bluuebunny/crossref_metadata_2025 huggingface dataset:
Unusual Presentation of Cyclic Cushing’s Syndrome
Authors: Morales Hernandez Maria del Mar , Castellanos-Diaz Jessica , Subbarayan Sreevidya
Published: May 2021

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 (<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

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

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 < 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

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.
A Case of Vocal Cord Paralysis and Severe Hypocalcemia
Authors: Iwuala Sandra Omozehio , Kirupakaran Johnathan , Trusty Rhonda , Curry Sumarah , Williams Belinda , Daruwala Orpah , Fenton Franklyn , Bahtiyar Gul , Rodriguez Giovanna
Published: May 2021

Background: Tetany is the hallmark of hypocalcemia. Vocal cord paralysis is a rare presenting symptom of hypocalcemia, especially without signs of overt tetany or seizures. Clinical case: 18 year old man with history of iron deficiency anemia and dyslipidemia presented with aphasia, right sided upper and lower extremity weakness and facial tingling for 3 days. Physical exam was notable for aphasia, pallor, positive Chvostek and Trousseau sign. Admission labs showed BUN 127 mg/dL (n 8–26 mg/dL), creatinine 12.74 mg/dL (n 0.8–2.00 mg/dL), calcium 5.2 mg/dL (n 8.5–10.5 mg/dL), magnesium (1.8–2.4 mg/dL), phosphorus 10.3 (2.4–4.8 mg/dL), alkaline phosphatase 126 (8–120 U/L), albumin 3.3 g/dL (n 3.0–5.0 g/dL), 25 OH VitD3 9.1 ng/mL (n 30–80 ng/mL), PTH 594 pg/mL (n 15–65 pg.mL), COVID 19 PCR negative. Aphasia resolved with 1 gram calcium gluconate infusion. Patient underwent emergent hemodialysis. He was placed on calcium carbonate 1500 mg oral three times daily, calcitriol 1 mcg oral twice daily, ergocalciferol 50,000 IU weekly, sevelamer carbonate 1600 mg tablet three times daily. Kidney biopsy showed membranoproliferative pattern glomerulonephritis with C3 deposits. He was discharged on hemodialysis and referred to a transplant center. Conclusion: Vocal cord paralysis is rare in adults and mostly seen in patients with pseudohypoparathyroidism caused by hypomagnesaemia.2,3 Identifying vocal cord paralysis as an atypical presentation of hypocalcemia secondary to acute kidney failure requires prompt recognition and treatment. References: 1.Shoback D, Marcus R, Bikle D. Metabolic bone disease. In: Greenspan FS, Gardner DG, editors. Basic and clinical endocrinology. 3rd ed Los Altos (CA): Lange Medical Publications; 2004. p. 3242.van Veelen, M J et al. “Hypocalcaemic laryngospasm in the emergency department.” BMJ case reports vol. 2011 bcr1120103555. 17 Feb. 2011, doi:10.1136/bcr.11.2010.35553.Guise TA, Mundy GR. Clinical review 69: evaluation of hypocalcemia in children and adults. J Clin Endocrinol Metab 1995;80:1473–8
A Curious Case of PTH Independent Hypercalcemia Secondary to Silicone Injections
Authors: Matos Moises , Farooq Ahsan , Peynado De Pena Heidi Jackeline , Yau Hanford , Uddin Asif
Published: May 2021

