scholarly journals A Rare Case of Perinatal Hypophosphatasia Treated With Asfotase Alfa

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A177-A178
Author(s):  
Priya S Srivastava ◽  
Abby Walch ◽  
Arpita Kalla Vyas ◽  
Gina Capodanno ◽  
Janet Yi Man Lee
Keyword(s):  
Vitamin D ◽  
Alkaline Phosphatase ◽  
Vitamin B6 ◽  
Clinical Case ◽  
Clinical Course ◽  
Bone Mineralization ◽  
Term Survival ◽  
Asfotase Alfa ◽  
Medullary Nephrocalcinosis ◽  
25 Oh Vitamin D

Abstract 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.

Low Dose Depot Oral Vitamin D3 Versus Daily Oral Vitamin D3 for Treating Nutritional Rickets: A Randomized Clinical Trial

2021 ◽  
pp. 1-18
Author(s):  
Ravneet Kaur Saluja ◽  
Pooja Dewan ◽  
Sunil Gomber ◽  
SV Madhu ◽  
Shuchi Bhatt ◽  
...  
Keyword(s):  
Vitamin D ◽  
Alkaline Phosphatase ◽  
Vitamin D3 ◽  
Low Dose ◽  
Care Hospital ◽  
Oral Vitamin ◽  
Nutritional Rickets ◽  
Vitamin D Levels ◽  
Radiological Healing ◽  
25 Oh Vitamin D

Abstract Objective: To compare the efficacy of daily versus low dose depot oral vitamin D3 for treating nutritional rickets. Design: Randomized Controlled Trial Setting: Paediatrics department of a tertiary care hospital catering to semi-urban and rural population in Delhi, India Methods: We randomized 66 children aged 3 months to 5 years with nutritional rickets to receive either daily oral vitamin D3 drops (3-12 months: 2000 IU; >12 months-5y: 4000 IU; n=33) for 12 weeks duration, or a single oral depot dose of vitamin D3 granules (3-12 months: 60,000 IU; >12 months-5y: 150,000 IU; n=33). Results: Participants in both groups had comparable demographic characteristics, laboratory features and radiological severity of rickets. 33 participants in each group received the assigned intervention and all were followed up till 12 weeks. At 12 weeks follow up, children in both groups showed a significant improvement in all biochemical parameters [serum calcium, phosphorus, alkaline phosphatase, parathormone and 25(OH) vitamin D levels] as well as radiological healing. At 12 weeks, the mean (SD) serum 25(OH) vitamin D levels (nmol/L) were statistically comparable in both groups [daily: 120.2 (83.2), depot: 108 (74), P=0.43] and 31 (94%) children in each group had radiological healing (Thacher score <1.5). Two children in each group persisted to have raised alkaline phosphatase and one child each in the daily group continued to have hypocalcemia and hypophosphatemia at 12 weeks. Conclusion: Low dose oral depot vitamin D3 is an effective alternative to daily oral vitamin D3 for nutritional rickets.

scholarly journals Case of Juvenile Onset Hypophosphatasia Diagnosed in an Adult Patient

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A187-A188
Author(s):  
Nirmal Nair
Keyword(s):  
Alkaline Phosphatase ◽  
Dental Caries ◽  
Ankle Fracture ◽  
Vitamin B6 ◽  
Serum Alkaline Phosphatase ◽  
Bone Mineralization ◽  
Multiple Fractures ◽  
History Of ◽  
Tissue Nonspecific Alkaline Phosphatase ◽  
Low Serum

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.

