Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency Presenting as Adrenal Incidentaloma: A Systematic Review and Meta-Analysis

Objective: Adrenal incidentalomas (AIs) may be due to congenital adrenal hyperplasia (CAH) due to homozygous CYP21A2 mutations, or perhaps from heterozygous carrier status. It is unclear if genetic or biochemical testing of CYP21A2 status in AI is justified, despite its potential for avoiding adrenal crises in those referred for adrenalectomy.Methods: We systematically searched PubMed/MEDLINE for articles published up to October 19, 2015 containing all terms associated with adrenal tumors and CAH. Meta-analyses were used to estimate the CAH or carrier prevalence in AI and assess clinical factors that may guide testing.Results: Thirty-six publications were included. Of AI patients biochemically screened for CAH, 58/990 (5.9%) were diagnosed with CAH. Genetic screening of all AIs revealed only 2/252 (0.8%) with clear CAH. The carrier prevalence was 10.2% (36/352). The rate of 0.8% (8/1,000) genetically confirmed CAH is higher than the 1/15,000 affected by classic CAH or 1/1,000 by nonclassic CAH in the Caucasian population. The rate of heterozygous CYP21A2 mutation frequency is similar to those in reported in population studies. Levels of both basal and stimulated 17-hydroxyprogesterone positively correlated with AI diameter. Although bilateral incidentalomata were frequent in CAH, their presence did not predict CYP21A2 status.Conclusion: The presence of an AI does not increase the probability of detection of CAH or CYP21A2 carrier status to the extent routine genetic testing is justified. Screening with 17-hydroxyprogesterone levels appears to lack specificity in the setting of an AI. CYP21A2 mutation analysis is probably the only reliable method for CAH diagnosis in AIs.Abbreviations:ACC = adrenocortical carcinomaACTH = adrenocorticotropic hormoneAI = adrenal incidentalomaCAH = congenital adrenal hyperplasiaNCAH = nonclassic congenital adrenal hyperplasia17OHP = 17-hydroxyprogesteroneSV = simple virilizing     

Adrenal Myelolipomas in Patients with Congenital Adrenal Hyperplasia: Review of the Literature and A Case Report

ObjectiveTo review the association between congenital adrenal hyperplasia (CAH) and adrenal myelolipomas and report a case of bilateral, giant adrenal myelolipomas in a patient with untreated CAH due to 21-hydroxylase deficiency.MethodsWe describe the patient’s clinical presentation, imaging findings, and laboratory test results and review the relevant English-language literature concerning patients with both CAH and myelolipomas.ResultsA 45-year-old man with untreated CAH due to 21-hydroxylase deficiency presented with increasing abdominal girth and abdominal pain. Computed tomography of the abdomen demonstrated very low-density adrenal masses (22 × 11 cm on the left side and 6 × 5.5-cm on the right side) consistent with adrenal myelolipomas. The left adrenal myelolipoma was resected (24.4 × 19.0 × 9.5 cm; 2557 g). The mass was composed of mature adipose tissue with areas of hematopoietic cells of myeloid, erythroid, and megakaryocytic cell lines. Islands of adrenal cortical cells were scattered between the adipose and hematopoietic tissue. Including the present case, we identified 31 patients with both CAH and myelolipomas who have been described in the English-language literature. The details of these cases were reviewed.ConclusionsPersons with CAH may be at increased risk of developing adrenal myelolipomas, particularly if their CAH is poorly controlled. How and whether chronic exposure of the adrenal glands to high corticotropin levels increases the risk of developing myelolipomas remains a matter of speculation. (Endocr Pract. 2011;17:441-447)     