Background: Hypercalcemia is a commonly encountered clinical problem with numerous etiologies. Granulomas formed secondary to foreign bodies are a rare but increasingly recognized cause of hypercalcemia. Clinical Case: A 49-year old African American woman, who had received silicone injections for buttock augmentation 15 years ago, was found to have severe hypercalcemia after she presented with complaints of chronic constipation, muscle cramping, polyuria, and mental fog. Her labs on admission showed severe hypercalcemia Ca 17.9mg/dL (normal: 8.4–10.6 mg/dL), with a suppressed PTH 4 pg/mL (normal 14–54 pg/mL). Prior labs from 5 years earlier, had shown an elevated 1,25(OH)2D, therefore differentials including lymphoma and chronic granulomatous diseases, particularly sarcoidosis, were high on the list of possible diagnosis. Additional labs showed a normal PTH-RP 19 pg/mL (normal 14–27 pg/mL), normal ACE levels 64 U/L (normal 9–67 U/L), low 25(OH)D2 1 ng/mL and normal 1,25(OH)2D 62 pg/mL. Her exam was notable for multiple indurated and firm masses palpable over the bilateral gluteal region and lateral thighs. CT abdomen/pelvis showed extensive and markedly confluent infiltration with intervening globules of macroscopic fat throughout the subcutaneous fat layers of the buttocks and lateral hips and speckled linear calcifications consistent with granulomatous reaction. With aggressive fluid hydration and calcitonin, her calcium levels decreased over the following 48 hours, but remained at 12–13 mg/dL. She was started on 30 mg of prednisone daily and her calcium levels dropped to 10.9 mg/dL the following day. She was discharged home on prednisone, her calcium levels remained suppressed, and her prednisone dose was slowly tapered during the following months. She was referred for plastic surgery evaluation and is being evaluated for possible surgical debridement. Conclusion: Hypercalcemia secondary to foreign body granulomas is a rare clinical entity. The diagnosis is usually established through a thorough history and examination. Lab findings may be variable. Treatment of these patients can be challenging, and corticosteroids are the mainstay of treatment in most cases1. Surgical debridement of granulomas has been reported with good results; however, further investigation and longer follow-up is needed2. References: 1.Tachamo, N., Donato, A., Timilsina, B., Nazir, S., Lohani, S., Dhital, R., & Basnet, S. Hypercalcemia associated with cosmetic injections: A systematic review. European Journal of Endocrinology, 2018; 178(4): 425–4302.Edwards, B.J., Saraykar, S., Suna, M., Murphy, W. A., Lin, P., Gagel, R. Resection of granulomatous tissue resolves silicone induced hypercalcemia, Bone Reports, 2016; 5:163–7
A Rare Case of Perinatal Hypophosphatasia Treated With Asfotase Alfa
Authors: Srivastava Priya S , Walch Abby , Vyas Arpita Kalla , Capodanno Gina , Lee Janet Yi Man
Published: May 2021

Background: Perinatal Hypophosphatasia (HPP) is a rare and lethal disorder associated with a 50–100% mortality rate, usually due to respiratory complications. HPP occurs due to a loss-of-function mutation in the ALPL gene, responsible for the function of tissue-nonspecific alkaline phosphatase (TNSALP). Clinically, HPP presents as a severe lack of bone mineralization leading to a rickets-like presentation.

Clinical Case: A 4-month-old female presented from an outside hospital for the ongoing care of perinatal HPP. Prenatal scans with long-bone fractures raised concern for Osteogenesis imperfecta. However, alkaline phosphatase (ALP) at birth was <11 U/L, and vitamin B6 was elevated >250 ng/mL. Calcium, 25-OH vitamin D, and urine phosphoethanolamine were normal. A genetics panel for HPP confirmed two pathogenic autosomal recessive mutations on the ALPL gene.

Treatment with asfotase alfa 3 mg/kg three times weekly was started on day two of life. The clinical course has been complicated by the need for mechanical ventilator support, seizure-event shortly after birth, recent EEG demonstrating epileptogenic potential in the bitemporal cortical regions now on treatment with Keppra, possible craniosynostosis with mild-to-moderate ventriculomegaly, and minimal grade 1 medullary nephrocalcinosis. Bone mineralization is monitored via skeletal surveys, and changes are measured using the Radiographic Global Impression of Change (RGI-C) and the Rickets Scoring Scale (RSS). After four months of asfotase alfa treatment, substantial progress in bone mineralization per RGI-C scoring has been noted, but RSS scoring still indicates severely low bone mineralization. ALP remains >3,000 U/L. Calcium, 25-OH vitamin D, and vitamin B6 are normal. Careful monitoring with weekly biochemical and urine profiles and monthly skeletal surveys, neuro assessments, and renal ultrasounds are ongoing.

Conclusions: This clinical case demonstrates the improvement in bone mineralization with asfotase alfa, but the clinical course is slow and arduous. Despite the early initiation of asfotase alfa the patient’s bone mineralization remains severely low and is not in a safe range to proceed with G-tube, broviac, or tracheostomy placement. The current management goal is to maximize bone mineralization in preparation for the life-sustaining procedures mentioned above. With only a handful of surviving cases in the world, current long-term survival and outcomes for patients with perinatal HPP are unclear.
A Treatable but Commonly Missed Etiology;An Unusual Presentation of Primary Hyperparathyroidism as Acute on Chronic Recurrent Pancreatitis- A Case Report
Authors: Abdelmasih Randa , Abdelmaseih Ramy , Monsour Elio Paul , Faya Marines , Nasser Hesham
Published: May 2021

Introduction: Acute pancreatitis is an identified, but uncommon presentation of Primary hyperparathyroidism with prevalence of 3.6%. Hypercalcemia is a rare but known cause of pancreatitis as it leads to premature intra pancreatic activation of protease and destruction of pancreatic tissue leading to pancreatitis. Here we present a case of primary hyperparathyroidism that went undiagnosed for years, and was finally diagnosed after recurrent episodes of pancreatitis of unclear etiology.

