Adrenal Enlargement Research Articles

Can evaluating adrenal glands in computed tomography contribute to predicting the prognosis of hospitalized COVID-19 patients?

The novel coronavirus disease 2019 (COVID-19) may affect the adrenal glands. Therefore, it is important to evaluate the morphologic appearance of the adrenal glands by thorax computed tomography (CT). On CT scans, stranding in peripheral fatty tissue with enlarged adrenal glands may indicate signs of adrenal infarction (SAI). The present study aimed to evaluate the incidence of SAI and determine whether this finding may contribute to predictions of the prognosis of COVID-19. A total of 343 patients who had been hospitalized at Malatya Training and Research Hospital between September 1 and 30, 2020, with a diagnosis of COVID-19 were enrolled in this study. All patients underwent thorax CT scans that included their adrenal glands. Of the enrolled patients, 16.0% had SAI. Moreover, 41.8% of patients with SAI and 15.3% of patients without SAI were treated in the Intensive Care Unit (ICU). Patients with SAI had a significantly higher rate of ICU admission (p < 0.001). Mortality rates were also significantly higher among patients with SAI than those without p < 0.001). In this study, it was found that COVID-19 patients with SAI may have a poorer prognosis. More comprehensive studies are needed on this subject, but the present study may provide helpful preliminary information in terms of prognosis.

Adrenal Histoplasmosis: An Uncommon Cause of Adrenal Crisis in an Immunocompetent Man

Abstract Background Histoplasmosis is a rare cause of primary adrenal insufficiency. Adrenal involvement is commonly encountered with disseminated disease in immunocompromised individuals though some have been reported in immunocompetent patients. Primary adrenal histoplasmosis where adrenals are the only organs with demonstrable disease is uncommon. Case Presentation A 33-year-old immunocompetent man presented with an adrenal crisis. Further evaluation of the underling etiology of primary adrenal insufficiency revealed bilateral adrenal enlargement that was confirmed to be histoplasmosis on adrenal biopsy. Conclusion The case highlights the importance of considering histoplasmosis as an underlying cause of primary adrenal insufficiency in patients from high endemic areas.

Out of Site, Out of Mind- A Rare Case of Adrenal Histoplasmosis from a Non Endemic Area

There has been a rising trend in the number of histoplasmosis cases reported in the recent years. However, in southern India, the number of cases is relatively less. This report is about a 46-year-old Indian male from Tamil Nadu who presented with decreased appetite, vomiting, and giddiness. In view of persistent hyponatremia and hypotension, a work-up for adrenal insufficiency was done, and serum cortisol was found to be low. Contrast Enhanced Computed Tomography (CECT) showed bilateral adrenal enlargement with peripheral rim enhancement and hypodense areas within. There was a diagnostic dilemma between tubercular and fungal aetiology. Fine Needle Aspiration Cytology (FNAC) of the adrenal gland showed features suggestive of histoplasmosis. The patient was treated with itraconazole along with steroid replacement therapy, leading to marked improvement in his overall condition. In immunocompetent individuals, disseminated histoplasmosis with adrenal gland involvement is a rare occurrence. As an unusual presentation of histoplasmosis, this case adds to the body of literature available from Tamil Nadu, which is a non endemic region for histoplasmosis, with only 15 cases being reported as of 2018.

Current Approach for Diagnosis and Treatment of Adrenal Tuberculosis-Our Experience and Review of Literature.

Addison's disease was first described by Thomas Addison in 1855. He demonstrated the destruction of bilateral adrenal gland by tuberculosis (TB) in six patients. Since then, the incidence of TB has declined in the Western world, but in developing countries, it is still the most common cause of adrenal insufficiency. Because of the introduction of antituberculous chemotherapy, the incidence of adrenal TB has been declined in the past decades. The most common symptoms are nonspecific; therefore, diagnosis is often delayed, and patients may first present with a life-threatening adrenal crisis. The most commonly identified organism for adrenal failure in adrenal TB is Mycobacterium tuberculosis infection. Adrenal TB involves bilateral adrenal glands more frequently than unilateral glands. Computed tomography (CT) scan and magnetic resonance imaging (MRI) are useful investigations to differentiate between tuberculous Addison's disease and the other causes of adrenal insufficiency. In CT scans or MRI, features of adrenal TB are bilateral adrenal enlargement and peripheral rim enhancement with or without calcifications. Antituberculous drugs, biochemical monitoring of adrenal function, and steroid therapy are essential for the management of adrenal TB and adrenal insufficiency. Here, we describe a case of adrenal TB with abscess formation followed by a review of the current literature of adrenal TB for better diagnosis and management of this condition.

