Macronodular Adrenal Hyperplasia Research Articles

Results of systematic KDM1A genotyping in a large series of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) patients and analysis of the genotype/phenotype correlation

Results of systematic KDM1A genotyping in a large series of Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) patients and analysis of the genotype/phenotype correlation

Primary unilateral macronodular adrenal hyperplasia with concomitant glucocorticoid and androgen excess and KDM1A inactivation

Primary unilateral macronodular adrenal hyperplasia with concomitant glucocorticoid and androgen excess and KDM1A inactivation

Primary bilateral macronodular adrenal hyperplasia caused by a novel variant in the ARMC5 gene

Primary bilateral macronodular adrenal hyperplasia caused by a novel variant in the ARMC5 gene

Bilateral adrenal macronodular hyperplasia successfully treated by unilateral adrenalectomy.

Bilateral adrenal macronodular hyperplasia successfully treated by unilateral adrenalectomy.

Bilateral adrenal macronodular hyperplasia successfully treated by unilateral adrenalectomy

Bilateral adrenal macronodular hyperplasia successfully treated by unilateral adrenalectomy

Familial bilateral macronodular adrenal hyperplasia due to a novel ARMC 5 germline mutation: Clinical status and possible association with other neoplasms

Introduction/ObjectivesMutations in the ARMC5 (armadillo repeat containing 5, OMIM 615549) gene, a putative tumor suppressor gene, have recently been identified as a common cause of sporadic and familial bilateral macronodular adrenal hyperplasia (BMAH). Familial BMAH is thought to be caused by two mutations, one germline and the other somatic, as suggested by the 2-hit theory. The objective is to describe a new mutation and develop its clinical characteristics and implications. Methods, Results and ConclusionsWe present an affected family with 11 members carrying a novel mutation of the ARMC5 gene (NM_001288767.1): c.2162T>C p. (Leu721Pro). Two of the carriers developed clinical Cushing's syndrome (CS), two mild autonomous cortisol secretion (MACS) and one presented with autonomous cortisol secretion (ACS). Four patients developed other tumors, three of whom died from this cause. It is not known whether these tumors could be related to the described mutation.

Familial bilateral macronodular adrenal hyperplasia due to a novel ARMC 5 germline mutation: Clinical status and possible association with other neoplasms

Introduction/ObjectivesMutations in the ARMC5 (armadillo repeat containing 5, OMIM 615549) gene, a putative tumor suppressor gene, have recently been identified as a common cause of sporadic and familial bilateral macronodular adrenal hyperplasia (BMAH). Familial BMAH is thought to be caused by two mutations, one germline and the other somatic, as suggested by the 2-hit theory. The objective is to describe a new mutation and develop its clinical characteristics and implications. Methods, Results and ConclusionsWe present an affected family with 11 members carrying a novel mutation of the ARMC5 gene (NM_001288767.1): c.2162T>C p. (Leu721Pro). Two of the carriers developed clinical Cushing's syndrome (CS), two mild autonomous cortisol secretion (MACS) and one presented with autonomous cortisol secretion (ACS). Four patients developed other tumors, three of whom died from this cause. It is not known whether these tumors could be related to the described mutation.

KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas.

A paradoxical increase of growth hormone (GH) following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants and somatic loss of heterozygosity of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expressions in somatotroph pituitary adenomas. We conducted a cohort study at university hospitals in France and in Italy. We collected pituitary adenoma specimens from acromegalic patients who had undergone pituitary surgery. We performed targeted exome sequencing (gene panel analysis) and array-comparative genomic hybridization on somatic DNA derived from adenomas and performed droplet digital PCR on adenoma samples to quantify KDM1A and GIPR expressions. One hundred and forty-six patients with sporadic acromegaly were studied; 72.6% presented unsuppressed classical GH response, whereas 27.4% displayed a paradoxical rise in GH after oral glucose load. We did not identify any pathogenic variant in the KDM1A gene in the adenomas of these patients. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 29 adenomas and observed a higher prevalence of paradoxical GH rise (P = .0166), lower KDM1A expression (4.47 ± 2.49 vs 8.56 ± 5.62, P < .0001), and higher GIPR expression (1.09 ± 0.92 vs 0.43 ± 0.51, P = .0012) in adenomas from patients with KDM1A haploinsufficiency compared with those with 2 KDM1A copies. Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus.