Case Presentation: A 46-year-old female with history of recurrent pancreatitis presented to the emergency department due to constant epigastric pain for 6 hours associated with nausea and vomiting. Patient reported recurrent episodes of pancreatitis over the past 4 years. Patient was told that etiology of pancreatitis is unclear despite workup. Patient was frustrated that her pancreatitis attacks were usually labeled as alcoholic pancreatitis as she works as a bartender. She strongly states she only drinks alcohol occasionally. She underwent cholecystectomy 2 years ago in attempt to prevent further pancreatitis attacks. Her vital signs were stable. Physical exam was remarkable for epigastric tenderness. CT abdomen and pelvis with contrast showed chronic pancreatitis, pseudocyst and free fluid in the pancreatic bed characteristic of acute pancreatitis. Abdominal US showed post cholecystectomy changes, with no biliary dilatation or stones. Initial labs showed: lipase 2001 U/L, Alcohol level < 10 mmol/L, Calcium 11.5 mg/dl, ionized calcium 4.9 mg/dl, phosphate 2.7 mg/dl, and Triglycerides 52 mg/dl. Subsequently parathyroid hormone was checked and was 116.8 pg/ml. Vitamin D was normal. NM parathyroid scan showed increased tracer activity demonstrating parathyroid adenoma. Patient was given IVF and supportive treatment and her symptoms improved. Endocrinology recommended parathyroidectomy. Patient elected to be discharged and undergoes parathyroidectomy outpatient.

Discusion: In this case we emphasize the importance of considering PHPT in acute pancreatitis of unclear etiology especially when Calcium level is elevated. PHPT was missed as a treatable etiology despite mildly elevated calcium level in prior hospitalizations. It is reported that pancreatitis is frequently associated with hypocalcemia with prevalence of 15–88%. Moreover, hypocalcemia is a component of Ranson’s scoring system for severity of pancreatitis. This is explained by precipitation of calcium soaps, hypoalbuminemia and increased calcitonin secondary to glucagon release. PTHT induced pancreatitis management has the same general principles of supportive management. All these patients, once stable, should undergo parathyroidectomy for definitive treatment. Data suggests nearly 100% improvement in pancreatitis symptoms and prevention of recurrent pancreatitis episodes after the cure of PHPT.
Acute Pancreatitis as an Initial Presentation of Primary Hyperparathyroidism
Authors: Yamane Laforteza Alexis Roberto , Villa Michael Lim
Published: May 2021

Background: Acute pancreatitis secondary to hypercalcemia is may be the initial presentation of a patient with primary hyperparathyroidism. However, because of its infrequency as a cause of pancreatitis, it can be easily missed during clinical management. Clinical Case: A 56-year old woman initially presented with epigastric pain with radiation to the back. She had no previous comorbidities, did not drink alcohol, and had no previous history of cholelithiasis, nephrolithiasis nor pathologic fractures. The diagnosis was confirmed by an elevated serum lipase level (59117 U/L, reference interval (RI): 73–393 U/L) and contrast-enhanced MRI findings suggestive of acute pancreatitis with hemorrhagic component in the pancreatic body and tail. Hypercalcemia was documented on two separate occasions during her confinement with a serum total calcium level of 10.5 mg/dL (RI: 8.5–10.1 mg/dL) and an ionized calcium level of 1.45 mmol/L (RI: 1.09–130 mmol/L), however, no further workup was done at that time. She was managed conservatively and was sent home with plans to do an ERCP and possible laparoscopic cholecystectomy once her condition had stabilized. However, she had recurrence of the epigastric pain about one month after her initial episode. Her serum lipase showed an interval increase from her last result (1426 U/L from 933 U/L) and contrast-MRI now showed the development of areas of walled-off necrosis in the body and tail of the pancreas. Serum ionized calcium was again elevated (2.17 mmol/L); she also had an elevated intact PTH level (780.6 pg/ml, RI: 18.5–88.0 pg/ml). Parathyroid SPECT-CT showed a sestamibi-avid lesion inferoposterior to the right thyroid lobe, indicating a probable parathyroid adenoma. She was given 1 dose of Denusomab 120 mg subcutaneously and started on Calcitonin nasal spray 200 IU twice a day. She underwent ultrasound-guided drainage of the pancreatic necrosis and was subsequently discharged. Due to difficulty in procurement of the Calcitonin nasal spray, she was maintained on Cinacalcet 30 mg/tablet, 1 tablet once a day upon discharge with plans to undergo parathyroidectomy once she was had fully recovered from her pancreatitis. Conclusion: Primary hyperparathyroidism should always be considered when hypercalcemia is noted during the clinical management of acute pancreatitis. Reference: Misgar RA, Bhat MH, Rather TA, Masoodi SR, Wani AI, Bashir MI, Wani MA, Malik AA. Primary hyperparathyroidism and pancreatitis. J Endocrinol Invest. 2020 Oct;43(10):1493–1498.
An Interesting Case of Isolated Bone Marrow Sarcoidosis
Authors: Iqbal Iqra , Minalyan Artem , Khan Muhammad Atique Alam , McGrath Glenn A
Published: May 2021

