bluuebunny/crossref_metadata_2025 huggingface dataset:
Transaminitis Evaluation Leads to the Incidental Diagnosis of Familial Paraganglioma Due to SDHB Mutation
Authors: Okafor Anderson , Yelangi Anitha , Samantray Julie
Published: May 2021

Background: Paragangliomas are rare neuroendocrine tumors. Patients with succinate dehydrogenase subunit B (SDHB) gene mutations are predisposed to developing paraganglioma/pheochromocytoma. We are presenting the case of an incidental finding of a paraganglioma during an evaluation for transaminitis.

Clinical Case: A 23-year-old male with a medical history of right hydrocele repair as a teenager was evaluated with an ultrasound of the abdomen for elevated liver enzymes and right upper quadrant discomfort. The ultrasound revealed a large lobular solid vascular 13.8 x 8.1 x 11.3 cm mass in the mid abdomen. He underwent a CT of the chest, abdomen and pelvis which demonstrated a large retroperitoneal mass measuring 16 x 10 x 13.7 cm within the right mid abdomen. The mass was described as a large centrally necrotic peripherally enhancing right retroperitoneal mass displacing the IVC anteriorly. The patient subsequently underwent an image-guided biopsy of the mass and the pathology revealed it was a paraganglioma. The patient denied any history of hypertension, orthostasis, headaches or palpitations. Biochemical workup for plasma catecholamines, plasma metanephrines, 24-hour urine catecholamines and metanephrines and cortisol were unremarkable. His transaminitis also resolved. He underwent a retroperitoneal paraganglioma excision and the final pathology was consistent with paraganglioma and negative for capsular invasion. He was referred to a genetic counsellor for testing since paragangliomas can be inherited. He also mentioned a family history of breast cancer in his mother and HTN and prostate cancer in his father. His test revealed that he had a c.289A>T mutation in his SDHB gene. He was encouraged to share the information with his family to help them understand the implications of his genetic test result. He underwent a surveillance PET scan which showed multiple osseous lesions in his temporal calvarium, sphenoid, spine and sacrum suggestive of metastasis. Repeat imaging with a DOTATATE PET scan showed stable disease. His transaminitis was transient, and we did not find a correlation to his paraganglioma. His imaging tests showed no liver metastasis. A CT of the head showed no evidence of intracranial metastasis. The current plan is to continue surveillance. His older brother underwent a genetic testing. He tested positive for the same SDHB mutation and underwent biochemical and imaging tests which were unremarkable. He too will continue surveillance.

Conclusions: Patients with a succinate dehydrogenase subunit B (SDHB) gene mutations are predisposed to developing paraganglioma/pheochromocytoma. The tumors produce catecholamines, but can be biochemically silent as in our patient. They are inherited in an autosomal dominant manner. Our case highlights the importance for genetic counseling which increases the chances of early screening and surveillance in affected family members for optimal multidisciplinary management of patients.
A Case of Psychosis Due to Acute Hypocalcemia From Hypoparathyroidism
Authors: Nehu Parimi Joseph Theressa , Liu John Chen , Gundluru Rajani , Naha Sowjanya , Gusov Timur , Syed Hasan , Gardner Michael J
Published: May 2021

A 61-year-old female with past medical history of depression, hypoparathyroidism (hypoPtH), and hypothyroidism had disappeared from her home and was found wandering a few hours away with persecutory delusions, visual and auditory hallucinations. Serum calcium (Ca) was 6.3 mg/dL (range 8.6–10.2), albumin 3.7 g/dL (range 3.5–5.2) and ionized Ca 0.89 mmol/L (range 1.12–1.30). She was admitted and treated with Ca and calcitriol. Work-up for altered mental status was negative except for hypocalcemia (hypoCa) and scattered bilateral basal ganglia calcifications (BGC) with cortical and subcortical frontal lobe calcifications on CT. Psychiatry diagnosed delirium due to hypoCa. Acute psychosis resolved once Ca levels improved. Diagnosis of idiopathic hypoPtH was in 1997. Her regimen included Ca citrate 1500mg daily and 10 mcg of Forteo twice daily. She had skipped her medications for at least 2 days prior to presentation.

Her medical records revealed that she was seen for severe depression, progressive gait abnormalities, slowed movements, and imbalance, in 2015. CT scan and MRI brain showed BGC. Her son gave a history of multiple admissions for psychosis, violence, delusions with agitation, and wandering at times when the patient was hypoCa, which was diagnosed as schizophrenia. Neuropsychiatric disturbances are commonly associated with hypercalcemia. Review of literature found a few case reports of psychosis and hypoPtH 1,2 BGC is common in hypoPtH. Psychotic symptoms due to BGC include auditory hallucinations, delusions of influence, paranoid states, and complex perceptual distortions.3,5 HypoCa is associated with cognitive impairment. Neurological manifestations tend to improve with Ca correction, but psychiatric symptoms do not improve substantially.4,5 Further studies are needed in hypoPtH with BGC to appropriately diagnose organic psychosis. This is important in management of the vicious cycle of psychiatric illness leading to noncompliance resulting in psychosis. Prevention of BGC will play a key role. References: 1. Finan M, Axelband J. This is your brain on calcium: psychosis as the presentation of isolated hypoparathyroidism. Am J Emerg Med. 2014;32:945.e1-4. 2. Ang AW, Ko SM, Tan CH. Calcium, magnesium, and psychotic symptoms in a girl with idiopathic hypoparathyroidism. Psychosom Med. 1995;57:299–302. 3. Burns K, Brodaty H. Fahr’s disease and psychosis. In: Sachdev PS, Keshavan MS, editors. Secondary schizophrenia. Cambridge: Cambridge University; 2010. p. 358–66. 4. Maiti A, Chatterjee S. Neuropsychiatric manifestations and their outcomes in chronic hypocalcaemia. J Indian Med Assoc. 2013;111:174–7.