O-02 Inactivation of KDM1A with the concurrent presence of MGUS in a patient with GIP-dependent Cushing's syndrome and the vanishing effect of octreotide therapy

Abstract Introduction Glucose-dependent insulinotropic peptide (GIP)-dependent primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. It has germline genetic predisposition and requires for personalized approaches to investigation and therapy. We aimed to present the rare case of a GIP-dependent PBMAH patient with unusually severe cortisol secretion and a KDM1A inactivation with an accompanying haematological co-morbidity related to that mutation. Clinical Case A 41-year-old woman presented with a 5-kg weight gain in last 6 months, irritability and fatique. Physical examination revealed elevated blood pressure, increased supraclavicular fat pads, and abdominal obesity. The cortisol level was 25.9 (6.7-22.6) µg/dL in the morning, 16.9 µg/dL in the late night, and 6.5 µg/dL in the morning after an overnight 1 mg of dexamethasone. Urinary free cortisol (UFC) level was also elevated to 2150 (58-403) µg/24-h. The early morning plasma ACTH level was 1.5 (7-63) pg/mL. Abdominal imaging revealed 29×23 mm adenomas on the right and 46×35 mm on the left with high fat content. Cortisol was stimulated by the administration of mixed meals (+537%) but not by TRH, GnRH, metoclopramide or upright posture. The response to mixed meals was blunted by pretreatment with subcutaneous 100 mg octreotide. Following the patient's diagnosis of GIP-dependent PBMAH, octreotide LAR therapy was initiated. Although inducing a significant acute suppression of UFC and improvement in symptoms during the first 3 months, the UFC began to rise due to the resistance in the following period (Figure 1). After 9 months of octreotide LAR treatment, left adrenalectomy was performed according to the adrenal volumetric assessment. Histopathology was reported as diffuse macronodular adrenal hyperplasia without internodular atrophy. Even though the patient had a unilateral adrenalectomy, adrenal insufficiency occurred in the postoperative period. Subsequently, the patient has been closely monitored and followed up with a physiological, divided-dose hydrocortisone replacement regimen for 7 months. A germline heterozygous variant in the KDM1A gene in the patient's blood sample and a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in the adrenal sample were identified. When screened for diseases associated with the KDM1A mutation, monoclonal gammopathy of undetermined significance (MGUS) was detected in the patient with mild anemia, and genetic counseling was also provided. Conclusion The management of GIP-dependent PBMAH remains controversial, and further therapeutic options are under investigation. Due to the very limited number of case reports and the heterogeneous nature of the disease, special features of our case, which are severe cortisol excess, accompanying MGUS, the vanishing effect of octreotide, and adrenal insufficiency after unilateral adrenalectomy, might contribute to the existing literature.Figure 1.Urinary free cortisol levels following octreotide therapyUFC: Urinary free cortisol, ULN: Upper limit normal, LAR: Long acting release