Introduction: About 30% cases of sarcoidosis have extrapulmonary manifestations but only 7% of patients present without any lung involvement. Among those 7%, most of the patients have manifestations on the skin but isolated bone marrow sarcoidosis has not been commonly reported. This case represents an unusual manifestation of isolated bone marrow sarcoidosis presenting with very high calcium levels.

Case Presentation: A 58-year-old female presented to us with fatigue, poor appetite, and nausea. She did not report any weight changes. Her cancer screening was up to date. On examination, she appeared dehydrated. No neck swelling was appreciated. Cardiac, respiratory, abdominal, and neurological examinations were normal. Complete blood count showed hemoglobin of 10.6 mg/dL, white blood cell count of 3.8 k/dL, and platelet count of 87 x109/L. Metabolic panel revealed hypercalcemia with corrected calcium levels as high as 12.6 mg/dL. Ionized calcium was 8.1 mg/dL (normal 4.8 - 5.6). Her parathyroid hormone (PTH) level was elevated up to 64.6 mg/dL and then further increased to 134.3 mg/dL. A 24-hour urinary calcium level was normal. 1, 25-dihydroxy (1,25-OH) and 25-OH vitamin D levels were 97 mg/dL (normal 18–72) and 31.2 mg/dL, respectively. Serum protein electrophoresis and light chain analysis were normal. Hyperparathyroidism was suggested as a cause of hypercalcemia. Ultrasound of the neck and sestamibi scan showed a right lower pole parathyroid adenoma. Paraneoplastic hypercalcemia was also one of the differentials. Parathyroid hormone related peptide (PTHrP) was 9 pg/mL (normal 14 - 27). Colonoscopy was normal. Computerized tomography showed normal lungs, liver and spleen. No masses and lymphadenopathy was seen. A bone marrow biopsy was done for pancytopenia. Patient underwent parathyroid adenoma removal followed by a drop in serum calcium level (8.2 mg/dL). Patient was discharged on calcium carbonate and vitamin D tablets. Upon outpatient follow-up, calcium level started to rise again up to 9.8 mg/dL. Despite discontinuation of supplemental calcium and vitamin D, calcium continued to uptrend (11.5 mg/dL 4 weeks later). Angiotensin converting enzyme (ACE) level came back as high as 129 (normal level < 40 mcg/L). Meanwhile, the bone marrow biopsy results showed that 40% of bone marrow was occupied by non-caseating granulomas suggesting sarcoidosis. Patient was started on steroids for isolated bone marrow sarcoidosis, and eventually her serum calcium level normalized.