Alkaline Phosphatase and Plasma-25-OH-Vitamin D in Hyperthyroidism

1977 ◽  
Vol 9 (06) ◽  
pp. 532-533 ◽  
Author(s):  
W. Hunstein ◽  
K. Gless ◽  
H. Schmidt-Gayk ◽  
G. v. Mittelstaedt ◽  
M. Hüfner
Keyword(s):  
Vitamin D ◽  
Alkaline Phosphatase ◽  
25 Oh Vitamin D

scholarly journals Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia

2021 ◽  
Vol 2021 ◽  
Author(s):  
Annabelle M Warren ◽  
Peter R Ebeling ◽  
Vivian Grill ◽  
Ego Seeman ◽  
Shoshana Sztal-Mazer
Keyword(s):  
Alkaline Phosphatase ◽  
Vitamin B6 ◽  
Serum Alkaline Phosphatase ◽  
Serum Vitamin ◽  
Femoral Fractures ◽  
Adult Onset ◽  
Antiresorptive Therapy ◽  
Atypical Femoral Fractures ◽  
Asfotase Alfa ◽  
Low Serum

Summary Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene. The patient was treated with teriparatide given the unavailability of ALP enzyme-replacement therapy (asfotase alfa). Fracture healing occurred, but impaired mobility persisted. HPP predisposes to atypical femoral fracture (AFF) during antiresorptive therapy; hence, bisphosphonates and denosumab are contraindicated in this condition. Screening patients with fracture or ‘osteoporosis’ to identify a low ALP level is recommended. Learning points Hypophosphatasia (HPP) is a rare and under-recognised cause of bone fragility produced by impaired matrix mineralisation that can be misdiagnosed as a fragility fracture due to age-related bone loss. Antiresorptive therapy is contraindicated in HPP. Low serum alkaline phosphatase (ALP) provides a clue to the diagnosis. Elevated serum vitamin B6 (an ALP substrate) is indicative of HPP, while identification of a mutation in the ALPL gene is confirmatory. Enzyme therapy with recombinant ALP (asfotase alfa) is currently prohibitively costly. Treatment with anabolic bone agents such as teriparatide has been reported, but whether normally mineralized bone is formed requires further study.

scholarly journals Hypocalcemia in a 15 Year Old With New Onset Type 2 Diabetes Mellitus

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A200-A200
Author(s):  
Carlos C Becerril Romero ◽  
Rebecca Schneider Aguirre ◽  
Erik Allen Imel ◽  
Linda A DiMeglio ◽  
Anisha Gohil
Keyword(s):  
Type 2 Diabetes ◽  
Vitamin D ◽  
Alkaline Phosphatase ◽  
Vitamin D Deficiency ◽  
Serum Calcium ◽  
Calcium Gluconate ◽  
25 Oh Vitamin D ◽  
Intravenous Calcium ◽  
New Onset