Delineating endogenous Cushing’s syndrome by GC-MS urinary steroid metabotyping

BackgroundDiagnosing Cushing’s syndrome (CS) is highly complex. As the diagnostic potential of urinary steroid metabolome analysis by gas chromatography-mass spectrometry (GC-MS) in combination with systems biology has not yet been fully exploited, we studied a large cohort of patients with CS. MethodsWe quantified daily urinary excretion rates of 36 steroid hormone metabolites. Applying cluster analysis, we investigated a control group and 168 patients: 44 with Cushing’s disease (CD) (70% female), 18 with unilateral cortisol-producing adrenal adenoma (83% female), 13 with primary bilateral macronodular adrenal hyperplasia (PBMAH) (77% female), and 93 ruled-out CS (73% female). FindingsCluster-Analysis delineated five urinary steroid metabotypes in CS. Metabotypes 1, 2 and 3 revealing average levels of cortisol and adrenal androgen metabolites included patients with exclusion of CS or and healthy controls. Metabotype 4 reflecting moderately elevated cortisol metabolites but decreased DHEA metabolites characterized the patients with unilateral adrenal CS and PBMAH. Metabotype 5 showing strong increases both in cortisol and DHEA metabolites, as well as overloaded enzymes of cortisol inactivation, was characteristic of CD patients. 11-oxygenated androgens were elevated in all patients with CS. The biomarkers THS, F, THF/THE, and (An + Et)/(11β-OH-An + 11β-OH-Et) correctly classified 97% of patients with CS and 95% of those without CS. An inverse relationship between 11-deoxygenated and 11-oxygenated androgens was typical for the ACTH independent (adrenal) forms of CS with an accuracy of 95%. InterpretationGC-MS based urinary steroid metabotyping allows excellent identification of patients with endogenous CS and differentiation of its subtypes. FundingThe study was funded by the Else-Kröner-Fresenius-Stiftung and the Eva-Luise-und-Horst-Köhler-Stiftung.

Adrenal Cushing's syndrome in children.

Adrenal Cushing's syndrome is a rare cause of endogenous hypercortisolism in neonatal and early childhood stages. The most common causes of adrenal CS are hyperfunctioning adrenal tumours, adenoma or carcinoma. Rarer causes are primary bilateral macronodular adrenal hyperplasia (PBAMH), primary pigmented adrenocortical disease (PPNAD) and McCune Albright syndrome. The diagnosis represents a challenge for clinicians. In cases of clinical suspicion, confirmatory tests of hypercortisolism should be performed, similarly to those performed in adults. Radiological imaging should be always combined with biochemical confirmatory tests, for the differential diagnosis of adrenal CS causes. Treatment strategies for adrenal CS include surgery and in specific cases medical drugs. An adequate treatment is associated to an improvement of growth, bone health, reproduction and body composition from childhood into and during adult life. After cure, lifelong glucocorticoid replacement therapy and endocrine follow-up are required, notably in patients with Carney's complex disease.

PPARG dysregulation as a potential molecular target in adrenal Cushing's syndrome.

We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing's syndrome (CS) to define areas of dysregulated and druggable targets. Next-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing's disease (BADX-CD, n=8). In vivo findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1). Pathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that PPARG (l2fc<-1.5) and related genes - FABP4 (l2fc<-5.5), PLIN1 (l2fc<-4.1) and ADIPOQ (l2fc<-3.3) - were significantly downregulated (p<0.005) in PBMAH. Significant downregulation of PPARG was also found in BADX-CD (l2fc<-1.9, p<0.0001) and CPA (l2fc<-1.4, p<0.0001). In vitro studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p<0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p<0.05), respectively. This therapeutic effect was independent of the actions of ACTH, postulating a promising application of PPARG activation in endogenous hypercortisolism.

Primary unilateral macronodular adrenal hyperplasia (pumah) with concomitant glucocorticoid and androgen excess due to kdm1a activation and constitute mc2r activation

Primary unilateral macronodular adrenal hyperplasia (pumah) with concomitant glucocorticoid and androgen excess due to kdm1a activation and constitute mc2r activation

FRI153 Genetic Variant In Armadillo Repeat Containing 5 Gene (ARMC5) Associates With Salt Sensitivity Of Blood Pressure And Aldosterone In A Caucasian Cohort