The Classic and Nonclassic Concenital Adrenal Hyperplasias

Objective: The American Association of Clinical Endocrinologists Adrenal Scientific Committee has developed a series of articles to update members on the genetics of adrenal diseases.Methods: Case presentation, discussion of literature, table, and bullet point conclusions.Results: The congenital adrenal hyperplasia (CAH) syndromes are autosomal recessive defects in cortisol biosynthesis. The phenotype of each CAH patient depends on the defective enzyme and the severity of the defect. Clinical manifestations derive from both failure to synthesize hormones distal to the enzymatic block, as well as consequences from cortisol precursor accumulation proximal to the block, often with diversion to other biologically active steroids. The most common form of CAH is 21-hydroxylase deficiency, which occurs in the classic form in 1 in 16,000 newborns and in a milder or nonclassic form in at least 1 in 1,000 people.Conclusion: This article reviews the various forms of CAH and pitfalls in the diagnosis and treatment of these conditions.Abbreviations: 11OHD = 11-hydroxylase deficiency 17OHD = 17-hydroxylase deficiency 17OHP = 17-hydroxyprogesterone 21OHD = 21-hydroxylase deficiency 3βHSD = 3β-hydroxysteroid dehydrogenase CAH = congenital adrenal hyperplasia CST = cosyntropin stimulation test CYP17A1 = cytochrome P450 17A1 (steroid 17-hydroxylase/17,20-lyase) DHEAS = dehydroepiandrosterone sulfate DSD = disorder of sex development LCAH = lipoid congenital adrenal hyperplasia NBS = newborn screening NCAH = nonclassic CAH PCOS = polycystic ovary syndrome PORD = P450-oxidoreductase deficiency     

Energy Expenditure in 21-Hydroxylase Congenital Adrenal Hyperplasia Patients and Comparison with Predictive Equations

Objective: To characterize resting energy expenditure (REE) in patients with classic 21-hydroxylase congenital adrenal hyperplasia (21-OH CAH) using indirect calorimetry and compare it to the most commonly used REE predictive equations.Methods: This case-control study comprised 29 post-pubertal 21-OH CAH patients regularly followed at the University of Campinas. Elevated serum 17-hydroxyprogesterone and CYP21 gene molecular analysis confirmed the diagnosis. A healthy control group paired by age, gender, and body mass index was examined. Dual-energy X-ray absorptiometry (DEXA) measured body compositions. A bioimpedance analyzer determined fat-free mass, and indirect calorimetry using a metabolic cart measured REE.Results: Unlike our initial hypothesis, REE was similar between the groups (18.7 ± 3.1 kcal/kg/day in CAH vs. 20.3 ± 3.5 kcal/kg/day in controls; P = .728). No predictive equations reached the stipulated accuracy criteria, thus lacking validity in REE assessment in adults with the characteristics of the group studied. DEXA analysis revealed higher body fat and diminished nonbone lean mass in 21-OH CAH. Anthropometric and bioelectrical impedance parameters were not significantly different.Conclusion: Classic 21-OH CAH is generally followed in reference centers, which may facilitate indirect calorimetry use for REE measurement. Alternatively, considering our REE findings in adult 21-OH CAH patients, nutrition management based on 25 kcal/body weight/day (measured REE × activity factor 1.2 to 1.3) may be reasonable for current body weight maintenance in these patients.Abbreviations: 17-OHP = 17-hydroxyprogesterone; 21-OH CAH = classic 21-hydroxylase deficiency congenital adrenal hyperplasia; BMI = body mass index; REE = resting energy expenditure; VO2 = volume of oxygen; VCO₂ = volume of carbon dioxide     

Bilateral Ovary Adrenal Rest Tumor in a Congenital Adrenal Hyperplasia Following Adrenalectomy

