Publications by authors named "Maya B Lodish"

60 Publications

Rare Germline Variants in Pediatric Patients With Cushing's Disease: What Is Their Role?

Front Endocrinol (Lausanne) 2020 3;11:433. Epub 2020 Jul 3.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States.

The DICER1 syndrome is a multiple neoplasia disorder caused by germline mutations in the gene. In DICER1 patients, aggressive congenital pituitary tumors lead to neonatal Cushing's disease (CD). The role of in other corticotropinomas, however, remains unknown. To perform a comprehensive screening for variants in a large cohort of CD patients, and to analyze their possible contribution to the phenotype. We included 192 CD cases: ten young-onset (age <30 years at diagnosis) patients were studied using a next generation sequencing panel, and 182 patients (170 pediatric and 12 adults) were screened via whole-exome sequencing. In seven cases, tumor samples were analyzed by Sanger sequencing. Rare germline variants were found in seven pediatric patients with no other known disease-associated germline defects or somatic second hits. By immunohistochemistry, DICER1 showed nuclear localization in 5/6 patients. Variant transmission from one of the parents was confirmed in 5/7 cases. One patient had a multinodular goiter; another had a family history of melanoma; no other patients had a history of neoplasms. Our findings suggest that gene variants may contribute to the pathogenesis of non-syndromic corticotropinomas. Clarifying whether loss-of-function is disease-causative or a mere disease-modifier in this setting, requires further studies. ClinicalTrials.gov: NCT00001595.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2020.00433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351020PMC
July 2020

The Association of ARMC5 with the Renin-Angiotensin-Aldosterone System, Blood Pressure, and Glycemia in African Americans.

J Clin Endocrinol Metab 2020 08;105(8)

The Ohio State University, Columbus, Ohio.

Context: Armadillo repeat containing 5 (ARMC5) on chromosome 16 is an adrenal gland tumor suppressor gene associated with primary aldosteronism, especially among African Americans (AAs). We examined the association of ARMC5 variants with aldosterone, plasma renin activity (PRA), blood pressure, glucose, and glycosylated hemoglobin A1c (HbA1c) in community-dwelling AAs.

Methods: The Jackson Heart Study is a prospective cardiovascular cohort study in AAs with baseline data collection from 2000 to 2004. Kernel machine method was used to perform a single joint test to analyze for an overall association between the phenotypes of interest (aldosterone, PRA, systolic and diastolic blood pressure [SBP, DBP], glucose, and HbA1c) and the ARMC5 single nucleotide variants (SNVs) adjusted for age, sex, BMI, and medications; followed by Baysian Lasso methodology to identify sets of SNVs in terms of associated haplotypes with specific phenotypes.

Results: Among 3223 participants (62% female; mean age 55.6 (SD ± 12.8) years), the average SBP and DBP were 127 and 76 mmHg, respectively. The average fasting plasma glucose and HbA1c were 101 mg/dL and 6.0%, respectively. ARMC5 variants were associated with all 6 phenotypes. Haplotype TCGCC (ch16:31476015-31476093) was negatively associated, whereas haplotype CCCCTTGCG (ch16:31477195-31477460) was positively associated with SBP, DBP, and glucose. Haplotypes GGACG (ch16:31477790-31478013) and ACGCG (ch16:31477834-31478113) were negatively associated with aldosterone and positively associated with HbA1c and glucose, respectively. Haplotype GCGCGAGC (ch16:31471193-ch16:31473597(rs114871627) was positively associated with PRA and negatively associated with HbA1c.

Conclusions: ARMC5 variants are associated with aldosterone, PRA, blood pressure, fasting glucose, and HbA1c in community-dwelling AAs, suggesting that germline mutations in ARMC5 may underlie cardiometabolic disease in AAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308077PMC
August 2020

Computerized Analysis of Brain MRI Parameter Dynamics in Young Patients With Cushing Syndrome-A Case-Control Study.

J Clin Endocrinol Metab 2020 05;105(5)

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Background: Young patients with Cushing Syndrome (CS) may develop cognitive and behavioral alterations during disease course.

Methods: To investigate the effects of CS on the brain, we analyzed consecutive MRI scans of patients with (n = 29) versus without CS (n = 8). Multiple brain compartments were processed for total and gray/white matter (GM/WM) volumes and intensities, and cortical volume, thickness, and surface area. Dynamics (last/baseline scans ratio per parameter) were analyzed versus cortisol levels and CS status (persistent, resolved, and non-CS).

Results: Twenty-four-hour urinary free cortisol (24hUFC) measurements had inverse correlation with the intensity of subcortical GM structures and of the corpus callosum, and with the cerebral WM intensity. 24hUFC dynamics had negative correlation with volume dynamics of multiple cerebral and cerebellar structures. Patients with persistent CS had less of an increase in cortical thickness and WM intensity, and less of a decrease in WM volume compared with patients with resolution of CS. Patients with resolution of their CS had less of an increase in subcortical GM and cerebral WM volumes, but a greater increase in cortical thickness of frontal lobe versus controls.

Conclusion: Changes in WM/GM consistency, intensity, and homogeneity in patients with CS may correlate with CS clinical consequences better than volume dynamics alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgz303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089850PMC
May 2020

ARMC 5 Variants and Risk of Hypertension in Blacks: MH- GRID Study.

J Am Heart Assoc 2019 07 3;8(14):e012508. Epub 2019 Jul 3.

