bluuebunny/crossref_metadata_2025_split huggingface dataset:
Case of Juvenile Onset Hypophosphatasia Diagnosed in an Adult Patient
Authors: Nair Nirmal 
Published: May 2021

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &lt; 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

Abstract
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 &lt; n &lt; 4.6 mg/dl), high serum FGF23 level (630 pg/ml, 16 pg/ml &lt; n &lt; 69 pg/ml), and decreased 1,25-dihydroxyvitamin D level (12.9 pg/ml, 20 pg/ml &lt; n &lt; 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.
Hypocalcemia in Setting of Malignancy of Unknown Origin: A Case Report
Authors: Fung Russell K , Jurado-Flores Marilu Margarita 
Published: May 2021

Abstract
Background: Hypercalcemia is a common finding well-recognized in up to 30% of cases of malignancy, associated with poor prognosis and advanced disease state. Hypocalcemia, while uncommon, can also be found in cases of malignancy facilitated by its own unique mechanism and etiologies. We present a case of severe hypocalcemia in the setting of malignancy of unknown origin.
Clinical Case: 72-year-old female with a history of metastatic carcinoma of unknown origin, followed actively by Oncology, presented acutely with shortness of breath, chest pain, stiff hands and clenched fist. Patient had reported a 20 lbs weight loss over three months with a “knot” in the epigastric area affecting appetite and interfering with eating. Prior CT showed diffuse adenopathy with diffuse permeative bone destruction highly suspicious for malignancy. Follow up PET-CT showed mixed lytic lesion and sclerotic changes throughout the entire skeleton from the skull to mid thighs compatible with osseous metastatic. Initial tests show severe hypocalcemia with appropriately PTH elevation and normal vitamin D25 (calcium 5.5 mg/dL, albumin 3.9 g/dL, phosphorus (PO4) 2.3 mg/dL, magnesium (Mg) 1.5 mg/dL, PTH 243 pg/mL, vitamin D25 31.44 ng/mL). Further workup shows normal creatinine levels (0.88 mmol/L) and elevated alkaline phosphatase (1140 IU/L). Physical exam revealed bilaterally clenched fist and positive Chvostek sign. After two doses of 2 grams calcium gluconate, calcium had improved up to 7.2 mg/dL (corrected 7.76 mg/dL, albumin 3.3 g/dL) with plans to replete Mg and PO4. Patient was started on Calcium-Vitamin-D 500-200 mg-units (Oscal) two tabs trice daily. However, calcium continues to drop the next day with levels at 5.7 mg/dL (corrected 6.42 mg/dL, albumin 3.1 g/dL). A calcium infusion of 10 grams was then given over 16 hours. Calcitriol 0.25 mg twice daily was started. 24-hour urine study showed low calcium excretion (&lt;0.8 mg/dL), normal Mg excretion (6.5 mg/dL) with an adequate creatinine collected (0.6 grams) showing no deficiencies in kidney resorption. Prior to discharge, patient’s calcium had stabilized (corrected 8.2 mg/dL, albumin 3.4 g/dL) and her associated symptoms had resolved. She was discharged on Oscal 2 tabs 4 times daily and Calcitriol 1 mcg twice daily.
Conclusion: Given these biochemical results and imaging evidence of bone metastases, this case highlights the uncommon findings of hypocalcemia in the setting of malignancy. With the combination of low 24-hour urine calcium, elevated PTH, normal vitamin D25, low PO4, normal kidney function and increased alkaline phosphatase, these findings most likely indicate hypocalcemia secondary to osteoblastic bone metastasis, resulting from deposition of calcium in osteoblastic lesions.
References: Schattner A, Dubin I, Huber R, Gelber M. Hypocalcaemia of malignancy. Neth J Med. 2016 Jul;74(6):231–9. PMID: 27571720
In Search of a Missing Adenoma
Authors: Tavdy Tammy , Mahali Lakshmi P 
Published: May 2021