5. Amara A, Novais C, Coelho M, Silva A, Curral R, Brandao I, Torres A. Organic psychosis due to hypoparathyroidism in an older adult: a case report. Braz. J. Psychiatry; 2016; 38(4)
A Case Report of Calcium-Sensing Receptor Gene Variant and Primary Hyperparathyroidism
Authors: Joad Sabaa Salim , Fang Mary Emily , Posey Jennifer E , Gaba Ruchi
Published: May 2021

Introduction: Primary hyperparathyroidism (PHPT) is an endocrinopathy that results from excessive production of parathyroid hormone from one or more overactive parathyroid gland(s). An estimated 90% of PHPT cases are sporadic, and 10% are inherited, comprising familial hyperparathyroidism (FHP). In FHP syndromes, variable clinical features are partly attributed to genetic heterogeneity. While there is not a consensus whether Familial hypocalciuric hypercalcemia (FHH) is a distinct entity or a form of FHP, accurate diagnosis is critical in guiding proper decision-making. The utility of genetic testing is multi-fold: help inform most likely diagnosis, guide prognosis and management, and inform familial recurrence risk. We report a patient with early-onset hypercalcemia, post subtotal parathyroidectomy, notable family history, with a likely pathogenic variant in the calcium-sensing receptor gene, CASR. Case Presentation: A 42 yo, female with history of nephrolithiasis and hypercalcemia diagnosed in her 20’s with PHPT was referred to our endocrinology clinic. Preoperative work up showed calcium of 11.1mg/dL, albumin 4.2g/dL, PTH of 177pg/mL, creatinine 0.92mg/dL. Sestamibi showed persistent activity in the mid to inferior aspect of right thyroid lobe suspicious for parathyroid adenoma. She underwent 3 gland parathyroidectomy and pathology showed mildly hypercellular parathyroid in left superior & right superior gland, normocellular left inferior gland. PTH levels normalized post-surgery. PTH levels normalized post surgery. Genetic evaluation was done, given her early-onset hypercalcemia, multi-gland involvement, and notable family history (maternal grandfather with parathyroidectomy for hypercalcemia and mother reportedly undergoing a hyperparathyroidism workup). Invitae hyperparathyroidism genetic panel revealed a likely pathogenic variant in CASR (c.659G>A; p.R220Q). Discussion: To date, our case with PHPT is the second report of the likely pathogenic variant CASR (c.659G>A; p.R220Q), which affects a conserved extracellular domain residue, thought to be important in sensing extracellular calcium. This variant has been previously reported in another family with FHH with 5 affected relatives. The reported 29-year old proband also had recurrent pancreatitis, which resolved with subtotal parathyroidectomy, but remained hypercalcemic. Despite the marked phenotypic heterogeneity in our patient and the case with FHH in terms of clinical presentation and response to treatment with surgery; both shared a history of hyperparathyroidism and a family history of hypercalcemia, suggesting contributions from the same CASR gene variant. With limited existing data about the variable expressivity of variants in genes implicated in the pathogenesis of both FHH and FHP; our case adds value to the existing evidence that supports its possible genetic contribution to PHPT
A Challenging Diagnosis of Primary Hyperparathyroidism in an Adolescent Female
Authors: Vining-Maravolo Patricia , Clemente Ethel , Ergun-Longmire Berrin
Published: May 2021

Background: Hypercalcemia secondary to primary hyperparathyroidism (PHPT) is less common in children than adults. Single parathyroid adenoma is commonly the cause of primary hyperparathyroidism in children. Clinical Case: We present a 15-year-old female with one-week history of abdominal pain despite taking over the counter antacids. Her initial work up by her primary care provider revealed serum calcium of 11.8 mg/dL (9.0–11.5) and creatinine of 0.8 mg/dL (0.4–1.2). A week later, she presented to the emergency department with same complaint. In ED, she was found to have hypercalcemia (12.8 mg/dl) with elevated parathyroid hormone (PTH) at 78.5 pg/mL (15–65). Her random urine calcium creatinine ratio was high at 2.1. Her 25OHD was 25 ng/mL (30–100). She had negative urine pregnancy test but had trace ketones, leukocyte esterase, blood and bacteria. CBC and CMP were otherwise unremarkable. She continued to complain abdominal pain with nausea, decrease appetite, fatigue, and general muscle weakness. There was no known family history of calcium or metabolic bone disorders. Her vital signs and physical exam were normal. Subsequent labs showed mild improvement of calcium between (11–12.3 mg/dL), PTH between 54.5 and 77 pg/mL, normal thyroid function. Ionized calcium was mildly elevated 6.0 mg/dL (4.5–5.3) but her repeat 25OHD was low at18 ng/mL. Serum phosphorus levels were relatively normal with lowest level of 2.5 mg/dL (2.7–4.5). Gliadin Deamidated IgA was detectable 15 U/mL (< 15.0 U/). Ultrasound of abdomen was significant for nonspecific mild hepatomegaly; kidneys were normal in size and appearance. Ultrasound of thyroid was significant for probably intrathyroid parathyroid, measuring 6 x 8 x 8 mm. Tc-Sestamibi scan did not confirm a parathyroid adenoma. Genetic testing for MEN-1 was negative. FHH- related genes (i.e. CASR) was positive for p.R990G variant resulting in a mild gain of function of the calcium-sensing receptor. Although previous Tc-Sestamibi scan was unremarkable, an over read of it raised a concern for questionable uptake in the left superior lobe. SPEC-CT demonstrated possible abnormal parathyroid tissue in the upper pole of the left thyroid. FNA of the left thyroid nodule confirmed likely intrathyroidal parathyroid adenoma. Subsequent follow up and treatment, including parathyroidectomy, was done by another institution. She underwent a left parathyroidectomy with normalization of serum calcium and PTH levels post operatively (10.1 mg/dl and 8 pg/mL, respectively) and has complete resolution of her previous abdominal and gastrointestinal symptoms. Conclusion: PHPT is uncommon in children and adolescents and is typically associated with a single parathyroid adenoma. High index of suspicion is key for early diagnosis of PHPT despite a negative Tc-Sestamibi initially.
A Novel Mutation in SOST Gene Causes Sclerosteosis
Authors: Alyusuf Ebtihal Y , Ekhzaimy Aishah A , Alzahrani Ali
Published: May 2021