Idiopathic bilateral adrenal hemorrhage presenting as acute abdomen in a 61-year-old male: A case report with review of literature

Introduction: Adrenal haemorrhage (AH) is a rare, life-threatening condition that requires prompt diagnosis and management. Case Report: A 61-year-old male presented with sudden-onset central abdominal pain, distended abdomen, and nausea. There was no history of trauma or any other predisposing factor for AH. The blood pressure was raised, while other vitals were normal. The patient was managed with intravenous Diclofenac, Tablet Amlodipine, and Ryle's tube insertion. Initial abdominal ultrasound revealed bilateral adrenal enlargement. However, non-contrast computed tomography of abdomen revealed changes suggestive of bilateral AH. These findings were confirmed on magnetic resonance imaging of abdomen. Though the serum cortisol and adrenocorticotropic hormone levels were normal, and the patients were not symptomatic of adrenal insufficiency, intravenous Methylprednisolone was initiated to prevent deterioration of adrenal function. All the known causes of AH were excluded, and a diagnosis of idiopathic bilateral AH was reached. On Day 7, an abdominal ultrasound revealed a non-progressive size of the bilateral adrenal lesions and the patient was discharged with well-controlled blood pressure. Conclusion: Idiopathic AH, in patients without any predisposing factors, should be included in the differential diagnosis of a patient with vague abdominal pain.

Effects of Fatty Acid Amide Hydroxylase Inhibitor URB597 on the Catecholaminergic Activity of the Adrenal Medulla in Stressed Male and Female Rats

Introduction: The present study examined the effects of fatty acid amide hydrolase inhibitor URB597 on the level of plasma catecholamine and their content, synthesis, and degradation in the adrenal medulla of male and female rats subjected to chronic unpredictable stress (CUS). Material and Methods: Male and female Wistar rats were exposed to the 6 weeks of CUS and treated intraperitoneally with either 0.3 mg/kg/day of URB597 or vehicle in the last 2 weeks of stress protocol. Catecholamines’ plasma levels and catecholamines’ levels in adrenal medulla were examined using Elabscience ELISA kits. Western blot analysis was used to detect the protein in the medulla. Results: The results of our experiment showed that adrenal weights and catecholamine of unstressed control were higher in females and that CUS induced further enlargement of adrenal glands and catecholamine content and its synthesis compared to male rats. CUS caused an increase of plasma norepinephrine and depletion of norepinephrine content as well as unchanged synthesis and degradation of catecholamine in the adrenal medulla of male rats. URB597 reduced enlarged adrenals and catecholamine content and its synthesis in stressed female rats. URB597 reduces increased plasma norepinephrine and restores its content in the adrenal medulla, unchanging the expression of enzyme synthesis, while reduced protein levels of monoamine oxidase A in male rats are exposed to CUS. Discussion: Our results support the role of endocannabinoids as an antistress mechanism that inhibits elevated adrenomedullary activation and promotes its recovery to baseline in both male and female stressed rats.

FETAL ADRENAL GLAND BIOMETRY: A POTENTIAL PREDICTOR OF PRETERM BIRTH

Background: Preterm birth is an important challenge in obstetrics and contemporary perinatology in India. Timely recognition, intervention and appropriate management is integral in curbing the upsurge in its incidence and consequent poor perinatal outcome. This study was conducted taking into account the potential mechanism of preterm labor: premature activation of the placental-adrenal endocrine axis wherein elevation of maternal cortisol leads to an increased production of placental corticotrophin releasing hormone which causes an increase in dehydroepiandrosterone produced by the fetal zone of the adrenal gland and its enlargement. This activates a cascade leading to early loss of uterine quiescence, consequently causing cervical modelling, ripening and preterm birth.&#x0D; Aim and Objectives: To assess fetal adrenal gland volume and fetal zone enlargement on ultrasound and evaluate its efficacy in the prediction of preterm birth. &#x0D; Methods: This was a hospital based prospective study in which pregnant women with an uncomplicated live singleton pregnancy between 28 to 34 weeks of gestation were subjected to obstetric ultrasonography wherein fetal adrenal gland volume and fetal zone enlargement was measured. They were then followed up until their delivery, whether term or preterm and its correlation with fetal adrenal gland parameters was assessed. &#x0D; Result: Corrected fetal adrenal gland volume showed the highest sensitivity of 90.0% and a specificity of 96.7% with a cut off value of 632.50 mm3/kg while fetal zone enlargement showed a sensitivity and specificity of 72.7% and 60.9% respectively. &#x0D; Conclusion: This study concludes that fetal adrenal gland biometry can be used as a noninvasive, cost effective and potential new marker for the prediction of preterm birth.

