patients with CAH after an adrenalectomy may experience recurrent hyperandrogenism due to adrenal rest tissue. 18F-FDG PET/CT with cosyntropin stimulation accurately identified adrenal rest tissue not visualized with conventional imaging, allowing for successful surgical resection.
    The Journal of Clinical Endocrinology and Metabolism 08/2012; · 6.31 Impact Factor
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    ABSTRACT: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of cortisol biosynthesis caused by CYP21A2 mutations. An increase in gene copy number variation (CNV) exists at the CYP21A2 locus. CNV of C4, a neighboring gene that encodes complement component 4, is associated with autoimmune disease susceptibility. In this study, we performed comprehensive genetic analysis of the RP-C4-CYP21-TNX (RCCX) region in 127 unrelated 21-OHD patients (100 classic, 27 nonclassic). C4 copy number was determined by Southern blot. C4 CNV and serum C4 levels were evaluated in relation to CYP21A2 mutations and relevant phenotypes. We found that the most common CYP21A2 mutation associated with the nonclassic form of CAH, V281L, was associated with high C4 copy number (p = 7.13 × 10(-16)). Large CYP21A2 deletion, a common mutation associated with the classic form of CAH, was associated with low C4 copy number (p = 1.61 × 10(-14)). Monomodular RCCX with a short C4 gene, a risk factor for autoimmune disease, was significantly less frequent in CAH patients compared to population estimates (2.8 vs. 10.6 %; p = 1.08 × 10(-4)). In conclusion, CAH patients have increased C4 CNV, with mutation-specific associations that may be protective for autoimmune disease. The study of CYP21A2 in relation to neighboring genes provides insight into the genetics of CNV hotspots, an important determinant of human health.
    Human Genetics 08/2012; · 4.63 Impact Factor
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    ABSTRACT: Chimeric CYP21A1P/CYP21A2 genes, caused by homologous recombination between CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) and its highly homologous pseudogene CYP21A1P (cytochrome P450, family 21, subfamily A, polypeptide 1 pseudogene), are common in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). A comprehensive junction site analysis of chimeric CYP21A1P/CYP21A2 genes is needed for optimizing genetic analysis strategy and determining clinical relevance. We conducted a comprehensive genetic analysis of chimeric CYP21A1P/CYP21A2 genes in a cohort of 202 unrelated 21-OHD patients. Targeted CYP21A2 mutation analysis was performed, and genotyping of chimeric CYP21A1P/CYP21A2 genes was cross-confirmed with Southern blot, RFLP, and multiplex ligation-dependent probe amplification analyses. Junction sites of chimera genes were determined by sequencing the long-PCR products amplified with primers CYP779f and Tena32F. An updated bioinformatics survey of Chi-like sequences was also performed. Of 100 probands with a chimeric allele, 96 had a chimera associated with the severe classic salt-wasting form of CAH, and the remaining 4 carried an uncommon attenuated chimera with junction sites upstream of In2G (c.293-13A/C>G), which is associated with a milder phenotype. In addition to 6 of 7 reported chimeras, we identified a novel classic chimera (CH-8) and a novel attenuated chimera (CH-9). Attenuated chimeras explained prior genotype-phenotype discrepancies in 3 of the patients. Sequencing the CYP779f/Tena32F amplicons accurately differentiated between classic and attenuated chimeras. The bioinformatics survey revealed enrichment of Chi-like sequences within or in the vicinity of intron 2. Junction site analysis can explain some genotype-phenotype discrepancies. Sequencing the well-established CYP779f/Tena32F amplicons is an unequivocal strategy for detecting attenuated chimeric CYP21A1P/CYP21A2 genes, which are clinically relevant.
