Background: Cherubism, caused by autosomal dominant mutations in the SH3BP2 gene, is characterized by increased bone resorption with development of bilateral fibro-osseous lesions limited to the maxilla and mandible. The SH3BP2 gene is thought to be involved in osteoclastogenesis. Affected children, while usually asymptomatic at birth, typically present at 2–5 years of age with cheek and jaw swelling with upward tilting of eyes due to expansion of fibrous tissues. Bone resorption and proliferation of lesions continues until puberty after which spontaneous regression occurs. RANKL is a cytokine expressed on the surface of osteoclast precursors and is responsible for inducing osteoclast differentiation. Denosumab is an anti-RANKL monoclonal antibody which prevents osteoclast maturation. However, it has a short half-life, and effects on bone turnover have been found to be rapidly reversible after drug discontinuation. The rebound increased bone turnover can lead to severe hypercalcemia. Clinical Case: A 4 year old boy with cherubism (c.1253C>G pathogenic variant in SH3BP2), after failing a 10-month trial of tacrolimus, was placed on monthly denosumab (2 mg/kg) for a total of 10 doses. During denosumab therapy, he received calcium and vitamin D to prevent hypocalcemia; these were stopped once denosumab was discontinued. He presented to the hospital 4 months after the final denosumab dose with polyuria, polydipsia, fatigue, nausea and abdominal pain. Work-up revealed serum Ca 15.3 mg/dL (N: 8.4–10.2), PTH <3 pg/mL (N: 24–86), 25-OH vitamin D 32 ng/mL (N: >19 ng/mL), 1,25-dihydroxyvitamin D 6.7 pg/mL (N: 19.9–79.3), and urine Ca/Cr 0.48. Renal ultrasound showed normal kidneys with a small amount of layering debris in the bladder. During hospitalization, he received IV fluids, 1 dose of furosemide, 3 doses of calcitonin, 24 hours of hydrocortisone, and a single 0.5 mg/kg dose of pamidronate. He was discharged 48 hours after the bisphosphonate with serum Ca 9.5 mg/dL. He returned with serum Ca 13.5 mg/dL 9 days after the pamidronate and was readmitted. He again received 4 doses of calcitonin and 1 dose of pamidronate (0.5 mg/kg). Calcium levels improved to 9.5 mg/dL at discharge but rose to 11.6 mg/dL a week later. He received a 0.05 mg/kg dose of zoledronate outpatient, with improvement in serum Ca to 10.1 mg/dL. A week later, he twisted his ankle, resulting in transverse impacted buckle fractures of his left distal tibia and fibula; no lytic or sclerotic lesions were noted on x-ray. His leg was immobilized by Orthopedics. Calcium levels remained within range (9.9 mg/dL) 7 months after the zoledronate. Conclusion: Rebound hypercalcemia can occur months after denosumab withdrawal, indicating the need for close monitoring of calcium levels in patients who receive this drug. The hypercalcemia appears to respond best to bisphosphonates, with a more sustained response to zoledrenate compared to pamidronate.
BACKGROUND: Autoimmune thyroiditis (AT) is a common cause of acquired hypothyroidism in children characterized by lymphocytic thyroid infiltration. Sometimes gradual thyroid failure occurs due to apoptosis of thyroid cells. It may occur via apoptotic cytokines, ligands and receptors, including T regulatory cells, tumor necrosis factors etc. AT can coexist with other organ specific autoimmune conditions. Rarely neurological autoimmunity due to glutamic acid decarboxylase (GAD) antigen may be associated with AT. In fact, up to 70% of patients with GAD 65 neuropathy may have other autoimmune disease (AT, type 1 diabetes, pernicious anemia). We present a case of AT that led to total destruction of the thyroid gland with coexisting neurological autoimmunity. CLINICAL