1 Section on Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD.

Background We recently found that ARMC 5 variants may be associated with primary aldosteronism in blacks. We investigated a cohort from the MH - GRID (Minority Health Genomics and Translational Research Bio-Repository Database) and tested the association between ARMC 5 variants and blood pressure in black s. Methods and Results Whole exome sequencing data of 1377 black s were analyzed. Target single-variant and gene-based association analyses of hypertension were performed for ARMC 5, and replicated in a subset of 3015 individuals of African descent from the UK Biobank cohort. Sixteen rare variants were significantly associated with hypertension ( P=0.0402) in the gene-based (optimized sequenced kernel association test) analysis; the 16 and one other, rs116201073, together, showed a strong association ( P=0.0003) with blood pressure in this data set. The presence of the rs116201073 variant was associated with lower blood pressure. We then used human embryonic kidney 293 and adrenocortical H295R cells transfected with an ARMC 5 construct containing rs116201073 (c.*920T>C). The latter was common in both the discovery ( MH - GRID ) and replication ( UK Biobank) data and reached statistical significance ( P=0.044 [odds ratio, 0.7] and P=0.007 [odds ratio, 0.76], respectively). The allele carrying rs116201073 increased levels of ARMC5 mRNA , consistent with its protective effect in the epidemiological data. Conclusions ARMC 5 shows an association with hypertension in black s when rare variants within the gene are considered. We also identified a protective variant of the ARMC 5 gene with an effect on ARMC 5 expression confirmed in vitro. These results extend our previous report of ARMC 5's possible involvement in the determination of blood pressure in blacks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.119.012508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662143PMC
July 2019

Germline USP8 Mutation Associated With Pediatric Cushing Disease and Other Clinical Features: A New Syndrome.

J Clin Endocrinol Metab 2019 10;104(10):4676-4682

Pediatric Endocrinology Unit, Ruth Rappaport Children's Hospital, Rambam Health Care Campus, Haifa, Israel.

Background: Somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene are common in corticotropinomas of children with Cushing disease (CD). We report a unique patient with a germline USP8 mutation who presented with CD and a constellation of other findings that constitute an intriguing genetic syndrome.

Case Description: We describe a 16-year-old female with CD, developmental delay, dysmorphic features, ichthyosiform hyperkeratosis, chronic lung disease, chronic kidney disease, hyperglycemia, dilated cardiomyopathy with congestive heart failure, and previous history of hyperinsulinism and partial GH deficiency. She was diagnosed with CD at 14 years old and underwent transsphenoidal surgery. Despite initial improvement, she developed recurrent CD.

Methods: DNA was extracted from peripheral blood and tumor DNA; whole-exome and Sanger confirmatory sequencing were performed. Immunohistochemistry was performed on the resected adenoma.

Results: A de novo germline heterozygous USP8 mutation (c.2155T>C, p.S719P) in the critical 14-3-3 binding motif hot spot locus of the gene was identified in both the peripheral blood and tumor DNA. Histopathologic evaluation of the resected tumor confirmed an ACTH-secreting adenoma.

Conclusion: Somatic USP8 mutations are common in adenomas causing CD, but to date, no germline defects have been reported. We describe a patient with a de novo germline USP8 mutation with recurrent CD and multiple other medical problems. This unique patient informs us of the multitude of signaling events that may be controlled by USP8.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2019-00697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736211PMC
October 2019

CRH stimulation improves F-FDG-PET detection of pituitary adenomas in Cushing's disease.

Endocrine 2019 07 6;65(1):155-165. Epub 2019 May 6.

Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Diseases and Stroke, Bethesda, MD, USA.

Objective: In MRI-negative cases Cushing's disease (CD), surgeons perform a more extensive exploration of the pituitary gland, with fewer instances of hormonal remission. F-fluoro-deoxy-glucose (F-FDG) positron emission tomography (PET) has a limited role in detecting adenomas that cause CD (corticotropinomas). Our previous work demonstrated corticotropin-releasing hormone (CRH) stimulation leads to delayed, selective glucose uptake in corticotropinomas. Here, we prospectively evaluated the utility of CRH stimulation in improving F-FDG-PET detection of adenomas in CD.

Methods: Subjects with a likely diagnosis of CD (n = 27, 20 females) each underwent two F-FDG-PET studies [without and with ovine-CRH (oCRH) stimulation] on a high-resolution PET platform. Standardized-uptake-values (SUV) in the sella were calculated. Two blinded neuroradiologists independently read F-FDG-PET images qualitatively. Adenomas were histopathologically confirmed, analyzed for mutations in the USP8 gene and for glycolytic pathway proteins.

Results: The mean-SUV of adenomas was significantly increased from baseline (3.6 ± 1.5) with oCRH administration (3.9 ± 1.7; one-tailed p = 0.003). Neuroradiologists agreed that adenomas were visible on 21 scans, not visible on 26 scans (disagreed about 7, kappa = 0.7). oCRH-stimulation led to the detection of additional adenomas (n = 6) not visible on baseline-PET study. Of the MRI-negative adenomas (n = 5), two were detected on PET imaging (one only after oCRH-stimulation). USP8 mutations or glycolytic pathway proteins were not associated with SUV in corticotropinomas.

Conclusions: The results of the current study suggest that oCRH-stimulation may lead to increased F-FDG uptake, and increased rate of detection of corticotropinomas in CD. These results also suggest that some MRI invisible adenomas may be detectable by oCRH-stimulated FDG-PET imaging.