Background: Sclerostin is a SOST gene product that inhibits osteoblasts activity and prevents excessive bone formation by antagonizing Wnt signaling pathway. Sclerosteosis has been linked to the loss of function mutation in SOST gene. It is a rare autosomal recessive disorder characterized by craniotubular hyperostosis leading to gigantism, cranial nerves entrapment, and fatal cerebellar herniation.

Objectives To report a novel mutation of SOST gene in a patient with sclerosteosis.

Clinical Case: A 25-year-old female was referred to the endocrine clinic for suspected GH excess. The patient noted the onset of headache, progressive bilateral blurred vision and hearing disturbance, irregular menses, and generalized arthralgia; at the age of 23 years. Subsequently, she observed a progressive increase in the size of shoes and hands, proptosis, and protrusion of the chin. She was the second of seven siblings from non-consanguineous parents with normal antenatal and neonatal history except for syndactyly. All family members were phenotypically normal except for a sister with similar physical appearance who had cranial decompression 20 years back. MRI pituitary was done initially due the suspicion of pituitary adenoma and it revealed an enlarged sella turcica with normal pituitary gland. Surprisingly, the MRI showed diffuse osseous thickening with narrowing of skull base foramina, narrowing of optic and internal auditory canals, secondary compression of cerebral parenchyma and bilateral cerebellar tonsillar herniation. Further image revealed extremely increased bone mass density with Z-score values of +12, generalized increase cortical thickness, vertebral end plates sclerosis, and deformed left index finger. Biochemical and endocrine tests revealed normal GH, IGF -1, TSH, prolactin, short Synacthen test, FSH, LH, estradiol, calcium, phosphorus, PTH and alkaline phosphatase. Due to progressive worsening of vision with compressive optic neuropathy, optic nerve fenestration with decompression hemicraniotomy was performed. Sclerosteosis was suspected due to the predominant craniotubular hyperostosis with syndactyly. There was no definite therapy. Management aimed at relieving symptoms and preventing complications, so she was commenced on calcitriol and prednisolone to suppress the osteoclasts. Genomic sequencing of the SOST was performed. We identified a novel deletion mutation in SOST gene (c.387delG, p.D131fs*) which disrupts the sclerostin function causing sclerosteosis in this patient.

Conclusion: We describe a novel mutation in the SOST gene in a patient with sclerosteosis in Saudi Arabia, that has not been previously described. Closing the gap between the genomic knowledge and clinical applications will add the benefit of success in development of targeted therapies in such a fatal disease.
A Rare Presentation of Non-Traumatic Recurring Bone Fractures in Adult Patient With Juvenile Onset Hypophosphatasia
Authors: Elmedani Sarah , Douedi Steven , Zin Khin , Ong Raquel , Cheng Jennifer
Published: May 2021

Background: Hypophosphatasia is a rare metabolic bone disease caused by mutations in the tissue-nonspecific alkaline (TNSALP) phosphatase gene. The disease is typically diagnosed in children but may be seen in adults with premature loss of adult teeth, poor bone healing, recurrent bone fractures, and limited mobility due to chronic pain. Clinical case: A 48-year-old female with Juvenile Onset hypophosphatasia and diabetes mellitus type 2 who presented to the endocrine clinic for diabetes mellitus. She had a telemedicine visit because she was not able to come to the office due to her recent rib fracture and pain. She had multiple fractures since she was 16-years-old with multiple fractures in her toes. She later developed a femur fracture when 20 years old and second at 28-years-old in the other femur. She was tested for juvenile hypophosphatasia and the diagnosis was confirmed. She received no treatment at that time. She subsequently had recurrent non-traumatic rib fractures that interfered with daily life. She is unable to exercise due to her frequent fractures and consequently having poor diabetic control. She has family history of brother with femur fracture. Labs showed decreased alkaline phosphatase (<5 normal: 38–126 U/L), elevated vitamin B6 levels (2296.2: normal 20–125 nmol/L) normal vitamin D (33: normal 30–100 ng/mL) and calcium levels. Chest x-ray showed multiple rib fractures with different healing stages. Dexa scan was also done and was normal to age with lowest Z-score being 8.2. Patient was started on Asfotase Alfa (an enzyme replacement therapy that contains the active site of TNSALP). Conclusion: This case illustrates the debilitating effects of hypophosphatasia and importance of recognizing previously untreated adult patients with hypophosphatasia. Many patients have very late diagnosis and suffer severe complications in their adulthood. Although this disease is rare, recognizing the symptoms of juvenile onset hypophosphatasia can help initiate early treatment to decrease these complications. Hypophosphatasia should be considered as a differential diagnosis in adults with multiple fractures and decreased alkaline phosphatase.
An Uncommon Case of Hypophophatasia Presenting With Galactorrhea, Diagnosed at a Later Age Than Expected
Authors: Bicchi Amelia Guzman , Heinsen Antonio Lubrano , Sevilla Marla , Tourtelot John , Gomez-Daspet Joaquin
Published: May 2021