Abstract Disclosure: W.W. Parksook: None. M. Heydarpour: None. L. Pojoga: None. A. Gaye: None. G.H. Gibbons: None. G.H. Williams: Advisory Board Member; Self; Cereno. Consulting Fee; Self; Alnylam, Crinetics, Damian, KBP bioscience, Paxel, Relapsa, Unicycive. Grant Recipient; Self; NIH 2 grants. J.S. Williams: Advisory Board Member; Self; Mellicell, Inc. Background: Genetic alterations of ARMC5 have been reported in various adrenal disorders, particularly in primary bilateral macronodular adrenal hyperplasia. Increasing evidence shows that polymorphic variants in ARMC5 are also associated with blood pressure (BP), hypertension, and the renin-angiotensin-aldosterone-system (RAAS) in individuals of African descent; however, little is known about these relationships in Caucasians. Herein, we conducted a deep phenotyping study to assess the association of ARMC5 variants with BP, salt sensitivity of BP (SSBP), and components of the RAAS in Caucasians. Methods: Normotensive and hypertensive, non-diabetic, non-chronic kidney disease, Caucasian participants underwent two dietary interventions at 5-7 days apart (200 mmol/day and 10 mmol/day sodium) to assess SSBP and other hormonal parameters. All participants were genotyped using a Multi-Ethnic-Genotyping-Array. Association analysis and the quality control of the genomic data were assessed by PLINK. Participants with complete data for SSBP and hormonal parameters, who were in salt balance, were included in the analysis (n= 306). Multiple linear regression models were used to assess the association between the genetic variant and outcome parameters. Results: There were 5 single nucleotide polymorphisms in the ARMC5 region. rs4889660 was significantly associated with SSBP in additive and dominant models when adjusted by Bonferroni correction. In a candidate gene analysis, rs4889660 risk allele carriers had greater SSBP than non-risk allele homozygotes (β= 4 mmHg, P= 0.03). Following dietary sodium restriction, rs4889660 risk allele carriers had lower serum aldosterone levels in an upright position (β= -6.9 ng/dl, P= 0.04) and serum aldosterone levels after angiotensin II stimulation (β= -3.0 ng/dl, P= 0.02). There were no differences between plasma renin activity, serum and urinary cortisol levels, and renal plasma flows between genotypes. Conclusions: There was an association between the ARMC5 rs4889660 variant and SSBP in Caucasians. With dietary sodium restriction, aldosterone responses to both upright posture and angiotensin II infusion were lower in the risk allele carriers. The reduced aldosterone responses suggest that an alteration in the RAAS system is not the cause of the SSBP, but is in response to a defect in another sodium-mediated homeostatic mechanism. Presentation: Friday, June 16, 2023

SAT330 Recurrence of Acth Independent Cushing Syndrome In Patient With Previously Operated On For Primary Bilateral Macronodular Adrenal Hyperplasia And Co-existence Of Papillary Thyroid Carcinoma