Objective:In contrast to the high incidence of testicular adrenal rest tumors in adult male patients with congenital adrenal hyperplasia (CAH), ovarian adrenal rest tumors (OARTs) in female CAH patients are rare. In this case report, we describe a case of bilateral OART in a female patient with CAH due to 21-hydroxylase deficiency.Methods:We present a detailed case report with the clinical, imaging, and laboratory findings of the patient. The pertinent literature is also reviewed.Results:A 17-year-old patient was known to have CAH due to 21-hydroxylase deficiency. Since the second month of her gestational age, her mother was treated with cortisone-replacement therapy. The patient was treated with hydrocortisone and fludrocortisone since the neonatal period. Her pertinent history included a bilateral adrenalectomy at the age of 13 years in 2006, and for 3 years she led a normal puberty life with no complaint with hormonal replacement therapy. Nevertheless, in 2009, she developed a virilizing syndrome. Subsequently, she underwent surgery in December 2009 for right adnexectomy. However, the regression of the masculinizing mass was not complete and worsened several months after the surgery. A new pelvic magnetic resonance image showed the activation of a contralateral ovarian mass, necessitating a left adnexectomy in August 2010.Conclusion:This case demonstrates some interesting features of OART that pose challenges to its management. If an OART is detected early enough and glucocorticoid therapy is received, it is possible that the OART will decrease in size following suppression of adrenocorticotropic hormone levels. (Endocr Pract. 2014;20:e69-e74)     

Asymptomatic Bilateral Giant Adrenal Myelolipomas: Case Report and Review of Literature

ObjectiveTo describe an unusual case of bilateral giant adrenal masses caused by a primary adrenal myelolipoma.MethodsWe present the clinical, laboratory, and pathologic findings in a 32-year-old man with bilateral adrenal masses. The previous reports of bilateral myelolipomas also were reviewed.ResultsDuring a routine examination, a 32-year-old Thai man was found to have an asymptomatic abdominal mass. A computed tomographic scan of the abdomen disclosed bilateral adrenal masses; the one on the left was approximately 27 by 24 by 12 cm, and the one on the right side was 9 by 5 by 5 cm. The computed tomographic scan characteristics showed that both masses consisted mainly of low-density tissues (-30 to -90 Hounsfield units), suggestive of fatty component. An endocrinologic evaluation revealed no evidence of adrenal cortical or medullary functional abnormalities. Bilateral adrenalectomy was performed because of the large size of the lesions and the inability to rule out malignant involvement.ConclusionMyelolipoma is a relatively rare benign tumor of the adrenal glands composed of adipose cells and mature hematopoietic elements. Most such lesions are small, asymptomatic, and unilateral; giant or bilateral myelolipomas are quite rare. To our knowledge, our current case may represent the largest bilateral lesions in the literature. (Endocr Pract. 2007;13:667-671)     

Genetic Forms of Adrenal Insufficiency

Objective: The American Association of Clinical Endocrinologists Adrenal Scientific Committee has developed a series of articles to update members on the genetics of adrenal diseases.Methods: Case presentation, discussion of literature, table, and bullet point conclusions.Results: The genetic mutations associated with several familial causes of adrenal insufficiency have now been identified. The most common ones that will be discussed here include Allgrove syndrome, adrenoleukodystrophy, adrenal hypoplasia congenita, autoimmune polyglandular syndrome type 1, congenital adrenal hyperplasia (CAH), lipoid CAH, and familial glucocorticoid deficiency. Although these diseases most commonly present in childhood, some rarely present in adulthood, and thus all endocrinologists must be familiar with these syndromes. Some patients only develop glucocorticoid deficiency, and others have both glucocorticoid and mineralocorticoid deficiency. These diseases may be associated with other conditions, especially neurologic disease, hypogonadism, or dermatologic problems. Diagnosis is suspected based on clinical presentation and laboratory findings. Gene testing may be necessary for confirmation of a diagnosis and/or screening of family members.Conclusion: This article briefly reviews the various familial adrenal insufficiency syndromes and the specific associated gene defects.Abbreviations: AAA = Allgrove syndrome (alachrima-achalasiaadrenal insufficiency) ACTH = adrenocorticotropic hormone AHC = adrenal hypoplasia congenita ALD = adrenoleukodystrophy CAH = congenital adrenal hyperplasia DAX1 = dosage-sensitive sex reversal, adrenal hypoplasia congenita, X-chromosome FGD = familial glucocorticoid deficiency LCAH = lipoid CAH MCM4 = mini-chromosome maintenancedeficient 4 SF1 = steroidogenic factor 1 VLCFA = very-long-chain fatty acid     