Hypophosphatasia is a rare genetic disorder which causes accumulation of inorganic pyrophosphate that in turn inhibits mineralization. It is caused by a mutation in the non-specific alkaline phosphatase gene (TNSALP). We will review the diagnosis during adulthood when the presentation is characterized by poor healing, recurrent metatarsal stress fractures and bone pain. We are reporting the case of a 38-year-old white female with history of Melanoma referred to the Pituitary Clinic due to galactorrhea. During the encounter it was noted that she had history of disseminated joint pain, myalgias, periodontal complications as well as biochemical evidence of low alkaline phosphatase. At age three she had premature teeth loss, and clumsy gait, which later resolved. She was evaluated for this and diagnosed with odontohypophophatasia at which time no treatment was initiated. As an adult patient had two non-traumatic ankle fractures with associated frail teeth, chipping, and cracking without significant trauma. At around 36 years of age, patient started developing worsening joint pain, stiffness, myalgias and 35 pounds weight gain. Family History is remarkable for her father, having history of low alkaline phosphate and odontogenic infections with no joint or muscle pain. Paternal grandmother had history of dental infections and frail teeth. The patient has four sons; her oldest son has low alkaline phosphate with no clinical symptoms. Patient’s biochemical analysis was unremarkable except for low alkaline phosphate range between 25–38 U/L (40–125 U/L) and elevated Vitamin B6 69.5 ng/mL (2.1–21.7 ng/mL). The physical exam was unremarkable. Brain MRI showed a 3 mm microadenoma with normal pituitary hormonal workup, including diluted prolactin. Mammogram did not show any abnormalities. It was determined that the pituitary microadenoma was non-functioning, and galactorrhea was not hormonal mediated. The patient was referred to a genetic specialist for evaluation of Hypophosphatasia. Testing for TNSALP mutation was done which showed an ALP Mutation variant c.1172G>A (p. Arg391His). She was started on asfotase alfa (Strensiq) an enzyme replacement for Hypophosphatasia, in November 2019. Hypophosphatasia is a rare condition often diagnosed during early life. Due to wide number of possible mutations in the TNSALP gene, the clinical presentation can vary between patients and diagnosis can be elusive. In our patient, despite being diagnosed with odontohypophophatasia at an early age, and having many periodontal complications, hypophosphatasia was not confirmed until more than 30 years after the initiation of symptoms. In the management of Hypophosphatasia, having an accurate timely diagnosis can provide patients with early intervention of advanced treatment modalities such as Strensiq that can improve symptoms.
An Unusual Presentation of Primary Hyperparathyroidism: Ectopic Parathyroid Gland and Multiglandular Disease
Authors: Perez-Cavero Sonia Helen , Aldana Marlon Augusto Yovera , Zubiate Carlos
Published: May 2021

Primary hyperparathyroidism (PHPT) can be associated as a single parathyroid adenoma in approximately 85% of patients, the remaining 15% of them correspond to individuals with hyperplasia. The multiglandular parathyroid disease varies in range 7–33% and contribute a persistent PHPT. We report a case of primary hyperparathyroidism with an unusual presentation of ectopic mediastinal parathyroid. The case was of a 54-year-old female, who started her illness 3 years ago, with frequent headache, regular fatigue and muscle pain, denied losing weight. She was admitted to emergency room for a urinary infection. During the hospitalization showed bilateral nephrocalcinosis, hypercalcemic crisis. She has a background of total thyroidectomy and subtotal parathyroidectomy because a thyroid adenomatous hyperplasia and parathyroid hyperplasia with removal of a total of three parathyroid glands. She had very high PTH level. Laboratory: serum calcium: 16.8mg/dl; ionic calcium: 2.37 mmol/L; P: 1.9 (2.7–4.5g/dL); Hb: 9 g/dL; Platelets: 558 000 per microliter; Leukocytes 9 600 cells/mcL; Albumin: 4g/dl; TSH: 0.06 mU/L; fT4: 1.29 (L-T4 doses were 100 ug). Four months after parathyroid surgery, the intact PTH level dropped from 1602 ng/l to 550 (15–65 ng/L). Computed tomography and Tc-sestamibi scintigraphy - SPECT revealed a residual cervicothoracic mass in retroesophageal region (D1-D2) (Fig1 -2). The patient underwent a new surgery and the intact PTH dropped 39ng/L. Histopathology revealed characteristic features of a parathyroid adenomatous (10 gram weight) (Fig.3); additionally a retroesternal ectopic thyroid tissue. There was not reappearance of high blood calcium and parathormone levels more than 6 months after second surgery for PHPT. An unusual case of PHPT caused by a multiglandular disease parathyroid varies (four glands and a ectopic gland), reliable histopathologic adenomatous and hyperplastic parathyroid disease, and persistent primary hyperparathyroidism with very high serum intact PTH level.

Reference: (1) Masi L. Primary Hyperparathyroidism. Brandi ML (ed): Parathyroid Disorders. Focusing on Unmet Needs. Front Horm Res. Basel, Karger, 2019, vol 51, pp 1–12. (2) Pecheva M, Mahendran K, Kadlec J, Lofthouse M1, Van Tornout F. Mediastinal giant parathyroid adenoma-a minimally invasive mediastinal surgical approach for an emergency presentation. Ann Cardiothorac Surg. 2016 Jan;5(1):70–3. (3) Cakmak H 1, Tokat AO, Karasu S, Özkan M. Adenoma paratiroideo mediastínico gigante. Tuberk Toraks. 2011; 59 (3): 263–5. (4)Thier M, Daudi S, Bergenfelz A, Almquist M. Predictors of multiglandular disease in primary hyperparathyroidism. Langenbecks Arch Surg. 2018;403(1):103–109.
Calcium of 19mg/dL and Yet Asymptomatic
Authors: Naqvi Syeda , Syed Sabah , Fathima Aquila , Edison Monica
Published: May 2021

Lithium is a commonly used medication for Bipolar disorder. Lithium induced hyperparathyroidism is a rare disorder but leading cause of hypercalcemia in patients receiving Lithium treatment. Lithium may lead to exacerbation of pre-existing hyperparathyroidism or it may increase set point for calcium for PTH suppression.