Clinical Trial Information: F-FDG-PET imaging with and without CRH stimulation was performed under the clinical trial NIH ID 12-N-0007 (clinicaltrials.gov identifier NCT01459237). The transsphenoidal surgeries and post-operative care was performed under the clinical trial NIH ID 03-N-0164 (clinicaltrials.gov identifier NCT00060541).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12020-019-01944-7DOI Listing
July 2019

Careful investigation of a rare disease: insights into multiple endocrine neoplasia type 2B.

Authors:
Maya B Lodish

Lancet Diabetes Endocrinol 2019 03 16;7(3):167-168. Epub 2019 Jan 16.

Department of Pediatric Endocrinology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-8587(18)30353-XDOI Listing
March 2019

Optical Imaging Technology: A Useful Tool to Identify Remission in Cushing Disease After Surgery.

Horm Metab Res 2019 Feb 2;51(2):120-126. Epub 2019 Jan 2.

Section on Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.

We recently reported the use of optical imaging technology to quantify facial plethora in endogenous Cushing syndrome (CS). In the present study, we studied a larger cohort of patients with Cushing disease (CD) and examined water content fraction as well as blood volume fraction as bio-optic markers for determining the efficacy of this methodology as a predictor of lasting remission after surgery for CS. We imaged 49 patients before and after transsphenoidal surgery (TSS) for Cushing disease (CD); 22 patients were also seen at 3-6 months, and 13 patients 12 months post-operatively. On all patients, we used multi-spectral imaging (MSI) to evaluate hemodynamic distributions as well as water content at a specific area of the face. We found a decrease in blood volume fraction after vs. before surgical treatment in the tested facial area in 37 of the 40 patients, as determined with biochemical markers (p<0.001). All patients that were followed up for up to 12 months showed the same decrease from preoperative values and they remained in remission from CD. We conclude that MSI can be used for the evaluation of remission from CD, at least in the immediate post-operative period and up to one year after surgery. The use of this technology can supplement biochemical and other testing for the evaluation of the various treatment modalities available for patients with CD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-0801-8917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753582PMC
February 2019

Large Genomic Aberrations in Corticotropinomas Are Associated With Greater Aggressiveness.

J Clin Endocrinol Metab 2019 05;104(5):1792-1801

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Context: Genomic losses/gains are associated with cancer progression and prognosis. In pituitary adenomas, analyses of copy number variations (CNVs) have shown that a subset of adenomas have higher genomic variability. However, whether CNVs are associated with tumor aggressiveness and prognosis has not been determined.

Objective: We hypothesized that somatic CNVs of pituitary tumors may play a role in the progression and aggressiveness of pituitary corticotropinomas in children and adolescents.

Samples And Design: Paired germline and tumor DNA samples from 27 pediatric patients with Cushing disease (CD), were subjected to whole exome sequencing. Somatic CNVs were identified using the ExomeDepth tool. Clinical, histological, and biochemical data from the patients were collected and correlated with the results of the CNV analysis.

Results: Chromosomal instability, involving 23% to 59% of the tumor genome, was noted in 5 of the 27 samples (18.5%). The patients with tumors showing chromosomal instability had similar clinical and biochemical characteristics to the remaining patients, except for tumor size, which was larger (median size 18 mm vs 5.5 mm, P = 0.005). Tumors with chromosomal instability were also associated with a higher rate of invasion of the cavernous sinus (P = 0.029). There was insufficient information on persistence or recurrence of CD to determine whether the risk was higher in those with chromosomal instability.

Conclusions: A subgroup of corticotropinomas demonstrates chromosomal instability that is associated with markers of aggressiveness of these adenomas. It appears that more genomic gains/losses in a few, rare corticotropinomas may predict poorer prognosis for pediatric patients with CD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2018-02164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452317PMC
May 2019

Xq26.3 Duplication in a Boy With Motor Delay and Low Muscle Tone Refines the X-Linked Acrogigantism Genetic Locus.

J Endocr Soc 2018 Oct 3;2(10):1100-1108. Epub 2018 Aug 3.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland.

We describe a 4-year-old boy with developmental delay who was found to carry by clinical grade (CG) molecular cytogenetics (MCs) a chromosome Xq26 microduplication. The report prompted a referral of the patient for possible X-linked acrogigantism (X-LAG), a well-defined condition (MIM300942) due to chromosomal microduplication of a nearby region. The patient was evaluated clinically and investigated for endocrine abnormalities related to X-LAG and not only did he not have acrogigantism, but his growth parameters and other hormones were all normal. We then performed high definition MCs and the duplication copy number variant (CNV) was confirmed to precisely map outside the X-LAG critical region and definitely did not harbor the X-LAG candidate gene, . The patient's phenotype resembled that of other patients with Xq26 CNVs. The case is instructive for the need for high definition MCs when CG MCs' results are inconsistent with the patient's phenotype. It is also useful for further supporting the contention that is the gene responsible for X-LAG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/js.2018-00156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137279PMC
October 2018

Mini-review of hair cortisol concentration for evaluation of Cushing syndrome.

Expert Rev Endocrinol Metab 2018 09 20;13(5):225-231. Epub 2018 Sep 20.

c Section on Endocrinology and Genetics , Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda , MD , USA.