ARMC5-associated Bilateral Macronodular Adrenocortical Hyperplasia: A Novel Germline Variant Associated with Concomitant Papillary Thyroid Carcinoma and Meningioma

Abstract Introduction/Objective Germline mutations in the tumor suppressor gene Armadillo-containing repeat protein 5 gene (ARMC5) have been very recently recognized as a cause for a familial form of bilateral macronodular adrenocortical hyperplasia (BMAH), itself a rare cause of Cushing syndrome. In patients with ARMC5 mutations, scattered case reports have also shown an association with meningiomas and cancers of the pancreas, breast, colon, and thyroid. Methods/Case Report We present the case of BMAH, arising in a 61-year-old female with a history of metastatic papillary thyroid carcinoma and meningioma. The patient presented with bilateral but asymmetric adrenal enlargement (right greater than left) and Cushing syndrome. Given history of thyroid cancer and meningioma, genetics referral was ordered. Counseling revealed a pedigree without a strongly evident familial pattern of hereditary endocrine neoplasia characteristic of any of the more common inherited dispositions to endocrine neoplasia. Additionally, a targeted capture-based NGS germline genetic sequencing study for variants in 12 genes associated with associated with hereditary thyroid cancer was performed and negative. However, based on recent scholarship regarding ARMC5, follow-up germline NGS and Sanger sequencing studies encompassing the entire coding sequences of ARMC5 were ordered. These identified a germline, heterozygous, novel (not in ClinVar) but likely pathogenic variant in (c.802C&amp;gt;T, p.Arg268*), providing a likely explanation for the patient’s BMAH. In attempt to control the patient’s Cushing symptoms, right-sided adrenalectomy was performed, revealing a 220g adrenal gland with marked multinodular hyperplasia with solid, nested, and tubular architecture. Results (if a Case Study enter NA) NA Conclusion While case reports exist describing an association between other ARMC5 mutations and BMAH with concomitant meningiomas and/or malignancies, greater study is needed in order to better characterize the phenotypic spectrum of this disease. Our experience with this case not only reports a novel, apparently pathogenic mutation, but it documents its association with BMAH and, additionally, papillary thyroid carcinoma and meningioma.

Erdheim\u2013Chester disease: with neurological manifestation and multisystem involvement: case report and radiological review

BackgroundErdheim–Chester disease (ECD) is a rarely encountered idiopathic systemic form of non-Langerhans cell histiocytosis. The clinical manifestations of ECD are highly heterogeneous, ranging from unifocal forms to life-threatening multisystem involvement. Patients with CNS involvement often do not show clinical remission.Case presentationWe present a case of a 60-year-old male patient with worsening complaints of loss of balance, involuntary jerky movements, emotional lability and scanning speech developing over a period of 5 years. Magnetic resonance imaging of the brain at present institute revealed signal abnormalities in the midbrain, pons, cerebellar peduncles and cerebellar white matter with mineral deposition and volume loss in the bilateral basal ganglia and midbrain. Positron emission tomography–computed tomography of chest and abdomen revealed 18-fluorodeoxyglucose avid soft tissues lesion in the retroperitoneum involving bilateral perinephric spaces with intra-renal sinus extension, in pre- and paraaortic regions with enlargement of both adrenal glands. The radiographs of the long bones revealed multiple areas of sclerosis. The suspected diagnosis of ECD was confirmed on histopathology. ECD is a rare disease and has a predilection towards middle-aged males and is usually diagnosed late after the onset of initial symptoms.ConclusionsOur case was an atypical presentation of an extremely rare disease, presenting with ataxia and choreoathetoid movements linked to ferromagnetic deposition on brain scans. Multiple other imaging feature characteristics of the disease like the hairy kidney sign, coated aorta sign, skeletal, extra-skeletal and central nervous system manifestations were noted in this single patient.