Adrenal Incidentalomas: Diagnostic Evaluation and Long-Term Follow-Up

ObjectiveTo evaluate the cause and the clinical and laboratory features of adrenal incidentalomas (AI) in 52 patients and to assess the evolution of nonsurgically treated lesions during long-term follow-up.MethodsWe retrospectively analyzed the medical records of 52 patients with AI undergoing routine followup in 2 Brazilian endocrine centers.ResultsIn our study group, nonfunctioning adenomas were the most frequent cause of AI (42%), followed by cortisol-secreting adenomas (15%), metastatic disease (10%), pheochromocytomas (8%), myelolipomas (6%), cysts (6%), carcinomas (4%), lymphomas (4%), tuberculosis (4%), and aldosteronoma (2%). Only 13 lesions (25%) were functioning (8 cortisol-secreting adenomas, 4 pheochromocytomas, and 1 aldosteronoma). Carcinomas were the largest adrenal masses (mean diameter, 11.7 ± 1.3 cm). With the exception of 1 pheochromocytoma, 1 cyst, and 1 myelolipoma, all AI larger than 6 cm were carcinomas. During follow-up of 21 patients with nonsurgically treated AI for 6 to 36 months (mean, 24.8 ± 8.9), no patient had tumor reduction or disappearance. After 12 months of follow-up, however, a 45-year-old woman had adrenal mass enlargement from 3.2 cm to 4.4 cm; the excised lesion proved to be an adenoma. Moreover, evidence of cortisol hypersecretion developed after 24 months of follow-up in a 30-year-old man with a 3.5-cm adenoma in the left adrenal gland.ConclusionOur findings demonstrate that most AI are nonfunctioning benign lesions and emphasize the need for long-term follow-up of patients with conservatively managed lesions, in light of the potential for evolution to hormonal hypersecretion or tumor growth. (Endocr Pract. 2008;14:269-278)     

Large Adrenal Incidentalomas Require a Dedicated Diagnostic Procedure

Objective: The management of large nonsecreting adrenal tumors (at least 4 cm) is still a matter of debate as it is unclear whether imaging, especially ¹⁸F-fluorodeoxyglucose (FDG), can be used to characterize their potential malignancy. Moreover, the risk of new hypersecretion in nonoperated tumors is uncertain. Our aim was to better characterize these large adrenal incidentalomas.Methods: Patients followed in our center for a nonsecreting large (at least 4 cm) adrenal incidentaloma, with an initial computed tomography (CT) and ¹⁸F-FDG positron emission tomography (PET) CT, were retrospectively included. Patients who were not operated after initial diagnosis had to be followed with clinical, biological, and imaging evaluations for at least 3 years or until delayed surgery.Results: Eighty-one patients were included in the study: 44 patients (54.3%) had initial surgery while 37 were followed, including 21 (25.9%) who were operated after a mean of 19 months. Among the 65 operated patients, 13 (20%) had a malignant lesion (3 with metastasis, and 10 with adrenocortical carcinoma). Unenhanced CT <10 showed 85.6% sensitivity and 78.8% specificity; all had a ¹⁸F-FDG uptake ratio >1.5. Among the 24 patients who were followed for at least 3 years, 5 (20.8%) finally presented hypercortisolism (4 subclinical).Conclusion: As expected, large adrenal tumors are at a higher risk of malignancy. The combination of unenhanced CT <10 and ¹⁸F-FDG PET ratio <1.5 prove to be reassuring and might lead to a close follow-up rather than immediate surgery. Hormonal follow-up should be focused on the risk of hypercortisolism.Abbreviations: CI = confidence interval; CT = Computed Tomography; ENSAT = European Network for the Study of Adrenal Tumors; ESE = European Society of Endocrinology; FDG = fluorodeoxyglucose; HU = Hounsfield units; PET = positron emission tomography; ROI = regions of interest; SUV = standard uptake value     