Introduction: The diagnosis of endogenous Cushing syndrome is often challenging and requires multiple repeated blood, urine, and saliva tests to detect elevated cortisol levels. Hair cortisol concentration has been described as a marker of long-term exposure to systemic cortisol in patients with Cushing syndrome. Like hemoglobin A1c is used to detect serum glucose exposure over months, segmental hair cortisol can help identify patients with milder forms of and/or periodic or cyclical Cushing syndrome, which may reduce time and costs associated with collection of urine, salivary, and serum cortisol.

Areas Covered: Success of hair cortisol in detection of Cushing syndrome will be discussed in context of current literature, including differences between total or segmental hair cortisol in accurately determining timeline of cortisol exposure. Optimal methods of hair collection, storage, processing, and analysis and efforts toward standardization will be a major focus.

Expert Commentary: Recent evidence suggests increased sensitivity and specificity of hair cortisol in detecting Cushing syndrome. Future guidelines should consider this test as a routine part of the repertoire of screening tests for Cushing syndrome. Possible confounders to explain discrepant results in the literature will be discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17446651.2018.1517043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378952PMC
September 2018

Cushing's Syndrome in Pediatrics: An Update.

Endocrinol Metab Clin North Am 2018 06;47(2):451-462

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1E-3330, MSC1103, Bethesda, MD 20892, USA.

Cushing syndrome (CS) is a multisystem disorder resulting from the prolonged exposure to excess glucocorticoids. In children, CS most commonly results from the exogenous administration of steroids and the typical presentation is height deceleration concomitant with weight gain. Endogenous and ectopic causes are rare. CS in children may be associated with distinct germline and somatic mutations. Clinical practice guidelines are available assist clinicians. Patients should be referred to multidisciplinary centers of excellence with experience in endocrinology and surgery. Early detection and treatment is essential to reduce associated acute and long-term morbidity and potential death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ecl.2018.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962291PMC
June 2018

Impaired Bone Mineral Density in Pediatric Patients with Chronic Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2018 07 1;24(7):1415-1423. Epub 2018 Mar 1.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Pediatric allogeneic hematopoietic stem cell transplantation (AHSCT) recipients with chronic graft-versus-host disease (cGVHD) are at high risk for endocrinopathies, particularly impaired bone mineral density (BMD). However, rates of BMD impairment in pediatric AHSCT recipients with cGVHD have not been well documented. We report 33 patients with cGVHD who were referred to the National Institutes of Health (NIH) for the Natural History of Clinical and Biological Factors Determining Outcomes in Chronic Graft-versus-Host Disease Study (NCT 0092235) and underwent formal BMD assessment via dual-energy X-ray absorptiometry (DEXA). Not surprisingly, we found much higher rates of BMD impairment than previously reported for pediatric AHSCT recipients who were not stratified by the presence or absence of cGVHD. Most of these patients (73%) had a z-score ≤-2 in at least 1 anatomic site. Although we expected the rate to be higher than that observed for pediatric AHSCT recipients in studies that did not analyze patients with cGVHD separately, this rate is nonetheless extremely high. Furthermore, the overall rate of occult vertebral compression fractures (VCFs) in our cohort was 17%, and the rate was 23% in patients with at least 1 z-score of ≤-2. The rates of BMD impairment and VCF in our pediatric cohort were significantly higher than those seen in the adult AHSCT recipients who were concurrently enrolled on the same study at the NIH and had similar cGVHD severity. We found that older age at cGVHD diagnosis and a greater number of systemic therapies were associated with occult VCF. Moreover, the intensity of current immunosuppression negatively impacted lumbar spine and total hip BMD in this cohort. Our study, although limited by small patient numbers and lack of a control AHSCT recipient group without cGVHD, indicates that children with cGVHD are at a greater risk for BMD impairment than previously appreciated. Given the rising incidence of cGVHD in AHSCT recipients and our findings, we recommend that pre-AHSCT DEXA be incorporated into routine pediatric pretransplantation screening studies. A baseline DEXA study could facilitate longitudinal monitoring of BMD in children, who may be more susceptible than adults to the negative effects of AHSCT on BMD. In addition, given the high risk of BMD impairment in pediatric AHSCT recipients with cGVHD, such patients should undergo BMD evaluation upon developing cGVHD, with continued monitoring thereafter to allow intervention before progression of the BMD impairment to its severe manifestation, VCF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2018.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045967PMC
July 2018

Incidence of Autoimmune and Related Disorders After Resolution of Endogenous Cushing Syndrome in Children.

Horm Metab Res 2018 Apr 19;50(4):290-295. Epub 2018 Feb 19.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA.

Glucocorticoids are widely used for immunosuppression in autoimmune diseases. After the resolution of hypercortisolemia, the immune system recovers allowing for autoimmune diseases to manifest. Here we investigated the presence of autoimmune and related diseases that developed after cure of endogenous Cushing syndrome (CS) in children. We identified 129 children who were diagnosed and successfully treated for endogenous CS at the National Institutes of Health from 1997 until 2017, and who were followed for at least 6 months after treatment. We performed a retrospective chart review analysis to identify the presence of autoimmune or related diseases after cure. Ten children were diagnosed with a new autoimmune or related disorder after resolution of hypercortisolemia. This results in a frequency of 7.8% of our pediatric CS population. The identified patients had a shorter duration of hypercortisolemia prior to diagnosis, but did not otherwise differ from the remaining patients. The various identified diseases were: celiac disease (n=1), psoriasis (n=1), Hashimoto thyroiditis (n=1), Graves disease (n=1), optic neuritis (n=2), skin hypopigmented lesions/vitiligo (n=2), allergic rhinitis/asthma (n=1), and neuropathy responding to glucocorticoid treatment (n=1). The reported time between the treatment of CS and diagnosis of autoimmune disorder ranged from 6 to 19 months. The presence of autoimmune or related diseases might be masked by the hypercortisolemic state in endogenous CS. After resolution of hypercortisolemia, the presentation of new autoimmune diseases or recurrence of previously known autoimmune conditions should be considered when concerning symptoms arise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0044-101144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341463PMC
April 2018

Corticotropinoma as a Component of Carney Complex.