Abstract Disclosure: N. Vashakmadze: None. D. Nikoleishvili: None. Background: Cushing syndrome is a rare and usually sporadic endocrine disorder. Herein we describe a case of ACTH-independent Cushing syndrome and ACTH-dependent Cushing disease in non-identical twins. Moreover, recurrence of Cushing syndrome after 25 years of non-complete resection of adrenal glands and co-existence of papillary thyroid cancer. Clinical Case: A 57-year woman presented with hypertension, depression, easy bruising, proximal muscle weakness, fatigue, and facial plethora. According to the patient, Cushing’s syndrome caused by bilateral macronodular adrenal hyperplasia was diagnosed in 1997. Surgical treatment - left adrenalectomy and right adrenal gland resection was performed. She was receiving HRT during the first 6 months, since then she was not receiving HRT and her cortisol was normal. It is extremely interesting that her nonidentical twin sister was diagnosed with ACTH-dependent Cushing disease in 2006 and was successfully treated with transsphenoidal surgery. In 2019 patient was diagnosed with papillary thyroid cancer (PTC), thyroidectomy was performed and multifocal PTC pT1b(m)N0M0 was diagnosed. Patient received adjuvant therapy with 80 mCi of RAI. In 2019 cortisol and ACTH levels were routinely evaluated, ACTH was undetectable &amp;lt;3 ng/dl (N: 7.2-63); 1 mg dexamethasone suppression test showed no suppression of cortisol 116 ng/ml (N: &amp;lt;1.8 ng/ml). However, patient did not consult an endocrinologist with the results of the mentioned investigations. She admitted to our clinic in December 2022 with above-mentioned complains to determine the tactics of further investigation/treatment. The data obtained during our consultation was consistent to recurrence of Cushing syndrome: midnight salivary cortisol– 0.46 mcg/dl (0.02-0.34), ACTH– 4.2 ng/l (7.2-63), 1 mg of dexamethasone suppression test – 217 nmol/l (&amp;lt;50). CT showed right adrenal noduls (2.5 cm and 1.2 cm). These data confirmed the diagnosis of recurrence of Cushing’s syndrome and right adrenalectomy with steroid coverage and postoperative hormone replacement therapy was recommended. Other data showed normal OGTT, moderate hypercholesterolemia, taking into account Cushing’s syndrome and smoking, statins were initiated. DXA showed osteoporosis (forearm T-score = -3.9 SD). 25(OH)D3 – 22.35 ng/ml, Ca – 1.09 mmol/l (1.1-1.3). Denosumab, calcium and vitamin D supplements were started to the patient. In addition, TSH was markedly suppressed on 125 mcg LT4 therapy, TSH – 0.005 mIU/l (0.4-3.8); Tg &amp;lt;0.17 g/l, anti-Tg - N and neck ultrasound was normal, that is consistent with excellent response and the target TSH was established 0.5-2.0 mIU/l. The dose of LT4 was reduced to 100 mcg. Conclusion: To our knowledge existence of Cushing syndrome and Cushing disease in non-identical twins has not been reported yet. Also, co-existence of Cushing syndrome and thyroid cancer is rare, and no connection is established yet. Presentation: Saturday, June 17, 2023

FRI266 Medical Management Of Cushing’s Syndrome Caused By Primary Bilateral Macronodular Adrenal Hyperplasia (PBMA) With Low Dose Of Ketoconazole

Abstract Disclosure: J.S. Hatfield: None. C.M. Godar: None. N.O. Vietor: None. T.D. Hoang: None. M.K. Shakir: None. Introduction: Primary bilateral macronodular adrenal hyperplasia (PBMA) is an uncommon cause of endogenous Cushing's syndrome, defined as both adrenal glands with multiple nodules &amp;gt; 10mm in diameter. It often presents as incidentally found, bilateral, macronodular adrenal glands in patients between 40-60 years of age, frequently with only mild cortisol elevation. Although surgical treatment is recommended in these patients, we report the effectiveness of low-dose ketoconazole to control excessive cortisol secretion. Clinical Case: A 62 y/o woman with type 2 diabetes mellitus and hypertension was found to have bilateral adrenal nodules in 2010 while undergoing evaluation for abdominal pain. An adrenal CT scan confirmed bilateral adrenal nodules (largest left adrenal nodule 3.2cm x 2.9cm and right adrenal nodule 1.0cm x 1.0 cm). She was first referred for endocrine biochemical evaluation nearly 9 years later. Cortisol after 1mg dexamethasone suppression test was 17.3 mcg/dL, with corresponding ACTH of 3.1 pg/mL and dexamethasone of 310 ng/d, 24H urine cortisol 61 mcg/24 hr (6-42), 11 pm salivary cortisol 0.141, 0.133, 0.142 mcg/dL, and DHEA-S 11.4 mcg/dL (18.9-205.0). Biochemical evaluation for pheochromocytoma and primary hyperaldosteronism were negative. Serum 17-Hydroxyprogesterone 27 ng/dL was normal. Clinically, beyond her hypertension and diabetes she has no stigmata of hypercortisolism. Her type 2 diabetes with HbA1c of 7.8 is controlled with sitagliptin, insulin glargine and correctional lispro, and hypertension is treated with lisinopril. Due to the patient’s hesitancy for surgery, she was initiated on fluconazole which initially normalized urine cortisol levels (24H cortisol 20 mcg/24hr), though a rise to 70 mcg/24hr was noted after 6 months of treatment. She was transitioned to ketoconazole 200mg BID with resultant lowering of cortisol. Treatment was complicated by severe body aches that impaired ambulation, and symptoms resolved after decrease of ketoconazole to 100mg daily and rosuvastatin from 10mg to 5mg daily. Urine cortisol has remained in the normal range (15-22 mcg/24hr) for the last 2.5 years with no further side effects from ketoconazole. Discussion: Our patient’s clinical features suggest a diagnosis of PBMA. Most patients with PBMA have only mild elevation of cortisol levels and present with bilateral adrenal incidentalomas as seen in our patient. The classical features of Cushing's syndrome may be absent, and the nodular adrenals are frequently identified when abdominal imaging is performed for unrelated reasons. The amount of cortisol secretion is often sufficient to produce mild or overt Cushing’s syndrome. Although surgical treatment was considered, our patient was successfully treated with low-dose ketoconazole and thus, this may be an option in patients with mild PBMA-related Cushing’s syndrome. Presentation: Friday, June 16, 2023