Clinical Outcomes in Adrenal Incidentaloma: Experience From one Center

Objective: To investigate the outcome in patients with adrenal incidentaloma (AI).Methods: A retrospective evaluation of 637 patients with AI referred to a tertiary center over 8 years. Radiologic and hormonal evaluations were performed at baseline. Follow-up imaging was carried out if necessary, and hormonal evaluation was performed at 24 months according to national guidelines.Results: The mean age was 62.7 ± 11.6 years, and the mean AI size was 25.3 ± 17.0 mm at presentation. Hormonal evaluation revealed that 85.4% of all tumors were nonfunctioning adenomas, 4.1% subclinical Cushing syndrome (SCS), 1.4% pheochromocytoma, 1.4% primary hyperaldosteronism, 0.8% Cushing syndrome, 0.6% adrenocortical carcinoma, 0.3% congenital adrenal hyperplasia, 2.2% metastasis to adrenals, and 3.8% other lesions of benign origin. Bilateral tumors were found in 11%, and compared to unilateral tumors, SCS was more prevalent. Only 2 cases were reclassified during follow-up, both as SCS, but neither had had a dexamethasone suppression test performed at initial work-up. In patients diagnosed with an adrenal metastasis, 92.9% were deceased within 2 years. Excluding those with malignant tumors, 12.9% of patients died during the study period of up to 11 years due to other causes than adrenal.Conclusion: Most AIs were benign, but a small fraction of tumors were functional and malignant. The prognosis of patients with adrenal metastasis was extremely poor, but otherwise, the mortality rate was similar to that for the general population. Follow-up of AIs <4 cm with an initial nonfunctional profile and benign radiologic appearance appears unwarranted, but screening for congenital adrenal hyperplasia should be considered.Abbreviations: 17OHP = 17-hydroxyprogesterone ACC = adrenal cortical carcinoma ACTH = adrenocorticotropic hormone AI = adrenal incidentaloma CAH = congenital adrenal hyperplasia CT = computed tomography CS = Cushing syndrome DST = dexamethasone suppression test HPA = hypothalamic-pituitary-adrenal axis MRI = magnetic resonance imaging SCS = subclinical Cushing syndrome T2DM = type 2 diabetes mellitus UFC = urinary free cortisol     

Investigation of CYP21A2 mutations in Turkish patients with 21-hydroxylase deficiency and a novel founder mutation

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessively inherited disorders characterized by impaired production of adrenal steroids. Approximately 95% of all CAH are caused by mutations of the CYP21A2 that encodes 21-hydroxylase. In this study, mutation analyses of CYP21A2 were performed in 48 CAH patients from 45 Turkish families with the clinical diagnosis of 21-hydroxylase deficiency (21OHD). While in 39 (86.7%) of 21OHD patients, disease causing CYP21A2 mutations were identified in both alleles, in two 21OHD patients CYP21A2 mutations were identified only in one allele. In four patients, mutation was not detected at all. In total, seventeen known and one novel, disease causing CYP21A2 mutations were observed. Among identified mutations, previously described c.293-13C/A>G, large rearrangements and p.Q319X mutations were the most common mutations accounting for 33.3%, 14.4% and 12.2% of all evaluated chromosomes, respectively. In six families (13.3%) a novel founder mutation, c.2T>C (p.M1?), inactivating the translation initiation codon was found. This mutation is not present in pseudogene CYP21A1P and causes the classical form of the disease in six patients. In addition, depending on the nature of the rearrangements CYP21A1P/CYP21A2 chimeras were further classified as CH^c/d, and CH-1^c was shown to be the most prominent chimera in our study group. In conclusion, with this study we identified a novel founder CYP21A2 mutation and suggest a further classification for CYP21A1P/CYP21A2 chimeras depending on the combination of junction site position and whether it is occurred as a result of deletion or conversion. Absence of disease causing mutation of CYP21A2 in ten of screened ninety chromosomes suggests the contribution of regulatory elements in occurrences of CAH due to the 21OHD.     