J Endocr Soc 2017 Jul 30;1(7):918-925. Epub 2017 May 30.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.

Known germline gene abnormalities cause one-fifth of the pituitary adenomas in children and adolescents, but, in contrast with other pituitary tumor types, the genetic causes of corticotropinomas are largely unknown. In this study, we report a case of Cushing disease (CD) due to a loss-of-function mutation in , providing evidence for association of this gene with a corticotropinoma. A 15-year-old male presenting with hypercortisolemia was diagnosed with CD. Remission was achieved after surgical resection of a corticotropin (ACTH)-producing pituitary microadenoma, but recurrence 3 years later prompted reoperation and radiotherapy. Five years after the original diagnosis, the patient developed ACTH-independent Cushing syndrome, and a diagnosis of primary pigmented nodular adrenocortical disease was confirmed. A mutation (c.671delG, p.G225Afs*16) was detected in a germline DNA sample from the patient, which displayed loss of heterozygosity in the corticotropinoma. No other germline or somatic mutations of interest were found. As corticotropinomas are not a known component of Carney complex (CNC), we performed loss of heterozygosity and messenger RNA stability studies in the patient's tissues, and analyzed the effect of silencing on AtT-20/D16v-F2 mouse corticotropinoma cells. No defects were found among 97 other pediatric CD patients studied. Our clinical case and experimental data support a role for in the pathogenesis of a corticotroph cell tumor. This is a molecularly confirmed report of a corticotropinoma presenting in association with CNC. We conclude that germline mutations are a novel, albeit apparently infrequent, cause of CD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/js.2017-00231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686778PMC
July 2017

Decreased lymphocytes and increased risk for infection are common in endogenous pediatric Cushing syndrome.

Pediatr Res 2018 02 6;83(2):431-437. Epub 2017 Dec 6.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland.

BackgroundHypercortisolemia results in changes of the immune system and elevated infection risk, but data on the WBC changes in pediatric Cushing syndrome (CS) are not known. We describe the changes of the WBC lineages in pediatric endogenous hypercortisolemia, their associations with the markers of disease severity, and the presence of infections.MethodsWe identified 197 children with endogenous CS. Clinical and biochemical data were recorded. Sixty-six children with similar age and gender, and normocortisolemia served as controls.ResultsThe absolute lymphocyte count of CS patients was significantly lower than that of controls, while the total WBC and the absolute neutrophil counts were significantly higher. These changes correlated with several markers of CS severity and improved after resolution of hypercortisolemia. Infections were identified in 35 patients (17.8%), and their presence correlated to elevated serum morning cortisol, midnight cortisol, and urinary free cortisol levels, as well as with the decrease in absolute lymphocyte count.ConclusionsChildren with endogenous CS have abnormal WBC counts, which correlate with the severity of CS, and normalize after cure. Infections are common in this population; clinicians should be aware of this complication of CS and have low threshold in diagnosis and treating infections in CS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/pr.2017.278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866174PMC
February 2018

Failure to Thrive in the Context of Carney Complex.

Horm Res Paediatr 2018 21;89(1):38-46. Epub 2017 Nov 21.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.

Background/aims: Carney complex (CNC) is a rare syndrome associated with multiple tumors and several other unique manifestations. We describe the clinical, genetic, and laboratory findings in a cohort of patients with CNC and failure to thrive (FTT).

Methods: A retrospective case series of pediatric patients with CNC presenting with FTT.

Results: We describe a patient with infantile Cushing syndrome (CS) who presented with severe FTT and liver disease; the patient was subsequently diagnosed with CNC. This led to the realization that at least 10 other patients with CNC and FTT have been investigated in the last 22 years at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Four of those had primary pigmented nodular adrenocortical disease (PPNAD), 2 had cardiac myxomas, and 3 had liver disease.

Conclusion: Pediatric patients with CNC may present with FTT whose primary cause is variable and includes CS due to PPNAD, hepatic involvement, and other manifestations of CNC. FTT due to liver disease and/or other causes is a unique new presentation of this rare syndrome with which clinicians need to be familiar.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000484690DOI Listing
October 2018

Delayed Diagnosis of Cushing's Disease in a Pediatric Patient due to Apparent Remission from Spontaneous Apoplexy.

J Clin Transl Endocrinol Case Rep 2016 Dec;2:30-34

Clinical Center of the National Institutes of Health (NIH) 10 Center Dr, Bethesda, MD 20814.