    Clinical Chemistry 12/2011; 58(2):421-30. · 7.15 Impact Factor
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    ABSTRACT: Major questions remain about the specific role of testosterone in human spatial navigation. We tested 10 boys (mean age 11.65 years) with an extremely rare disorder of androgen excess (Familial Male Precocious Puberty, FMPP) and 40 healthy boys (mean age 12.81 years) on a virtual version of the Morris Water Maze task. In addition, anatomical magnetic resonance images were collected for all patients and a subsample of the controls (n=21) after task completion. Behaviourally, no significant differences were found between both groups. However, in the MRI analyses, grey matter volume (GMV) was correlated with performance using voxel-based morphometry (VBM). Group differences in correlations of performance with GMV were apparent in medial regions of the prefrontal cortex as well as the middle occipital gyrus and the cuneus. By comparison, similar correlations for both groups were found in the inferior parietal lobule. These data provide novel insight into the relation between testosterone and brain development and suggest that morphological differences in a spatial navigation network covary with performance in spatial ability.
    Neuroscience 09/2011; 197:225-32. · 3.12 Impact Factor
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    ABSTRACT: Major questions remain about how sex hormones influence human brain development and cognition. Studies in humans and animals suggest a strong impact of androgen on the structure and function of the medial temporal lobe (MTL) and striatum. Using voxel-based morphometry (DARTEL), we compared MTL and striatal structures in 13 [mean age (±S.D.) 12.7±3.2 yr, mean bone age 14.8±3.2 yr] boys with familial male precocious puberty (FMPP), characterized by early excess androgen secretion, and 39 healthy age-matched boys (mean age 14.3±2.5 yr). The FMPP group showed significantly larger grey-matter volume (GMV) in parahippocampal and fusiform gyri as well as putamen relative to controls. By comparison, larger GMV for controls relative to patients was only apparent in the precentral gyrus. Exploratory regression analyses that examined the impact of age on the current findings revealed a significant increase of GMV in the putamen with age in patients suffering from excess androgen but not in controls. Finally, current levels of free testosterone were obtained in the patient group. Analyses revealed a significant negative association indicating that FMPP boys with low levels of bioavailable testosterone exhibited high GMV in the bilateral striatum. The findings suggest a critical influence of androgen on human brain development and are discussed in relation to male-dominant psychiatric childhood disorders.
    The International Journal of Neuropsychopharmacology 05/2011; 14(4):445-57. · 5.64 Impact Factor
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    ABSTRACT: Hormonal imbalances during development may have long-lasting effects. Using functional magnetic resonance imaging (fMRI), we compared 14 youths with Congenital Adrenal Hyperplasia (CAH), a genetic disorder of hormonal dysfunction, with 22 healthy controls on memory encoding of emotional faces. Patients remembered fewer faces than controls, particularly fearful faces. FMRI data to successfully encoded fearful faces revealed that males with CAH showed significant activations in amygdala, hippocampus, and anterior cingulate relative to unaffected males, while females with CAH demonstrated deactivations relative to unaffected females in these regions. Findings indicate that steroid abnormalities during development can have important effects on neural correlates of emotional memory.
    Developmental Neuropsychology 05/2011; 36(4):473-92. · 2.90 Impact Factor
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    ABSTRACT: To comprehensively phenotype parents identified with nonclassic congenital adrenal hyperplasia (NCCAH) by family genetic studies, termed here as cryptic NCCAH and to define the incidence of cryptic NCCAH in the parents of a large cohort of patients with 21-hydroxylase deficiency. Genotyping was performed on 249 parents of 145 unrelated congenital adrenal hyperplasia (CAH) patients. Parents with two CYP21A2 mutations underwent extensive evaluation. Of the 249 parents, ten (4%; seven females and three males) were identified as having cryptic NCCAH. The majority was of ethnicities previously reported to have a higher incidence of NCCAH. Cosyntropin stimulation performed in eight parents provided biochemical confirmation (17-hydroxyprogesterone range 56-364 nmol/l) and cortisol response was ≤500 nmol/l in three parents (38%). Of the seven women (27-54 years) with cryptic NCCAH, four had prior infertility, two reported irregular menses, two had treatment for hirsutism, one had androgenic alopecia. Men were asymptomatic. All cryptic NCCAH parents reported normal puberty and had normal height. Adrenal hypertrophy and a small adrenal myelolipoma were observed in two parents; testicular adrenal rest tissue was not found. Parents diagnosed with NCCAH by genetic testing are mostly asymptomatic. Temporary female infertility and suboptimal cortisol response were commonly observed. Ongoing glucocorticoid therapy is not indicated in adults with CAH identified by family genotype studies unless symptomatic, but glucocorticoid stress coverage should be considered in select cases. Parents of a child with CAH have a 1:25 risk of having NCCAH; if the mother of a child with CAH has infertility, evaluation for NCCAH is indicated.
