bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pitfalls of Prenatal Diagnosis guiding Postnatal Management in Congenital Adrenal Hyperplasia(CAH)
Authors: Murthy Deepa Badrinath , Litao Melissa Kaori , Shah Bina Cherryl , Kohn Brenda , Breidbart Emily Nicole 
Published: May 2021

Abstract
Background: 21-hydroxylase deficiency is the most common form of CAH and is associated with a variety of clinical phenotypes (salt wasting SW, simple virilizing SV and non-classic NCCAH). Commonly, there is a strong genotype-phenotype correlation for SW and NCCAH, but this is less predictable with the SV forms. We present a case with prenatal diagnosis of classic CAH which demonstrated genotype-phenotype discordance. Clinical Case: Ex 39 weeker female born to non-consanguineous parents was prenatally diagnosed with CAH based on routine genetic screen. Mother was noted to be a carrier for Intron 2G and father was a carrier of p.I172N both known to be pathogenic variants on CYP21A2. At 23 weeks gestational age, DNA analysis revealed fetus was compound heterozygous for both mutations which is most commonly associated with either SV or SW phenotype. At birth, infant had mild edema of the labia majora which resolved; the clitoris was not enlarged. There was no genital virilization or urogenital sinus. Newborn screen sent at 15 hours of life:17 OHP 132 ng/ml, repeat on DOL 3:77 ng/ml and DOL 13:59.9 ng/ml. High dose cosyntropin stim test on DOL 3 at 0 min: Cortisol not done, 17 OHP 1279 ng/dl; 60 min: Cortisol 12.3mcg/dl, 17OHP 3394 ng/dl. DOL 5 at 0 min: Cortisol 2.7 mcg/dl, ACTH 164.5 pg/ml, 17OHP 803.7 ng/dl; 60 minute: Cortisol 7.6mcg/dl, 17OHP 5920 ng/dl. Using available 17OHP normograms, the infant’s stimulated 17 OHP levels were not consistent with classic CAH. Unstimulated testosterone on DOL 3: 25ng/dl, DOL 5: 14 ng/dl. Ultrasound showed adrenal gland thickness 4mm bilaterally (upper limit of normal). Hydrocortisone (HC) was started on DOL 5 at 35 mg/m2/day after the stim test. On DOL 7, HC was increased to 100 mg/m2/day; fludrocortisone 0.1 mg twice daily and NaCl 0.5 g/day were started (Na 131, K 6.5, plasma renin activity 80.2). Upon discharge (DOL 13), infant was on HC 35 mg/m2/day, Fludrocortisone 0.1mg twice daily and NaCl 2g/day. Doses were adjusted accordingly during outpatient follow up. Currently infant is 4 months of age, thriving and remains on HC 11.3 mg /m2/day, Fludrocortisone 0.05 mg twice daily and NaCl 750 mg daily. Postnatal genetic analysis confirmed prenatal genotype. Conclusion: In general, genotype-phenotype correlation has 80–90% concordance. However clinicians should be aware of genotype/phenotype discrepancies that exist in order to carefully guide postnatal management based on prenatal genetic analysis. Our patient’s 17-ohp was done by LC/MS, which is standard now for most specialized endocrine laboratories. However, the 17-ohp nomograms for CAH, which are frequently used for subtype categorization, are based on RIA levels. Further studies would be helpful in creating an updated normogram using LCMS specifically for the neonatal period, as confirmatory screening of CAH will become more common with the rise in parental prenatal carrier screening.
Pituitary Macroadenoma Masked by Iatrogenic Adrenal Insufficiency: A Diagnostic Blind Spot
Authors: Yee Ng Ivy Hoi , Cheung Elaine Yun Ning 
Published: May 2021

Abstract
Background: Exogenous steroid use is the most common cause of central adrenal insufficiency. Depending on the duration and strength used, it may take months to years for the hypothalamic-pituitary-adrenal (HPA) axis to recover after the steroid is stopped. We report a case of iatrogenic hypoadrenalism with persistent suppression of the HPA axis for 13 years, discovered later to be due to a second pathology.