Conclusion: An isolated bone marrow sarcoidosis is an extremely rare manifestation of extrapulmonary sarcoidosis. It can present with pancytopenia and should be sought in patients with persistent hypercalcemia. In addition, our case was challenging due to the presence of a concurrent hyperparathyroidism which was initially thought to be the only explanation of our patient’s hypercalcemia.
Bilateral Sacral Stress Fracture in Pregnancy without Osteoporosis - A Case Report and Literature Review
Authors: Wu Yu-Fang , Lu Kenneth , Girgis Christian M , Preda Martina , Preda Veronica Angela
Published: May 2021

Purpose: Sacral stress fractures are rare complications which can arise during pregnancy or in the early postpartum period. We report a case and discuss the findings of a confirmed postpartum sacral stress fracture in a 39-year-old multiparous woman and review previous case reports in the literature of sacral stress fracture related to pregnancy. Methods: A review of the literature was conducted to examine the main characteristics of sacral stress fractures related to pregnancy. The Ovid/Medline, Embase and Google Scholar databases were searched with the inclusion criteria: human studies, English language, intrapartum, postpartum (within 6 months of parturition), sacrum and stress fracture. Our exclusion criteria included pubic fractures, vertebral fractures and non-English articles. The search terms included “stress fracture”, “postpartum”, “pregnancy”, “atraumatic” and the wildcard “sacr*”. 34 cases were found and summarised in Table 2. Results: 65% of patients had onset of symptoms postpartum. Most patients did not have risk factors for sacral stress fractures including macrosomia, excessive pregnancy weight gain, heparin exposure, rapid vaginal delivery or predisposition to accelerated osteoporosis. Lumbar radiculopathy can be a feature of sacral stress fracture and it is more common (17.6%) than reported in the literature (2%). MRI is the preferred imaging modality for its safety profile in pregnancy and high sensitivity. 70% of reported normal bone mineral density (BMD). The mainstay treatment for sacral stress fractures includes relative bedrest, analgesia and modified weight bearing exercises. Most patients have favourable outcome with complete symptom resolution. Conclusion: Sacral stress fractures in the absence of osteoporosis are rare complications of pregnancy that can present with lumbar radiculopathy. Conservative management often produces good clinical outcomes.
Calcitriol-Mediated Hypercalcemia from Hepatic Granulomatosis Following Percutaneous Cholecystostomy Tube
Authors: Cater Taylor , Hassan Ayesha , Haider Adnan , Turner Jennifer
Published: May 2021

Granulomatous conditions can present with calcitriol-mediated hypercalcemia via increased 1-hydroxylase activity—activity that is not inhibited by calcium or calcitriol—indicating a lack of feedback inhibition. Differential diagnosis of granulomatosis is quite broad and can require extensive workup as highlighted by this case. Our patient is a 69-year-old white female admitted to the hospital with altered mental status and hypotension. Initial evaluation was concerning for infection, due to leukopenia and thrombocytopenia. CT abdomen revealed cholecystitis, percutaneous cholecystostomy tube was placed, and the patient’s mental status improved. One month after discharge, the patient presented to the hospital with a corrected calcium of 15.2 mg/dl. PTH was 22 pg/mL with normal renal function and phosphorus. The patient was treated with intravenous fluids, calcitonin, and zoledronic acid. Calcitriol was 69 pg/ml (18–75 pg/ml) and corrected calcium responded by time of discharge. During outpatient follow up, she was found to have corrected calcium 11.2 mg/dl and calcitriol 166 pg/ml with appropriately low PTH. Additional workup of apparent calcitriol-mediated hypercalcemia with whole-body CT imaging, tuberculosis screening, and flow cytometry only notable for possible right cervical lymphadenopathy on CT. Subsequent lymph node biopsy was benign. The patient completed a 30-day course of prednisone 20 mg daily followed by prednisone taper and her corrected calcium and calcitriol levels normalized. However, after discontinuation of prednisone, lab work demonstrated increase in calcium and liver enzymes. Repeat CT scan showed multiple hypoechoic areas with subsequent biopsy consistent with necrotizing hepatic granulomatosis. PAS-A, Fite, and AFB stains were negative for fungi and mycobacteria. Removal of cholecystostomy tube resulted in complete resolution of hypercalcemia and elevated calcitriol levels. Foreign body-induced granulomatosis is associated with PTH-independent hypercalcemia. Silicone has been implicated in foreign body granuloma. Hepatic granulomatosis is associated with percutaneous tube, especially with prolonged placement (approximately 11 months in this case). Removal of the foreign body is associated with improvement in hypercalcemia. Follow-up liver ultrasound demonstrated complete resolution of hepatic granulomas at three months following removal of the cholecystostomy tube.
Case of Juvenile Onset Hypophosphatasia Diagnosed in an Adult Patient
Authors: Nair Nirmal
Published: May 2021