Ultrasound predictors of left adrenal metastasis in patients with lung cancer: a comparison of computed tomography, positron emission tomography-computed tomography, and endoscopic ultrasound using ultrasound bronchoscope.

Patients with resectable lung cancer require invasive evaluation of the enlarged left adrenal gland (LAG). Few studies showed the utility of endoscopic ultrasound using ultrasound bronchoscope (EUS‑B) in LAG assessment. Moreover, little is known on the combination of computed tomography (CT), positron emission tomography-computed tomography (PET‑CT), and EUS‑B for predicting left adrenal metastasis. In this retrospective cohort study performed from 2012 to 2019, patients with left adrenal enlargement were evaluated by CT, PET‑CT, and EUS‑B, followed by complete endoscopic mediastinal staging. The adrenal glands were sampled by EUS‑B-guided fine‑needle aspiration. Patients were followed for 6 months. During the staging of lung cancer in 2176 patients, 113 enlarged LAGs (5.19%) were biopsied. Malignancy was reported in 51 LAGs (45.13%). Endoscopic ultrasound upstaged 7 patients (6.2%) and downstaged 11 patients (9.37%) after false CT or PET‑CT findings. There were no biopsy‑related complications. Radiologic predictors of left adrenal metastases had the highest yield at the following cutoff points: Hounsfield units >23, standardized uptake value >4.2, and LAG size >25 mm. Hypoechogenic LAGs with loss of sea‑gull shape on EUS‑B were associated with a 28.67‑fold higher likelihood of metastases. The sensitivity, specificity, accuracy, negative predictive value, and positive predictive value for all ultrasound predictors were 86.21%, 85.45%, 85.84%, 85.45%, and 86.21%, respectively. When combined with radiologic features, the respective values were 93.10%, 94.55%, 93.81%, 92.86%, and 94.74%. Hypoechogenicity and loss of sea‑gull shape on EUS‑B are the most reliable predictors of left adrenal metastasis. The combination of CT, PET‑CT, and EUS‑B improves the noninvasive diagnosis of left adrenal metastases in lung cancer patients.

Non-Hemorrhagic Adrenal Infarction during Pregnancy: The Diagnostic Imaging Keys.

Background: non-hemorrhagic adrenal infarction (NHAI) is a rare cause of acute abdominal/flank pain during pregnancy; in order to ensure prompt and appropriate treatment, this diagnosis should not be overlooked. This case series highlights pertinent imaging findings, including ultrasounds (USs), computed tomography (CT), and magnetic resonance imaging (MRI) of recent NHAI cases. Methods: we compiled all consecutive NHAI cases from two university hospitals over a two-year period and checked the relevant clinical, laboratory, and imaging findings. Relevant articles on NHAI published from January 2010 to March 2021 were analyzed. Results: six cases were found in our database. CT-scans typically showed enlarged, hypodense, and non-enhanced adrenal glands. Unenhanced MRIs allowed for diagnoses and showed enlarged adrenal glands in the signal hyperintensity on T2 and diffusion-weighted imaging, without any signal hyperintensity on T1. In two of our six cases, USs showed swollen adrenal glands with fluid collection. Conclusion: NHAI and its differential diagnosis—in cases of acute pain during pregnancy—highlight the crucial roles of integrated radiological examination and cooperation between obstetricians and radiologists, both of whom should consider the location of the pain, the accessibility and tolerance of MRI, and the radiation exposure of CT. Despite its supposed poor sensitivity, an US performed because the patient reports pain should also be used to examine the adrenal gland regions. Non-enhanced MRI is clearly of value and access to it in emergencies is important to avoid radiation exposure

Adrenal insufficiency in immunochemotherapy for small-cell lung cancer with ectopic ACTH syndrome.