Case: A 48 year old lady presented in 2005 with weight gain of 20 kg over 1 year and florid Cushingoid features. 9AM cortisol was undetectable (&lt;12 nmol/L). History taking revealed use of oral dexamethasone at various dosages over the past 9 years for her knee pains. A diagnosis of iatrogenic adrenal insufficiency was made. She was started on hydrocortisone replacement, and was advised to stop the over-the-counter steroids. By 2011 her short Synacthen test (SST) showed much improved functioning of the HPA axis (cortisol 182 (0 min) -&gt; 329 (30 min) -&gt; 408 nmol/L (60 min) [N peak&gt;500 nmol/L]), and she was back to her usual body weight. However, subsequent monitoring revealed declining trend of 9AM cortisol from 135 nmol/L (2013) -&gt; 99 nmol/L (2014) -&gt; 57 nmol/L (2015) -&gt; 64 nmol/L (2016) -&gt; 18 nmol/L (2017) [N 166–507 nmol/L]. Hydrocortisone compliance and abstinence from exogenous steroids was confirmed with the patient. The ongoing hypofunction of the HPA axis was continually attributed by multiple physicians to her history of prolonged use of dexamethasone. In 2018, at the age of 60, the lady presented with new onset headaches, blurred vision, and bitemporal hemianopia for 3 months. MRI showed a 1.8x1.8x3.5 cm (WxAPxH) pituitary mass with suprasellar extension compressing the optic chiasm. Blood tests revealed panhypopituitarism: SST cortisol 17 -&gt; 59 -&gt; 49 nmol/L, ACTH 2.7 pmol/L [N &lt;10.1 pmol/L]; fT4 9.5 pmol/L [N 12–22 pmol/L], TSH 0.97 mIU/L [N 0.27–4.2 mIU/L]; LH &lt;0.1 IU/L, FSH 0.52 IU/L (menopause at age of 48); IGF-1 27 µg/L [N 41–279 µg/L]; prolactin 17 mIU/L [N 102–496 mIU/L]. After partial excision of the mass her vision improved, but remained dependent on hydrocortisone and thyroxine supplements. The lesion was pathologically proven to be a pituitary macroadenoma.
Discussion: This case presents the uncommon course of a patient who had almost recovered from iatrogenic hypoadrenalism, only to lapse back into worsened central adrenal insufficiency, as part of panhypopituitarism related to an undiagnosed pituitary mass. In retrospect, the unusually protracted state of hypocortisolemia and the atypical waxing and waning HPA axis should have alerted one to consider alternative etiologies at work. As LH-FSH and GH deficiencies commonly develop before ACTH and TSH deficiencies in most pituitary macroadenomas, a lower threshold for testing the other anterior pituitary hormones followed by imaging of the pituitary could have picked up the tumor earlier in this patient.
Two Cases of Pembrolizumab-Induced Secondary Adrenal Insufficiency
Authors: Kanzaki Akinori , Otsuki Taiichirou , Arii Tohru , Koyama Hidenori , Katayama Satoru 
Published: May 2021

Abstract
Title: Two cases of pembrolizumab-induced secondary adrenal insufficiency Background: Although few cases regarding pembrolizumab-induced secondary adrenal insufficiency were reported, it has recently been published that significantly higher prevalence of human leucocyte antigen (HLA)-DR15, B52, and Cw12 was revealed in 11 Japanese patients with immune checkpoint inhibitor-induced secondary adrenal insufficiency as compared with healthy controls and DR15 might be a predictive marker. This is based on the evidence that DR15 has associations with IL-17-mediated autoimmune disease such as Hashimoto’s thyroiditis, and that anti-programmed death 1 (PD-1) inhibitors activate the Th1 and Th17 pathways. We here introduce two Japanese patients with pembrolizumab-induced secondary adrenal insufficiency from a viewpoint of their HLA typing test results.