Abstract Background: Diabetic ketoacidosis and significant hyperglycemia are associated with known electrolyte derangements in sodium, potassium, and phosphorus. Hypocalcemia and hypoparathyroidism occurring in uncontrolled diabetes are rare. We present a case of new-onset diabetes with severe hypocalcemia. Case: A 15-year-old obese Caucasian male with ADHD and autism presented to the Emergency room due to hyperglycemia found on laboratory evaluation for hypertension. Serum glucose was 563 mg/dL, serum bicarbonate 24 meq/L (21 - 31 meq/L), and HgbA1C 11.4% (4.0 - 5.6%). He was admitted to initiate insulin and for diabetes education. On admission, hypocalcemia was noted: serum calcium 6.6 mg/dL (8.5 - 10.5 mg/dL), alkaline phosphatase 352 units/L (48 - 277 units/L), and albumin 4.6 g/dL (3.5 - 5.0 g/dL). Repeat testing revealed serum calcium 5.1 mg/dL, phosphorus 4.3 mg/dL (2.5 - 4.5 mg/dL), and magnesium 1.7 mg/dL (1.6 - 2.9 mg/dL). He endorsed a 2 month history of tetany, paresthesia, and muscle weakness. Due to food aversions, his dietary intake of calcium and vitamin D was minimal. He had limited sun exposure. Subsequent PTH was 40 pg/mL (10 - 65 pg/mL) with concurrent serum calcium of 6.5 mg/dL. QTc was prolonged [529 msec (&lt;440 msec)], prompting transfer to the intensive care unit for telemetry, intravenous calcium gluconate, and regular calcium monitoring. Treatment was commenced with cholecalciferol 2000 international units daily and oral calcium carbonate (50 mg elemental calcium/kg/day) in divided doses for presumed Vitamin D deficiency. After several intravenous calcium gluconate doses over 24 hours, the patient’s QTc and ionized calcium normalized. At discharge, calcium was 8.5 mg/dL. He was discharged on the above regimen of calcium and cholecalciferol, and basal and bolus insulin. After discharge, laboratory results returned indicating negative diabetes autoantibodies (GAD 65, Insulin, IA-2) and 25-OH Vitamin D &lt;10 ng/mL (30 - 100ng/mL). Two days after discharge, calcium was 7.3 mg/dL. Two weeks later, labs were: 25-OH Vitamin D 11.3 ng/mL, PTH 10.4 pg/mL, and calcium 9.6 mg/dL. Conclusion: This teen presented with new-onset type 2 diabetes and symptomatic hypocalcemia, an atypical feature of new-onset diabetes. This patient’s hypocalcemia was likely due to both vitamin D deficiency and hypoparathyroidism. He had a low vitamin D level and poor calcium intake with elevated alkaline phosphatase; however, his high normal serum phosphorus and inappropriately normal PTH (instead of elevated in the setting of severe hypocalcemia) indicated a component of hypoparathyroidism. Calcium normalized with detectable 25-OH Vitamin D levels but PTH remained low. Our case highlights the importance of recognizing both that electrolyte abnormalities at diabetes onset may not be directly attributable to diabetes/hyperglycemia and that vitamin D deficiency and hypoparathyroidism may co-exist.

scholarly journals MON-372 Treatment-Resistant Vitamin D Deficiency: Is It a Vitamin D Binding Protein Issue?

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Sirisha Thambuluru ◽  
Imran Unal ◽  
Stuart Frank ◽  
Amy Warriner ◽  
Fernando Ovalle ◽  
...  
Keyword(s):  
Vitamin D ◽  
Alkaline Phosphatase ◽  
Vitamin D Deficiency ◽  
Binding Protein ◽  
High Dose ◽  
Vitamin D Metabolites ◽  
Vitamin D Binding Protein ◽  
Treatment Resistant ◽  
Vitamin D Levels ◽  
25 Oh Vitamin D

Abstract Introduction Vitamin D is present in free and bound forms; the bound form is complexed mainly to vitamin D binding protein (DBP). Vitamin D levels are affected by age, pregnancy, liver disease, obesity, and DBP mutations. We report a patient with treatment-resistant vitamin D deficiency suggestive of a DBP with abnormal vitamin D binding. Clinical Case A 58-year-old Pakistani male with a history of hypertension, sleep apnea and hypogonadism presented to endocrine clinic with symptoms including fatigue, generalized muscle cramps, and joint pain. Evaluation of common causes of fatigue, such as anemia, thyroid dysfunction and adrenal insufficiency were ruled out with CBC, thyroid hormone levels and ACTH stimulation test results all within normal ranges. A 25-OH vitamin D level was profoundly low (4.2 ng/ml; normal 30-100), and a 1,25-OH vitamin D level was undetectable (&lt;8 pg/ml; normal 18-72), leading to a presumptive diagnosis of severe vitamin D deficiency. However, his calcium, phosphorus, alkaline phosphatase and kidney function were in the normal range. Furthermore, the absence of osteoporosis, fracture history, or kidney stones suggested adequate vitamin D action at target tissues; PTH levels were high-normal to minimally elevated, ranging 70-94 pg/ml (12-88pg/mL). Aggressive supplementation with vitamin D3 at 50,000 IU 3 times a week and 5,000 IU daily failed to normalize 25-OH vitamin D (ranged 4.6-10ng/ml; normal 30-100) and 1,25-OH vitamin D levels remained undetectable. Addition of calcitriol resulted in mild hypercalcemia and was discontinued. Malabsorption did not appear to be a contributing factor, as a negative tTG antibody (with normal IgA) excluded celiac disease. Vitamin D metabolites levels measured with mass spectrometry showed undetectable 25-OH vitamin D levels (D2 &lt;4 ng/ml, D3 &lt;2 ng/ml; total &lt;6ng/ml; normal 20-50) and 1,25-OH vitamin D levels (&lt;8 pg/ml). Urine N-telopeptide, 24-hour urine calcium (177mg; 100-240) and bone-specific alkaline phosphatase were all normal. Repeat testing over more than five years showed similar results. DBP levels of 269 ug/ml [104-477] excluded DBP deficiency. Clinical Lesson Vitamin D deficiency is increasingly part of routine testing in internal medicine and endocrinology clinics, as is repletion with high-dose vitamin D. However, in rare cases such as this, relying on 25-OH vitamin D levels can be misleading, and supplementation unnecessary or potentially harmful. Thus, treatment decisions should consider the full clinical context and further evaluation performed when warranted. This patient’s labs are suggestive of an abnormality in the DBP, supporting future examination using molecular testing.