FRI188 Exploratory Genomic Analysis From A Brazilian PMAH-Family With ARMC5 Alteration With Insidious Pattern Progression Of The Disease

Abstract Disclosure: H.L. Charchar: None. A.W. Kuhn: None. B.M. Mariani: None. M.Y. Nishi: None. F.L. Ledesma: None. M.C. Zerbini: None. F.Y. Tanno: None. V. Srougi: None. J.L. Chambo: None. M.Q. Almeida: None. B.B. Mendonca: None. M.C. Fragoso: None. Background: The clinical evolution of primary macronodular adrenal hyperplasia (PMAH) is usually slow over many years and is related to the insidious progression of hypercortisolism. The disease presents an autosomal dominant inheritance pattern with incomplete penetrance. Germline heterozygous mutations in the ARMC5 are present in 10% to 55% of the patients. The long-term follow-up of patients harboring germline ARMC5 pathogenic variants with normal evaluation will provide us with important insights regarding the outcomes. Clinical case: A 53-year-old man (index-case) was referred by the cardiologist to our service in October 2012, due to resistant hypertension (HTA), type 2 diabetes mellitus, dyslipidemia, and BMI of 32.4 kg/m2. Hormonal data: low ACTH (&amp;lt;5 pg/mL) and no suppression of cortisol after the overnight DST-1mg (22.7 µg/dL); late-night salivary cortisol, urinary free cortisol, aldosterone/renin ratio and plasma metanephrines were in the normal range. A CT scan showed bilateral enlargement of the adrenals associated with multiple macronodules. He underwent an adrenal-sparing surgery (total adrenalectomy of the left adrenal and partial adrenalectomy of the right adrenal). The macroscopic and histological appearance was consistent with PMAH. Leucocyte DNA genotyping identified the germline heterozygous ARMC5 pathogenic variant in exon 1 c.280del, p.(Ser94Argfs*43). This variant was identified in 3 of the 10 relatives investigated (son#1, daughter#2 and grandson#3). In 2021, the 37-year-old son#1 presented with a BMI of 32.6 kg/m2. Autonomous cortisol secretion was confirmed (cortisol after DST-1mg = 6.7 µg/dL). CT scan showed bilateral enlargement of the adrenals, similar to his father (index-case), with a larger left adrenal. Unilateral left adrenalectomy was performed, and PMAH was histologically confirmed. In 2018, the 21-year-old daugher#2 had normal adrenal function. More recently, in December 2022, she presented with an important weight gain (44kg in 4 years), without any specific signs and symptoms of hypercortisolism. Hormonal investigation showed a possible autonomous cortisol secretion (cortisol after DST-1mg = 2.2 µg/dL); the CT scan demonstrated an adrenal diffusely thickened with several nodules, especially on the left side, as the other relatives. Up to now, she has been using ketoconazole. All of them did not present meningioma of CNS. The grandson#3 with 11-year-old, is asymptomatic so far. Clinical Lesson: PMAH is a heterogenous and underdiagnosed disorder and is more genetically associated than previously thought. Therefore, a careful hormonal-genetic-clinical-radiological study of the relatives of index cases permits the diagnosis of many unsuspected familial-cases, including asymptomatic patients. Surgical or medical treatment should be considered for these patients to avoid progression to a possible overt Cushing syndrome. Presentation: Friday, June 16, 2023