Analysis of the Association between the HLA-DQA1 Alleles and the Steroid 21-Hydroxylase Gene Mutations in the Patients with Congenital Adrenal Hyperplasia

In 96 patients with congenital adrenal hyperplasia (CAH) and 50 healthy donors from northwestern Russia the distribution of the HLA-DQA1 alleles and the mutation spectrum and frequency at the CYP21B gene were examined. In the patients with nonclassical (NC) CAH, the distribution of the HLA-DQA1 polymorphic alleles was similar to that in the population sample. In the patients with the salt-wasting form of the disease a statistically significant decrease of the *0401 or *0501major allele frequency was observed. The prevalence of certain HLA-DQA1 genotypes, namely, HLA5, HLA3, and HLA4, was observed in the patients with the NC, salt-wasting (SW), and simple virilizing CAH, respectively. Each clinical group was characterized by a specific spectrum of clinically valuable mutations. An association between theCYP21B mutations most frequently found in case of SW and SV CAH (delB, I2splice, and I172N) and certain HLA-DQA1alleles was demonstrated. The necessity of more precise clinical diagnostics of the NC CAH cases along with detailed examination of this group for determination of the major mutations typical of the NC CAH cases from northwestern Russia is discussed.     

Health-Related Quality of Life in Children and Adolescents with Nonclassic Congenital Adrenal Hyperplasia

Objective: Nonclassic congenital adrenal hyperplasia (NCCAH) is a late-onset milder form of congenital adrenal hyperplasia that differs dramatically from the classic form. Health-related quality of life (HRQOL) in pediatric patients with the sole diagnosis of NCCAH has not been determined; therefore, in this study, we aimed to determine whether HRQOL is compromised in comparison to the general population.Methods: Single-center, cross-sectional, case-control study. Twenty-three hydrocortisone-treated children and adolescents (7 males) diagnosed with NCCAH by cosyntropin stimulation test and CYP21A2 gene mutation analysis were recruited to this study; 6 healthy siblings were also recruited. HRQOL was assessed by the child and parent-proxy PedsQL Inventory and compared between NCCAH subjects and healthy siblings. HRQOL scores of NCCAH subjects were compared with known standards from the U.S. and Israeli general healthy populations. Anthropometric measurements of children and parents were performed and compared between NCCAH subjects and healthy siblings. Pearson correlation coefficients were calculated.Results: HRQOL scores of the participants and parents did not differ between NCCAH subjects and healthy siblings. The HRQOL emotional domain scores of the NCCAH patients and parent were significantly lower than the healthy U.S. pediatric population (P = .046) but not different from established standards of the healthy Israeli population (P = .583). Anthropometric measurements were within the normal range and did not differ between NCCAH subjects and their siblings. Total, school functioning, and psychosocial HRQOL domain scores were positively correlated with body mass index–standard deviation score in NCCAH subjects.Conclusion: HRQOL was not adversely affected by NCCAH among adequately treated children and adolescents.Abbreviations: BMI = body mass index; CAH = congenital adrenal hyperplasia; HRQOL = health-related quality of life; NCCAH = nonclassic congenital adrenal hyperplasia; PedsQL = Pediatric Quality of Life Inventory; SDS = standard deviation score     

Complement component 4 copy number variation and CYP21A2 genotype associations in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

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.     

Complete sequencing and mRNA expression analysis of the MEN-I gene in adrenal myelolipoma.

The molecular pathogenesis of adrenal myelolipoma is unclear. Endocrine activity of these tumors and association with other endocrine tumors have stimulated the hypothesis that it may belong to the group of sporadic tumors caused by defects of the gene responsible for multiple endocrine neoplasia type I (MEN-I). DNA of blood and tumoral sections from two patients with adrenal myelolipoma were analyzed by examination of variable number of tandem repeats (VNTR) loci PYGM, D11S987, D11S480, and D11S449 on chromosome 11q13 and by complete direct DNA sequencing of all coding exons and splice junctions of the MEN-I gene. Menin expression was examined by RT-PCR. RT-PCR did not detect menin expression in one adrenal myelolipoma. No loss of heterozygozity on chromosome 11q13 was identified. Intragenic heterozygozity was retained in codon 418 of the menin gene in both patients. No mutation was identified in the coding exons of the menin gene. Complete DNA sequencing yielded no hint that defects of the MEN-I gene are responsible for the formation of adrenal myelolipomas. Adrenal myelolipomas do not share the loss of heterozygozity on chromosome 11q13 observed in some benign adenomatous and many malignant adrenocortical tumors.     