SummaryEctopic ACTH (adrenocorticotrophic hormone) syndrome (EAS) is rarely associated with small-cell lung cancer (SCLC). Although chemotherapy is initially effective for SCLC, complicated EAS scarcely improves. Recently, immune checkpoint inhibitors have been used to treat SCLC. Atezolizumab plus chemotherapy for SCLC improved progression-free survival compared to conventional chemotherapy. However, little has been reported on the efficacy of the combination therapy for SCLC with EAS. We report a 72-year-old male who presented with 4-week history of leg oedema, proximal myopathy, weight loss, and worsened symptoms of diabetes and hypertension. Laboratory findings revealed hypokalaemia, increased plasma ACTH, and serum cortisol levels. Cortisol levels were not suppressed by the high-dose dexamethasone test. Chest and abdominal CT revealed a right lower lobe tumour with multiple metastases on the hilar lymph nodes, liver, lumbar spine, and bilateral enlarged adrenal glands. The patient was diagnosed with stage 4B SCLC with EAS. Hypercortisolaemia was then treated with metyrapone and atezolizumab plus chemotherapy, which was started for SCLC. After 10 days, the tumour shrank noticeably, and the ACTH level drastically decreased concomitantly with low cortisol levels with symptoms of fever, appetite loss, and general fatigue. Hydrocortisone treatment was initiated, and the symptoms resolved immediately. We describe a case of SCLC with EAS treated with atezolizumab plus chemotherapy, presenting with adrenal insufficiency. Close observation is required for patients with adrenal insufficiency receiving atezolizumab plus chemotherapy because of its stronger effect. Furthermore, advances in cancer therapy and care for endocrine paraneoplastic syndrome needs to be adapted.Learning pointsThe immune checkpoint inhibitor atezolizumab has recently been approved for the treatment of small-cell lung cancer (SCLC).Approximately 1–6% of tumour ectopically produce ACTH and cause ectopic ACTH syndrome (EAS) as an endocrine paraneoplastic syndrome.The use of combined chemotherapy and atezolizumab in the ectopic ACTH syndrome secondary to small-cell lung cancer may cause a precipitous fall in circulating ACTH/cortisol, resulting in symptomatic adrenal insufficiencyThe advances in cancer therapy and treatment for endocrine paraneoplastic syndrome need to be adapted.

Diagnostic Impact of Adrenal Vein Sampling in Adrenal Cushing's Syndrome

Adrenal Cushing's syndrome is characterized by ACTH-independent hypercortisolism. Adrenal vein sampling (AVS) is not routinely employed prior to management decisions, and few studies have investigated the value of AVS in this population. We assessed whether AVS provides a diagnostic benefit for treatment planning. Six patients with imaging and biochemical evidence of adrenal Cushing's syndrome undergoing AVS at our institution from 2015 to 2020 were analyzed retrospectively, including demographic and clinical characteristics. AVS lateralization index was determined by comparing the (cortisol/ipsilateral reference hormone) ratios of both adrenal veins. lateralization index of 2 or greater was considered diagnostic of unilateral disease. Post-management clinical improvement was defined as serum cortisol normalization, symptomatic improvement, or both. Cross-sectional imaging noted bilateral adrenal enlargement or nodules in three patients, and unilateral nodules in three patients. AVS results were discordant with imaging in three patients. Treatment included medical management in two patients, percutaneous radiofrequency ablation in one patient, and laparoscopic adrenalectomy in two patients. One patient was lost to follow up. AVS results aided management planning in five patients, definitively changing treatment from surgery to medical management in one patient. All five patients demonstrated clinical improvement. AVS offered useful information for determining appropriate management of adrenal Cushing's syndrome, especially distinguishing unilateral from bilateral disease. Even in bilateral disease, AVS may show a dominant gland, potentially allowing a staged unilateral adrenalectomy, before assessing the need for completion adrenalectomy or medical management. Larger studies are needed to better establish whether AVS offers significant benefit for this population.

Primary adrenal insufficiency due to bilateral adrenal infarction in COVID-19: a case report.