Clinical Case: Case 1. A 52-year old male diagnosed with stage IV lung cancer (squamous non-small cell lung cancer) was treated with chemotherapy consisting of carboplatin, nab-paclitaxel, and pembrolizumab. Six days after the fourth cycle of pembrolizumab, he suffered from hypoglycemia and hyponatremia. Endocrinological examination findings showed ACTH and cortisol deficiency throughout the day, after which a diagnosis of secondary adrenal insufficiency was made based on no response shown in insulin tolerance, anterior pituitary function, and rapid ACTH stimulation tests. Pituitary cell antibody-1 was negative, and no evidence of a swollen/atrophied pituitary gland or space occupying lesion was observed in magnetic resonance imaging (MRI) results. Furthermore, Hashimoto’s thyroiditis was suspected based on anti-thyroid peroxidase antibody positivity. HLA typing test results highly corresponded with the reported results (A24, B52, Cw12, DR4, DR15).
Case 2. A 70-year old male was treated with pembrolizumab for recurrence of lung squamous cell carcinoma (stage IV). Two weeks after completion of five cycles, severe diarrhea occurred, suspected to be a side effect of pembrolizumab, which was relieved with temporary use of prednisolone. However, diarrhea recured accompanied with a high fever,
eosinophilia, and acute hyponatremia. Based on results showing deficiency of ACTH and cortisol, adrenal insufficiency was suspected. Anterior pituitary function and rapid ACTH stimulation test results supported that diagnosis, while pituitary cell antibody-1 was negative and MRI findings were not remarkable. Notably, completely different HLA typing test results were observed. Conclusion: Similar to the previous report, HLA-A24, B52, Cw12, DR4, and DR15 were found in case 1, whereas all subtypes including HLA-DR15 were lacking in case 2. We think that it should not be given low priority for cases lacking DR15 and the possibility of an association with IL-17 in such cases is required in feature study.
Unlikely Coexistence of Sporadic Pheochromocytoma and Bilateral Macronodular Adrenal Hyperplasia: A Challenge to Manage
Authors: Dinh Kathryn , Failor Richard A 
Published: May 2021

Abstract
Background: The incidence of bilateral macronodular adrenal hyperplasia (BMAH) is unknown, but growing in an era of increased utilization of imaging. Coexistence of BMAH and pheochromocytoma has not previously been reported.
Clinical Case: A 63-year man presented with enlarging left chest-wall mass found to have a poorly differentiated sarcoma. Staging PET/CT identified a hypermetabolic 2.0 cm left adrenal nodule with SVU of 16.6 concerning for metastasis. Hormonal evaluation included dexamethasone suppression test with 7AM serum cortisol of 24.7 ug/dL (&lt;1.8 ug/dL) without dexamethasone level, serum ACTH &lt;5.0 pg/mL (7.2–63 pg/mL), plasma metanephrine of &lt;0.20 nmol/L (0–0.49 nmol/L), and plasma normetanephrine of 0.76 nmol/L (0.00–0.89 nmol/L). Biopsy of this left adrenal nodule was consistent with pheochromocytoma. By history, he lacked any classical symptoms of pheochromocytoma. Repeat testing demonstrated only slight elevations in normetanephrine (1.3 nmol/L and 1.2 nmol/L); he remains asymptomatic at follow-up 4 months later. However, history and exam revealed central obesity, thin skin, type 2 diabetes mellitus on insulin, and hypertension controlled on three agents concerning for Cushing’s. Repeat evaluation showed AM cortisol of 17.9 ug/dL (&lt;1.8 mcg/dL) with dexamethasone level of 917 ng/dL (180–550 ng/dL), ACTH of 6.4 pg/mL with concordant cortisol of 23.1 ug/dL, and 24 hour urine collection with 0.98 L volume, creatinine of 0.58 g/24h (1–2 g/24hr), and urinary free cortisol of 67 ug/24h (3.5–45) altogether suggesting ACTH-independent hypercortisolism. On review of CT abdomen, he has bilateral adrenal nodules measuring &gt;1cm with bilateral gland enlargement consistent with BMAH. Resection of his left adrenal gland was not pursued due to cormorbidities as well as biochemically-silent nature of his pheochromocytoma. To manage his hypercortisolism, he was recently initiated on osilodrostat after completing radiation therapy for his chest-wall sarcoma.