We report here a pediatric patient whose Cushing's Disease was diagnosed late because of her cyclical presentation, presumably due to subclinical pituitary apoplexy. Starting at age 8, she presented with observable signs of Cushing's but was not clinically assessed for Cushing's Syndrome until the age of 15. Initial tests at age 15 were consistent with Cushing's Disease, however, the patient presented with spontaneous remission of hypercortisolemia just a few short months later. Her cushingoid features never subsided, and at age 17, her MRI showed a partially empty sella; this finding of an empty sella contributed evidence to our suspicion of asymptomatic apoplexy, especially since the patient never reported an episode of acute headache. Pituitary apoplexy in corticotroph adenomas is very uncommon, but even more rare in microadenomas, making this case very unusual. Lost to follow-up, she was not reevaluated for Cushing's Disease until age 25, and her laboratory tests were consistent with an adrenocorticotrophic-dependent pituitary tumor; Pituitary magnetic resonance imaging revealed a 9 mm X 6 mm X 8 mm mass projecting on the superior aspect of pituitary and abutting the wall of the right cavernous sinus. The patient had a transsphenoidal surgery to remove the microadenoma and is planned to undergo radiation therapy. To the best of our knowledge, this is the first report of subclinical apoplexy of a microadenoma in a pediatric patient with Cushing's Disease. It brings to light the importance of long term follow up for pediatric patients presenting with clinical symptoms of Cushing's Syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jecr.2016.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571867PMC
December 2016

Obesity and the diagnostic accuracy for primary aldosteronism.

J Clin Hypertens (Greenwich) 2017 Aug 13;19(8):790-797. Epub 2017 Jun 13.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

The effects of body mass index on the diagnostic accuracy of primary aldosteronism (PA) are inconsistent and yet important considering the high prevalence and frequent co-occurrence of obesity and hypertension. The current study included 59 adult patients who underwent a stepwise evaluation for PA, using aldosterone to renin ratio for case detection and plasma aldosterone concentration after saline suppression test and/or 24-hour urinary aldosterone after oral sodium loading for case confirmation. Body mass index had a quadratic (U-shaped) correlation with plasma aldosterone concentration, plasma renin activity, aldosterone to renin ratio, and plasma aldosterone concentration after saline suppression test. Among patients with a body mass index ≥30 kg/m , the aldosterone to renin ratio yielded lower case detection accuracy of PA. We conclude that obesity results in a nonlinear correlation with plasma aldosterone concentration, plasma renin activity, and aldosterone to renin ratio, which affects the accuracy of case detection for PA. Patients with a body mass index ≥30 kg/m are less accurately identified as having PA when saline suppression and/or oral salt loading tests are used for case confirmation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jch.13041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602533PMC
August 2017

Loss-of-function mutations in the gene are a novel cause of Cushing's disease.

Endocr Relat Cancer 2017 08 22;24(8):379-392. Epub 2017 May 22.

Section on Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

The cell cycle regulator participates in the adrenal-pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing's disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/ERC-17-0131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510591PMC
August 2017

Bone mineral density in patients with inherited bone marrow failure syndromes.

Pediatr Res 2017 Sep 31;82(3):458-464. Epub 2017 May 31.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.

BackgroundPatients with inherited bone marrow failure syndromes (IBMFS) may have several risk factors for low bone mineral density (BMD). We aimed to evaluate the prevalence of low BMD in IBMFS and determine the associated risk factors.MethodsPatients with IBMFS with at least one dual-energy X-ray absorptiometry (DXA) scan were evaluated. Diagnosis of each IBMFS, Fanconi anemia (FA), dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome was confirmed by syndrome-specific tests. Data were gathered on age, height, and clinical history. DXA scans were completed at the lumbar spine, femoral neck, and forearm. BMD was adjusted for height (HAZ) in children (age ≤20 years). Low BMD was defined as a BMD Z-score and HAZ ≤-2 in adults and children, respectively, in addition to patients currently on bisphosphonate therapy.ResultsNine of thirty-five adults (26%) and eleven of forty children (27%) had low BMD. Adults with FA had significantly lower BMD Z-scores than those with other diagnoses; however, HAZ did not vary significantly in children by diagnosis. Risk factors included hypogonadism, iron overload, and glucocorticoid use.ConclusionsAdults and children with IBMFS have high prevalence of low BMD. Prompt recognition of risk factors and management are essential to optimize bone health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/pr.2017.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570650PMC
September 2017

3D Volumetric Measurements of GH Secreting Adenomas Correlate with Baseline Pituitary Function, Initial Surgery Success Rate, and Disease Control.

Horm Metab Res 2017 Jun 4;49(6):440-445. Epub 2017 May 4.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

There is scarce data on the clinical utility of volume measurement for growth hormone (GH)-secreting pituitary adenomas. The current study objective was to assess the association between pituitary adenoma volumes and baseline endocrine evaluation, initial surgical success rate, and disease control among patients with acromegaly. A retrospective cohort study was conducted at a clinical research center including patients with acromegaly due to GH-secreting pituitary adenomas. Baseline hormonal evaluation and adenoma characteristics according to MRI were collected. Volumetric measurements of pituitary adenomas were performed using a semi-automated lesion segmentation and tumor-volume assessment tools. Rates of post-operative medical treatment, radiation therapy, and re-operation were gathered from the patients' medical records. Twenty seven patients (11 females) were included, median age 21.0 years (interquartile range 29 years, range 3-61 years). Patients harboring adenomas with a volume <2 000 mm had higher chance to achieve disease remission [94.1% (n=16) vs. 50.0% (n=4), p<0.05]. Adenoma volumes positively correlated with baseline plasma GH levels before and after oral glucose administration, and with plasma IGF-I and PRL levels. Adenoma volume had negative correlation with morning plasma cortisol levels. Finally, patients harboring larger adenomas required 2nd surgery and/or medical treatment more often compared with subjects with smaller adenomas. Accurate 3D volume measurement of GH-secreting pituitary adenomas may be used for the prediction of initial surgery success and for disease control rates among patients with a GH-secreting pituitary adenomas and performs better than standard size assessments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0043-107245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309337PMC
June 2017

Circadian Plasma Cortisol Measurements Reflect Severity of Hypercortisolemia in Children with Different Etiologies of Endogenous Cushing Syndrome.