Coronavirus disease 2019 (COVID-19) is a proinflammatory and prothrombotic condition, but its impact on adrenal function has not been adequately evaluated. A 46-year-old woman presented with abdominal pain, hypotension, skin hyperpigmentation after COVID-19 infection. The patient had hyponatremia, serum cortisol <1.0 ug/dL, ACTH of 807 pg/mL and aldosterone <3ng/dL. Computed tomography (CT) findings of adrenal enlargement with no parenchymal and minimal peripheral capsular enhancement after contrast were consistent with bilateral adrenal infarction. The patient had autoimmune hepatitis and positive antiphospholipid antibodies, but no previous thrombotic events. The patient was treated with intravenous hydrocortisone, followed by oral hydrocortisone and fludrocortisone. Among 115 articles, we identified nine articles, including case reports, of new-onset adrenal insufficiency and/or adrenal hemorrhage/infarction on CT in COVID-19. Adrenal insufficiency was hormonally diagnosed in five cases, but ACTH levels were measured in only three cases (high in one case and normal/low in other two cases). Bilateral adrenal non- or hemorrhagic infarction was identified in five reports (two had adrenal insufficiency, two had normal cortisol levels and one case had no data). Interestingly, the only case with well-characterized new-onset acute primary adrenal insufficiency after COVID-19 had a previous diagnosis of antiphospholipid syndrome. In our case, antiphospholipid syndrome diagnosis was established only after the adrenal infarction triggered by COVID-19. Our findings support the association between bilateral adrenal infarction and antiphospholipid syndrome triggered by COVID-19. Therefore, patients with positive antiphospholipid antibodies should be closely monitored for symptoms or signs of acute adrenal insufficiency during COVID-19.

An interesting case of masculine voice in a girl: A case report of 11 beta hydroxylase deficiency

A 7-year-old girl presented to our outpatient department (OPD) with masculine voice, hyperpigmentation of skin, and genital ambiguity. On clinical examination, she had hypertension, hyperpigmentation of skin, pubarche, clitoromegaly, and low-pitched voice. Karyotype was 46 XX and ultrasound showed bilateral enlarged adrenals, uterus, and ovaries. Hormonal workup revealed elevated levels of 17-?-hydroxyprogesterone, testosterone, 11-deoxycortisol, and deoxycorticosterone. Due to the presence of hypertension, genital ambiguity and elevated 11-deoxycortisol, a diagnosis of 11-?-hydroxylase deficiency variant of Congenital Adrenal Hyperplasia was made. The child was started on hydrocortisone and amlodipine after which her symptoms such as hyperpigmentation improved.

A Pedigree and Clinical Analysis of 11β-Hydroxylase Deficiency with Homozygous Mutation of CYP11B1 Gene

Abstract Background To analyze the clinical features and the mutation of CYP11B1 gene in a family with 11β-hydroxylase deficiency. Methods The clinical and laboratory tests data of the patient were collected. The complete sequences of CYP11B1 gene in the proband and potential mutations in other seven family members were analyzed by polymerase chain reaction and direct sequencing technique. Results A 25-year female patient showed complicated clinical symptoms, comprising hypertension, heart failure, renal failure, and pulmonary infections. Laboratory results showed higher levels of 17α-hydoxy progesterone, dehydroepiandrosterone (DHS) and adrenocorticotropic hormone (ACTH), and lower levels of cortisol and potassium in serum. Additionally, a positive reaction in mid-dose dexamethasone suppression test and a significant enlargement of bilateral adrenal glands from computed tomography scan were exhibited in this patient. Furthermore, a homozygous c.1157C&amp;gt;T (p.Ala386Val) in exon 7 of the CYP11B1 gene was identified in this patient. Four family members (father, mother, maternal grandmother, and aunt of proband) were heterozygous of the same mutation. Conclusion 11β-hydroxylase deficiency in this patient is caused by homozygous c.1157C&amp;gt;T (p.Ala386Val) in the CYP11B1 gene.

New genetic and clinical evidence associated with fetal Beckwith-Wiedemann syndrome.

Early detection of Beckwith-Wiedemann syndrome (BWS) is very important since it is very useful regarding counseling of parents concerning the risk of developing embryonic tumors, selection of the mode of delivery due to potential adrenal cysts that might bleed during labor, prevention of neonatal hypoglycemia and even options of pregnancy termination in non-viable fetuses. This report describes the prenatal classic sonographic triad of fetal BWS (omphalocele, macrosomia, macroglossia) and other supporting findings (hepatomegaly, adrenal enlargement) as well as additional postnatal evidence. Also, it demonstrates new molecular genetic evidence potentially associated with the disease (the presence of a novel heterozygous c.358G>T variant of the CDKN1C gene). Importantly, we provide new evidence indicating that elevated levels of the four serum biomarkers (alpha-fetoprotein, beta-human gonadotropin, unconjugated estriol, and inhibin-A) in late first or early second trimester might be strongly suggestive of BWS which may facilitate early detection especially in cases of no obvious anomaly. In conclusion, this study emphasizes on early detection of BWS as early as at 14 weeks of gestation, based on the abnormal rise of the four serum biomarkers together with omphalocele. To the best of our knowledge, this is the earliest prenatal detection of BWS ever reported. Finally, we provide new molecular genetic evidence that is, potentially associated with BWS.