CASE: A 7 yr old male presented with tiredness, heat intolerance and weight loss for 4 months, unsteady gait with frequent falls for 2 weeks. Exam showed tachycardia, firm thyromegaly and difficulty with tandem walking without other cerebellar signs. Labs showed undetectable TSH, elevated FT3, FT4 with positive thyroid antibodies, and negative for viral serology. MRI brain was normal and neurological symptoms resolved within few weeks. Thyroid ultrasound (TUS) showed hypervascularity and heterogenecity with right lobe volume (RLV) 2.8 cc, left lobe volume (LLV) 2.3cc with 0.9cm nodule. Thyroid scan showed increased uptake (52% and 61% at 4, 24 hrs). He required methimazole for 2.2 yrs. Five months later, at age 9.6 yrs he was hypothyroid and was started on Levothyroxine(LT4). TUS showed RLV 4.6cc, LLV 2.5cc and solid left nodule 1.2cm. FNA was consistent with AT. At age 14.4 yrs,TUS showed near complete involution of RL and isthmus with LLV 4.9cc and 0.6cm nodule and thyroid scan was negative for uptake. Repeat FNA reconfirmed AT. Due to progressive atrophic thyroiditis he had hyperthyrotropinemia with euthyroxinemia (TSH range 12–165, Normal FT4 1.15–1.73) requiring increasing dose of LT4 over nearly 7.6 yrs. At 14.8 yrs, he developed focal epilepsy treated with Levetiracetam and new-onset left fourth cranial nerve palsy. Autoimmune workup revealed extremely elevated GAD 65 antibodies in serum and cerebral spinal fluid, 1703 and 14.2 nmol/L respectively (N<0.02), confirming a diagnosis of GAD-65 central nervous system disease. He is currently receiving monthly IVIG. At 15.3 yrs, complete atrophy of RL with involuting LLV 2.4cc was noted. He remains euthyroid and seizure free on anti-epileptics with recovering cranial nerve palsy. CONCLUSION: This is an unusual and extreme form of atrophic thyroiditis leading to near total destruction of thyroid gland related to apoptosis with autoimmunity. GAD-65 CNS autoimmunity is important to be considered in children with AT presenting with seizures or focal neurological signs. Continued vigilance and follow up for the development of other autoimmune conditions is warranted.
ObjectivesWe sought to examine in individuals with SARS-CoV-2 infection whether risk for thrombotic and thromboembolic events (TTE) is modified by presence of a diabetes diagnosis. Furthermore, we analysed whether differential risk for TTEs exists in type 1 diabetes mellitus (T1DM) versus type 2 diabetes mellitus (T2DM).DesignRetrospective case–control study.SettingThe December 2020 version of theCerner Real-World DataCOVID-19 database is a deidentified, nationwide database containing electronic medical record (EMR) data from 87 US-based health systems.ParticipantsWe analysed EMR data for 322 482 patients >17 years old with suspected or confirmed SARS-CoV-2 infection who received care between December 2019 and mid-September 2020. Of these, 2750 had T1DM; 57 811 had T2DM; and 261 921 did not have diabetes.OutcomeTTE, defined as presence of a diagnosis code for myocardial infarction, thrombotic stroke, pulmonary embolism, deep vein thrombosis or other TTE.ResultsOdds of TTE were substantially higher in patients with T1DM (adjusted OR (AOR) 2.23 (1.93–2.59)) and T2DM (AOR 1.52 (1.46–1.58)) versus no diabetes. Among patients with diabetes, odds of TTE were lower in T2DM versus T1DM (AOR 0.84 (0.72–0.98)).ConclusionsRisk of TTE during COVID-19 illness is substantially higher in patients with diabetes. Further, risk for TTEs is higher in those with T1DM versus T2DM. Confirmation of increased diabetes-associated clotting risk in future studies may warrant incorporation of diabetes status into SARS-CoV-2 infection treatment algorithms.