Horm Res Paediatr 2017 21;87(5):295-300. Epub 2017 Apr 21.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.

Background: The utility of circadian cortisol variation in estimating the degree of hypercortisolemia in different forms of endogenous Cushing syndrome (CS) has not been evaluated in children yet.

Methods: A retrospective cohort study, including children who underwent surgery due to CS (n = 115), was divided into children with a pituitary adenoma (Cushing disease) (n = 88), primary adrenal CS (n = 21), or ectopic adrenocorticotropin- or corticotropin-releasing hormone (ACTH-/CRH)-secreting tumors (n = 6). Circadian plasma cortisol measurements were obtained at 11: 30 p.m. and at midnight, and at 7: 30 and 8: 00 a.m. The ratios between the morning and late-night concentrations were calculated.

Results: Plasma cortisol early-morning and midnight (AM/PM) ratios negatively correlated with 24-h urinary free cortisol (UFC) collections among the full study population and in each of the individual etiologies. Plasma ACTH concentrations positively correlated with plasma cortisol AM/PM ratios among patients with ACTH-independent CS. Finally, patients with primary pigmented nodular adrenocortical disease showed no correlation between UFC collections and the plasma cortisol AM/PM ratio, in contrast with other etiologies for primary adrenal CS, which showed a strong negative correlation between them.

Conclusion: Our study shows the association between the plasma cortisol AM/PM ratio and the degree of hypercortisolemia in children with CS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000464463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506540PMC
March 2018

Pediatric Cushing disease: disparities in disease severity and outcomes in the Hispanic and African-American populations.

Pediatr Res 2017 Aug 17;82(2):272-277. Epub 2017 May 17.

Section on Endocrinology and Genetics, Developmental Endocrinology Branch, and Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

BackgroundLittle is known about the contribution of racial and socioeconomic disparities to severity and outcomes in children with Cushing disease (CD).MethodsA total of 129 children with CD, 45 Hispanic/Latino or African-American (HI/AA) and 84 non-Hispanic White (non-HW), were included in this study. A 10-point index for rating severity (CD severity) incorporated the degree of hypercortisolemia, glucose tolerance, hypertension, anthropomorphic measurements, disease duration, and tumor characteristics. Race, ethnicity, age, gender, local obesity prevalence, estimated median income, and access to care were assessed in regression analyses of CD severity.ResultsThe mean CD severity in the HI/AA group was worse than that in the non-HW group (4.9±2.0 vs. 4.1±1.9, P=0.023); driving factors included higher cortisol levels and larger tumor size. Multiple regression models confirmed that race (P=0.027) and older age (P=0.014) were the most important predictors of worse CD severity. When followed up a median of 2.3 years after surgery, the relative risk for persistent CD combined with recurrence was 2.8 times higher in the HI/AA group compared with that in the non-HW group (95% confidence interval: 1.2-6.5).ConclusionOur data show that the driving forces for the discrepancy in severity of CD are older age and race/ethnicity. Importantly, the risk for persistent and recurrent CD was higher in minority children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/pr.2017.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552413PMC
August 2017

Quantification of Thyroid Cancer and Multinodular Goiter Risk in the DICER1 Syndrome: A Family-Based Cohort Study.

J Clin Endocrinol Metab 2017 05;102(5):1614-1622

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20850.

Context: The risk of thyroid cancer and multinodular goiter (MNG) in DICER1 syndrome, a rare tumor-predisposition disorder, is unknown.

Objective: To quantify the risk of thyroid cancer and MNG in individuals with DICER1 syndrome.

Design: Family-based cohort study.

Setting: National Institutes of Health (NIH) Clinical Center (CC).

Participants: The National Cancer Institute DICER1 syndrome cohort included 145 individuals with a DICER1 germline mutation and 135 family controls from 48 families.

Interventions: Each individual completed a detailed medical history questionnaire. A subset underwent a 3-day evaluation at the NIH CC.

Main Outcome Measures: The cumulative incidence of MNG (or thyroidectomy) was quantified using the complement of the Kaplan-Meier product limit estimator. We compared the observed number of thyroid cancers in the NCI DICER1 cohort with matched data from the Surveillance, Epidemiology, and End Results (SEER) Program. We performed germline and somatic (thyroid cancer, MNG) DICER1 sequencing.

Results: By the age of 40 years, the cumulative incidence of MNG or thyroidectomy was 75% in women and 17% in men with DICER1 syndrome compared with 8% of control women (P < 0.001) and 0% of control men (P = 0.0096). During 3937 person-years of observation, individuals with DICER1 syndrome had a 16-fold increased risk of thyroid cancer (95% confidence interval, 4.3 to 41; P < 0.05) compared with the SEER rates. Of 19 MNG nodules and 3 thyroid cancers, 16 (84%) and 3 (100%), respectively, harbored germline and somatic pathogenic DICER1 mutations.

Conclusions: We propose a model of thyroid carcinogenesis in DICER1 syndrome. Early-onset, familial, or male MNG should prompt consideration of the presence of DICER1 syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2016-2954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443331PMC
May 2017

Hair cortisol in the evaluation of Cushing syndrome.