Background: Hypophosphatasia is a rare multisystem disease caused by mutations in genes encoding tissue nonspecific alkaline phosphatase, a key player in promoting bone mineralization1. Here we present a case of hypophosphatasia in a patient with history of recurrent fractures and dental caries since childhood. Case Report: Patient is a 52-year-old woman with history of multiple fractures who initially presented for follow up of osteoporosis following an atraumatic ankle fracture. Further questioning revealed a history of 16 atraumatic fractures since the age of 4, involving ankles, toes, and fingers. Several adult teeth had never developed requiring braces to fill in gaps at age 13, dental caries and tooth fractures involving the majority of her adult teeth. DEXA scan in 2019 revealed T score of -2.4 in the left femoral neck. Suspicion for hypophosphatasia in February 2019 following an ankle fracture and patient’s prior history prompted further workup, revealing low serum alkaline phosphatase levels of 29 and 32 (bone fraction 62 percent, liver fraction 38 percent), and Vitamin B6 levels elevated to 66.2. Remainder of workup, with Vitamin D, PTH, Magnesium, and Calcium was normal. A childhood history of multiple atraumatic fractures, various dental issues, with elevated Vitamin B6 and low serum alkaline phosphatase suggested Hypophosphatasia. As bisphosphonates are contraindicated in these patients due to their potential to reduce ALP, teriparatide was initiated. Discussion: Hypophosphatasia involves mutations in tissue nonspecific alkaline phosphatase, a key player in bone mineralization. In normal individuals, this enzyme dephosphorylates inorganic pyrophosphate (PPi), which otherwise inhibits bone mineralization. The mutated TNSALP leads to accumulation of PPi, and thereby unmineralized osteoid.1 Although individual presentations can vary, developmental abnormalities, such as delayed growth, early loss of primary or secondary teeth, or history of multiple fractures are characteristic. Due to the rarity of the disease, and its potential to be confused for more common bone and rheumatologic diseases, diagnosis is often delayed1. Patients in whom suspicion for hypophosphatasia is present, should undergo further testing with bone specific Alkaline phosphatase and Vitamin B6 which would be low and elevated, respectively and may be candidates for enzyme replacement therapy with bone-targeting recombinant alkaline phosphatase1. Traditional treatments such as bisphosphonates potentially decrease ALP and worsen disease, making accurate diagnosis all the more crucial. References1 Bishop N. Clinical management of hypophosphatasia. Clin Cases Miner Bone Metab. 2015;12(2):170–173.
Delayed Diagnosis of Congenital Hypoparathyroidism in a Kindred of Three Patients With Autosomal Dominant Deafness
Authors: Dandurand Karel , Ali Dalal , Tran Susan , Zhou Tina , Khan Aliya Aziz
Published: May 2021

Background: Congenital hypoparathyroidism can be related to autosomal dominant mutations or deletions in GATA-binding protein 3 gene on chromosome 101,2. Affected patients present with a triad of hypoparathyroidism, renal dysplasia and neurosensorial deafness. We hereby present the case of a patient with the rare Barakat syndrome, also known as HDR syndrome. Clinical Case: A 11-year-old girl, diagnosed with deafness at birth, was brought to medical attention because of menorrhagia requiring blood transfusions two months after menarche. A pelvic ultrasound demonstrated a septate uterus as well as right multicystic dysplastic kidney with solitary left kidney and ovary. As her maternal grandmother, mother and older sister suffered from congenital deafness and her mother also had a kidney cyst, the patient was referred to genetics to identify a unifying cause of the autosomal dominant pattern of deafness and urogenital anomalies. Chromosome microarray analysis revealed a copy number change on chromosome 10p14 of 1925 kb predicted to result in the deletion of a single protein coding gene, GATA3. Embryonically, GATA3 is involved in the development of the inner ear, kidneys and parathyroid glands. The patient was lost to follow up so that a serum calcium was drawn three years later, revealing low ionized calcium of 1.06 mmol/L (N 1.16–1.29), low corrected total calcium of 2.11 mmol/L (N 2.30–2.62) along with PTH of 1.1 pmol/L (N 2.0–9.4), PO4 of 1.73 mmol/L (N 1.03–1.78) and creatinine of 64 umol/L (N 50–71). She was started on calcium carbonate 1000 mg TID and calcitriol 0.5 mcg BID and genetic analysis of the mother and sister revealed the same mutation compatible with Barakat syndrome. Compliance has been difficult, and when the patient transitioned to adult endocrinology three years later, she was on alfacalcidiol 2 mcg daily along with calcium carbonate 1500 mg daily and her labs were still suboptimal with a total corrected calcium of 1.82 mmol/L (N 2.22–2.54) and ionized calcium 0.98 mmol/L (N 1.16–1.29). Renal function determines the prognosis, and reassuringly her creatinine remains normal. Upon further questioning of the mother, she recalls that the patient had to be intubated for respiratory failure as a newborn, she had delayed milestones and also had seizure like activity during her infancy and early childhood. She had brought these symptoms to her family physician’s attention however no further investigations were completed and serum calcium was not checked.