    European Journal of Endocrinology 03/2011; 164(6):977-84. · 3.14 Impact Factor
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    ABSTRACT: Very little is known about the mental health status in children with genetic causes of hyperandrogenism. This study sought to characterize psychiatric morbidity in this group. Children (8-18 years) with the diagnosis of classic congenital adrenal hyperplasia (CAH) or familial male precocious puberty (FMPP) underwent a semi-structured psychiatric interview, the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version. According to sex and the literature, incidence of identified psychopathology was compared between the two endocrinological groups. We evaluated 72 patients: 54 CAH (21 females) and 18 FMPP. Twenty-four (44.4%) CAH patients and 10 (55.6%) FMPP patients met the criteria for at least one lifetime psychiatric diagnosis. Attention-deficit hyperactivity disorder (ADHD) was present in 18.2% of CAH males, 44.4% of FMPP males, and one case (4.8%) in CAH females. A high rate of anxiety disorders was also found in all the three groups (17-21%). Relative to females with CAH, the FMPP patients exhibited higher rates of ADHD. Age at diagnosis and the treatment modalities were not associated with psychopathology. Rates of psychiatric disorder, specifically ADHD and anxiety disorders, were higher than in the general population. Although anxiety disorders may occur at an increased rate in children with chronic illness, androgens may contribute to higher risk for psychopathology in pediatric patients with genetic cause of excess androgen. Early diagnosis and treatment of childhood hyperandrogenism is essential for optimal development. The results suggest that assessment for psychiatric disorders should be part of the routine evaluation of these patients.
    European Journal of Endocrinology 11/2010; 163(5):801-10. · 3.14 Impact Factor
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    ABSTRACT: Genetic analysis is commonly performed in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The objective of the study was to describe comprehensive CYP21A2 mutation analysis in a large cohort of CAH patients. Targeted CYP21A2 mutation analysis was performed in 213 patients and 232 parents from 182 unrelated families. Complete exons of CYP21A2 were sequenced in patients in whom positive mutations were not identified by targeted mutation analysis. Copy number variation and deletions were determined using Southern blot analysis and PCR methods. Genotype was correlated with phenotype. In our heterogeneous U.S. cohort, targeted CYP21A2 mutation analysis did not identify mutations on one allele in 19 probands (10.4%). Sequencing identified six novel mutations (p.Gln262fs, IVS8+1G>A, IVS9-1G>A, p.R408H, p.Gly424fs, p.R426P) and nine previously reported rare mutations. The majority of patients (79%) were compound heterozygotes and 69% of nonclassic (NC) patients were compound heterozygous for a classic and a NC mutation. Duplicated CYP21A2 haplotypes, de novo mutations and uniparental disomy were present in 2.7% of probands and 1.9 and 0.9% of patients from informative families, respectively. Genotype accurately predicted phenotype in 90.5, 85.1, and 97.8% of patients with salt-wasting, simple virilizing, and NC mutations, respectively. Extensive genetic analysis beyond targeted CYP21A2 mutational detection is often required to accurately determine genotype in patients with CAH due to the high frequency of complex genetic variation.