OR17-05 Lysine Demethylase KDM1A And Ectopic Expression Of GIP-Receptor In Somatotropinomas Of Patients With Paradoxical Response To Oral Glucose

Abstract Disclosure: F. Chasseloup: None. L. Tosca: None. D. Regazzo: None. A. Proust: None. M. Hage: None. E. Kuhn: None. C. Jublanc: None. K. Mokhtari: None. S. Salenave: None. S. Gaillard: None. F. Parker: None. A. Boch: None. G. Tachdjian: None. P. Chanson: None. J. Bouligand: None. G. Occhi: None. P. Kamenicky: None. Introduction: Paradoxical increase of GH following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing’s syndrome. Most patients also displayed a deletion of chromosome 1p, including the KDM1A locus in their adrenal tissues, resulting in complete loss of KDM1A expression. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. The aim of our study was to search for genetic abnormalities of KDM1A in somatotroph pituitary adenomas. Methods: We collected somatotropinoma specimens from acromegalic patients followed in two tertiary endocrine centers in France and one in Italy. Somatic DNA was studied by targeted exome NGS and array-CGH. GIPR and KDM1A expression was quantified in the tumors using digital droplet PCR. Results: We included 186 patients: 108 patients (70.6 %) had a classic pathological GH response after oral glucose load, whereas 45 patients (29.4%) displayed a paradoxical rise of GH concentrations. Patients with a paradoxical response displayed higher IGF-1 levels (360 ± 111.8 % above ULN vs. 309.8 ± 107.3 %, p= 0.0130) and less invasive and smaller tumors (14.5 ± 5.58 mm vs. 18.5 ± 8.73 m, p= 0.0066). Amongst the 146 somatotropinoma specimens analyzed by targeted-NGS, no tumor harbored a KDM1A pathogenic variant, and 35 tumors harbored GNAS mutations (6 with and 29 without paradoxical GH responses). We identified a recurrent 1p deletion encompassing the KDM1A locus in 26 tumors, which were more frequently but not exclusively found in patients with paradoxical GH response compared to those with classic GH response. Somatic deletion of one KMD1A allele was associated with lower KDM1A expression (p=4.5e-5) and higher GIPR expression (p=0.0005). Discussion: Unlike in GIP-dependent PBMAH, we did not identify KDM1A genetic variants in a large cohort of acromegalic patients, independently of their GH response pattern to oral glucose loading. We identified recurrent 1p deletion in some tumors. Pituitary adenomas with a loss of one KDM1A copy due to chromosome 1p deletion harbored higher levels of GIPR transcripts than adenomas diploid for the KDM1A locus. If KDM1A haploinsufficiency leads to partial transcriptional derepression at the GIPR locus and a paradoxical rise of GH after glucose load warrants further investigations. Presentation: Saturday, June 17, 2023

FRI220 Primary Bilateral Macronodular Adrenal Hyperplasia: A Rare Cause Of Cushing Syndrome