Fine Needle Aspiration of Adrenal Myelolipoma: A Case Report

A case of an adrenal myelolipoma in a 50-year-old woman with endometrial carcinoma is described. The diagnosis was established by computed tomography-guided fine needle aspiration, which is particularly useful for the pre-operative evaluation of adrenal tumours in asymptomatic, high-risk or cancer patients. The criteria used to distinguish extra-adrenal myelolipomas from mass-forming extramedullary haematopoiesis are discussed.     

Cardiac Abnormalities Associated with Pheochromocytoma and other Adrenal Tumors

ObjectiveTo study the specific cardiac abnormalities associated with pheochromocytoma and to suggest a strategy for evaluating cardiac function in patients with pheochromocytoma.MethodsIn this case-control study, we reviewed pathology records of patients seen at Cedars-Sinai Medical Center between 1997 and 2007; patients with adrenal or extra-adrenal pheochromocytoma and those with nonfunctioning benign or malignant adrenal tumors were identified. Patients with functioning adrenal adenomas that secreted cortisol or aldosterone were excluded. Clinical history, imaging, pathology, biochemical test results, electrocardiographic findings, and echocardiographic findings were compared between patients with pheochromocytoma and patients with nonfunctioning adrenal tumors.ResultsThe charts of 22 patients with pheochromocytoma and 35 patients with nonfunctioning adrenal tumors were included. No perioperative mortality was observed. The average age of patients with pheochromocytoma was similar to that of control patients (51.9 ± 3.9 years vs 60.2 ± 2.5 years, respectively), as was the number of patients with known cardiovascular diseases (2 [9%] in the pheochromocytoma group vs 5 [14%] in the control group). Two patients with pheochromocytoma (9%) exhibited myocardial damage. Abnormal electrocardiographic findings were present in 16 patients with pheochromocytoma (73%) and in 17 control patients (49%) (P = .1). QTc was prolonged in patients with pheochromocytoma compared with control patients (448.3 ± 9.7 ms vs 424.7 ± 4.5 ms, respectively; P = .02) and was correlated with levels of norepinephrine and normetanephrine, but not with levels of epinephrine and metanephrine or tumor size. ST-T abnormalities were present in 11 patients with pheochromocytoma (50%) and in 8 control patients (23%) (P = .04). Echocardiographic findings were normal in most patients with pheochromocytoma; abnormal left ventricular wall motion was documented in 3 patients with long QTc.ConclusionsThe specific electrocardiographic findings in patients with pheochromocytoma are prolonged QTc and ST-T abnormalities. Performing an electrocardiogram in patients with pheochromocytoma would be prudent. Echocardiography would be useful to examine LV wall motion in patients with long QTc. Coronary artery disease should be excluded in patients with significant ST- T changes. (Endocr Pract. 2009;15:10-16)     

Divergent Gender Identity in Three Siblings With 46Xx Karyotype and Severely Virilizing Congenital Adrenal Hyperplasia Caused by A Novel Cyp11B1 Mutation

ObjectiveTo describe conflicting gender identities in three karyotypically female siblings with congenital adrenal hyperplasia (CAH) caused by a novel mutation in the CYP11B1 gene, who were assigned as males at birth and followed up to adulthood.MethodsWe present 3 siblings (16, 14 and 10 years old) who were born with severe genital virilization and raised as males. Clinical examination showed Prader IV to V external genitalia with a stretched penile length of 7 to 11 cm. Adrenocorticotrophic hormone (ACTH) stimulation test showed a stimulated 11 deoxycortisol (11DOC) level of 12,300-18,700 μg/L (normal 0-5 μg/L). Their karyotypes were 46 XX, and they had normal-sized uterus and ovaries on pelvic ultrasound. DNA was isolated from peripheral leukocytes, and polymerase chain reaction (PCR) and direct sequencing revealed a novel CYP11B1 mutation. This mutation leads to a c.53_54 T insertion (c.53_54insT) with frameshift and truncation at c.115 (codon 39) of CYP11B1.ResultsPsychological evaluation of the oldest sibling suggested a female gender identity, and she declared herself as female, and female sex was re-assigned after 1 year of psychosocial adjustment. Psychological assessment for the 2 younger siblings and a fourth 46XY sibling with the same condition revealed male gender identities, and they continued their lives as males without significant difficulties.ConclusionDivergent gender identity was observed in three severely masculinized 46XX siblings with CAH who carried the same CYP11B1 mutation and had comparable postnatal and probably prenatal androgen exposure and environmental circumstances. These cases suggest that the basis of gender identity is more complex than chromosomal, biochemical, and genetic constitution. (Endocr Pract. 2014;20:e191-e197)     