Abstract
Background:
The most common cause of primary hyperparathyroidism (PHPT) is overproduction of PTH by a parathyroid gland adenoma. While definitive therapy is parathyroidectomy, 4% of patients develop persistent PHPT - a sustained hypercalcemic state that is detected within six months of parathyroidectomy. A missed parathyroid adenoma is the most common cause of persistent PHPT, and accurately locating these glands presents a diagnostic challenge. We describe a rare case of persistent PHPT due to a missed mediastinal parathyroid adenoma.
Case:
A 54-year-old woman with a history of PHPT presented with abdominal pain, nausea, and decreased oral intake. She underwent parathyroidectomy six months ago with reimplantation of one parathyroid gland into the right sternocleidomastoid muscle (SCM). She was now hypercalcemic to 13.9 mg/dL (8.5–10.5) with intact PTH 1273 pg/mL (15.0–65.0), vitamin D 25-OH 31.4 ng/mL (&gt;30.0), and normal PTHrP. She was not taking calcium, and other causes of hyperparathyroidism were excluded. Sestamibi scintigraphy localized only to the right SCM, and the initial impression was recurrent HPT due to the previously implanted gland. Follow-up CT neck with and without contrast failed to localize any regrowth in the SCM, but did reveal a 1.4 cm mediastinal soft tissue mass, suspicious for an ectopic parathyroid adenoma. She subsequently underwent video-assisted thoracoscopic excision, and pathology was consistent with ectopic hypercellular parathyroid tissue. Post-operatively, her PTH down-trended and calcium normalized.
Conclusion:
This case describes a small yet biochemically aggressive mediastinal adenoma causing persistent PHPT. While sestamibi scans have ~90% sensitivity for localization of ectopic adenomas, they can fail to identify a small culprit lesion in 12% of patients, whereas CT imaging with and without contrast has increased sensitivity for adenomas &lt;2 cm. Thus, diagnosing persistent PHPT requires sestamibi scan in combination with other imaging modalities for accurate diagnosis of missed adenomas.
Paget ‘s Disease: Not So Typical for Atypical Femur Fracture
Authors: Mittal Ashima , Gordon Murray B 
Published: May 2021

Abstract
Introduction: Atypical femur fractures (AFF) are reported in patients taking prolonged bisphosphonate therapy, but Paget’s disease (PD) has been rarely reported as a cause of AFF. Case: 71-year-old female with past medical history of right hip osteoarthritis, seizure disorder, hypertension, and Hashimoto’s thyroiditis presented with persistent right hip pain. There was no history of trauma or fall. She had otosclerosis with bilateral hearing loss and bilateral stapedectomies. Her medications were primidone, levothyroxine, lisinopril-hydrochlorothiazide, and vitamin D. She did not smoke tobacco or drink alcohol. She had elevated serum alkaline phosphatase of 300 U/L (35–104). The X-ray of the skull was negative for any cortical thickening. CT of right femur revealed cortical thickening and coarsening of trabeculae of the proximal right femur consistent with PD and incomplete atypical subtrochanteric proximal fracture. Urine NTx 303 BCE/mM Cr (&lt;89). Bone scan showed uptake in the R proximal femur, L distal tibia, and L3-L4 vertebral bodies suspicious of PD. DXA showed osteopenia. She was given zoledronic acid 5 mg IV. Discussion: PD leads to an increased incidence of fractures particularly of the lower extremities with most fractures transverse in nature. Non-union is not uncommon1. Stress fractures in PD are caused by disorganized bone remodeling due to excessive breakdown and formation of bone. Our patient met the major criteria for AFF as per the ASBMR 2010 task force report but there was no exposure to bisphosphonates2. The ASBMR task force recommended that bisphosphonates should be discontinued
in patients with bisphosphonate-associated AFF due to their severely suppressed bone turnover status. On the other hand, the AFF in patients with PD may heal in response to bisphosphonate treatment. References: 1. Singer FR. Bone Quality in Paget’s Disease of Bone. Curr Osteoporos Rep. 2016;14(2):39–42. DOI:10.1007/s11914-016-0303-62. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA et.al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010; 25:2267–2294.