Background Proton Pump Inhibitors (PPI) are commonly in clinical practice as agents to treat multiple acid-related gastrointestinal disorders. Studies have shown that long-term PPI-based therapy may be associated with decreased bone mineral density that could be related to hypochlorhydria-associated malabsorption of calcium and gastrin-induced parathyroid hyperplasia. Clinical Case We report the case of a 6-year-old female born premature at 25 weeks, with global developmental delay, chronic lung disease, G-tube and tracheostomy dependent that was admitted for tracheal reconstruction surgery. She was on a PPI (lansoprazole) since the age of 4 years. She was found to have mild hypocalcemia 8.5 mg/dL (Ref 8.8-10.4 mg/dL), mild hypomagnesemia 1.5 mg/dL (Ref 1.6-2.6 mg/dL), and hyperparathyroidism 117 pg/dL (Ref 14-72 pg/dL). Her vitamin D 25 hydroxy level was 28 ng/dL (Ref<19 ng/dL) and vitamin D 1,25 dihydroxy 44.8 pg/dL (Ref 19.9-79.3 pg/dL). In addition, her bone x-ray showed evidence of demineralization, with nofracture. PTH (308.6, 429.4, 253.1pg/mL) continue to rise over the next 2 months despite normal Ca/vitamin D level. We suspected the etiology of hypocalcemia and hyperPTH was related to chronic PPI use. This was also associated with markedly elevated, hypergastrinemia of 574 pg/dL (Ref <100 pg/dL), PTHrp was not detectable. Due to high risk of aspiration, her pulmonologist noted that her PPI needed to be continued at the time. She was fed via G-tube and took Pediasure 1.4 L daily which contained elemental calcium of 32 mg/kg/day. Her vitamin D intake was 1000 units daily. However, we suspected that she had calcium malabosoprtion in light of hypochlorhydria and hypergastrinemia, both leading to hyperPTH. Subsequently, she was started on oral calcium citrate 1200mg daily as the absorption of calcium citrate is non PH dependent. One month later, her PPI was discontinued as well. She responded well to therapy and calcium normalized to 9.7 mg/dl (Ref 8.8-10.4 mg/dl) after 3 months, Gastrin 85 pg/dL (Ref<100 pg/dL) and PTH 90.1 pg/dL (Ref 14-72 pg/dL). Conclusion Bone health status of patients on long-term PPI treatment should be addressed with particular attention to calcium/vitamin D intake. The possible mechanisms of hyperPTH and bone demineralization induced by PPIs include calcium malabsorption. In addition, hypochlohydria induced hypergastrinemia can also exacerbate hyperPTH by causing parathyroid hyperplasia. Bone health and mineral status of patients on long-term PPIs should be regularly monitored. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
Background There is a wide spectrum of maternal autoimmune thyroid disorders (AITD) in pregnancy ranging from Graves’ hyperthyroidism (GD) to Hashimoto thyroiditis (HT), both of which share similar immunological properties. A variety of maternal thyroid autoantibodies can cross transplacentally which may potentially cause varying degrees of neonatal thyroid dysfunction. Objective To study the neonatal outcomes of thyroid function in mothers with AITD in urban setting. Methods Mothers with AITD and newborns were included for retrospective analysis over 12 months. AITD encompassed all mothers diagnosed prior/during pregnancy with either HT or GD. Results Maternal Data: A total of 147 mothers were included (HT 87%, GD 13.6%). Among mothers with HT, thyroid auto-Abs were tested in 51/127 (40%) mothers, of which 32/47(68%) were positive for TPO, 11/21(2%) positive for ATA, 2/6(33%) positive for TSI, 1/2 (50%) positive for TRAb. L-Thyroxine was administered to 90% HT mothers. Among mothers with GD, thyroid auto-Abs were tested in 17/20 (85%) mothers, of which 7/17(41%) were positive for TSI, 6/10(60%) positive for TRAb, 7/14(50%) were positive for TPO, 3/5 positive for ATA. Methimazole (MMI) was administered to 25% GD mothers. Neonatal outcome: A total of 150 neonates (115 FT, 35 PT) were born to AITD mothers. Newborn screen was abnormal in 2 infants. 7 neonates (4.6%) were tested for thyroid auto-Abs, of which 1/2 was positive for TPO, 1/2 positive for ATA, 3/3 negative for TSI, 5/5 negative for TRAb. Serum TFTs were performed in 62/150 neonates; majority 57/62(92%) were normal, 3 had mild compensated hyperthyrotropinemia (mean TSH 17.1 mIU/L, FT4 1.93 ng/dl) and were followed elsewhere. 2 neonates developed congenital hypothyroidism requiring L-Thyroxine. Infant 1: TSH 4.56mIU/L, FT4 1.1 ng/dl, TPO and ATA positive on DOL7 and had ectopic thyroid, infant born to TPO positive HT mother on Synthroid. Infant 2: TSH 149.5mIU/L, FT4 0.8 ng/dl, TSI negative on DOL7 and had hyperemic thyroid, born to TSI, TPO and TRAb positive GD mother on MMI. Overall, only 3.3% of neonates had evidence of thyroid function abnormality which may have either been transient or permanent. Conclusion Although rare, mothers with AITD might potentially impair neonatal thyroid function. This may be due to various thyroid auto-Abs or anti- thyroid medication that cross transplacentally. Maternal history of AITD should therefore raise suspicion to screen neonates and thus warrants continued vigilance. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
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