Increasing Prevalence Of Addison Disease: Results From A Nationwide Study

Objective: Primary adrenal insufficiency is a life-threatening endocrine disease unless properly treated. However, few studies on the prevalence, concomitances of the disease, and prescribing of drugs have been published. The goal of the study was to establish the prevalence of primary adrenal insufficiency in Iceland and additionally, to study the most common concomitant diseases in patients with primary adrenal insufficiency, as well as the mode of glucocorticoid replacement therapies.Methods: To achieve this, the medical records of all patients in Iceland who had received the International Classification of Diseases and Related Health Problems, 10th Revision, diagnosis code E27, were evaluated for true primary adrenal insufficiency. Additionally, these records were evaluated for concomitant diseases, as well as the mode of glucocorticoid replacement therapy. The study covered the whole population of Iceland over 18 years of age. It was thus a nationwide study. The records were retrieved from large hospitals and clinics and every practicing specialist in endocrinology.Results: Primary adrenal insufficiency was found in 53 individuals, 26 women and 27 men, yielding a prevalence of 22.1 per 100,000 population. Hypothyroidism was by far the most common concomitant disease. Most patients had their glucocorticoid deficiency replaced with shortacting glucocorticoids.Conclusion: The prevalence of primary adrenal insufficiency in Iceland is higher than in earlier reports, with comorbidities being in line with recent studies. Treatment is according to the latest protocols.Abbreviations:CAH = congenital adrenal hyperplasiaCVD = cardiovascular diseaseDM = diabetes mellitusGC = glucocorticoidLSH = Landspitali National University HospitalPAI = primary adrenal insufficiencyPAS = polyendocrine autoimmune syndrome     

Primary Adrenal Lymphoma: a Single-Center Experience

Objective: To describe the clinical presentation, biochemistry, imaging features, and treatment outcome of patients with primary adrenal lymphoma (PAL) presenting to a single tertiary care center.Methods: We performed a retrospective analysis of case records of 7 patients diagnosed with PAL between January 2011 and May 2014 at our institution in Mumbai, India.Results: Median age of presentation in our series was 48 years (range, 41 to 60 years), with a male to female ratio of 6:1. Bilateral adrenal involvement was seen in 4 of 7 patients (58%). Adrenal insufficiency (AI) was seen in 3 of the 4 patients with bilateral involvement (75%). Computed tomography showed slight to moderate contrast enhancement of adrenal masses in 4 of 5 patients (80%). Diffuse, large, B-cell lymphoma (DLBCL) was the most common immunophenotype (85%). One patient died due to rapid disease progression even before starting chemotherapy. Six patients were treated with chemotherapy and/or external beam radiotherapy. After 1 year, 2 more patients had died, whereas 4 patients were in remission.Conclusion: PAL should always be considered in differential diagnosis of bilateral adrenal mass with AI. DLBCL is the most common histologic subtype of PAL. Despite treatment, long-term prognosis of PAL remains poor.Abbreviations: AI = adrenal insufficiency B/L = bilateral CT = computed tomography DLBCL = diffuse, large, B-cell lymphoma EBRT = external beam radiotherapy ¹⁸F-FDG PET/CT= ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography PAL = primary adrenal lymphoma T/NK = T cell/natural killer cell