Abstract Disclosure: Y. Ortiz: None. A.M. Aviles Melendez: None. M.M. Mangual Garcia: None. J.M. Garcia-Mateo: None. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a highly heterogenous entity whose pathophysiology remains largely unclear, representing less than 2% of Cushing syndrome (CS) cases, which leads to a challenging diagnosis. Many patients have a mild clinical picture and remain undiagnosed until abdominal imaging for unrelated reasons reveals bilateral adrenal enlargement. Hereby, we describe the case of a patient presented with abdominal pain and clinical hypercortisolism due to PBMAH. Case of a 42-year-old female with past medical history of arterial hypertension, referred for evaluation due to bilateral adrenal masses found on abdominal CT scan performed after patient presented with abdominal discomfort. On initial evaluation, patient refers a 50 pounds weight gain, increase in abdominal circumference, muscle weakness and sudden onset of facial and abdominal hair growth. Physical examination reveals dorsocervical fat pad, proximal muscle weakness, moon facies, facial and abdominal hirsutism. Abdominal CT scan with adrenal protocol showed bilateral adrenal lesions, with largest measuring 2.8 and 3.9 cm on the left side, with attenuation of 16 and 7.4 Hounsfield units. The absolute and relative washouts for the first were 76.6% and 61.6%, and for the second 73.5% and 67.1%, both consistent with adenomas. Laboratory results showed late night salivary cortisol levels of 4.60 ug/dl and 4.80 ug/dl, values which may be high or even normal due to ineffective steroidogenesis on PBMAH. Other labs consisted of low dose 1 mg dexamethasone suppression test: 4.80 ug/dl, and ACTH level: 9.60 pg/ml, which confirms clinical hypercortisolism, indeterminate for ACTH-independent cause. Desmopressin test was not performed, since levels may not be fully suppressed in PBMAH due to ectopic production by adrenal glands, leading to an erroneous diagnosis of ACTH-dependent CS. DHEA level of 618 ug/dl can also be increased, which could lead to a diagnosis of adrenocortical carcinoma. Considering risk of recurrence, risk for adrenal insufficiency, and lower documented complications, unilateral left-sided adrenalectomy was chosen as the best surgical treatment, despite bilateral adrenalectomy being the gold standard for diagnosis. Surgical pathology report showed Adrenocortical adenoma with associated myelolipomatous foci of 7.5 cm in greatest dimension. Despite limited data regarding unilateral adrenalectomy, it appears to convey clinical and biochemical benefits in most cases. Initial remission reported reaches more than 90% with low risk of recurrence between 10-15%. Adrenal insufficiency, despite the presence of residual hyperplastic adrenal tissue, occurs in about one-third of patients and is usually transient. Our case is a great example of the importance of individualization of management options based on therapy benefits, and decreased risks of future complications. Presentation: Friday, June 16, 2023

Unexpected exacerbation of cryptococcal meningitis after unilateral adrenalectomy in a PMAH patient: a case report and literature review

BackgroundPrimary bilateral macronodular adrenal hyperplasia (PMAH) combined with infection by an opportunistic pathogen is complicated. Clinical evidence on managing PMAH patients with infections by opportunistic pathogens is insufficient.Case presentationA 66-year-old male was admitted with bilateral adrenal masses and was diagnosed with PMAH. Fever and disturbance of consciousness appeared after laparoscopic left adrenalectomy. Cryptococcal meningitis was confirmed by cerebrospinal fluid (CSF) culture. The exacerbation of his medical condition was suspected to result from immune reconstitution inflammatory syndrome (IRIS), and he had been treated with antifungal therapy and glucocorticoid replacement, but he responded poorly and eventually died of multiorgan failure. We summarized the clinical observations of 12 Cushing's syndrome (CS) patients infected by Cryptococcus. Seven out of nine patients who were treated for cryptococcus infection before receiving CS survived, while three patients treated for cryptococcus infection after CS treatment developed signs of IRIS and eventually died.ConclusionCushing's syndrome, complicated with cryptococcal infection, has a high mortality rate, mainly when IRIS emerges. Carefully identifying the presence of the suspected infection, and controlling cryptococcal infection before removing the culprit adrenals could be the rational choice.