A Simple Regimen to Correct Vitamin D Deficiency In Transfusion-Dependent Thalassemia with High-Dose Ergocalciferol

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4261-4261
Author(s):  
Ashutosh Lal ◽  
Ida Micaily ◽  
Drucilla Foote ◽  
Ellen Fung
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Conflicts Of Interest ◽  
Bone Mineralization ◽  
High Dose ◽  
Vitamin D Status ◽  
Non Invasive ◽  
Dose Oral ◽  
The Mean ◽  
25 Oh Vitamin D

Abstract Abstract 4261 Osteoporosis in thalassemia is extremely common and preventive approaches are required to avoid serious complications in adults. Vitamin D deficiency, which contributes to suboptimal bone mineralization, is frequently observed in thalassemia despite routine prescription for supplementation with 400–800 IU vitamin D per day. Screening for vitamin D status was conducted in 71 patients with thalassemia, of which 52 were transfusion-dependent and 19 were transfusion-independent (including 11 patients with hemoglobin H or H Constant Spring disease). Baseline assessment of plasma 25-OH vitamin D revealed 57 (80.3%) patients were either deficient (<20 ng/mL, 47.9%) or insufficient (20-30 ng/mL, 32.4%). Significantly more patients in the transfusion-independent group were deficient in vitamin D compared with transfusion-dependent group (78.9% versus 36.5%, p=0.003). The mean parathyroid hormone level in patients with 25-OH D <20 ng/mL was 35.4 ± 19.6 pg/mL compared to 28.2 ± 17.1 pg/mL in those with ≥20 ng/mL (p=NS). We studied the efficacy of supervised adminstration of high-dose (50,000 IU) oral ergocalciferol every 3 weeks during transfusion visits in 20 patients with transfusion-dependent thalassemia. The mean 25-OH D level increased from 14.0 to 22.9 ng/mL (p<0.001) over a four-month period. A single dose of ergocalciferol given every 3 weeks increased the plasma 25-OH D level by 2.2 ± 2.3 ng/mL. No patient developed toxic 25-OH D level (>80 ng/mL) during the course of the study. These results show that vitamin D deficiency remains widespread despite daily low-dose supplementation. Non-transfused patients are at even greater risk of vitamin D deficiency, which may reflect less attention to nutrition in this group compared to the transfusion-dependent patients. We have found that supervised high-dose oral ergocalciferol supplementation is simple, safe, non-invasive and predictable method to improve vitamin D status in thalassemia. Disclosures: No relevant conflicts of interest to declare.

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