We present a case of 65 year old female presented with hypercalcemia of 19mg/dl. She was sent by PCP office for hypercalcemia. She did not have any complains and was completely asymptomatic. Her history includes hypertension, Bipolar disorder and Diabetes mellitus type 2. She has not been able to get her labs drawn because of COVID-19. She was only having Tele visits with Psychiatrist. Her mood and bipolar symptoms were under controlled. She denies any abdominal pain, headache, visual problems, polyuria, polydipsia, numbness or tingling. She was given IV fluids and calcium was monitored. Her PTH was 65mg/dl, CBC and metabolic panel normal otherwise. Her Sestamibi scan was negative for parathyroid adenoma. Her lithium level was 4mg/dl. Lithium was discontinued after Psychiatry consultation. Her calcium came down to 9mg/dl after aggressive fluid resuscitation. Her calcium, parathyroid and lithium levels were monitored for next 6 months. Given her asymptomatic course she was not started on any calcium lowering medication. Her lithium level normalizes after one year of abstinence.

A patient who is started on Lithium therapy should be monitored for hypercalcemia, hyperparathyroidism and nephrogenic diabetes.
Coexistent CYP24A1 and PHEX Gene Mutations With Hypervitaminosis D Plus Hypercalcemia Treated With Fluconazole
Authors: Bawden David , Fraser William , Green Darrell , Rehman Shoib Ur
Published: May 2021

Background: CYP24A1 and PHEX gene mutations are rare and can cause hypercalcemia, hypervitaminosis D and elevated FGF23 levels. Fluconazole, an antifungal medication, has shown therapeutic benefit in achieving normocalcemia plus normalisation of vitamin D levels in this case report. Clinical Case: A 42 year old man was referred to the endocrine clinic with a history of severe nephrocalcinosis and recurrent nephrolithiasis requiring surgical intervention and gradual decline in kidney function over 20 years. Biochemical investigations revealed hypercalcaemia with adjusted calcium levels of 2.83 mmol/L (R 2.2–2.6 nmol/L) and suppressed PTH 1.1 pmol/L(R 1.6–6.9 pmol/L). Twenty-four hour urine calcium/creatinine clearance ratio was above 0.0578 mmol/mmol indicating hypercalciuria. Vitamin D metabolites 25 OH Vitamin D was elevated at 201 nmol/L, (R 50–120 nmol/L) along with intermittently elevated 1,25 OH Vitamin D 147 pmol/L(R 55–139 pml/L). 24,25 Vitamin D was low at 2.0 nmol/L producing a 25:24,25 dihydroxyvitamin D ratio of 80 (n<25). This biochemical data was highly suggestive of a loss of function mutation in the CYP24A1 gene that codes for the enzyme 24-hydroxylase, which is responsible for conversion of 1,25 vitamin D to 24,25 vitamin D. A pathogenic variant (heterozygous c.756G>A) was confirmed on genetic testing.

Plasma FGF23 (immutopics) was raised (with a peak of 596 RU/mL, n<100 RU/mL) but a full body octreotide scan did not reveal malignancy or other paraneoplastic syndromes such as oncogenic osteomalacia. A pathogenic variant in his PHEX gene (homozygous c.1874A>T) was also identified that has been associated with increased levels of FGF23 plus hypophosphataemia. Fluconazole at 50 mg once daily was initiated. Azoles inhibit cytochrome P450 enzymes and have been used in sarcoidosis to block vitamin D-synthesizing enzymes such as 25-hydroxylases and 1-α-hydroxylase that are P450 dependent. Few cases of CYP24A1 gene defects have been treated with fluconazole, which has a favourable side effect profile and yields good results. Adjusted calcium reduced to 2.62 nmol/L, 25 OH Vitamin D normalised to 111 nmol/L and 24:24,25 dihydroxyvitamin D ratio is now 17. Patient’s liver functions and full blood count has been monitored regularly during the course of treatment and the drug was well tolerated. Conclusion: Genetic causes of hypercalcemia can be left undiagnosed for long periods and there is a lack of proven or definitive therapeutic agents for correction of elevated calcium. Here fluconazole has been shown to reduce the hypercalcaemic burden and effectively lowered the Vitamin D levels in this case of a CYP24A1 mutation. This study augments fluconazole use in these cases but further studies are needed to elucidate the long term safe usage.
Ectopic Intact PTH Secretion Causing Humoral Hypercalcemia of Malignancy
Authors: Rauf Mohammad Talha , Nhan Winnie , Clines Gregory A , Khairi Shafaq
Published: May 2021

Background: Tumor-generated ectopic intact PTH is difficult to diagnose and should be suspected in patients with apparent primary hyperparathyroidism but with normal parathyroid glands.