Variations in the Initial Presentation of a Rare Congenital Adrenal Hyperplasia: Steroidogenic Acute Regulatory Deficiency

Background: Steroidogenic Acute Regulatory (StAR) deficiency is a rare form of congenital adrenal hyperplasia characterized by dysregulated cholesterol transport mediated by StAR enzyme across mitochondrial membranes. Adrenal dysfunction is due to the two-hit hypothesis: 1) defective StAR protein and 2) cholesterol accumulation in the adrenals and gonads. With variable cellular damage, adrenal crisis can occur early or late. Clinical cases: We present two cases of StAR deficiency with contrasting presentations. Case 1: A 9-day old ex full term female from a nonconsanguineous union presented to a rural hospital with hypothermia, lethargy, and poor feeding. She had hypoglycemia 41 mg/dL (60–105), hyponatremia 120 mEq/L (135–145), hyperkalemia 7.7 mEq/L (3.5–5.5) and cortisol < 0.4 ug/dL (4.5–23). Baby was started on hydrocortisone (HCT) 100 mg/m2 and one-time fludrocortisone (FCT). She decompensated requiring chest compressions, intubation and pressors. She was transferred to our institution. Newborn screen was normal; she had typical female external genitalia. US demonstrated a uterus; ovaries and adrenals were not identified. Upon extubation and clinical improvement, her HCT was weaned to physiologic doses. She became hyponatremic requiring FCT and salt supplements. Post-HCT wean, ACTH level was 304 pg/mL (7–63) with aldosterone < 4.0 ng/dL (6.5–86). Karyotype was 46,XX. Genetic analysis revealed a novel heterozygous likely pathogenic variant in the STAR gene, (STAR c.65-12_68del variant) without defect in the other STAR gene. Case 2: A 9-month-old ex full-term female of Iraqi descent from a nonconsanguineous union presented with fatigue, poor oral intake and weight loss from 50%-ile to 3%-ile. She had hyponatremia 122 mEq/L, hyperkalemia 8.0 mEq/L, but was normoglycemic. She was normotensive; EKG was normal. Parents noted progressive hyperpigmentation including her gums, palmar and plantar creases. She had typical external female genitalia with a hypoplastic clitoris (2 mm x 2 mm). ACTH stimulation test showed low cortisol (0.5 ug/dL) at 60 minutes. She was treated with HCT 100 mg/m2 for 5 days, then tapered to maintenance dosing, with FCT and salt supplements. Her ACTH level returned > 5000 pg/ml. Aldosterone, 17-OH-Progesterone, 17-OH-Pregnenolone, 11-Deoxycortisol and androstenedione were undetectable. Pelvic US did not identify uterus or ovaries. Pelvic MRI identified bilateral inguinal testes with enlarged adrenal glands. Karyotype was 46, XY. We suspected StAR deficiency with sex-reversal. Genetic analysis revealed a known homozygous mutation in STAR (c.545G>A). Conclusion: StAR deficiency is clinically indistinguishable from P450scc deficiency and genetic testing is needed. Both entities can present with early or delayed adrenal crisis. While classic for StAR deficiency, adrenal enlargement is inconsistent. Karyotype is vital to identify sex reversal.

Resistant Hypertension Due to Familial Hyperaldosteronism Type III: First Report From Indian Sub-Continent