Conclusion: Early recognition of hypocalcemia symptoms is critical in identifying patients with congenital hypoparathyroidism, even more so when associated with other features that are part of complex familial syndrome such as Barakat syndrome.

1. Barakat, AJ. Barakat syndrome revisited. Am J of Med Genet A. 2018, Jun; 176(6):1341–13482. Barakat, AY. Familial nephrosis, nerve deafness and hypoparathyroidism. J Pediatri. 1977;9(1):61
Early Osteoporosis in RYR1-Related Central Core Disease
Authors: Tariq Ezza , Mirza Lubna
Published: May 2021

Background: Central core disease(CDC) is a congenital neuromuscular myopathy with a wide range of phenotypic presentations, ranging from delayed motor development, frequent falls, and difficulty maintaining posture. CDC is a rare presentation of RYR1 (Calcium release channel gene) mutation, which is also linked with the etiology of malignant hyperthermia. Clinical Case: We present a case of a 57-year-old woman who was diagnosed with osteoporosis at age of 52 with a T score of -2.3 after she had a fragility fracture of the knee. She suffered from multiple falls from poor balance. Her most recent DXA bone density scan from December of 2018 showed a T score of -2.6. On genetic testing, she was found to have a RYR1 heterozygous mutation, on exon 28.c.3800C to G(p.P1267 Arg). This sequence change led to the replacement of proline with arginine at codon 1267 of RyR1 protein. None of her immediate and extended family members showed any signs of CDC. We assume that the loss of sufficient muscle strain on bone and the catabolic effect of RYR1 myopathy are major causes of osteoporosis in our patient, although menopause, personal history of smoking, and alcohol intake could also be contributing factors. Teriparatide along with daily Calcium and Vitamin-D was prescribed. Later on, denosumab injection was also added to the regimen. The patient still has at least one episode of unprovoked fall in a month, but luckily she has not had any more fractures. Conclusion: To our knowledge, this is the first case where early osteoporosis in RYR1 myopathy has been reported.
Fanconi’s Syndrome and Dementia in a Patient With Chronic Hepatitis B Taking Nucleoside/ Nucleotide Analogue
Authors: Ho Cheuk Wah , Cheung Yun Ning Elaine , Kam Yee Wai Grace
Published: May 2021

A 58-year-old Chinese man was referred to the Endocrine Clinic for osteomalacia in Aug 2014. He started to have generalized bone pain since Apr 2013. Bone scan in Aug 2013 showed multiple active bone lesions especially at right femur. Magnetic resonance imaging (MRI) found avascular necrosis of both femoral heads with fractured right femoral neck and he underwent screw fixation of right hip in Feb 2014.

In Aug 2014, his lab were as follows: serum (S) PO4 1.35(2.5–4.49)mg/dL; ALP 270 IU/ml (40–129); S creatinine (Cr) 1.36 (0.7–1.2) mg/dL; spot urine (U) PO4 23.2mg/dL.; U Cr 44.5mg/dL; parathyroid hormone 20.7 (15.1–65.1) pg/mL; 25-hydroxyvitamin D3 16.4ng/mL; TSH 3.4 uU/mL; S urate 1.7 mg/dL (3.4–7.0) mg/dL. U amino acid was increased to 5x upper limit of normal signifying U PO4 loss.

He had hepatitis B (HBV) liver cirrhosis and took lamivudine 100mg qd (LAM) since 2005. Because of LAM resistance, adefovir dipivoxil 10mg qd (ADV) was added in Jul 2007.

He was diagnosed Fanconi’s syndrome and osteomalacia after taking ADV for 6 years.

ADV was changed to tenofovir disoproxil fumarate 300mg qd (TDF) in Dec 2014. He was given alfacalcidol 1mcg bd and PO4 mixture 1250mg/d. His S PO4 rose to 2.82mg/dL but later dropped to 2.14mg/dL because of poor drug compliance. ALP dropped to 126IU/L. His bone pain improved and could walk with stick. TDF was then switched to tenofovir alafenamide (TAF) 25mg qd in Mar 2019. His S PO4 further normalized to 3.13mg/dL in Jul 2019. His HBV remained suppressed. Alfacalcidol and PO4 solution were stopped.