Conclusion: This is the first case demonstrating clinical, biochemical, and imaging results consistent with bilateral macronodular adrenal hyperplasia and hypercortisolism also found to have a clinically and biochemically silent, biopsy proven pheochromocytoma. This is also a unique use of osilodrostat to manage BMAH.
Unusual Presentation of Cyclic Cushing’s Syndrome
Authors: Morales Hernandez Maria del Mar , Castellanos-Diaz Jessica , Subbarayan Sreevidya 
Published: May 2021

Abstract
Introduction:
About 20–40% of patients with Cushing’s syndrome present with cyclic Cushing’s Syndrome characterized by episodes of cortisol excess interspersed with periods of normal cortisol secretion. A high degree of suspicion is needed to identify patients with cyclical hypercortisolism. Fluctuations in cortisol levels can make this a diagnostic challenge. Rarely, hypocortisolemia and frank adrenal insufficiency can occur.
Case Report:
A 77-year-old female with history of Cushing’s syndrome and transsphenoidal surgery with no adenoma identified on pathology presented with fatigue and concern for recurrence with ACTH of 358 pg/mL (6–50 pg/mL) and morning serum cortisol of 41.4 mcg/dL. Brain MRI showed a possible 4 mm pituitary adenoma. However, when she was transferred to our hospital, there was no evidence of hypercortisolism with cortisol of 9.5 mcg/dL, ACTH of 33pg/mL, 24 hr urine free cortisol (UFC) of 4.4ug/d (&lt;45ug/d) and she was discharged home after neurosurgery recommended no surgical intervention. A week later, the patient returned to the hospital with nausea and weakness, and found to have cortisol of 4.4mcg/dL, ACTH of 12 pg/mL and UFC of 2.8 ug/d requiring short course of hydrocortisone for adrenal insufficiency. One year later, she presented with hip fracture, worsening weakness, plethora, and facial swelling. UFC was 1,338.3mcg/24 hr(4.0–50.0 mcg/24 hr), AM serum cortisol 58.8mcg/dL and ACTH 304.7 pg/mL. In addition to severe osteoporosis with hip fracture, she had hypertension and impaired fasting glucose. She was treated with Ketoconazole 200mg daily which was titrated until AM cortisol levels decreased from 58.8 mcg/dL to 20 mcg/dL. Patient was discharged on Ketoconazole with plan to complete a Dotatate scan to evaluate for ectopic ACTH production which resulted negative. Shortly thereafter, she returned with hypotension, nausea, and fatigue. Repeat cortisol level was 2.3 mcg/dL with ACTH of 27.6 pg/ml. Ketoconazole was discontinued and patient was started on hydrocortisone for adrenal insufficiency. Hydrocortisone was gradually tapered off. Pituitary MRI and IPSS are planned for further evaluation.
Discussion:
Cyclic Cushing’s syndrome is diagnosed with three peaks and two troughs of cortisol production. Diagnosis and treatment are challenging since the cycles of hypercortisolism can occur sporadically and rapid fluctuations in cortisol makes it difficult to localize a source. Cortisol fluctuations can affect quality of life and result in complications such as diabetes, hypertension, and osteoporosis. Prompt identification of the source of the Cyclic Cushing’s syndrome is vital to pursue definitive therapy. However, in 9% of cases, there is no identifiable source. In such cases, medical therapy is warranted.