    The Journal of Clinical Endocrinology and Metabolism 10/2010; 96(1):E161-72. · 6.31 Impact Factor
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    ABSTRACT: We developed clinical practice guidelines for congenital adrenal hyperplasia (CAH). The Task Force included a chair, selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), ten additional clinicians experienced in treating CAH, a methodologist, and a medical writer. Additional experts were also consulted. The authors received no corporate funding or remuneration. Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS 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. We recommend universal newborn screening for severe steroid 21-hydroxylase deficiency followed by confirmatory tests. We recommend that prenatal treatment of CAH continue to be regarded as experimental. The diagnosis rests on clinical and hormonal data; genotyping is reserved for equivocal cases and genetic counseling. Glucocorticoid dosage should be minimized to avoid iatrogenic Cushing's syndrome. Mineralocorticoids and, in infants, supplemental sodium are recommended in classic CAH patients. We recommend against the routine use of experimental therapies to promote growth and delay puberty; we suggest patients avoid adrenalectomy. Surgical guidelines emphasize early single-stage genital repair for severely virilized girls, performed by experienced surgeons. Clinicians should consider patients' quality of life, consulting mental health professionals as appropriate. At the transition to adulthood, we recommend monitoring for potential complications of CAH. Finally, we recommend judicious use of medication during pregnancy and in symptomatic patients with nonclassic CAH.
    The Journal of Clinical Endocrinology and Metabolism 09/2010; 95(9):4133-60. · 6.31 Impact Factor
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    ABSTRACT: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is classified into three types based on disease severity: classic salt-wasting, classic simple virilizing, and nonclassic. Adrenomedullary dysplasia and epinephrine deficiency have been described in classic CAH, resulting in glucose dysregulation. Our objective was to investigate adrenomedullary function in nonclassic CAH and to evaluate adrenomedullary function according to disease severity. Adrenomedullary function was evaluated in response to a standardized cycle ergonometer test in 23 CAH patients (14 females, age 9-38 years; 6 salt-wasting, 7 simple virilizing, 5 nonclassic receiving glucocorticoid treatment, 5 nonclassic not receiving glucocorticoid), and 14 controls (7 females, age 12-38 years). Epinephrine, glucose, and cortisol were measured at baseline and peak exercise. CAH patients and controls were similar in age and anthropometric measures. Patients with nonclassic CAH who were not receiving glucocorticoid and controls experienced the expected stress-induced rise in epinephrine, glucose, and cortisol. Compared to controls, patients with all types of CAH receiving glucocorticoid had impaired exercise-induced changes in epinephrine (salt-wasting: p=0.01;simple virilizing: p=0.01; nonclassic: p=0.03), and cortisol (salt-wasting: p=0.004; simple virilizing: p=0.006; nonclassic: p=0.03). Salt-wasting patients displayed the most significant impairment, including impairment in glucose response relative to controls (p=0.03). Hydrocortisone dose was negatively correlated with epinephrine response (r=-0.58; p=0.007) and glucose response (r=-0.60; p=0.002). The present study demonstrates that untreated patients with nonclassic CAH have normal adrenomedullary function. The degree of epinephrine deficiency in patients with CAH is associated with the severity of adrenocortical dysfunction, as well as glucocorticoid therapy.
    Hormone and Metabolic Research 05/2010; 42(8):607-12. · 2.15 Impact Factor

Publication Stats

2k Citations
541.61 Total Impact Points

Institutions

  • 1999–2014
    • National Institutes of Health
      • • Center for Clinical Research
      • • Branch of Mood and Anxiety Disorders
      • • Section on Reproductive Endocrinology
      Maryland, United States
  • 2009–2013
    • National Institute on Aging
      • Laboratory of Clinical Investigation (LCI)
      Baltimore, MD, United States
  • 2004–2012
    • National Institute of Mental Health (NIMH)
      • Child Psychiatry Branch
      Maryland, United States
  • 2011
    • University of Catania
      Catania, Sicily, Italy
  • 2008–2011
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      • Program in Developmental Endocrinology and Genetics (PDEGEN)
      Maryland, United States
  • 1996–2008
    • National Institute of Child Health and Human Development
      Maryland, United States
  • 2002
    • New York Presbyterian Hospital
      • Department of Pediatrics
      New York City, New York, United States