Clinical Case: A 72-year-old man presented with symptoms of hypercalcemia including generalized weakness, polyuria, and polydipsia. Initial labs were consistent with primary hyperparathyroidism: calcium 12.1 mg/dL (n 8.6–10.3 mg/dL, albumin-corrected 12.5 mg/dL), intact PTH (iPTH) 115.6 pg/mL (n 10–65 pg/mL), low normal 25-OH vitamin D (25 ng/mL, n 25–100 ng/mL), and relatively high normal 1,25 dihydroxyvitamin D (52 pg/mL, n 18–78 pg/mL). 24-hour urine calcium was 381 mg/day (n 100–300 mg/day) and PTHrP was 1.6 pmol/L (n <4.2 pmol/L). Neck ultrasound demonstrated a 0.5 x 1 cm hypoechoic mass near right thyroid inferior pole, though sestamibi SPECT/CT scan did not reveal scintographic evidence of a parathyroid adenoma. He underwent subtotal parathyroidectomy with largest excised gland weighing 0.262 grams. The left inferior parathyroid gland appeared normal intraoperatively, thus was clipped and left in place. PTH decreased from 194 pg/mL to 98 pg/mL postoperatively. Pathological examination revealed three normocellular parathyroid glands with enlargement of only the right superior gland. Venous sampling of the parathyroid vasculature failed to identify the source of autonomous iPTH post operatively. Due to refractory hypercalcemia, cinacalcet was initiated. However, hypercalcemia as high as 12.6 mg/dl and hyperparathyroidism to 672 pg/mL persisted despite dose escalation. He eventually received pamidronate with subsequent transition to denosumab due to declining renal function. A  68Ga DOTATATE scan was performed to locate occult ectopic parathyroid, which reported multiple foci of presumed somatostatin receptor expression involving the liver and intra-abdominal lymph nodes without significant uptake in the neck concerning for metastatic disease. Liver lesion biopsy was consistent with pancreato-biliary adenocarcinoma. Surprisingly, the biopsy was negative for iPTH and neuroendocrine tumor markers on staining/immunohistochemistry. Given his poor prognosis and multiple comorbidities, the patient opted not to pursue any further workup or therapy for his malignancy.

Conclusion: Occult malignancy should be suspected for a patient with persistent hyperparathyroidism after parathyroidectomy. Treatment of the malignancy may lead to an improvement in hypercalcemia and iPTH levels. Employment of iPTH mRNA testing or intra-abdominal venous sampling to prove ectopic iPTH secretion would be ideal, as iPTH staining could be falsely negative. Further testing was not completed as the patient declined further evaluation.
Falsely Positive Parathyroid Scan in a Patient With Medullary Thyroid Cancer
Authors: Khthir Rodhan Abass
Published: May 2021

Background: Technitium 99m sestamibi is a very useful method for preoperative localization in hyperparathyroidism. It have some limitations including false positivity due to thyroid pathology. We present a patient with positive Technitium 99m sestamibi uptake by a medullary thyroid cancer Case Presentation: A 67-year-old female referred to the endocrine clinic for evaluation of medullary thyroid cancer diagnosed by fine needle aspiration of left side thyroid nodule. TSH level was normal with high normal serum calcium and high PTH levels. No family history of medullary thyroid cancer, hyperparathyroidism or pheochromocytoma. Her plasma metanephrines were normal. Preoperative evaluation included a parathyroid scan with oral I-123 and Intravenous Technitium 99m sestamibi. I-123 scan showed a cold nodule in the left thyroid lobe and the subtraction images demonstrated persistent uptake of Technitium 99M sestamibi which was reported by the radiologist as a parathyroid adenoma. Repeated serum calcium was normal and intraoperative evaluation of parathyroid glands demonstrated no abnormal enlargement confirming that parathyroid scan was falsely positive secondary to medullary thyroid cancer. Conclusion: This case highlights the importance of careful interpretation of nuclear parathyroid scan results. False positive results have been reported with both benign and malignant thyroid disease including medullary thyroid cancer.
Glomus Tumor: An Unusual Cause of Hypophosphatemic Osteomalacia
Authors: Raj Rishi , Hasanzadeh Samaneh , Dashtizadeh Mitra , Kalantarhormozi Mohammadreza , Vahdat Katayoun , Dabbaghmanesh Mohammad Hossein , Nabipour Iraj , Ravanbod Mohammdreza , Assadi Majid , Hashemi Basir , Asadipooya Kamyar
Published: May 2021

Background: Tumor-induced osteomalacia (TIO) is a rare condition resulting in hypophosphatemic osteomalacia. We present a rare case of TIO secondary to glomus tumor. Clinical Case: A 39-year-old woman with history of chronic sinusitis presented with progressively worsening generalized body pain and muscle weakness of eight months duration. Examination showed decreased muscle strength in bilateral upper and lower extremities and congenital cleft palate. Laboratory work up revealed elevated alkaline phosphatase 603 U/L (44–147 U/L), low serum phosphorus 1.5 mg/dL (3.5–5.0 mg/dL), normal serum calcium 8.9 mg/dL (8.3–10.4 mg/dL), normal 25-hydroxyvitamin D 32 ng/dL (30–100 ng/dL), elevated 1,25-dihydroxyvitamin D 62 g/mL (20–45 pg/mL), elevated intact PTH level 99.01 pg/mL (8–74 pg/mL), high normal 24 hour urinary phosphate levels 1100 mg/dl, and elevated FGF23 level 128 RU/mL (<108 RU/mL). Fractional excretion of filtered phosphate (FEPO4) [FEPO4 = (Urine phosphate / Serum phosphate) / (Urine creatinine / Serum creatinine) * 100] was 107.54 % (normal range <20%). Tubular reabsorption of phosphate (TRP) [Percentage TRP = 100 * {1- (Urine phosphate / Serum phosphate) / (Urine creatinine / Serum creatinine)}] was -7.54 %. Tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) calculated using formula [TmP/GFR = TRP x serum phosphate] was -0.1131 mg /dL (2.8–4.2 mg/dL). Bone densitometry revealed normal bone density and parathyroid scintigraphy was negative for adenoma. Clinical symptoms along with biochemical evidence of phosphate wasting confirmed by low TRP and an unsuppressed FGF23 levels suggested oncogenic osteomalacia as underlying etiology. Whole body bone scan demonstrated increased radiotracer uptake in the elbows, spine, sacroiliac joints, knees, ankles and multiple ribs suggestive of inflammatory process. MRI of paranasal sinuses revealed large soft tissue mass occupying right frontal, ethmoid, maxillary and sphenoid sinuses suggestive of sinonasal polyposis. 99mTc-Octreotide scan confirmed increased uptake in the nasopharynx. The sinonasal mass was resected and pathology revealed the mass to be a glomus tumor confirmed on immune histochemical studies with positive staining for vimentin and SMA and Ki67 of 5–10 %. Postoperatively, phosphorus levels normalized to 3 mg/dl on day 7. Conclusion: Glomus tumor as cause of TIO is extremely rare however localization and surgical resection of tumor can result in complete resolution of biochemical and clinical manifestations. References: 1. Minisola, S., et al., Tumour-induced osteomalacia. Nat Rev Dis Primers, 2017. 3: p. 17044.
Low Bone Mineral Density and Recurrent Fractures During and After Pregnancy: Dilemma of an Overlooked Diagnosis
Authors: Jodeh Wade S , Nachawi Noura , Khan Leila Zeinab
Published: May 2021