Effects of CRN04894, a Nonpeptide Orally Bioavailable ACTH Antagonist, on Corticosterone in Rodent Models of ACTH Excess
Authors: Fowler Melissa A , Kusnetzow Ana Karin , Han Sangdon , Reinhart Greg , Kim Sun Hee , Johns Michael , Kredel Taylor A , Antwan Agnes , Athanacio Jon , Tsivkovski Oleg , Luo Rosa , Madan Ajay , Zhu Yun Fei , Betz Stephen F , Struthers Scott , Markison Stacy 
Published: May 2021

Abstract
CRN04894 is an orally administered nonpeptide that is a potent and selective antagonist for adrenocorticotropic hormone (ACTH) acting at the melanocortin 2 receptor (MC2R) and is currently under development for the treatment of diseases of ACTH excess such as Cushing’s disease, congenital adrenal hyperplasia, and ectopic ACTH-secreting tumors. Cushing’s disease results from an adenoma derived from pituitary corticotropic cells that secrete excess ACTH, whereas ectopic ACTH syndrome arises from nonpituitary ACTH secreting tumors. Congenital adrenal hyperplasia is a genetic disease that results in cortisol deficiency leading to high levels of ACTH and adrenal androgens. Each of these indications is characterized by high ACTH levels that act on MC2R expressed in the adrenal cortex to drive pathological elevations of adrenally derived steroid hormones. CRN04894 blocks the action of ACTH at MC2R, providing a potential novel treatment for these diseases. Preclinical models of chronic hypercortisolemia include implantation of ACTH-secreting pituitary tumor cells in mice and continuous administration of ACTH via subcutaneously implanted osmotic pumps in rats. These models induce features consistent with human diseases of ACTH excess including hypercortisolemia and hypertrophy of the adrenal glands. We employed both rodent models to examine the pharmacodynamic effects of CRN04894 on corticosterone levels and adrenal gland morphology. In the mouse pituitary tumor model, subcutaneous inoculation of the ACTH-secreting mouse pituitary tumor cell line, AtT-20, into immunodeficient mice resulted in formation of tumors and increased plasma ACTH and corticosterone levels. Repeated daily oral administration of CRN04894 for 14 days dose-dependently and robustly suppressed plasma corticosterone levels in mice with AtT-20 tumors. In the rat model, subcutaneous implantation of osmotic pumps delivering ACTH resulted in increased corticosterone levels, reduction in body weight, and hypertrophy of the adrenal glands after 7 days. Daily oral administration of CRN04894 over 7 days dose-dependently suppressed corticosterone levels, mitigated the effect of ACTH excess on body weight, and rescued the adrenal gland hypertrophy. These findings provide evidence that CRN04894 functions as an effective ACTH antagonist at MC2R to suppress adrenal corticosterone secretion in both mouse and rat models of ACTH excess and hypercortisolemia, thus providing a strong rationale for its potential therapeutic utility in diseases of ACTH excess. This work was supported in part by an SBIR grant from the NIH awarded to Dr. Struthers (R43- DK115245)
Genome-Wide Association Study Links Autoimmune Addison’s Disease to Break of Central Tolerance
Authors: Guillen Maribel Aranda , Røyrvik Ellen Christine , Eriksson Daniel , Berger Amund Holte , Landegren Nils , Alvarez Haydee Artaza , Hallgren Åsa , Grytaas Marianne Aardal , Ström Sara , Bratland Eirik , Botusan Ileana , Oftedal Bergithe , Breivik Lars , Vaudel Mark , Helgeland Øyvind , Falorni Alberto , Jørgensen Anders , Hulting Anna-Lena , Svartberg Johan Bernhard , Ekwall Olov , Fougner Kristian , Hughes Jeanette Wahlberg , Nedrebø Bjørn , Dahlqvist Per Mikael , Knappskog Per Morten , Wolff Anette Susanne Bøe , Bensing Sophie , Johansson Stefan , Kämpe Olle , Husebye Eystein Sverre 
Published: May 2021

Abstract
Autoimmune Addison’s disease is the predominant cause of primary adrenal failure, and is highly heritable. The genetic background has remained poorly understood due to the low prevalence and complex inheritance of the disease. We performed a genome-wide association study, which identified nine independent risk loci (P &lt; 5 × 10–8). In addition to novel and previous risk loci involved in lymphocyte functionality, we further associated autoimmune Addison’s disease with two independent protein-coding alterations in the gene Autoimmune Regulator (AIRE). The most striking is the amino-acid substitution p.R471C (rs74203920, OR = 3.4 (2.7–4.3), P = 9.0 × 10–25), which introduces an additional cysteine residue in the zinc-finger motif of the PHD2 domain of AIRE. This unbiased elucidation of the genetic contribution to development of autoimmune Addison’s disease points to the importance of central immunological tolerance, and explains 35–41 percent of heritability.
