bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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&gt;A; p.R220Q). Discussion: To date, our case with PHPT is the second report of the likely pathogenic variant CASR (c.659G&gt;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

Abstract
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 (&lt; 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

Abstract
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

Abstract
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 (&lt;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

Abstract
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&gt;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

Abstract
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

Abstract
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

Abstract
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&lt;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&gt;A) was confirmed on genetic testing.
Plasma FGF23 (immutopics) was raised (with a peak of 596 RU/mL, n&lt;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&gt;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.