Background: Decreased bone mineral density (BMD) during pregnancy and lactation are rarely described in literature. We present this case of multiple compression fractures during and after pregnancy, highlighting the diagnostic and therapeutic dilemma of an overlooked diagnosis.

Clinical Case: A 23-year-old female without significant past medical history, suffers from an acute onset lower back pain in the third trimester of her first pregnancy. On initial evaluation, this back pain was thought to be musculoskeletal and was dismissed by her medical team. No imaging was ordered throughout the duration of pregnancy, despite the pain remaining unrelenting. On her second day post-partum, she heard a “pop” in her back and fell while holding her newborn. Imaging revealed multiple vertebral compression fractures, in different stages of acuity. Due to debilitating pain, the patient quit breastfeeding and ultimately would never hold her baby again. Her simple activities of daily living were stymied, both as a mother and secretary. It wasn’t long before she couldn’t even fax forms in her office and had to leave work with debility. Traumatized by these life events and continuing to be afflicted by this chronic pain, the patient decided against having any future children. Her compression fractures were managed with different types of analgesics in addition to vitamin D and calcium supplements.

At age 53 and 57, BMD scans showed a T-score >1 at both the lumbar spine and total hip. Forearm BMD was not evaluated at these times. At age 58, a CT spine demonstrated new compression fractures at T5-T12 & L1-L5. She subsequently underwent kyphoplasty of T5, T7 and T8. Fortunately, a bone core biopsy of these 3 vertebrae showed no malignant pathology. A follow up CT scan 6 months later showed stable compression fractures, along with multilevel degenerative changes and neural foraminal stenosis. At age 60, the patient would receive L4-L5 trans-foraminal epidural corticosteroid injection and referral to the bone clinic at a tertiary health center. Initial lab work on referral was significant for normal calcium, albumin, parathyroid hormone, vitamin D, kidney function, liver function, serum and urine protein electrophoresis and cross link N-telopeptide. Osteocalcin was low at 3.9 ng/mL (NL 8.8–37.6 ng/mL). Repeat BMD scan showed T-scores of 0.6, 1.1 and -2.6 at her lumbar spine, total hip and distal forearm respectively. Her osteoporosis is currently managed with teriparatide without active issues.

Conclusion: This case highlights the rare development of low BMD in pregnant and breastfeeding women, without prior risk factors, jeopardizing future quality of life. The evidence behind the incidence and pathophysiology underlying these changes remains deficient. There remains a dearth of guidelines for definition and treatment of osteoporosis and low BMD in young peripartum women.
Osteitis Fibrosa Cystica A Rare Presentation of Primary Hyperparathyroidism
Authors: Pierrard Patricia Luengo , Tortolero Giamate Laura M , Guerrero Belén Porrero , Ramírez Joaquín Gómez , Nuñez Jordi Nuñez
Published: May 2021

Introduction: Osteitis fibrosa cystica (OFC) is the most serious bone involvement of primary hyperparathyroidism (PHPT), it is characterized by subperiosteal resorption, lytic lesions and the appearance of brown tumors; this is why, in some cases, this condition can easily be mistaken for a malignant neoplasm. Its prevalence in developed countries is only 5%.

Clinical Case: We present a 58-year-old woman, with no relevant personal history, who came to the emergency room with pain in her right shoulder after an accidental fall on the bus. The humerus radiograph shows a pathological fracture of the right humerus, with significant osteopenia. In the emergency analysis, serum Calcium 13.3 mg / d), Ionic Calcium 7.03 mg / dL, Phosphorus 2.4 mg / dL, Alkaline Phosphatase 248 U / L and normal kidney function stand out. With a diagnosis of severe hypercalcemia, treatment was started in the emergency room with serum therapy (1000 ml of 0.9% physiological saline in 4 hours) and intravenous diuretic treatment (furosemide 40mg) with a decrease in calcemia to 12.8mg / dL. Later, she was admitted to the Internal Medicine hospital ward to perform a differential diagnosis of hypercalcemia secondary to a primary tumor, Multiple Myeloma or Primary Hyperparathyroidism. The study findings are: Calcium metabolism: PTH 660 pg / ml (12 - 65), 25 Hydroxyvitamin D: 14.00. Thyroid ultrasound: Posterocaudal to right thyroid lobe, an area of ​​echogenicity slightly lower than the thyroid is identified, of dimensions not estimated by endothoracic component, which could correspond to a parathyroid adenoma. Body CT: Neck: Heterogeneous nodule dependent on the posterior region of the right thyroid nodule with endothoracic extension. Skeleton: Lytic lesions with a tumor aspect in the humerus, right scapula and bilateral seventh rib and right pubic branch. Skull: Diffuse increase in bone density of the calvaria, showing multiple punctate lytic lesions with a permeative appearance. Bone densitometry: Femur neck: - <1.5, Lumbar spine: - <3.0 With the diagnosis of PHPT causing osteitis fibrosa cystica, surgical intervention was decided. Under general anesthesia, a selective right approach was performed, finding a large parathyroid adenoma weighing 17 grams. PTH fell to 36 pg / ml after surgery. At 9 months after surgery, the patient presented calcium levels of 9 mg / dl and PTH 146 pg / ml with clear radiological improvement.