Background: Familial hyperaldosteronism type III (FH-III) is caused by germline mutations in KCNJ5 gene. FH-III presents with phenotypic variability from spironolactone-responsive hypertension to massive adrenal hyperplasia requiring bilateral adrenalectomy. Till date, seven different pathogenic mutations in KCNJ5 gene have been identified. Here we describe a sporadic FH-III case, due to a Gly151Arg mutation, first from Indian subcontinent, presenting with extremely high plasma aldosterone concentration (PAC) values, further expanding our knowledge of this rare condition. Clinical Case: A 24-year-old female, symptomatic since age of 5 years with periodic limb weakness and gradual increase in frequency of episodes over the years. Her blood pressure (BP) was recorded for first time at 9 years of age, and it was 170/110 mm Hg. On evaluation at this time, PAC was highly elevated at 1007 ng/dL and plasma renin activity (PRA) was suppressed at 0.04 ng/ml/h with aldosterone renin ratio (ARR) of 25,175 ng/dL per ng/mL/h (>20 suggestive of primary aldosteronism). CT scan demonstrated mild enlargement of bilateral adrenal glands. A presumptive diagnosis of Glucocorticoid-remediable aldosteronism was made. She was started on dexamethasone, spironolactone and nifedipine but was not improved. Dexamethasone was stopped after 1 year of initiation. Before presenting to our referral center in 2018, she was having uncontrolled hypertension with recurrent episodes of hypokalemic paralysis. She was on maximal doses on four antihypertensive agents, further increased to six agents (including spironolactone 100 mg BD), and potassium chloride supplementation (120 mEq/day). Despite this, she had a serum potassium of 2.6 mEq/L. Her biochemical investigations demonstrated that PAC was 2070 ng/dL, direct renin concentration (DRC) was 2.35 µIU/mL (PRA 0.2 ng/ml/h) and ARR was 880.9 ng/dL per µIU/mL. CT scan revealed massive bilateral adrenal hyperplasia. Genetic analysis by whole exome sequencing detected KCNJ5 (p.Gly151Arg) mutation, confirming the diagnosis of FH-III. She was subjected to bilateral adrenalectomy and she became normokalemic. Dramatic reduction in antihypertensives with BP control achieved only on amlodipine post-operatively. Genetic testing of family members was not done but they were normotensive and normokalemic. Histopathological examination revealed bilateral adrenal hyperplasia. PAC levels up to 297 ng/dL have been described previously in FH-III but our patient had exceedingly high-level of 2070 ng/dL. Conclusion: This case demonstrates florid clinical and biochemical manifestations of FH-III and gradual worsening of symptoms, consistent with progression of disease with age. It illustrates that proper investigations and treatment can lead to remission of symptoms. Further studies are warranted to elucidate the full clinical and biochemical spectrum of FH-III.

Surgically Treated Resistant Hypertension Due to Bilateral Adrenal Hyperplasia

Background: Treatment resistant hypertension (TRH) may affect about 15% of patients with hypertension. While primary hyperaldosteronism is a known etiology of TRH, clinicians must consider the possibility of elevations of other adrenal hormones. Early identification of an etiology may prevent or delay the onset of complications. Case Report: Endocrinology was consulted on a 46 years-old man for evaluation of TRH. His past medical history is significant for TRH, nonischemic cardiomyopathy, congestive heart failure (Ejection Fraction 45–50%), and chronic kidney disease. Physical examination was unremarkable except for a blood pressure of 193/124 mmHg while on furosemide, isosorbide mononitrate, hydralazine, carvedilol, spironolactone, and clonidine. Chart review revealed mild hypokalemia. Computed tomography (CT) of the abdomen without contrast showed bilateral enlarged nodular adrenal glands with an increase in size over the last three years (left adrenal gland: 6.3 cm, right adrenal gland: 5.6 cm). Initial workup showed normal free plasma metanephrine, normetanephrine, aldosterone renin ratio, 17-hydroxyprogesterone, and undetectable random adrenocorticotropic hormone (ACTH) with random cortisol of 29 mcg/dl. Subsequent evaluation revealed elevated deoxycorticosterone (3030 ng/dL), 11-deoxycorticosterone (42 ng/d) and 18-Hydroxycorticosterone (640 ng/dL). He subsequently developed Cushing’s syndrome and diabetes mellitus. The patient underwent laparoscopic left adrenalectomy and subtotal right adrenalectomy. Pathology showed macro-nodular adrenal cortical hyperplasia. He was started on hydrocortisone for postoperative adrenal insufficiency. On his most recent follow-up, his blood pressure was well controlled on bumetanide, carvedilol, metolazone, and nifedipine. (Hydralazine, isosorbide mononitrate, spironolactone, and clonidine were stopped). After surgery, Corticosterone (92.10 ng/dL), 11-Deoxycorticosterone (<5.00 ng/dL) and ACTH(9 pg/mL) normalized. Conclusion: Determining the etiology of TRH should not be stopped after ruling out the “usual suspects” since malignant hypertension with end-organ dysfunction can develop, if not appropriately treated. In our patient, TRH was due to elevated 18-Hydroxycorticosterone (precursor of aldosterone), which improved after adrenalectomy.