Endocrine 2017 Apr 13;56(1):164-174. Epub 2017 Feb 13.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.

Purpose: Hair cortisol evaluation has been used to help detect patients with suspected Cushing syndrome. Our goal was to correlate segmental hair cortisol with biochemical testing in patients with Cushing syndrome and controls. This study was a prospective analysis of hair cortisol in confirmed Cushing syndrome cases over 16 months.

Methods: Thirty-six subjects (26.5 ± 18.9 years, 75% female, and 75% Caucasian) were analyzed by diurnal serum cortisol, 24 h urinary free cortisol corrected for body surface area (UFC/BSA), and 24 h urinary 17-hydroxysteroids corrected for creatinine (17OHS/Cr). Thirty patients were diagnosed with Cushing syndrome, and six were defined as controls. 3-cm hair samples nearest to the scalp, cut into 1-cm segments (proximal, medial, and distal), were analyzed for cortisol by enzyme immunoassay and measured as pmol cortisol/g dry hair. Hair cortisol levels were compared with laboratory testing done within previous 2 months of the evaluation.

Results: Proximal hair cortisol was higher in Cushing syndrome patients (266.6 ± 738.4 pmol/g) than control patients (38.9 ± 25.3 pmol/g) (p = 0.003). Proximal hair cortisol was highest of all segments in 25/36 (69%) patients. Among all subjects, proximal hair cortisol was strongly correlated with UFC/BSA (r = 0.5, p = 0.005), midnight serum cortisol (r = 0.4, p = 0.03), and 17OHS/Cr, which trended towards significance (r = 0.3, p = 0.06).

Conclusions: Among the three examined hair segments, proximal hair contained the highest cortisol levels and correlated the most with the initial biochemical tests for Cushing syndrome in our study. Further studies are needed to validate proximal hair cortisol in the diagnostic workup for Cushing syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12020-017-1231-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437744PMC
April 2017

Case 1: Poor Growth With Presence of a Pituitary Lesion in an 11-year-old Boy.

Pediatr Rev 2017 Jan;38(1):44-45

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/pir.2014-0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343498PMC
January 2017

Spontaneously Resolving Hyperreninemic Hypertension Caused by Accessory Renal Artery Stenosis in a 13-Year-Old Girl: A Case Report.

J Clin Hypertens (Greenwich) 2017 01 15;19(1):100-102. Epub 2016 Aug 15.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

The authors describe the clinical investigation and progress of a 13-year-old girl diagnosed with hypertension 4 years prior to her admission. A thorough history was taken and physical examination performed. Laboratory analysis and relevant radiological evaluation were obtained in order to determine the etiology for suspected secondary hypertension, and later to differentiate between the possible causes of hyperreninemic hypertension. The patient had an accessory left renal artery, presumptively leading to renin secretion by the underperfused kidney. The patient was treated medically with spontaneous resolution of her hypertension and near normalization of plasma renin activity. On repeat imaging, the artery was not demonstrated. The authors concluded that the diagnosis of hyperreninemic hypertension in young ages should prompt investigation for the etiology. However, cautious observation is a valid option that might lead to spontaneous resolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jch.12893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341473PMC
January 2017

Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene.

Endocrinol Diabetes Metab Case Rep 2016 7;2016:150104. Epub 2016 Jan 7.

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, BG 10-CRC, Room 1-3216, 10 Center Drive, Bethesda, Maryland, 20814, USA; Johns Hopkins University School of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Baltimore, Maryland, 21287, USA; Suburban Hospital, Bethesda, Maryland, 20814, USA.

Unlabelled: Autosomal recessive pseudohypoaldosteronism type 1 (PHA1) is a rare disorder characterized by sodium wasting, failure to thrive, hyperkalemia, hypovolemia and metabolic acidosis. It is due to mutations in the amiloride-sensitive epithelial sodium channel (ENaC) and is characterized by diminished response to aldosterone. Patients may present with life-threatening hyperkalemia, which must be recognized and appropriately treated. A 32-year-old female was referred to the National Institutes of Health (NIH) for evaluation of hyperkalemia and muscle pain. Her condition started in the second week of life, when she was brought to an outside hospital lethargic and unresponsive. At that time, she was hypovolemic, hyperkalemic and acidotic, and was eventually treated with sodium bicarbonate and potassium chelation. At the time of the presentation to the NIH, her laboratory evaluation revealed serum potassium 5.1 mmol/l (reference range: 3.4-5.1 mmol/l), aldosterone 2800 ng/dl (reference range: ≤21 ng/dl) and plasma renin activity 90 ng/ml/h (reference range: 0.6-4.3 ng/ml per h). Diagnosis of PHA1 was suspected. Sequencing of the SCNN1B gene, which codes for ENaC, revealed that the patient is a compound heterozygote for two novel variants (c.1288delC and c.1466+1 G>A), confirming the suspected diagnosis of PHA1. In conclusion, we report a patient with novel variants of the SCNN1B gene causing PHA1 with persistent, symptomatic hyperkalemia.

Learning Points: PHA1 is a rare genetic condition, causing functional abnormalities of the amiloride-sensitive ENaC.PHA1 was caused by previously unreported SCNN1B gene mutations (c.1288delC and c.1466+1 G>A).Early recognition of this condition and adherence to symptomatic therapy is important, as the electrolyte abnormalities found may lead to severe dehydration, cardiac arrhythmias and even death.High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EDM-15-0104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722246PMC
January 2016