Discussion: Osteitis fibrosa cystica is rare in our environment, it is often confused with other neoplasms. After parathyroidectomy, patients with PHPT have a marked and sustained recovery from OFC, although in some cases this recovery can only be achieved after several years. We consider this case of interest, since it illustrates the importance of evaluating the study of phospho-calcium metabolism and parathyroid function in all patients with bone lesions to rule out Primary Hyperparathyroidism with OFC.
Osteogenesis Imperfecta With Cerebral Atherosclerosis: A Family Report
Authors: He Junyu , Liao Zhihong
Published: May 2021

Background: Osteogenesis imperfecta (OI) is a rare hereditary connective tissue disease. It is mainly associated with pathogenic variants in COL1A1 or COL1A2. Patients with OI usually have repeated history of bone fractures. Besides, osteogenesis imperfecta is associated with some cardiovascular complications, such as aortic and mitral valve dysfunction, aneurysm and aortic dissection. But the relationship between these diseases has not been well studied.

Case Presentation: A 55-year-old man was admitted to our hospital mainly due to “dizziness for 2 hours”. He had a 4-month history of hypertension and a history of smoking for more than 20 years. He had no history of drinking alcohol. He had hunchback and O-type legs. Besides, the patient and some of his relatives had a history of repeated brittle fractures,which was considered as “osteogenesis imperfecta”. The clinical manifestation of OI in this family varies to a certain extent, from simple tooth disintegration to severe fracture deformity. The most serious patient of his family was unable to walk. CT and MRI revealed multiple systemic arteriosclerosis, including vertebral artery, posterior inferior cerebellar artery, cervical artery, and bilateral cerebellar multiple lacunar cerebral infarction. The blood sample of the patient was tested by whole exome sequencing, and the saliva samples of the patient’s family members were tested by Sanger sequencing. A mutation c.3159 + 2T > A was detected in COL1A2 gene associated with OI, also found in the other affected family members, which had not been reported before. It was a segregating mutation in the family. The clinical severity of the family members was heterogeneous.

Discussion:

This case is worth learning from the following aspects: 1. A pathogenic heterozygous mutation, c.3159 + 2T > A was detected in COL1A2 gene in the patient with OI, which is not reported in previous cases of OI. 2. The clinical manifestation of OI in this family varies to a certain extent, from simple tooth disintegration to severe fracture deformity. The most serious patient of his family was unable to walk. It presented the clinical heterogeneity of OI. Further basic researh on the mutation site of related gene of OI are needed. 3. We found the possibility of developing cerebral atherosclerosis in patients with OI. Therefore, patients with OI should give up smooking, exercise properly and keep on a low fat diet. They should pay attention to control blood pressure and blood lipid so as to reduce the risk of atherosclerosis.

Conclusion: A c.3159 + 2T>A mutation in COL1A2 gene detected by whole exome sequencing was the causing reason of OI, the discovery enriched the gene mutation spectrum of OI. We also found that OI may have relationship with premature atherosclerosis, and the abnormal bones of the cervical spine may lead to vertebrobasilar ischemia.
Osteopetrosis - A Case Series Exploring Complications and Multidisciplinary Management
Authors: Stewart Catherine , Loughrey Paul Benjamin , Lindsay John R
Published: May 2021

Background: Osteopetrosis is a group of rare inherited skeletal dysplasias, with each variant sharing the hallmark of increased bone mineral density (BMD). Abnormal osteoclast activity produces overly dense bone predisposing to fracture and skeletal deformities. Whilst no cure for these disorders exists, endocrinologists play an important role in surveillance and management of complications.

Clinical Cases: A 43-year-old female had findings suggestive of increased BMD on radiographic imaging performed to investigate shoulder and back pain. X-ray of lumbar spine demonstrated a ‘rugger jersey’ spine appearance, while shoulder X-ray revealed mixed lucency and sclerosis of the humeral head. DXA scan showed T-scores of +11 at the hip and +12.5 at the lumbar spine. MRI of head displayed bilateral narrowing and elongation of the internal acoustic meatus and narrowing of the orbital foramina. Genetic assessment confirmed autosomal dominant osteopetrosis with a CLCN7 variant. Oral colecalciferol supplementation was commenced and multi-disciplinary management instigated with referral to ophthalmology and ENT teams. A 25-year-old male presented with a seven-year history of low back pain and prominent bony swelling around the tibial tuberosities and nape of neck. Past medical history included repeated left scaphoid fracture in 2008 and 2018. Recovery from his scaphoid fracture was complicated by non-union requiring bone grafting with open reduction and fixation. Plain X-rays of the spine again demonstrated ‘rugger jersey’ spine. DXA scan was notable for elevated T scores; +2.9 at hip and +5.8 lumbar spine. MRI spine showed vertebral endplate cortical thickening and sclerosis at multiple levels. The patient declined genetic testing and is under clinical review. A 62-year-old male was referred to the bone metabolism service following a DXA scan showing T scores of +11. 7 at the hip and +13 at the lumbar spine. His primary complaint was of neck pain and on MRI there was multi-level nerve root impingement secondary to facet joint hypertrophy. Past medical history was significant for a long history of widespread joint pains; previous X-ray reports described generalized bony sclerosis up to 11 years previously. Clinical and radiological monitoring continues. Conclusion: Individuals with osteopetrosis require a multidisciplinary approach to management. There is no curative treatment and mainstay of therapy is supportive with active surveillance for complications.