A Case of Chronic Bone Pain in Mc-CuneAlbright Syndrome
Authors: Nallu Ravali , Sliwinska Aleksandra , Taxel Pamela 
Published: May 2021

Abstract
Introduction: McCune-Albright syndrome (MAS) is a rare genetic disorder that effects the endocrine, skin and bone systems and caused by a somatic mutation in the G protein activating adenylyl cyclase resulting in abnormal osteoblast differentiation and development of fibrous dysplasia (FD). We describe a patient with extensive fibrous dysplasia and severe bone pain in the setting of MAS.
Case: A 56-year-old female with a history of MAS was evaluated in the osteoporosis clinic for chronic bone pain. She was diagnosed with MAS at the age of two when she presented with precocious puberty and treated with hormonal blockade. She had multiple orthopedic issues including chronic left hip and lower back pain with impending fracture and pelvic microfractures treated with prophylactic rodding and cement osteoplasty at age 46 and 51 respectively. She was taking Tramadol as needed. The patient reported an inch of height loss, and imaging revealed T4 compression fracture. She was treated with zoledronic acid 4 mg IV on a monthly basis for 1 year without any improvement in bone density or pain symptoms She reached menarche at age 12, and is currently menopausal. Her calcium intake was limited but vitamin D intake was adequate. The patient was quite active performing intense cardio exercises several times a week. Physical exam was remarkable for café-au-lait spots on her left trunk and abdomen not crossing the mid-line. Bone density showed spine DJD, right femoral neck and forearm T scores of -1.1 and -1.6 respectively. Recent CT scan demonstrated multiple lucent lesions in the thoracic spine, bilateral ribs and sternum consistent with fibrous dysplasia. Biochemical evaluation showed high bone turnover; urine NTX of 74 nM BCE/mM creatinine (26–124 nM BCE/mM) and bone specific alkaline phosphatase 80.7 U/L (14.2–42.7) Calcium and vitamin D levels were within limits. The patient initiated denosumab 60mg every 6 months to determine if significant reduction in bone turnover and bone pain would follow.
Discussion: As patients with MAS and FD have elevated RANKL levels and increased bone resorption, treatments that reduce bone turnover markers (BTMs) have been studied. Bisphosphonates have demonstrated decline in BTMs but with mixed results regarding improvement of clinical symptoms (1). In a recent study, denosumab, a monoclonal antibody to RANK-L was given at either 3- or 6-month intervals. Patients who received 3-month interval injections demonstrated a sustained suppression of BTM and improvement of pain (2). Thus, denosumab is a promising and well-tolerated agent that may be effective in FD, especially when response to bisphosphonates is inadequate. References:
1. Boyce et al, A randomized, double blind placebo-controlled trial of Alendronate treatment for fibrous dysplasia of the bone
2. Bas C.J Majoor Outcome of Long-term Bisphosphonate therapy in McCune-Albright Syndrome and Polyostotic Fibrous Dysplasia.