The patient developed depression since Sep 2017. He had poor short term memory since 2018 and was confirmed mild cognitive impairment in Apr 2019. MRI brain in May 2019 found moderate global cerebral atrophy with bilateral parietal lobes and cerebellar predilection. His cognitive assessment further declined to < 2%ile in Jan 2020. He was admitted for recurrent fall in Sep 2020 and showed Parkinsonism feature. He was given Sinemet 25/100 and rivastigmine by neurologist with some improvement. He now walked with frame.

Nucleotide and nucleoside analogues (NA) can impose long term side effect on kidney. ADV and TDF are excreted from proximal renal tubule and can accumulate in the cytoplasm causing mitochondrial dysfunction. In this patient, hypoPO4 persisted after switching from ADV to TDF. TAF did not enter proximal renal tubular cells and the plasma concentration is lower than TDF and hence less nephrotoxic. The PO4 level in this patient normalized one month after changing to TAF.

Low serum phosphorus level was found to have correlation with cerebral amyloid deposition on Pittburgh compound B positron tomography in a Korean study. The chronic hypoPO4 may be a contributing factor for the development of dementia in this patient which did not show reversibility.

In summary, this case illustrates the nephrotoxicity of NA and importance of multi-disciplinary care as the side effect can be multi-systemic.
Favorable Effects of Burosumab on Fibroblast Growth Factor 23-Related Osteomalacia: A Case Report
Authors: Oe Yuki , Kameda Hiraku , Nomoto Hiroshi , Sakamoto Keita , Soyama Takeshi , Cho Kyu Yong , Nakamura Akinobu , Abo Daisuke , Kudo Kohsuke , Atsumi Tatsuya , Miyoshi Hideaki
Published: May 2021

Background: Fibroblast growth factor 23 (FGF23) decreases serum phosphate levels by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption by decreasing serum 1,25-dihydroxyvitamin D level, thereby regulating phosphate metabolism. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by FGF23 overproduction by tumor tissue. Resecting the responsible tumor is a radical treatment for TIO. When the responsible tumor is undetectable, phosphate and active vitamin D administration is recommended. However, supplementation alone is frequently insufficient to maintain phosphate levels and it is difficult to prevent the complications associated with medical therapy, including hypercalciuria and nephrocalcinosis. Recently, burosumab, a human monoclonal anti-FGF23 antibody, has been approved in Japan as a therapeutic agent for FGF23-related hypophosphatemia. Here, we present a patient with TIO effectively treated with burosumab in the absence of identification of tumour location. Clinical case: A 47-year-old female developed pain and edema of the feet; however, the cause could not be determined at local hospitals. Afterwards, she developed marked bone atrophy in the feet and was referred to our hospital. Her age at symptom onset, hypophosphatemia (serum P, 1.9 mg/dl, 2.7 mg/dl < n < 4.6 mg/dl), high serum FGF23 level (630 pg/ml, 16 pg/ml < n < 69 pg/ml), and decreased 1,25-dihydroxyvitamin D level (12.9 pg/ml, 20 pg/ml < n < 60 pg/ml) indicated FGF23-related osteomalacia. She was not having any medication at the time of diagnosis, including saccharified iron oxide or iron polymaltose. Urinary phosphate excretion increased without renal tubular defect; therefore, hypophosphatemic osteomalacia was diagnosed. MRI showed high signal intensity in the talus, sacral, and L5 vertebral regions, indicating multiple pseudofractures. Comprehensive imaging studies, including systemic CT scan and 111In-pentetreotide scintigraphy, did not reveal any tumors despite the suspicion of TIO. Next, we performed systemic venous sampling, which revealed high FGF23 level in the left external iliac vein. Second venous sampling limited to the left lower limb exhibited high FGF23 level in the posterior tibial vein. However, an additional imaging study limited to the left foot could not identify any tumors. Genetic variation was negative for potentially responsible genes, including PHEX and FGF23. We decided to administer burosumab to normalize serum phosphate level without phosphate supplementation. Within 2 months, pain was relieved and the visual analog scale scores also improved from 10 to 6. Moreover, bone MRI showed improved pseudofractures. Conclusion: Burosumab administration was effective for TIO of unknown origin, and it improved not only laboratory findings but also clinical symptoms in this case.